2026 7th Tang Prize Master's Forums - Biopharmaceutical Science (English) transcript

Good morning ladies and gentlemen and distinguished guests and online viewers worldwide. Welcome to the 2026 Tom Price Masters Forum in Biioharmaceutical Science. This forum is organized by National Taiwan University and the National Taiwan University College of Medicine in collaboration with the Tong Prize Foundation. Today's topic is targeting cancer cells by bioengineered immune weapons current success and future perspectives.

We're honored to have the 2026 tongue prize laurates with us. Dr. Steven Rosenberg, Dr. Michelle Satellane, and Dr. Carl Jun, >> before the forum starts, we would like to take a group photo and please remain in your seats. Our photographer will take a photo from the stage. Everyone, please face the stage. Three, two, one. The cheese. And we'll take a second one with our thumbs up. the Taiwanese style. All right, on one three, two, one, please.

Throughout this forum, our moderator will collect questions from the audience via slido. Please scan the QR code on screen or click the slido link posted below the live stream channel to submit your questions. Please note that all questions will be addressed during the final Q&A session. Thank you for your cooperation. We will now begin today's forum. >> Now we would like to invite executive vice President James who is also the moderator of today's forum to the stage to deliver opening months and introduce your laureates.

Ladies and gentlemen, please join us in welcoming executive vice president Yang. [applause] Thank you everybody for coming to um National Hawe University. On behalf of the National uh University, I'm very privileged and honored to have this chance to uh hold this panel uh to introduce this year's TJ uh town prize uh award. uh T prize obviously is the most prestigious award that Taiwan has given to worldwide uh experts in this field.

Uh several years experience have taught us that many of the time prize winner had achieved great and uh uh contribute a lot to the humans lives. So this year is no uh special. This year we have very advanced immune imunology advances uh that were given to three distinguished um professors. Um unfortunately the first uh ste professor Steve Rosenberg cannot be with us uh this time but uh she he had videoed a uh uh a videotapes for us to uh tell us his uh achievement in this past uh 50 plus years that he work as a cancer iminologist.

So I I will give you a very brief introduction of uh Dr. Steve Rosenberg um this 2026 uh Tom Prize award in biioharmaceutical science. This is he had received his bachelor degree in Johns Hopkins 1961 and uh uh then MD degree for four four years later in the same university and then four years later he had a PhD degree in biohysics at Harvard University and uh after that he had uh been trained in immunology branch national cancer institute 1997. uh then four years later he became the chief of surgery branch uh of national can national cancer institute and since then he is still the the branch chief of surgery branch so uh more than 50 years of uh chief I I think that's already break the records of any institutions being the uh chief um he also was appointed as a professor of surgery in in unifor service university, George Washington University uh as well as uh Kolinska Institute.

He uh had received numerous award. We know him from very earlier time when I even was a fellow being trained. He is already the chief. Um so we all admire his achievement. today um he will give us a uh talk about the infiltration lymphocy we know that recently also had a good achievement in the approval of this uh treatment uh by FDA so okay let's have the >> subject of today's forum is the genetic engineering of lymphosytes to improve cancer immunotherapy.

I'd like to discuss our work uh in this uh in this area. Many people don't realize just how recent cellular immunology is. Antibodies were first described in the 1980s and they dominated studies of immunology until the 1960s. Uh and in fact in 1958 the journal of immunology did not even include the word lymphosy in its index. one didn't understand what these small circulating lymphosytes did. Only in 1960s that we began to understand cellular immunology and delayed hypersensitivity.

And when I began my work in the night late 1970s, there was no convincing evidence or that human lymphosytes could be reactive with cancer that they were human cancer antigens and certainly there were no successful imunotherapies for cancer in humans. You can learn a lot from patients that you cannot find in textbooks. And there were two patients I encountered during my surgical residency whose clinical course suggested that imunotherapy could work in humans.

The first was that a patient who developed a metastatic kidney cancer after receiving a kidney transplant that inadvertently contained uh a renal cancer. This cancer then spread through the patient. But when imunosuppressive drugs were withdrawn, the kidney was rejected and the cancer was rejected as well. And this told me that in fact if you could get a strong enough immune stimulus, you could cause a rejection of large vascularized tumors in the humans.

The second was a patient with metastatic stomach cancer that I personally took care of who had a spontaneous regression of liver metastases in the absence of any treatment. Apparently his body had learned how to destroy uh the disease. Well, this led me to studies of interlucan 2, a T- cell growth factor that was described in 1976. Uh thinking that if we could administer enough interlucan 2 to patients, we could stimulate lymphosytes that might have anti-tumor activity.

This worked in mice. uh and so we began clinical trials and in fact showed that in two p in two different hisytologic types of cancers melanoma and kidney cancer that was metastatic and refractory to other treatments we could get about a 17% objective response rate by recess criteria about a third to a half of those patients had complete responses and this uh study turned out uh to be the first FDA uh US uh FDA approved uh treatment for any cancer for renal cancer in in 1992 and melanoma in 1998.

Well, we then began to ask what cells were responsible for the regression of melanoma in patients treated with this 2 base imunotherapy and what more logical place to look than within the tumor itself. And we studied tumor infiltrating lymphosytes that we could grow an interlucan to and administer to patients. And in fact when we did that uh we in fact uh ultimately could show uh that the administration of these cells could cause objective regressions in patients with metastatic melanoma and about uh over half of patients about a quarter of which will undergo complete regressions.

And of the 46 patients that had complete regressions only two ever went on uh to recur. And that then led uh because of the durability of those responses uh to the FDA's approval of TIL for ultimately for refractory patients with metastatic melanoma. Now it's important to realize that the major challenge confronting cancer imunotherapy today is the our patients with the metastatic solid epithelial cancers. these solid cancers that start in organs in the body that cannot be cured by any available treatment and result in 90% of cancer deaths.

And one of the questions we asked is whether or not till could be effective for the treatment of these uh these patients. And this took us in two directions. Could we use till and could we genetic engineer lymphosytes that could target these solid cancers? Well, the way we grew lymphosytes, all tumor infiltrating lymphosytes on patients with melanoma did not work. Uh, and that led us to identify the exact antigens being recognized by these te- cells. uh and it turned out to be uh the products of the mutations you virtually unique to each cancer that gave rise to neo antigens and te- cells that could then uh recognize them and virtually all were unique to the individual uh cancer itself.

When we then began studies to utilize these cells to uh in these patients with solid cancers and we recently published this about seven months ago, uh we found that till could be used to cause regression in about 25% of patients uh with till grown uh selected for reactivity against uh against that patient's tumor antigens. And these were dramatic responses other than this patient with collangio carcinoma uh who's now free of disease 12 years later of large lung metastases and liver metastases that went away.

Breast cancer uh this patient again uh had a treatment uh now uh ongoing about 10 years later complete regression. In the study we just published, they were gastrointestinal cancers. And in each one of these different hisystologies, about a quarter of patients would undergo recess uh responses. Uh and that taught us a great deal about the imunologic response to tumors. It turns out that any intracellular protein could potentially be a cancer antigen if it was mutated or processed intracellularly to a peptide that could bind to that patient's own autogus MHC molecule.

About one in every 70 mutated neoepitopes were neo antigens. And the good news was that many patients of varied histologies could potentially be eligible because we were studying the mutations that basically caused the cancers in the first place and virtually all cancers did have uh these kinds of mutations. The bad news is that because it was highly ini individualized the treatment was going to be uh be quite complex uh to administer.

Well, the second direction and the subject of this particular forum is whether we could genetically engineer normal peripheral blood lymphosytes to give them anti-tumor activity by inserting anti-tumor T- cell uh receptors. And so two years after our description of till in patients with melanoma, I began work with French Anderson and Mike Blae pictured here at the NIH. They were studying uh inborn errors of metabolism in pediatric patients.

And I worked with them to see if in fact we couldn't use genetically modified lymphosytes administered to patients. Now nobody had ever given gene modified cells uh to patients or introduced foreign genes into uh into patients and this turned out then to be a rather difficult uh protocol to get to get approved. I took here a page from our uh from my notebooks about the 14 different review groups that we had to get permission from uh especially the recominant DNA advisory committee led by the director of the NIH James Weingard.

They finally approved this at a 16 to5 vote but Dr. Weingard felt that because this was the first time we're actually tampering with the human genome in patients it required unanimous approval. uh we had to go back through all the review groups. We finally got unanimous approval only to have a biotechnology activist uh file a lawsuit to prevent us from doing it. And finally in May of 188 1989 we did the first uh treatment of genetically modified uh peripheral blood lymphosytes with a gene encoding neomy phosphot transansferase.

So we could in fact follow the traffic of these cells in patients and this turned out to be safe in 10 patients and pave the way for all of the subsequent gene therapy efforts in uh performed in the human. Now our major goal was to insert not genes to identify where the cells traffic but T- cell receptors or CAR TE- cells chimeic and receptors that could recognize tumors uh to convert normal cells into cells that could be used in vivo.

Now T- cell receptors as immunologists know are two are results from two receptor molecules that then recognize small peptides and an MHC molecule of the patient. But our discussion today is predominantly about chimeriic antigen receptors which was developed by Zelagashar at the Whitesman Institute uh in which you can convert a lymphosy into the recognition of an antibbody by putting single chain antibodies of their heavy chain and light chain uh into intracellular signaling molecules in a lymphosy.

Well, this turned out to be the first FDA approval of a gene therapy for cancer. And that is inserting genes encoding cell surface receptors targeting CD19 originally worked on by uh Michelle Satellane who you've heard from uh that could convert normal circulating lymphosytes into cells capable of recognizing and destroying cancer cells. And uh the FDA approved this in 2017 as the first cell gene therapy uh in humans.

We first published this work uh in 2010. A patient we treated in 2009 uh with a uh refractory uh lymphoma. This patient, the first to receive these CARTT cells and undergo regression, had received multiple different treatments with chemotherapy, epilumab, checkpoint modulators, more chemotherapy, finally came to us with very aggressive uh disease. We treated him in May of 2009. Uh you can see here in this uh X-ray CAT scan on the left these yellow arrows pointing to massive disease in his mediainum, huge spleens, lymphosytes encompassing his vennea and aorta, large iliac vessels which underwent a complete regression.

He remains disease-free now over 15 years later. First six of our first 10 patients underwent a complete regression with lymph. Carl Jun you'll hear from subsequently developed this uh for the treatment of patients with leukemias uh as well and now a variety of bell leukemas are being studied by CART cells. This patient also uh underwent complete regression of uh bone marrow that had been largely replaced by uh by this tumor.

Well, I think CARTT cells are unlikely to be very effective uh in the treatment of patients with metastatic uh epithelial cancers. And this is not a very popular view. But my reason for it is the following. Monoconal antibodies that recognize molecules on the cell surface described first in 1975 uh were described. But there's no monoconal antibbody that identified cell surface molecules unique to epithelial cancers. And we've shown unfortunately that normal cells expressing the target of monoconal antibodies are highly sensitive to destruction and major clinical toxicities have been seen by targeting antigens present on normal cells.

One has to be very careful uh and that's one of the advantages of T- cell receptors that target target mutated neo antigens on the solid epithelial cancers. We began our work putting in T- cell receptors against melanocy differentiation antigens or uh again nonmutated uh c uh germ cell antigens. But again although we could see regressions these are potentially dangerous because they could be expressed on some normal cells that would then get destroyed as well.

And so our attention turned to inserting the T- cell receptors against these cancer neo antigens that we had described was because we could identify the antigen. We could quite easily identify the receptor measuring uh that recognized it and in nature medicine in 2024. We published our first results targeting these cancer neo antigens inserting T- cell receptors. But in fact much more exciting to us uh because this had to be unique to each patient is to take shared KFS or p-53 mutations present uh in over half of all patients with cancers from libraries uh to see if we couldn't insert those shared receptors as off-the-shelf reagents much as we did with CARTT cells targeting CD19.

Well, two fellows in the laboratory developed libraries against antigens against T- cell against antigens against p-53 mutations or Kass mutations uh each one for different restriction elements for p-53 or KAS mutations and we published the exact sequences of these T- cell receptors in this library so anyone could have access uh to them for studies. turned out p-53 turned out to be a shared antigen that could well be dis targeted and R175 antigen which was a more common of the p-53 TCRs.

Uh we've now treated uh six uh five patients with that. Three of the five patients have undergone objective regressions and we've seen one against a p-53 Y223 mutation uh patient with rectal cancer who also had an ongoing response and these studies showed that in fact by targeting these shared p-53 or kass antigens we could see regressions and this patient with rectal cancer received his own normal lymphosytes that had been genetically modified to receive this T- cell receptor targeting the R175 5 HP P-53 antigen and you can see dramatic regressions of large uh lesions in this uh in this patient.

This patient had multiple almost countless lung metastases almost all of which disappeared and these patients had good recessed uh responses. Uh this patient again with a rectal cancer received our class 2 p-53 Y223 antigen and many of his liver metastases disappeared uh and the largest ones uh shrank. This patient with a pancreatic cancer underwent a near complete regression uh of that pancreatic cancer targeting a G12V kass mutation with normalization of his serum uh markers.

Now these were partial responses and we're working hard to try to improve upon uh upon these uh these results to get complete uh complete regressions. Another way to improve cancer amunotherapy that time prevents me from going into in any detail is to insert genes that alter the tumor micro environment. And we've emphasized in our studies interlucan 12 uh because it's the most pro-inflammatory uh cytoine uh that's been uh discovered and we published our first results in clinical cancer research using a normal lymphosytes that received uh T- cell receptors uh with uh genes uh that uh encoded a secreted IL12 gene that was driven by an NFAT promoter.

This was also done in patients with till. The NFAT promoter was designed to only enable the secretion of IL12 uh when the uh cell source antigen and NFAT uh was then prevented presented inside the cell. Well, we treated 33 patients with melanoma with this approach. uh one patient uh that progressed at 3 * 10 the 10 cells had a durable complete regression at 1,000 cells fewer indicating the power of IL12 uh in these patients uh but in fact at these high doses of cells because the leakage led to secreted IL12 uh the toxicity was such that we could not continue with these uh with these studies.

We therefore developed a membranebound IL12 that was not secreted at all and showed now that this membranebound IL12 and these unpublished studies could dramatically increase the expression of uh T- cell receptors that were transduced into cells when they were given along with membrane bound 12. If you give as few as five million cells to mice bearing a known uh tumor uh you could get regression not with just the normal TCR alone but with T- cell with this membrane bound IL12 and this 1.5 million uh times 15 million cells you can see complete regression in these mice and this has now led us to clinical protocols attempting to put membrane bound IL12 uh into patient PBLO.

Uh and this uh IND has now been submitted to the US Food and Drug Administration to seek approval to perform this kind of trial uh with cells transduced with T- cell receptors that could recognize tumors. Well, in this study and in the laurate lecture that I gave earlier, we showed that a recent data that objective responses could be achieved in patients with chemractory epithelial cancers using adoptive cell transfer with selected tumor infiltrating lymphosytes or PBL transutes with T- cell receptors targeting unique or shared mutated antigens.

And finally, experimental evidence suggests that clinical results may be improved. uh I've shown you the results here with membrane bound dial 12 in my earlier lecture with these other uh attempts to improve upon this is an area of very active uh research and I think the likelihood that we'll be able to improve upon results using the genetically modified uh lymphosytes as shown uh with the chimeriic antigen receptors targeting CDE19 uh that can result in successful treatment of additional patients with solid epithelial cancers targeting true mutated neo antigens.

Well, thank you for your very kind attention. [applause] So although uh professor uh Steve Rosenberg cannot be here with us, I hope that after uh his um family uh instance, he can we can invite him back to uh our campus for uh giving his uh truly very uh long experience of uh giving infiltrating lymphosytes and engineer lymphosytes to uh patients. uh as you can hear from his lecture that he had uh although although he it seems that it's simple to do this but you know uh uh for more than 40 years he's been struggling with all kind of uh obstacles to give um uh more and more advanced uh lymphosytes adopted te- cells into uh patients and he have shown several very important important um remissions uh examples that will certainly change how we view cell therapy as a effective treatment for our cancer patients.

Although it's just a start but uh it's very important. Uh so let's welcome uh the next uh we have three uh laurate uh winners this year. So we have two with us. Um let me introduce the second one. uh Dr. Mheld Tadelane has was a graduate from University of Paris at uh in 1984 and he has a master's in iminology University of Paris and then PhD imunology University of Aalta um and he uh had trained in internal medicine in University of Paris in 1983 a postpark fellow in White Hat Institute MIT uh between ' 89 to 94 and then he went to throne uh throne Katherine cancer center um act as a Steven and Barbara Freeman chair uh and was a head of gene transfer and gene expression laboratory at uh memorial ketaring cancer center and he is a founding director of this center for cell engineer uh memorial ketarine cancer center uh And since 20 2024 he is the director of cancer cell therapy initiative HICC and until today he's a director of Colombia initiative in cell engineer and therapy and also hold the title of Herbert and Florence Irving professor of medicine Colombia University. um he has received many award here that I'm not going to read through all all of that but we know that his uh achievement in uh carti therapy is uh very very important so let me uh allow him to tell you the story professor satan >> [applause] [music] >> Thank you for this very kind introduction.

I would like to first um thank of course the tank prize foundation. Extraordinary uh honor. Uh the bank prize is one of the prize prizes uh in medicine and biioharmaceutical um research the world. Thank um professor for selecting um our work for for this year's um award and I want to express my gratitude to you for hosting us um today. It's a real pleasure to be here. Multisellular organisms and vertebrates like us are are constantly exposed uh to a number of pathogens that can uh enter uh our our body and and threaten us.

Parasites um bacteras bacteria and of course um viruses. And it's thanks to uh our immune system uh that these multisellular organisms remain uh alive uh and well. Our earliest ancestors fish uh only had a few mechanisms encoded in their germline to protect them against some of these pathogens. And it wasn't um until uh Jaw fishes uh acquired the ability to reshuffle genes that we could create antigen specific um receptors and those as you know come in in two main forms. one uh the T- cell receptor uh that is the hallmark of TE-C cells which is anchored in in the membrane of cells and recognizes um HLA peptide complexes and the other one uh in B cells the B cell receptor and its secreted form the imogloabbulin uh which recognizes uh antigens independently uh of HLA and can surveil uh extracellular millers as well as the cell surface through it direct binding uh to antigens. uh CARTT cells represent a a human-made uh reallocation of these uh physiological properties uh creating a new cell type that we call the cartis cell that uh like a T- cell can uh engage antigen but which uh more like a B cell uh can do so independently of HLA and therefore uh can function independent independently of a patient's uh MHC hletype or could even engage a tumor cell that lacks HLA expression or fails to process uh peptides.

Furthermore, these CAR molecules not only target TE-C cells like a T- cell receptor, but they reprogram the metabolism and functional properties of those TE- cells. So, I'll try to summarize uh the history over 35 years. in in four major steps and the first highlighted here in the upper left part of the slide is the ability to efficiently introduce genes into primary tea cells. Uh I emphasize the efficiency of this process rapidly not requiring an extended culture of those tea cells such as would be needed if you use neomy phosphot transferase which uh Dr.

Rosenberg just mentioned which then obliges to an extended culture. What was needed for for the birth of the CARTT cell field really was a method a tool that would allow rapid transduction intro introduction of genes into primary T- cells and this work dates back as you see here to 1992 in particular showing before the GFP gene existed with the lac z gene that it could be integrated into the genome of primary tea cells.

The second pillar is really the the design of these uh receptors themselves which uh uh in my view anyway we can trace back in panel A here to the cloning of the CD3 zeta chain. It has nothing to do with cars but three groups cloned these uh this gene created the fusion receptors that you see here because the the zeta chain lacks an extracellular domain. So it simply wasn't necessary to to create a fusion protein and introduce it introduced these fusion genes into T- cell leukemas and by cross-linking realized that the Z chain could initiate T- cell activation and then a few years later two groups um Zeligashar in Israel but also already mentioned but also Thomas Brocker in Basel uh substituted as the extracellular domain the heavy and light chains of an iminoglobulin called an SCFV. shown here in panel B.

And here I go back to the uh critical contribution of introducing genes in primary tea cells because we could do so when we tested these um zeta chain fusions. We soon realized that they were incapable of sustaining an immune response. You could redirect a cytoolytic activity briefly but then these tea cells would fail to proliferate and often undergo activation induced cell death. And that led us to investigate um throughout the '9s different immune receptors using coinatory molecules such as the one shown in panel C here which we call the chimeic cointory receptor redirecting these uh different co-matory functions in primary tea cells and we finally understood that we needed to combine these receptor these signaling domains. uh something that may seem so obvious today, but back then you have to go back in time.

Uh this was not accepted as a legitimate biology if you like and our paper was rejected several times until it was published in January of 2002. And now when you combine the two signaling domains um a co-stimatory domain and an activating domain for example you could uh create tea cells that no not only were redirected to a cell surface antigen of your choosing but that could expand um uh upon repeated exposure to antigen.

And for this we to study this further we needed to identify a target that we might pursue first in vitro then in animal models and maybe maybe someday in the clinic and we focused on CD19 and in 2003 we reported this the study shown here in the lower left part where we could take human peripheral blood tea cells engineer them with a recombinant retroviral vector harboring a synthetic gene coding for a what we called that year a car a chimeic antigen receptor specific to CD19 and a single infusion of these tea cells intravenously and tumor bearing mice could induce the the long-term emissions and even cures that you see here in this slide.

I just uh the fourth pillar I'm sorry the fourth pillar of this was to establish manufacturing methods that would be acceptable uh to our center and to of course the FDA so that we could initiate clinical studies and uh we did use some of the reagents uh discovered by Carl Jun that you will hear from and it's my colleague uh Isabelle Rivier who you see in the lower left here in the right but whom you can also see here right here in the front row um [applause] who made it possible to develop a process uh that we brought to the clinic and allowed us to open uh CD19 car trial which I think was the the first trial uh in the US and in the world.

We infused the first patient actually in June uh of 2007. It took a few years till um uh clinical reports uh showed dramatic outcomes in patients with various uh relapse and refractory bell malignancies. You will hear from Carl's work in a in a minute. Um and we were the first to report on patients with acute lymphoplastic leukemia u reporting on five adults with relapse disease. And the lower left panel you might see there in this uh fax profile CD19 positive cells in the marrow immediately pre-infusion and very soon after the complete obliteration of any CD19 positive cell in the marrow or lymph nodes of these patients and I think that because uh Carl also reported these results and so did we I think that gained rapid uh uh acceptance by the world community that that these um results uh were not just a chance occurrence but a profound new new medical advance.

Actually at the end of 2013 the journal science proclaimed cancer imunotherapy to be the the breakthrough of the year. Sometimes it's physics or psychiatry or other topics. This was cancer imunotherapy. This was of course for checkpoint blockade uh the use of antibodies that that overcome uh immune suppression in some circumstances. But the editors also noted the rise of this second form of imunotherapy using cells. And as you know these uh clinical results all from academia were soon uh extended in our centers and and in others.

It's in a conversation with my local uh newspaper uh in New York when explaining all of this um to to to a journalist that I I introduced this term of of living drugs. What we create are living drugs starting from human cells. We repurpose their function uh to achieve therapeutic benefits. These are the two first cars that were approved by the US FDA in 2017. Both of them recognize CD19. Both of them adopt this dual signaling structure. uh the one on the left um incorporates the cytoplasmic domain of CD28 and the one on the right the cytoplasmic domain of another co-stimulatory receptor called 41BB a member of the TNF receptor family which I believe you will hear about from Carl.

I'll just say that today there are seven CARTT cell therapies that are approved in the US uh in the United States. Five of them target CD19. Two of them B cell maturation antigen or BCMA, [clears throat] an antigen that is relevant to to multiple myyoma in particular. And some use the 41BB structure, some use the CD28 structure. And as you can see quickly in the table below, I won't go through the numbers. uh in real world data.

So beyond clinical trials, uh you can see the the quite remarkable complete remission rates obtained in a variety uh of B cell uh malignancies. Now a second uh tsunami uh occurred really in the medical field um when investigators in Germany tested these CD19 cartis cells in patients with relapsed and or rather refractory systemic lupus. No research done there. They used the same method, the same car molecule that was developed for oncology in these patients.

And in the first patients with lupus uh induced a remarkable response. The patient uh improved her clinical condition many of her auto antibbody titers uh decreased and most importantly she didn't require any more imunosuppression or corticosteroids and I believe that that her response is still ongoing after several years. This is more recent but it's al only five years. This has triggered enormous interest in CARTT cells in the field of autoimmunity with a number of trials today in US, Europe, Canada, Australia and and China and beyond rheumatology.

Now CT cells are making their uh entry if I can say in neurology in diseases such as me myastthenia gravis um or multiple scerosis or stiff man syndrome and others CARTT cells targeting either CD19 or BCMA are being um explored in in in clinical trials. So we believe and hope especially that that this uh C19 cartis cell paradigm is a is only a a first foray in in the new world of synthetic immunology which can be at least in principle applied in many areas of medicine.

Um we know that these uh CARTT cells which are so remarkable in in hematological malignancies and apparently in autoimmunity um still cannot be used in their current format successfully against solid tumors. Well there the good news though is that we've identified we as the field a number of the obstacles that need to be overcome. They're listed here. First uh unlike uh leukemas or lymphoma cartis cells don't always penetrate a tumor whether it's a till cell or or a checkpoint blockade imunotherapy or a cartis cell therapy this is a general barrier if the tea cells don't enter the tumor of course they can't do anything and there are creative ways to engineer tea cells to facilitate this process the second is imunosuppression even if the cart cell entered the tumor it may be down reggulated or suppressed by by a number micro environmental mechanisms.

And here again, genetic engineering offers a number of possibilities for creating tea cells that resist these mechanisms. The third bullet that you see here is sustaining their function over time. Uh we all recognize that um uh a CT cell may need more time to overcome a solid tumor than it does for example a leukemia in the bone marrow. And a fourth challenge um that is also well recognized is the need to identify suitable molecular targets and there's a lot of work in that area ongoing and no time to talk about that today.

That's for solid tumors. But there's also great hope that CT cells will be useful in in neurology. I mentioned some antibbody mediated diseases like mythenia gravis. Beyond that to abate neuroinflammation uh te- cells can enter the central nervous system they can be engineered to to do so and there's a lot of interest in reprogramming you know astroitic or microgle um um properties if you like that that expose to to neurodeeneration and other pathologies.

Another area uh recently opened up is um preventing regraph rejection or or transfusion intolerance uh in patients who for example have anti-HLA antibodies or anti- red blood cell uh group antibodies and who cannot receive either transfusions or or alls and fourthly uh another big direction I would say is uh uh addressing scinessence and fibrosis in a number of disorders uh there are now carti cells that have been designed to uh eliminate scinesscent cells in some animal models.

Uh we've shown that they can also reverse fibrosis for example in liver disease. Uh others uh in the mioardium and this is another direction. There are more for example than listed here. I'll just mention one more uh refractory viral infections with virus reservoirs that cannot be uh eliminated with current therapies. So I want to just finish by um a few more slides with a few more slides to give you a sense of where I at least we we are focusing our attention and that is to further evolve the car design so that it can uh overcome those barriers in solid tumors.

And here I just show you again the two foundational car designs the CD28 on the left and the 41BB car. And I just want to uh from this slide show you how different um their their signaling pathways are which have been worked out by many over the years. And it's quite remarkable to me anyway that that cars that are so different uh in their signaling properties uh can achieve such dramatic results at least in hematological malignancies and autoimmunity.

But this is not good enough for solid tumors. And so we need to further evolve these receptors and I think create more chimeas. You see here classical chimeas on the left and the right. And that means that this structure needs to further uh evolve. And I'll show you three quickly three examples that we call 1xx hit and 1a. And I just want to a bit tongue and cheek u make a parallel to the the Cambrian explosion that very long ago in evolution tested all of these different forms life forms and most of them never survived but a few of them uh did and I think that that's what the field of uh car um the car field today and synthetic immunology in general is bringing out an explosion of new designs s that need to be tested and some of which I hope will enable us to overcome solid tumors and many other diseases.

So in one slide each I'll just give you the the flavor of this research. This is the 1xx car. In the upper left of the part we go back to the origins of these cars by fusing a coinator activating domain together. The clinic taught us that these CD28 CARTT cells are obviously effective but short-lived. most of the time within a few weeks their numbers decreased greatly. We originally thought like I think everyone else that that was an intrinsic property of the CD28 cosinatory receptor but we eventually revisited this question um by mutating these green boxes that you see here in the zeta chain which are the three well-known parts that initiate T- cell activation and we could mutate them and reduce their their their ability to initiate T- cell activation.

Note that I said reduce not increase but reduce in the context of the CD28 coinatory domain and we showed in animal models and you can see these uh graphics in the middle part of of this slide I think uh I'm not sure this works but anyway that the car that bore only one of these items not three items like the natural uh zeta chain performed much better and our mechanistic studies revealed that it still induced strongector functions but didn't compromise TE- cell survival and then uh with my colleagues including Isabel Riviera again uh we brought this to to a clinic uh with a new SCFV which you see in the lower part of the graphic here and we obtained really uh excellent results in um patients with refractory diffuse large B cell lymphoma but the important point here was that we didn't need 10 to the 8 or 10^ the 9 T- cells or Dr.

Rosenberg even mentioned 10 to the 10 in some of his studies. Uh but with just 25 million CARTT cells, we can induce these profound and durable uh uh complete responses. Well, that's one way of of reshaping the properties of the CARTT cell. Uh another um one uses this receptor that you see here up at the top in the middle that we call HIT. On the left is the physiological T- cell receptor which signals via that CD3 complex and on the right is the CAR molecule that we've been that I've been talking about for the last few minutes.

We know from the basic immunology literature that the T- cell receptor is very sensitive to low levels of antigen and we wanted to compare CARS and TCL receptors and to do that created the structure in the middle with HIT stands for HLA independent T- cell receptor. So we use crisper cast 9 and remodeled the T- cell receptor and the CAR inside the peripheral blood T- cells of of healthy volunteers. And when we created this receptor, we realized it could indeed be a lot more sensitive than the most sensitive of all car classical cars, if I can say, at least 10fold, sometimes 50fold.

And we think this will be useful in settings where you need to eliminate cells with very low androgen densities. And the the work below I don't have time to go to is a recent study where we showed this targeting CD70 in renal cell carcinoma. and actually other tumors. And the third example I want to give of this evolution of cars um is one where uh we introduced uh a signaling component uh borrowed from what's called the pre-T cell receptor.

In the upper part of the slide, you see the sequence of events in natural T- cell development. Upon rearrangement of that of the beta chain, it pairs with a pre-TCR and those cells then uh undergo formidable expansion as they try to rearrange the alpha chain to ultimately produce a functional T- cell receptor. And we were intrigued by what the what might be the mechanism that allows these future TE-C cells to to expand without becoming exhausted.

And so we took a segment of this pretel receptor and introduced it in our CD28 CAR that's the lower part of this uh slide shown here and indeed found that we could create far more potent persistent CARTT cells that that were functionally uh um very strong if I can say um but didn't undergo exhaustion for a long time and the mechanism of this is in this paper mentioned in the lower left but it has to do with regulation of mRNA a translation in primary tea cells.

And so I think that um uh we now have a a third major um pillar if you like uh in in in in the world of medicine to um to take control of TE- cell responses. Of course, the most the first and perhaps the most important is active immunization or or vaccination. if you like um to amplify naturally existing tea cells and that's good for the prevention of of some viral infections. The second is to derpress again existing T- cell receptors T- cells in patients with cancer and that's checkpoint uh blockade and the third now is the path of synthetic immunology to actually create te- cells that do not exist naturally and I will stop here just by saying that this is the beautiful world of uh T- cell engineering and I think that there's uh a lot lot more to do.

Thank you very much. [applause] >> Thank you very much, Professor Sing. Uh I think through his work we uh found that karthi uh is a a tremendous uh work that um the scientists have done to the cancer patients and it is first time that we engineer a te- cell that um had changed the life of can cancer patients who desperately um seeking for medications and life cells obviously has become a very important medications and through his work we also found that uh the old saying that for success men successful men there was there is always a successful a very important lady behind okay so let's move to the third uh master's lecture um let me allow me to introduce uh professor Kajjun professor kajun has his uh um master degree of biology at US Navy Academy and then MD degree uh 1974 uh 78 at Bayer's College of Medicine [snorts] um and he then become a research fellow at WHO immunology center in Geneva and uh fellow in oncology Fred Hutchinson's cancer center [snorts] uh and he um because of his um uh uh um uh Navy nature.

He is a medical officer at the uh US Navy uh for the uh 21 years of services and retire at the and become a professor of medicine at the uniform service of university. Actually this is Tri service uh general hospital similar to uh here in Taiwan and 1999 till present he's is the director of translational research program at University of Pennsylvania and from 2012 to present he is Richard uh W professor in uh iminology University of Pennsylvania and from 2015 to present he is a director uh of the center for cellular immunotherapies at UPEN and from 2016 he is the director of Parker Institute for cancer imunotherapy at University of Pennsylvania and in the right hand side you can see that uh professor Kajjun had received numerous reward as well.

Um and uh we are very happy that uh 10 years ago he was invited to Taiwan and gave a talk to us and we also sent uh a fellow to his um sites for to learn how to um uh treat patients and and create cartis. So uh we are very happy that uh professor kajun can win this award and come back to Taiwan. So um let's welcome Professor Kajun to give his talk. [applause and music] [music] >> Well, thank you very much. It's a really a huge honor to return and to receive and share this prize with Michelle Saddelin.

And um uh I want to also thank my wife uh who has contributed to me being here very much, Lisa Spiker. Thank you. Um [applause] and you know, I'm going to take some advantage of the fact that Michelle just you know showed you 30 years or more of background on carcels and I'll skip most of that. um and show some you know status of where uh the field is here and in the US uh and then some next generation designs um so-called armored CARTT cells and uh synthetic enhancement of CAR cells and and the use of AI you know and on the right is you know the so-called cancer wheel which is really what happens when we try to um uh provoke a tumor rejection And you know that was initially looked at as a way to you know make endogenous responses and you know what we can do now with synthetic biology and artificial tea cells really changes that wheel uh dramatically.

So um I just wanted to show that you know we have had real progress in the field of cancer. Some of that's due to less smoking and so on, but there's been about a 30% decline in the death rate um over the last 20 years or so. And a lot of that really is imunotherapy. Um and so we have um uh and two points about that. It was developed really um in academic settings um and then it's been and they have been paradigm shifts.

Checkpoint therapy and now as you're seeing today cell therapy. So with cell therapy now there are um really four kinds in active uh development. And on the upper left is what you heard from Michelle which is Xvivo autotogus car cells uh that are genetically modified. Um and then um uh you know there is a lot of work on upper right which is offtheshelf allergenic cells and they can be derived from cord blood or pur potent stem cells or so on.

So these are a next wave of cell therapies that are on the way. And then on the bottom are the actually skipping the manufacturing of cells but the invivo delivery either in the lower left with lentiviral vectors for instance to to transduce cells right in the body and um and that's been pioneered in China and with an amazing way now with many trials underway. And then the lower right is the use of nanop particles such as lipid nanop particles that are targeted and and can achieve the expression of RNA and make transient CAR cells which I think are going to have major applications for uh autoimmune disease and non-malignant uh disorders.

Uh so um you heard about the design of CAR cells where the borrowed receptor the zeta chain from the T- cell receptor was was fused in cyst with um antibbody fragments and then you know our lab uh and Michelle's really made second generation car cells and they worked where the first generation car cells did not in the clinic. They work great in uh in vitro models but in humans they did not proliferate and achieve the envir you know the effective to target ratio that you need to clear out large tumors.

And now there's many designs of CAR cells. On the right some people say a fourth generation car is a um one that's armored to secrete cytoines. So um you know there was a lot of development of these uh and it was on the back of CAR cells that didn't work on the initial trials when they were first generation and um you know so over the years we worked on the foreign BB molecule as a co-stimulatory domain which promotes memory cell development actually one of the first papers on that to show that in humans was came out of uh Korea and then um so human tea cells use foreign VB as a signaling domain to become memory cells.

Uh and they activate and then have lots of active proliferation through CD28. Um so you know we made that second generation CAR and then treated leukemia patients initially adult and then later um uh pediatric patients uh leading to FDA approval in 2017. So that was a second generation car using autotogus cells. Our first pediatric patient was shown here um and she taught us about the cytoine release syndrome or CRS which she almost died from.

On the left is the publication showing her cytoine levels after an infusion of autotogus car cells and um uh she had a thousandfold increases in in cytoines like 6 and 2 and interfering gamma and um uh was in multi-organ failure and on life support uh from that. uh but yet she survived that and then went on to have now a complete remission that's more than 15 years in duration. And um so there's a movie about that. There's, you know, it's really helped galvanize a recognition that car cells can have very potent activity, but they can have side effects which we're learning to manage.

Um and so now in 2026 um there are uh seven FDA approved forms of uh CAR cells for blood cancer leukemas lymphas and myyoma and then tumor infiltrating lymphosytes that you heard about tills and then uh just a year ago T- cell receptor TE- cells were approved for a rare saroma um in the US and and we now have as Michelle coined living drugs. I mean, our first patients, Emily Whitehead, still has CAR cells, and our first adults do as well.

So, a a major paradigm shift where a single infusion or treatment could lead to long-term persistence of a therapeutic. Um, you know, the the downside right now is access and cost. And so, we have these only in, you know, um developed economies now. And most patients that have cancer are not being treated. So it needs to be by various man approaches, manufacturing approaches, automation and so on the cost of goods reduced um so that everyone can benefit um and you know uh you know this slide here from one of the investment houses shows us now in Europe and the US more than 60,000 patients have been treated with these peripherally um manufactured autotogus cells.

So, but there's a lot of uh development now preclinally of much more potent cells than what we have. And that's my major mission me a major um uh message to you. And then and you saw that from Michelle Satellite as well. There are much more potent cells on the way. And I'll talk some about armored cars which are on the upper left where you can not only make a CAR cell but have it deliver uh cytoines or make dominant negative switch receptors for instance to stop the effects of tumor iminosuppressive uh TGF beta and and there's an an emerging issue which is antigen escape and uh where tumors uh can come back because they've lost their target antigen and there's multiple ways of of dealing dealing with that.

And then uh the on the lower right are issues with the tumor micro environment or TME where uh the CARTT cells don't even get into the tumor or they rapidly uh shut the CAR cells down. So I had a a posttock from China named Bong Hoo who worked uh for a couple years in my lab to make an armored CAR cell against uh C19. This was all in mice in genetic mice and um uh but he also encoded the cytoine 18 and 18 is a a cytoine not like the common gamma chain family like isle 2 but it's a cytoine that's made through the NLRP3 inflammosome and has its own checkpoint.

So Steve Rosenberg mentioned that is 12 can be lethal and that's been it's a very potent cytoine but it's very toxic. Isle 18 combines many of the same signaling pathways and also has its own built-in checkpoint which is IL18 binding protein. So uh blank showed that work in mouse tea cells and then with Jacob soo at pen we started a human trial in patients who had uh lymphas that were refractory. So they had been treated with the commercially approved CAR cells and then relapsed and so they had been either treated with Axisel, the one that Michelle designed or the one in my lab from marketed now by Novartis Kim Rya and have the tumor come back and then we treated them with now an armored car and in this phase one design this just shows what Blang made.

It's a car that's a standard foreign BB zeta car, but now makes a mature form of 18 that's secreted through a um a bicistronic lentiviral construct and um and so the car makes 18 target C19 and uh there were two other groups that published in pre-clinical models uh soon after we did uh the same finding that 18 armorin really looks really promising and especially given the fact that isle 12 is toxic and 18 has its own checkpoint the 18 binding protein.

So we started this phase one trial 5 years ago and you know started with a very low dose the dose of Kimaya is 100 million CAR cells given um and so we had no idea whether there would be significant toxicity or not due to the cytoine. So what we just negotiated with the FDA was to start at a 100fold lower dose which was 3 million total cells and that's literally the dose we use normally to treat mice. So um that dose uh we expected no responses but in fact the very first patient who had had nine lines of prior therapy um had and had uh relapsed after axis cell uh C19 FDA approved CAR treatment u and she had um uh after that micro dose you know she had a complete metabolic response and remains in uh clinical remission. now and and reported that last year.

So in that trial we treated 21 patients like that and we had dose escalation and found that there were uh complete responses across all dose ranges tested and that there were uh the overall survival which normally is 3 months after a patient's relapsed. There's a a French trial uh that's looked at in Europe what happens if you relapse after car tri treatment and there's no salvage therapy at this point and we found that we had an 80% uh um response rate um and across many um lymphoma subtypes large B cell lymphoma transformed follicular lymphoma and mantal cell lymphoma and that the overall survival is much better than than what's in the literature.

So that that was a phase one trial and we found when we looked at the coralates of response that the CARTT cells uh proliferated massively in the patient basically you know we we had very few cells infused but they proliferated to the same level we see in patients when we give them 100fold more CAR cells and on the right is what's I think a paradigm changing finding which is you can make pharmictites cells that not only are retargeted but can encode um uh recominant proteins in this case is 18 and we could in the blue lines uh see that the is 18 appeared in the serum between 7 and 14 days after infusion and that didn't happen as shown in green and red uh that um in patients treat with standard CAR cells.

So this shows I think a wide open field of new ways to make much more potent cells than what we have. This is unpublished data from that trial using by Andrew Re who uh was a posttock in my lab and this is using spatial biology with a 10x genomics a terra thing. So this is using FFP embedded specimens at baseline from the patients and then at time of biopsy which is 2 weeks after treatment and and this particular patient relapsed a year later on day 310 and that was biopsied.

And what we could find um uh would would be um that at baseline on the lower left uh on single cell um imaging 91% of the cells there uh on the biopsy mass were were tumor cells and so they had B cell signatures and then at the time of response 2 weeks after uh the B cells were gone and now there were 52% CAR cells there there were no CAR cells or T- cells in the baseline biopsy. So it was very cold and then at relapse now 86% now again were tumor cells.

So so we now have very um promising spatial biology assays to work out mechanisms of relapse and here it was not target loss it was a tumor suppressive u um um myoid environment um that that was in the patient. So, so in blood cancer, you know, we have very potent therapies targeting CD19 and BCMA. Um, and there's really interesting issues of what the most potent CAR cell can be and how it's been cultured. uh armoring in trials um across both in China and in the US shows isle 15 armoring makes cells more potent.

Isle 18 armoring does and a number of other cytoines including now is 36 which Reneer Brenens is now has as a trial um he's a former trainer in Michelle's lab. So armoring looks really promising in addition to retargeting. The real issue is scaling, automation, decreasing cost of goods and so on. So lots of work um on blood cancer which on the left, you know, we've had lots of um very promising results and I think it's going to become frontline therapy for most hemologic malignancies.

On solid tumors though, CARTT cells really have not had such promising results. There are some examples which I'll show but basically we have a lot of work to do there and a lot of that is due to the very imunosuppressive tumor micro environment with both checkpoints such as PD1 PDL1 and metabolic checkpoints in the tumor micro environment such as um low oxygen acidosis and um uh loss of the so-called tumor uh T-C cell tugofwar where the tumor then can starve tea cells by taking the uh sugar away the glucose for instance.

So we have been working for a long time in solid tumors um and learned a lot of the reasons why they don't work. And what I'll show you is some data in misothelin which is where we've have started in trials in pancreatic and ovarian cancer. And so misothelan is a GPI linked protein uh that's uh not tumor specific but it's much overexpressed in uh tumors such as pancreatic cancer um and msotheloma. And so in our first trial which we published here in 2018, we had a CAR targeting the end terminal epitope of misothelin um and we treated six patients um their um you know tumor uh uh mass measured by PET imaging is shown on lower left and you know what happened a month after we treated and one patient had in green patient 113 a regression u although not um a resist u mediated clinical regression but regression on imaging and in the middle panel um you can see at baseline there was me a lot of PET uptake which is tumor in the liver so metastatic pancreatic cancer in the liver and a month later that was gone I mean by imaging much better but the pancreatic tumor actually progressed in the center and so that showed um that in this case and there's many mouse models the the metastatic kassd driven tumor is more susceptible to car cells than the uh where the primary is and that's and there's lots of data that's due to more uh um and more potent tumor micro environment that's imunosuppressive with more fibrosis in the primary than the metastasis.

So, so in three different trials that we've done now in pancreatic cancer, we've learned on the left one mechanism of failure is failure of the CAR cells to even get into the tumor. And that's much worse in primary tumor than in the metastasis. In pancre in prostate cancer, for instance, in men, we have very good success in getting CT cells into the prostate tumor, but not in pancreatic cancer. So it it depends on a lot on the tumor micro environment and there's much stroma in pancreatic cancer that prevents CAR cells from getting in and we need strategies to overcome that.

On the right then is the other main issue I think fa facing the field in solid tumors which is the rapid induction of um exhaustion and dysfunction in the CAR cells. This has not been a major problem in um in blood cancer. So I'll switch gears now to a little bit of you know can we use AI and machine learning to make some of these projects better and um and problems solve them. So Dan Baker is a graduate student in my lab and in this summer he published this paper in cell where he used um AI as I'll show to look for targets of CAR cells in uh solid tumors which there are CAR targets there that and but this one question was which ones would be the best and where could could we find any that might be useful for many tumors.

So what Dan did was use the three major uh uh algorithms ChatGBT cloud cloud and Gemini and upload all data that we could find including all of PubMed and Tobula Sapiens. So Tobula Sapiens is an RNA sequencing database. It's the human atlas. It's got 24 donors in there and about 30 different organs. So uploading all the different single cell translucent and then asking AI what's the best target and and we used either human in the loop or human not using these large language models and ask um you know for you know tumor specificity is there any um you know what's might be offtarget and so on and ran through these three large language models many independent simulations and came up with actually a rank list of 100 targets, but the top ones are shown here with GPNMBB, which is glyoprotein non- metastatic B.

It's a looal protein, which I never thought you could target. And um but all three large language models picked that as the best CAR target across multiple different tumor antigens. This is an aluvial plot showing uh what GPT chat GPT came up with Claude and Gemini on these targets such as GPNMBB um Ephrine A2 and and PML an antigen that we've seen targeted in melanoma and then ranking them as far as whether they're um they would have tumor specificity offtarget issues or has anyone actually tried them in a trial.

And um on the lower part now is what's called an upset plot. And uh with PML it it you know it was ranked highly by the three um uh large language models. Um and um uh but not as far as for all tumors. And when we looked at GPNMMBB it was much better across all tumors. And this is not just surface expression. It's in the tumor micro environment as well. looking here um is how this is ranked. And so then after we got that data from the AI, Dan then looked at um looking across other tumors using bulk RNA sequencing uh from um multiple areas and we found in fact GPNMMBB is overexpressed in many different uh tumors shown here in the middle melanoma lung cancer kidney and bladder and it's on the tumor cells it's most highly expressed in melanoma but it's on very highly expressed in the stroma many uh tumors.

So then Dan um a previous trial had tested an ADC against GPNMMBB uh and he made that into a form BBB zeta based CAR and tested and this is showing in melanoma and colarctal cancer, lung cancer, kidney, thyroid and pancreatic cancer excelligence killing in vitro and and several different ET ratios. these CAR cells killed all of these uh tumor lines uh rapidly. And then he did a few um invivo uh NSG flank models. In this case here, a melanoma and mice uh were the tumors were eradicated.

Same thing in another colarctal solid tumor and in an AML model. So so then that that came out in July of this summer. This is an explosion of literature in July of GPNMBB. So we were number six there where we found GPNMNB by AI but uh number two for instance was from Sheila Singh's group in McMaster where they found GPNMBB was a highly uh a promising target in glyobblasto and and there's many other issues that that have come out now.

So I never thought it could be a CAR target because it's mostly a lossal protein, but it turns out it does go to the surface for a brief period of time and then in stress cells and then it can become target with a car. Uh so anyway, we've learned a lot that way. So misothelan has been as I mentioned a long-term interest in my lab. It's a GPI linked protein uh that is you know both on cancer and then lower level on healthy cells. and it has a um um it's been crystallized the end terminus and Iraasten made an antibbody to that end terminus and that's called SS1.

There's a number of glycans that are on misothelin and we have tested one against uh called M5 uh that's between the two glycans on the cyan and then uh there's this stump at the GPI where there's a cleavage uh and and we've looked at and made antibbody recently against that stump and then there's a an intrinsically disordered region there and intrinsically disordered regions are hard to make antibodies to uh because they flop around all the time.

So if you immunize animals even though RS are about onethird of transcriptto you don't get antibodies against them in general and um so we've worked now in this unpublished work uh with VJ um Krishna VJ Andrren in my lab and then um uh David Baker's lab at the University of Washington to ask could we make binders denovo design binders against this intrinsically disordered region of misothelan And uh the answer is David Baker's lab was able to find binders.

So all by incilico and running through alpha fold three in the pipeline that he's developed. Um and then on the right we took our our best clinical car which is called M5 which is an antibbody based SCFB and then this denovo design binder called 2D1 which is on the right and tested that in mice with a pancreatic tumor. And uh this intrinsically disordered regioned binder 2:1 works as well as our clinical binder. So I think AI is going to have massive ability to make targets against whatever many different targets now that that you have and and speed up uh research.

So misothelan you know has safety challenges but it has had some nice responses but there's a limited therapeutic index. I think targeting the correct and improved epitopes can increase the therapeutic index and AI enabled binder discovery looks uh really promising on this to improve the therapeutic index of those kinds of targets. So I'll close here. There are four modes of CARTT cell therapy. I showed you the one that's commercially available now but there'll be many new kinds developed um over this next years and decades.

And it's very exciting time. There's a huge investment now in cell therapies. This just shows in this radar plot the commercially marketed cars in the center. And then on the outside, you know, our phase one and first in human trials with not just alpha beta T cells but allergenic cell sources, NK cells etc. And um so I want to thank uh you all for uh your attention. >> [applause] >> Thank you Dr. Jim for the wonderful speech.

As we now move into the panel discussion, Dr. Jim, please kindly stay on the stage. Thank you. And ladies and gentlemen, we would like to invite the other 2026 town prize laurate Dr. Michelle Saladin to join us on stage. We would also like to invite executive vice President James Young to moderate the session and we would also like to invite our distinguished panelists upstage. U please welcome Dr. Panchu Yang, academicians of the academia cynica also a former president of National Taiwan University and also professor Aniun an honorary director of the National Taiwan University Cancer Center and Dr.

Wenzo, chief of hematology of National Taiwan University Hospital, and Dr. Shinzen, Deputy Director, Center for Frontier Medicine, National Taiwan University Hospital. And finally, Dr. Lee Junu, founder, chairman, and president of Eerogenics. >> As a reminder, please scan the QR code to submit your question online via Slido for our Q&A session. Now we will hand the time to our moderator. >> Okay. Um I have a privilege to uh ask uh um professor uh kajun and professor satellin uh to summarize that how how difficult it is to face the challenge of uh these new technologies in terms of um asking the regulatory agencies.

In addition, uh a lot of activists who do not like uh the genomic uh altered cells into humans and uh we the the challenge we have right now is in vital no which I think will face even more difficult times. So perhaps start with Dr. Seden. There have been indeed uh challenges uh historic challenges. Um I can uh go back in time to to two of them. um when we proposed to um test CARTT cells uh in um back in New York in 2007 which I mentioned before uh we went to the FDA with our proposal um which consisted in a conditioning a mild conditioning of a low dose of cycloposomide and then cartis cells and the FDA said that we couldn't do that They said we were combining two therapies.

And so they um uh forced us, I could say, to start just infusing CARTT cells alone in the first patients. That's why you didn't hear about those patients, those very first patients because um you know, nothing um helpful to the patient. There was no toxicity, but nothing helpful happened to the patient. And uh it wasn't until we then developed an animal model demonstrating that you really need some conditioning before infused cartis cells um that we could go back to the FDA together with showing the the ineffectiveness of cartis cells alone and then they allowed us to um to proceed with conditioning followed by cartis cells.

By that time other centers also then could open their trials and they didn't have to go through that. They could do conditioning right away but we had two years uh lost uh doing that in the very very beginning. So that's an example where the perhaps the conservatism uh of the regulatory agency uh wasn't uh helpful is a second that I'll mention from the past is the that that um Steve Rosenberg brought up was the reccominant DNA advisory committee. uh he mentioned that in in in the first trials at the NIH there were activists who were opposed to the introduction of genetically modified cells in patients and this was reviewed by a committee called the rack uh of which I was a member uh at some point by the way um but while it was initially useful to place some selfguards and to demand the establishment of robust sensitive uh assays for detection of replication coughing viruses etc.

Uh it became um more of an obstacle and many in the scientific field and in industry advocated its um uh removal and in fact it it no longer um exists. Um so those are two examples from the past and um but it's not over and maybe Carl wants to address some present uh examples. >> So thank you M there it's it's a major issue over the years on um getting you know because it's been sort of like a lightning rod cell and gene therapy if there is a side effect.

I mean, we need to remember incology that patients die every day from chemotherapy and that's never in the newspapers and and it's something you know medical practice takes into account and um uh in my first trial uh that we did with gene modified te- cells you know we had to go through 11 different committees including the rack committee that was just mentioned and then and I think Steve Rosenberg mentioned his was in earlier in you know for the neomy and phosphot transansferase trial that that was initially stopped and that had to go through I think 15 or so committee so and and years years to get that done so that's clearly not correct I mean I think I think we need a system in cancer where the patient is front and center and that the patient needs to have more of a voice in deciding what risk they would accept rather than you know federal agencies are more worried about um that they would have guilt if they approve something and then there is a toxicity.

I mean we have systems to stop trials if there is toxicity and that needs to be in place. Um and uh you know we we need to have systems that are balanced for for instance what happens in someone with endstage cancer and the risk they will take compared to for instance an autoimmune disease you know which Michelle mentioned those are not immediately face uh you know um lethal disorders and so there the risk balance you need to have much more protection and you know before it would be ethical to start those trials.

So I think we need right now we seem to have in the US at least the criteria are across the board the same whether it's endstage cancer a child needing a vaccine or someone with refractory arthritis. So so that needs I think needs to be changed. Another lesson actually is is geography. And right here in Asia, you know, I've seen since CARTT cells came on much more conservative um regulatory approach in Japan, for instance, compared to China, you know, and yet, you know, the you know, Japan had lots of very good basic science data on that, but they were very very conservative about allowing those trials to occur.

And China has been on the other end as we all know with single center approval of investigator initiated trials and they're much more rapid and efficient in that and we don't have that system in the US and I think we need to have that for initial discovery. I mean there needs to be transparency and so on but the initial discovery right now is much too slow and expensive uh in in our system and and I think in it's shared in Europe in general.

So, and China has had a mo mod which is now changing but it's the IIT investigator initiated trial should have a separate regulatory pathway I think than one where you're going for commercial approval and right now in the US they're the same which really slows things down and and it's been very frustrating us because we have these many more potent cell designs which we can't test in patients really in any um you know in a in a efficient manner. >> Thank you so much for your the the um important lesson instructions that you have.

Uh I think we learned this three three things. First is to uh be persistent in what you believe that can help the patient. Second is to work with the patients to work out these uh obstacles. And uh third most importantly is to have the best science to persuade people who are against these uh concepts. So let me go to uh profess uh young um our pre uh uh president of university. Uh professor young do you want to um ask the uh comp prize winner a few questions?

Uh yes actually I was quite impressed by the AI that can help us to identify the uh treatable target. Um actually you know in East Asia we have the lung cancer is a serious problem here and and half of the our lung cancer patient actually they have the u they are lucky to have a eje mutation. So we have target therapy that the uh very good response but eventually all the patient relapse. So uh did you think because the EJ mutant tumor relatively they are immune code they don't respondse to the uh immune checkpoint inhibitor.

So do you think the KTI uh is can help? Another very interesting question is that the AI actually they identify the GBNMBB uh which we found that is highly expressed EJ bar mutant tumor. Do you think that would be a good target for the [laughter] carditherapy for the EJ mutant tumor? So you know I think you know till therapy has worked really you know all the years at that Steve Rosenberg and others have done in hot tumors where the immune system already has recognized the tumor and you have endogenous tea cells um as you mentioned uh lung cancer particular here in Asia in non-smokers is usually a very cold tumor and the immune system is not responding and that is the ideal area for synthetic um immunology you know to make cells retargeted and then strategies to get them into the tumor um because as you mentioned checkpoint therapies don't work so I think um we have both you know to identify targets there are many sophisticated designs of you know so-called like a boolean logic gated car so that you could target and Michelle's lab has done done this approach where a single target may be um have a limiting you know it may have expression on non-malignant cells and so you can have gating and so on so that that then could be um uh you'll have targets that would be specific for the mutated lung cancer cell and then but we need to get the cells into the tumor and there are many strategies there uh to overcome the barriers and and so um you know I think Um it's it's just now becoming worked on.

There's very you know I think uh amazing data cuz like small cell lung cancer is also a cold tumor and and now the fact that we have you know a therapy that targets DLL 3 you know it's an amazing thing that an ADC could work in some small cell lung cancer. uh and so I think we're going to see rapid progress now in lung cancer which has really been lagging behind >> uh that said professor mentioned a very important question that this carti work on in majority hot tumors whereas cold tumors probably has some obstacles and you mentioned fibrosis for example that these cannot go into um so what else are there to for these these type of uh imotherapies to work in addition to uh the car T- cell itself.

Do we have other cells that need to be helped or your experience? >> I think this speaks to one of the um um strongest arguments for developing cell therapies and that is that that a cell can accomplish multiple tasks. you you can program a T- cell to express you know a car or a TCR that's step one that's what's been happening for the last you know decade or two uh and now we are starting to introduce a second or third or fourth gene um there's the beautiful example provided by Carl with 18 you can ablate genes for example involved in uh in pro-exaustive uh functions uh you can create cartis cells that that secrete enzymes some of which can at least [clears throat] uh in vitro uh melt down some some proteins encountered in the micro environment. uh some CARTT cells secrete antibodies, some CARTT cells secrete uh SCFVS uh and they can do so either constitutively or upon you know uh encountering a Q in the tumor micro environment so that they are not uh constitutively um uh expressed.

We we all heard about the the toxicity of 12 or 2. you can't make cells that secrete IL2 or IL12, but if they're um restrained in some way, uh you you can contain their or confine their expression into the micro environment. So that that's the strongest I think argument for using a CARTT cell which is not just a a a cytoolytic agent. It is also an agent that can remodel the micro environment. >> So a lot of uh possibilities to follow. uh, Professor Chen uh, also our honorary uh, president of National Taiwan University Cancer Center.

Uh, thank you so much. I'm a clinician. So uh we really appreciate the great breakthrough uh done by Karti therapy but we do hope that the karti in someday can be more user friendly for examp the use of new technology for example for Xvivo autogenic carti and also uh some invivo carti using novel uh messenger RNA technology so I would like to know how you envision the progress along this line >> well you know that's a great question I mean um one of the major rationale for invivo delivery is as you mentioned the vein deain time, you know, can we get rid of the lag time between uh that requires for XVivo manufacturing?

So offtheshelf allergenic cells do that and then invivo delivery can do that and um and so that's really important. Um and um you know we the field's just beginning these uh invivo delivered uh viral vectors and there's a number of issues when you give a virus I mean and the the the um invivo I mean viruses are inherently imunogenic our immune system sees them. So when you inject a virus you will get an immune response to it and and so that needs to be taken into account.

You may not be able to do repeated dosing for instance. There are lots of lessons on that with adnaviral vectors for instance. And so lentiviral vectors have you know the potential of integrating into cells um and then um you know could have ongoing uh expansion uh and expression of the cells just like we see with Xvivo manufacturing. Um but we have to remember that there are issues in the field with insertional encogenesis where plenty of our vectors insert into a gene that may and then may activate an anka gene.

Um and that that's happened with stem cell engineering for instance you know the the famous cases two decades ago in um uh severe combined immuno deficiency they had very good effects with the stem cells that were engineered uh but then um later they had the emergence of transformed cells and they were leukemia either myoid or bell and very interestingly the lag time was about three years. So we are not far enough along now to know that the patients who've been treated now with integrating vectors in vivo if that's going to happen.

So offtarget integration is a major issue that and and it's unless we have long-term followup we just won't know the safety. So we're really at the very interesting and early area Chinese that Chinese are leading this now and but there are trials um elsewhere. They're just getting underway in the US. >> Thank you. >> Dr. Is there anything to add? >> Uh maybe I'll say a word um on on the allergenic offtheshelf products.

Um a few years few years ago there was great hope that those could be um rapidly developed. Um turns out not to be so simple. It's not surprising. uh this is one instance where you you pay a price for having a cell-based therapy. It can be rejected uh by someone uh if it's not autogus. Um having said that there are many solutions in the in the in the pipeline uh largely based on on selection of uh appropriate donors with certain you know HLA hlet types and above all engineering there the uh puropotent stem cell technology seems particularly attractive because it can allow for uh you know safe engineering and clones of cells multiple edits 6 7 8 nine edits and characterize the clone and then produce cells.

Uh there are trials in the US and in China with IPS cells, very few I have to say. We started this work uh over 15 years ago. One of the many challenges is that we no one yet knows how to generate a very good T- cell from pur potent stem cells. Uh but again that's a great topic for research. uh and with engineering maybe there there will be uh allergenic solutions uh in addition to by the way NK cells uh that may also or gamma delta T cells that may u also serve this purpose so the invivo is clearly very exciting um but but I wouldn't discount neither the autotogus or the allergenic the autotogus is getting simpler faster cheaper and the allergenic has all these possibilities And what do you make of a patient that has very few tea cells or very damaged tea cells?

Well, neither an autotogus or invivo approach might be good enough if if they have very poor quality tea cells. And so there the allergen egg would be uh particularly useful. So um professor to is the chief of division of hematology and uh he and his group had uh performed many hearty therapies in national town university hospital and cancer center um and I'm happy to say that it it is reimbursible now in Taiwan that u but it cost 300,000 US dollar per patient although I think it's feel very compared very cheap compared to other places.

Uh, Professor Joe, do you have any uh question to ask our experts? >> Yeah. Yeah. Thank you. I'm privileged to be here. Uh, I'm a clinician and taking a patient with some hematology migrant disease. So my question is uh is so impressive to to know that there are still carti persisting in long-term survivors accuring for braille leukemia and but as far as I know for the informal patients the persistence of carti seems does not seem so highly correlated with the disease responsive status.

So my question is uh why are why are those carty cells persistent in those patients? Are there still some kind of stimulation to keep those cies surrounding in the patients and uh for following these patients uh does it mean that when the cy becomes undetectable that may imply impending relapse for these patients? >> Mr. J. So I'll start off. We we both worked on this for many years. Um and and I think there's many, you know, until you do human trials, uh there's a lot of there have been a lot of surprises.

So uh I mean Michelle is has been a leader in finding that CD19 was the best target for you know B cell malignancies. the industry was just focused on CD20 which developmentally comes on later. So CD19 has been ideal then and and we switched to that cuz I was initially working on CD20. Then um what has been surprising is you know CD19 is now approved for acute leukemia, chronic leukemia and large you know lymphas as you mentioned and what's amazing to me is the mechanism of resistance is different for each of those the same target and in some cases it's target loss which is a main thing in CD you know for acute leukemia in uh chronic leukemia it's much more of an issue with exhaustion of the tea cells and uh and much less target loss and in um uh you know lymphoma it's complex and and there can be down regulation of or tumor micro environment issues and but that the other issue is it you don't have to have long-term persistence of CAR cells in lymphoma to get cures.

It does seem to be in in leukemia that you know you need long-term imia surveillance and so persistence of cars is correlated with leukemia free survival unless you cross over into like an aloe transplant. So it's it's amazing to me that there's these differences uh of the tumor biology with the same target and then you know there are uh you know many other uh lessons now of you know you can have short or long-term persisting cells.

Um and you know we can and even in now we're seeing in autoimmune disease you may not need uh you may only need persistence for a a month. So that's the beauty of cell therapy is is you can you can engineer that um uh depending on what the clinical uh situation is and and we found you know the different co-stimulatory domains can lead to one of the things that correlates with long or short-term persistence. So bell plasia seems to be important in acute leukemia and to help predict danger of relapse and and those are from you know cross-sectional studies but in lymphoma and really no data on that.

I I think Carl addressed made the the central point that it's uh remarkably it's uh disease specific. So that's fascinating and that tells us we have to work with clinicians to study this and understand it. Um in autoimmunity that's uh of interest at this moment. Um should one start with longlasting CARTT cells which tend to be these uh 41B based designs uh or not if uh if there is no gain from a having a bellasia for months or years and in fact there are only uh disadvantages you know such as susceptibility to infection then a a limited um durability of these cells would be preferred but we need to know what what the boundaries are and I think there's a there's a lot to learn from the clinic. >> So following this uh very important question of resistance as well as many patient uh actually did not respond to hearty therapies.

Um I think uh imunotherapy always work when it was applied first meaning that when we give other treatment to patients the these cancer cell evolve and uh know hetrogenity is the biggest obstacle for imunotherapy. So do you uh think that uh when carti becomes safe um are we going to give carti as a firstline treatment as soon as we discover these patients at initial diagnosis? I mean I think both patients and clinicians would prefer not to use chemotherapy which is you know alkalating agents for instance are mutagenic and there's very recent data so showing that that actually can promote tumor progression and resistance.

So avoiding chemotherapy uh and is going to be I think important that's really going to be an issue in autoimmune disease where if you um you know in general rheumatologists haven't given lipid depleting therapy and so they they're really going to be an important medical need to have uh therapies where you don't have to give cytotoxic therapy. So it it's um frustrating how long it takes these things to move to front line and you know the now randomized trials have shown that in uh myoma and lymphoma that second line treatment is is superior to standard of care.

And that that's really it's amazing because the initial trial patients that we treated you know in our academic setting had all had you know in general four or five previous lines of therapy or more and and yet we could still show potent responses. So um it will be both um better for the patient and financially much less expensive if we can move these front line. >> You also think this is feasible as a first line treatment.

I I could not agree more. Uh I would expect that these uh treatments will eventually um uh reach the front line and expect them to be successful. This however cannot be done by academics. Uh you need large larger trials, comparative trials with different arms and this uh is more in the um within the range of of what pharmaceutical companies can do. And I hope that some of them will be brave enough to do it. >> It's just like the L3 uh T- cell engagers now been tested in first line small cell we see a amazing plateau of survival.

Um I guess uh we always have to test in refractory patients yet these are the worst patients to uh respond. Um but but then um moving forward is so important. Uh Professor Thai is our uh pulmonologist but she specialized in iminology. Uh do you have any questions for our panelists? >> Um thank you. Very honored to be here. So uh we all know cancer is extraordinary heterogeneous. So um uh but the cell therapy is going to reach a large number of patients.

Um I don't know if we can still make every product as a completely personalized therapy. Um so I'm curious how you see that balance. So uh is it possible we have personalized biology without personalized engine manufacturing? Well, you know, we have to we have a paradigm now that's based on cell culture and technologies that are, you know, 20 years old. And now, you know, there is there's a lot of data that um shortterm manufacturing can make more potent, but then it improves the vein-to- vein manufacturing time and um and could decrease the cost of goods.

So I I think the major thing can be instead of having central manufacturing if we could have local manufacturing at the site of where the patients are then it could be same day and then the logistics can get much better so that you know it it could scale and um so you know so that's a technology development issue. I think the biology now is pretty clear that short manufacturing can be done as to short as z you know with including invivo delivery of integrating viral vectors so I think we're going to see this uh evolve um and then and that's how it can be scaled the introduc you know getting rid of the complex logistics um and then you know improving with turnkey um you know robotic and you know device development I think this becomes something that can be done locally. um you know we never thought that bone marrow transplants could be done um and scaled and they've that's happened you know and and now they're done at you know very I'm not sure here in Taiwan for sure but and across the United States now they're done in many rural areas you know so you need to train the physicians and right now um you know many of our physicians don't know what a car T- cell is and the patients are learning you know so we have a time scale for the workforce to learn about this and then I think the technology is going to allow you know local on-site manufacturing. >> Yeah, I again agree with Carl.

Um I just want to add that um um in addition to the the technological um uh needs which I think will be met you know of a rapid overnight production that can be um implanted in in multiple centers not only the largest centers. I I hope that that day will come. I believe that the advances in the technologies tell us that that that day will come. Um but I also want to emphasize the the sort of regulatory and and and um let's say um um institutional barriers that come uh who owns the medicine, who is liable for the production of the medicine.

Right now we entrust all of this to to the to the pharmaceutical company that produces the drug. But if it is produced now um locally somewhere well will the process be the same everywhere? Will it be a bit different? Uh who's who's making that that that vector? Will they allow it to be manufactured not just in different places but in different ways? Um I I think there's a a wonderful set of issues that you know actually government insurance companies and regulators need to reflect on in in laying the ground for these uh future I hope widespread cell therapies. >> So speaking about this uh Dr.

Leo is um one of the largest uh biotech company in Taiwan. Um so are we ready to uh produce cart cells to service our hospitals now? I [clears throat] think it probably very difficult. Uh however I do want to ask a question uh for both of you is uh Taiwan has a strength you know in clinical research just like you see you know uh we have all the doctors here you know they do the wonderful research but we do have a decent and uh I think it's a very good biio manufacturing capability genomic data bio bank and also uh this advanced technology uh IC industry Uh plus you know I think uh I do want to emphasize that uh just uh only uh year ago you know we passed this uh probably the cell therapy favorable legislation and regulation uh that is the regenerative medicine act and the regen regenerative uh medicine product.

So that's will make uh I think a research progress early research progress would be easier. Uh from your respect you know uh where can Taiwan make the most meaningful uh contribution to next uh generation of the therapy. I I like this idea you know using the cell as a as a medicine. I think basically as a delivery tool for the medicine uh for gene therapy I I spent uh almost more than 12 years working in the US on the different gene therapy company.

I see that uh uh maybe with uh sale as a gene delivery or a medicine delivery would be a uh what great idea you know if we can uh make that success uh and what type of academia and industry collaboration uh would create the uh greatest impact uh for the whole globally. Yeah. from from you know your your point of view. >> Yeah, I guess uh we are we are mostly academicians here. So um that will represent the other side which is industry.

Um and the main question is how do we work with them? [snorts] >> Uh maybe to start with uh professor Jun, >> you know I um each I think we've learned geographically each place sort of has uh you know their own sweet spots and how they can implement something and and how you implement a new therapy is different in you know Japan than it is here in Taiwan. So I mean that's one thing getting harmony and regulations and and then the society to make decisions on who wants to bear the risk because whenever you change there is risk and then um but then there's also the cost and access democratizing access to everyone and um you know so I think Taiwan's going to have its own solutions.

I mean, you can look at what for sure the workforce here in Taiwan, the fact, you know, like you're the lead world's leader in computer chips. I I think you should be have a high priority to making cell design uh manufacturing, you know, because that, you know, that may be a sweet spot here. I mean, we, you know, haven't had that really happen much in the United States. Um, and so that needs to happen. And then our we don't have right now I mean our pileup right now is it's not the science it used to be that but now with gene editing crisper base editing you know all different platforms it's really become an engineering problem. um we have the proof that we can make almost any kind of cell you want but our problem is is you know getting just first in human trials and you don't need a lot of patients to do that but we don't have funding mechanisms in the US to do you know just a five or 10 patient trial which will often times say is a new approach um you know should we pursue that or or kill it and go back to the drawing board and make next generation So we're not good at that.

China has the best mechanism uh of sorting through um you know with IIT trial designs and then it needs to be you know then you need to have a regulatory pathway then to make sure it's safe everywhere and then you know but you also have to have the issue of of how do you pay for it and in the United States right now our government is supporting less of that you know the only you know so we need to have support for research and development of these new engineering approaches and different uh geographic areas have um you know have have been better at that. >> Your advice? >> No, I don't have any advice but I do I'll just make a general point.

I do think um it's essential to have a good academia industry uh cooperation. I really think that's uh key to advance things. Uh [cough and clears throat] excuse me. Uh you know in academia there's a lot of great ideas uh experts who really know the disease and they have access to the patients. So they have uh things that industry does not have. Uh on the other side, industry has the um capability of uh optimizing uh scaling up and distributing.

Uh it's really fundamental that they they work together. There are barriers. Uh I'll mention three. Uh intellectual property. You work together. Well, who owns what? Um you have to come to an agreement. Another barrier uh conflict of interest often on the university side uh it says well you can't do this or that with the company that's uh perhaps justified in some instances but it's also a barrier. Um, another one is um manufacturing uh secret um oh the company does it this way won't share it with the investigators so maybe therefore they can't contribute to further development.

So I think there are multiple um aspects of this uh collaboration that that that institutions can if they want uh facilitate and uh and I think that's to the benefit of advancing the field. Um I have like uh 46 questions but I don't think we can finish this on time but uh I I will just pick a few that I think is interesting. Forgive me that I have my own preference. Uh this is quite interesting that as CRT advances into invivo manufacturing in sightsp specific integration shall regulation transition from a product specific which you sell as a drug to platform based mo model.

If this can be happening, what core attributes should be defined? [laughter] >> Well, um >> I don't think any regulator agencies here. You can speak whatever you want. >> Well, [clears throat] I think there's a a big push right now to have certain platforms approve approved. Um the idea would be that a a method of delivery or perhaps also you know in vivo delivery or xvivo or targeted to a genomic location or not um would be um approved as a platform make it making it easier then for new products to be more rapidly developed and approved as long as they use that same platform.

So yes, I I I see the um I see the virtue of that. Um I don't think the question was specifically about genomic uh integration, but um I I'll say that we see the benefit of that. Um because if your gene always goes in a particular location, you can better predict how it will work. If there's semi- random integration, you know, it works a bit differently in one cell to the next, that's a source of variability, sometimes toxicities.

So, um I I do think that uh or I do hope that there will be um platforms for for targeted integration that over time uh are approved whether it's in immune cells or later uh you know in liver cells or muscle cells and others. Do you have anything to add? No. Uh I have a few interesting questions. I can just pull them together. Um of course uh the audience want to know whether there are um a good aspect of adding combination therapies with scarti maybe with cancer vaccines or checkpoint inhibitors etc.

So that you know that is has the idea of combinatorial therapies you know it's how we the whole foundation for chemotherapy I think um there's very strong pre-clinical data to combining different platforms so for instance you know checkpoint therapies with car cells and Michelle's done trials on that uh we've just completed a trial giving an anklettic virus and then CT cells and it looks very promising. Um and then uh there are trials uh for instance um you know combining uh uh recominant antibodies or vaccines with car cell therapies.

So all of those look very promising. The the two uh drawbacks one is it's very hard to get them open in a regulatory approval through when you have combining different modalities. So, and then the second aspect I found is that in general there may be it's two different companies may be involved you know because it's two different platforms and then to get them play in the so-called same sandbox is hard because they have to decide you know what's the value of each individual component.

So it's that's the the problem. We need a place and a way to be able to combine these and to test different therapies like that in a way that's uh because right now we have lots of logistical and regulatory constraints. Okay. Um [clears throat] I have a interesting question here. uh what key attributes such as viability, purity, potency, memory, phenotypes and uh metabolic profile should be evaluated to ensure optimal therapeutic efficiencies in T- cell products.

I think these are very technical questions. Uh how do you define that initially? I think the question is really about um you know what's the optimal cell type and we now know I mean there's many kinds of tea cells I mean even alpha beta tea cells whether it's a a so-called memory cell or actor cell I mean we found that they each have different roles in killing tumor cells and and you may want to have imunos surveillance you may want to have um you know the initial expansion and killing or and then and then just the fact that the immune system normally works like an orchestra with some cell types supporting others.

I mean that's why initially um when TE-C cells were discovered they they were called helper cells and basically killer cells you know they were and then they found out CD4 and CD8 you know correlated with whether you're a helper cell or a killer cell and and so all of those have different independent contributions and then we have the fact now that there's very different cell types like natural killer cells you have a delta T cells and so one each have things that look very promising or and you know that they might have specializations that the alpha beta tea cells don't.

So they require different manufacturing streams and they're hard to implement. Um and you know so we haven't seen you know we've seen a lot of ENK cell work done but very little done. I mean there's invariant NK cells there um there are you know the gamma delta cells and and different so it's it's something that's going to take time I think um and what we have now is a platform of alpha beta tea cells and then question of do you want to have a whole population of them or make them more monoconal where they have a single cell subtype such as a stem central memory cell or and so on.

So there's a lot of interesting work here that's you know based on cell biology. >> Uh and there's one interesting question uh is checkpoint involved in cult uh whether KY cells eventually may develop checkpoints or tumor cells who inhibit KT to be effective. Uh were there any activation for this? We conducted a trial a few years ago in um misotheloma with a cartis cell targeting misothelin uh which in his second arm was um combined with PD1 um blockade.

Um it showed a modest improvement. I can't say that the result was um uh dramatic um but probably enough to say that uh and it's just one dose, one regimen uh one condition, one cartisel, one disease and so um I think it's uh quite possible that this combination will be fruitful. Uh I don't think it's been yet um fully developed and established. Can you take PD1 out of T- cells? >> Yes. But um actually actually Carl has a story to tell you about ablating PD1 I think. >> Yeah.

So I mean it's complicated. It depends on the tumor micro environment. Some tumors have a lot of checkpoints expressed and others don't. And then you have to look at so that is the cell exttrinsic issues and then you have this T- cell intrinsic issue itself of you know should it have checkpoints or not and so we did a trial it's only four patients but we use crisper uh and guide RNAs to knock PD1 out of T- cells and we also put in a a T- cell receptor and what we found was was that you know in competition in the patient the cells that had PD1 knockout proliferated better initially but then they didn't survive to be memory cells and and it turns out there's data in mice for instance using chronic antigen exposure and LCMV in a mouse that if and you do adopted transfer with wild type uh LCMV specific T- cells or those that have a knockout of PD1 the knockout of PD1 they work better for about a month but then they don't persist.

So, so anyway, that's So, it turns out you need a PD1 signal and there's now molecular signaling pathways worked out. You know, why this is true in order to convert to a memory cell state. >> It's uh it's quite interesting in our own laboratory, we found that PD1 actually activate uh cancer cells to express uh met phosphorilation. Um therefore there are a lot of things that we don't know. Uh obviously we we just have to do to figure out um so uh we have few minutes to talk about TCR CARTT.

I think uh this is uh the audience most interest um for TCRT to be effective you have to have a new antigen right you um bind with this TCR. Um so we we see some examples. Um how do you foresee this uh to advance whether this can be applicable to know uh which proportion of patients? >> Okay, [clears throat] last question. Actually we have only two two minutes left. >> Two minutes. So I'll try to be quick. I'll just lay the the ground and let Carl conclude.

Um the TCR is obviously very attractive. Uh it can see a broad range of proteins including intracellular proteins uh which in the form of peptides are brought to the cell surface. Now point number one cars can do that too. You can just make an SCV that recognizes an HLA peptide antibbody. So anyway, you don't need a T- cell receptor to recognize HLA peptide. Uh you can do it with a T- cell receptor or you can do it with an antibbody that recognizes HLA peptide from which you derive a car.

So obviously it opens up a a larger repertoire of of targets, but it's HLA restricted and um you know I I call it the curse of HLA restriction. It's great for our species that we don't all have the same hlet types. So there should always be somebody resisting the next pandemic hope hopefully. But in terms of um therapeutic development it's challenging. It also requires that the T- cell expresses HLA and that it its ability to process antigen be maintained.

Having said that, um you know there are uh clearly settings where we we have not yet identified car targets and where the TCR would be uh the preferred way to go. Uh so I I love it that some people invest their their energy in in that and we do so in cars. I mean, um, the T- cell receptor has, you know, it's very sensitive, but that's not the real issue. The issue is this HLA restriction, which makes it hard often with a T- cell receptor to find the right patient.

Um, but you have to remember that um, tumors naturally have resistance to TE- cell receptors by downregulating class one expression. And there are studies in um initially solid tumor it was seldom feron showed in ovarian cancer at the time of presentation about onethird of the patients already don't present HLA and they can have al specific loss of chromosome 6 of just the restricting arm of the chromosome that presents the tumor antigen or or they can lose the whole distal arm of chromosome 6 and but remain so that this the tumor cells aren't killed by a natural killer cell.

So that is natural biology. I mean and um even someone one of the best tumor geneticists in the US Ricardo Dela Fava when he did sequencing lymphas he found out that about half of the tumors have natural immune resistance. They've either deleted the class one presentation or they have NK cell resistance engineered into them. So that the tumors have already avoided imunos surveillance. So and then [clears throat] the very first T- cell receptors against K RAS which is a great target because it's a driving encogen.

So if you can have a T- cell receptor that sees only a G12 mutation on the K RAS encoaging that's great but already the patients the resistance is loss of class one. It's already been seen in a high fraction of patients. So that's the beauty of CAR cells that can target independent of HLA and not have to worry about class one loss. So I mean I think T- cell receptors may work well with CAR cells. Um and because they're orthogonal in how they target and that escape is a big issue.

We know it it's a tumor escape is a problem with CAR cells especially in acute leukemia and it's going to be and it's an emerging problem in BCMA and and T- cell receptors their Achilles heel is loss of class one. >> Thank you. Um unfortunately our time is up. I think there are many questions left. Um but I I hope that uh today we have a very very uh interesting discussion about uh uh clinic basic science as well as how we uh work with industries to achieve all of these.

Thank you very much Dr. Adam, Dr. Jun and Professor Yang, Professor Chen, Professor Joe, Professor Thai and Dr. Lou for your kind uh participation of this panel discussion. So uh thank you very much uh for your participation as well. Um I last uh I will call this uh panel panel discussion a close and then I will like to invite as our um guests to come up for a group photo. Uh, Professor Chen and Professor Jang, please come up stage for our group photo.

Thank you very much. [applause] Let's give a big round of applause for our moderators, panelists, laureates, and attendees. This brings the 2026 Tom Price Master Forum in biioharmaceutical science to a successful close. >> [applause] >> for what's happen.