NECTA Meeting 2026 - Drug Development in China and T-cell Engagers

[ Inaudible Remark ] >> Okay, good morning, everyone. We might get started with our second session just so that we keep on running on time. So my name is Andrew Parsonson. I'm a medical oncologist at McRae University. And we'll be -- we have two very great speakers coming into this second session today. So first speaker today is Professor Yushang Ma from Sun Yat Sen University Cancer Center. Professor Ma is a medical oncologist with a PhD in oncology and associate chief physician Masters degrees of Vice-Sun Yat Sen University Cancer Center. His main research focus is on developmental and investigational new drugs for solid tumors, including lung cancer and nasal found geocalcinoma. He's a secretary of the lung cancer position therapy and clinical research committee of Grand Don Provincial Clinical Medical Association. And member of the Chemo Therapy Professional Youth Committee on Grand Don Provincial Anti-Cancer Association. Professor Ma, will we talking to us about drug development insights from China and as investigated working in early phase trials in Australia, we share a lot of trials across with Sun Yat Sen University Cancer Center. So very much looking forward to hearing his insights and thoughts. Please welcome Professor Ma. (audience applauding) - Thank you session chair. Hello everyone. I'm honored to stand here to present this introduction. I'm from Sun Yat Sen University Cancer Center, which is located in Guangzhou. The topic is drug development and early phase clinical trials in China. It's called insights from the Sun Yat Sen University Cancer Center. Here is the contents. And in the part one, I'm gonna give a short, a brief introduction of Sun Yat Sen University Cancer Center. Our center, we are located in Guangzhou and we have two campuses. Everything goes very big in China. So it's our hospital. We have a very big hospital. We have 2,000 and 247 beds. And in 2024, we have over two million outpatients visits and over 200,000 inpatients. About 4,300 employees including over 1,000 with physicians, 500 of the researchers. It's a big hospital. And this is inpatient care and we have surgical and departments with the therapy departments, and the platform internal medicines. And most importantly, we have two departments before research departments. It's the clinical research departments and experimental research departments. Here is the top 10 malignancies treated in our hospital in 2024. We have lung cancer patients and the chalorectocaine patients and the Nassau-Ferringio-Casinoma ranks top three. And the total about 1,600 new cases, 1,600,000 new cases. And this slide shows the research capability of the nature index ranking. The left table shows the nature ranking index of all domestic hospitals, including General Hospital and Speciality Hospital, our center ranked number five. For all cancer centers globally, our center ranked number five, too. The first ones, MSKCC and NADN CERN, and we are the fifth. So the research capability relies on several research platforms. We have cutting edge of translational research. We have the animal facilities and the protein science platform, gym editing platform, et cetera. And for clinical research, we have a liquid-bounce platform, molecular imaging platform. And also we have a combination of an engineer with the medicine. We have a big data platform and the nano-medicine platform, et cetera. For the most importantly, we have a bio-medicine platform for the analysis. So here shows the, it's worth mentioning our bio bank and pathology departments. We have intent to, you know, construct our bio bank for over 20 years. This video, this clip, shows the daily procedure of the automatic sample collection, delivery, and storage. So as we can see, we have a lot of the specimens from biopsy or surgery and have cell slides, total platissue sample and the tissue samples. So also we have a very complete digital database, which is a reprogrammed by the module setting for over 100,000 cases with 42 cancer types. All these cases are available for elementary, advanced research, which is very convenient if we want to do a post-hog analysis. So this is, you know, the database is very complete. The slides shows the clinical trials in our whole cancer sensor. The bar on the left shows the newly initiated clinical trial every year. And from 2020 to 2024. As we can see in 2024, the newly received research funding is on the right figures is more than 30, 39 million US dollars. So here, finally, the slides shows the publication by employees from our cancer sensor. Either as a first-author or the corresponding also, here's the achievements of the last six years from 2020 to 2025, for the top journals, including new immunogenic medicine, Lenserts and JAMA and BMJ, also in cell nature and science. A lot of journals, which published recent six years. So it's the part two I would like to talk about the transition of clinical trials in China in the latest 20 years. So this data was obtained from the clinical trial, the registration website. It shows the global distribution of clinical trials, which is mainly in the North America, Europe and East Asia and Australia. The rapid increase of the clinical trial number is observed in China from 2018 until now. In the last eight years, as you can see, back in 2018, clinical trials in China is 800. Until now, the increasing is very dramatically. And distribution of clinical trial phases in China was basically consistent with the global change. The majority trial was set in early phases, like phase one and phase two, and nearly half of the trials registered, and early phase trials. And phase three and phase four trial is the minority. So back in about 10 years ago, just before 2017, most of the investigation, new drug, IND drug in China, were from international pharmaceutical companies. So here, this figure shows the classic model of the China registration of IND back in 10 years ago. China did not, like model one and model two, in China did not participate in the international phase one of phase two trial. And model one shows the China join in the international phase three, multi-center, randomized clinical trials, as a center. And after the drug was globally first approval, the drug do not do go domestically approval based on the clinical trials locally data. This is a very classic trial, such as Jivetini and Alotini, they're following the same pattern with the model one. And the model two shows the China did not join international phase one and phase two trial also. But did not join international phase three trial either. But after the drug was globally first approval, there is, you know, multi-center clinical trial is conducted in China for the China dominance multi-center RCT just for the registration in China. And after the, another, the same identical RCT doing mainly in China with a simplified phase one p-case trials, the drug. international drug will be registration approval domestically, such as Avastin. So which brings serious problems here? Let's take a look at this table. Above is the FDA approved time and the bottom is the Chinese FDA approved time. There is a serious gap between approval times severe delay. If the drug follows the model one such as G5T, or low TN, and the OCEM-ERT-TN, the gap is small about 1 to 2 years because China have joined the international phase 3 trials of this drug for approval. But if the drug was following the model two such as Pemberlizumab and Newellumab, the gap is big. After the global phase 3 international trial completes and the guards approval globally, and we have done the same identical Chinese version of the phase 3 trial domestically and the gulla approval. So the gap is at least three years or more. That's back to 2010 years ago, 2017. So what is the reason? The reason for the most investigation new drug from the international pharmaceutical companies is the major step back in 2015, which I call it like a fierce growing pain. Why is that? Because most of the clinical trial data domestically investigation new drug suspected to be fraudulent. A major audition and data retrieval was conducted 10 years ago. That's a wide back in 10 years ago. The domestic IND did not thrive. So major step back. So after that we have to construct what's the rebuild from ruins in 2017. China Food and Drug Administration released two major revision of the regulation to address the relevance matter from imports, drug registration, and the relevance of the policy to encourage drug and medical device, innovation, and reform, the management of the clinical trials. From that on, the domestic IND clinical trial were regulated and thrived ever since. So here is the figure of the current operational model for clinical research currently. The model one refers to also international IND. The China joined in early in the phase three randomized clinical trial and finished the Chinese phase over at the same time. And completed the CFDA approval based on the local clinical trial data with only a short gap after the global approval, the gap is short. Because we joined in the multi-centre trial early and have independent finished Chinese PK, phase one PK for the international drug. The model two refers to domestic or international IND. China joined in the international phase one trial first in human trial whether it's from domestic company or from international company. And dominates the global multi-centre RCT, which finally the drug finished the phase three child which is dominated in China. Gala first approval, the first approval is in China. The model three refers to a domestic IND, the whole course, including phase one to phase three, were all conducted in China. And Gala first approval in China too. Afterwards, the drug got approval in China and the pharmaceutical company sticking for the opportunity to go abroad, such as the toilet polymab and the BTK inhibitor from Beijing, the three model currently. So, the part three I would like to focus on the innovative drug research and development in China, the current status and the main challenge. Back in 2019, we have really, as you know, investigated in the phase one units from CSE University, we have released annual reports on clinical research of new oncology drug in China. As in 2017, as the comments or the land certain college. So, the main problem back then, in 2017, for IND China back then was, first is an uneven distribution of the clinical trials. The major of the clinical trials were conducted with only 18 institutions. We have 180 ongoing phase one child, but we have only 18 hospital can run it. So, we have a very low level of innovative, back in then. General, a genetic drug research dominates with only 9% of the drug was being the first in human trial for new therapy. Most of the drug were me too trial. The innovative first in human trial was low. And also, we have a very serious problem of insufficient collaboration. The collaboration, the communication among investigators, sponsor and institution have many difficulties. Here's the figure shows the main hospitals can run a phase one child. Back in then, only 18 hospital can do that. But we have improved in 2020. We have released annual reports of 2019 on the Journal of Hematology and Nancology. It's also a comment. As it's a tutorial, the situation gets better from the surgical regulatory reform promoting the clinical developments of new oncology drug. We have seen a much more balanced distribution. The increasing number of institutions conducted in phase one clinical study. As you can see in the map, there are more institutions that's cool around the phase one child. And we also have innovative driven drugs. The National Push from regulatory to for the biomedical innovation is strong. It leads to a very increasing percentage of domestic capability to developing the novel oncology G-Chark. The novel targets and the rights of first-in-class medications. Also, we call cooperation is the establishment of phase one union. We call it phase one oncology clinical research consortium. It's also established this year. We have the titan of the cooperation of this all pharmaceutical company and phase one child, the hospitals. Here shows the clinical trials being conducted back in 2019. As we can see in the figure, it's the overall phase one pipeline, which is getting more diverse. We have lots of first-in-class trials. The targets include the mature and innovative and distribution of targets are more enthusiastic. Both of the trial numbers and the cancer type involved were much better in 2019 compared to 2017. In 2022, we have gathered six top cancer sensors, including us, CIS University Cancer Center and Beijing Cancer Hospital. Also, the Shanghai Cancer Center in Fudan University, the Cancer Hospital of Chinese Academy of Medical Science and the Shanghai East Hospital and the Tianjin Medical University, along with the big data was collected from Pharmacube to publish a letter to cancer cell. The letter is to analyze the transition rates of phase one program on anti-cancer drug in China. It's the sum results as we're looking into this data of phase one successful trial and the final rectory approval or suspension termination rates. We have concluded several conclusions. About 40% of the IND fail at early stage clinical research during the whole courses. Only 5.6% of the anti-cancer IND, which completes the phase one trial, which successfully completes the phase one trial, will finally get approval. The major key lead to approval instead of suspension or termination. We think one of the reasons is the well-designed clinical study, especially in the early stage of drug development. Also, in 2024, the phase one unit team at Shanghai University were invited to contribute commentary on the opportunity and challenge in China on college clinical research for the cell press. 50 anniversary special issue. We can see the increasing number of IND and NDF application for the innovative drug in China year by year. Here is the data from 2018 to 2022. As a comparison, with China, United States, Europe, and Japan can see the numbers of Chinese growth and the number of the clinical trials for innovative drug is among the highest in the internationally. So in the part four, I'd like to share three examples of the early drug development domestic drug leading by us. The first one is a BLB01D1 is consists of a EGF and HER3 by specific antibody is ADC is a by specific antibody ADC. With the top one as a payload and a cleavable linker, he's the structure of this drug. There's some problem with the title. Here is the-- It's very-- [LAUGHTER] I've been doing without titles. [LAUGHTER] Sorry. Yeah, yeah, here's the title. This map shows the multi-center Facebook and clinical trials involving a lot of numerous hospital cross-virus region of the country. We are the leading site by Professor Zhang Li and have another six centers to perform this multi-center Facebook one trial. Here's the study design, also with no titles. This is a study design about inclusion criteria. We enrolled patients with advanced metastatic non-Somosalan cancer or other solid tumors. In the Phase I study design, we have-- this is a first-- because this is a first in human trial, we have explored in those escalation phase for my regime to search for the best of OP2D. In those escalation phase, we have explored once per week and the day one, day eight, a per three week, and once per three week, those in method. So by exploring night-dosing level and three different dosing intervals, the optimal dose and the regimens were finally determined. So in this Phase I trial, we have a very tough to achieve the OP2D, stopping a design to two doses and we have those expansion phase, mainly in the Q3 weeks dosing and the day one, day eight, Q3 week dosing. And the result is promising. We have the data published in Lenson College, 2024. In each of the mutants, non-Somosalan cancer, we can see a much increasing of the object response rates. And also in the wild type non-Somosalan cancer, we have seen maybe a double of the increasing with ORR and also in the suffrageocasinoma. The objective response rate is nearly about 40%. So as we have gathered this data, we have the oral presentation in askle meeting and the data was published in Lenson College. Also, we have seven, the same drug, seven, Phase I clinical study are underway, domestically and internationally. The study is a new global error for the specific antibody ADC in cancer therapy. This is the first example. The second example is a normal B7H3 ADC, it's called YL201. The sponsor is a meta-link. This is the first in human, also first in human, Phase I trial of this drug is stopping a design to two phases, also is a dose escalation and the dose expansion. The dose escalation is quite simple. Once every three weeks, and we finally found the RP2D is 2.4 mg/kg and 2.0 mg/kg. This structure of this drug, by exploring six dose levels, the optimal dosage and the regimen were ultimately determined. The dose expansion, we explore several cohorts in small cell lung cancer, the NPC and in LERC and S of Agio, Schoemokseol, Casinoma. This drug is what we call the model 2. This is a domestic drug, but the Phase I trial is performed internationally. As a matter of fact, the first patient was enrolled in MD Anderson. We have three hospitals in the United States, which are participating in this trial, and also 51 hospitals in China, participating in this trial too. The first patient was enrolled in America, but in China we have a very large amount of patients. We have the very high speed of the enrollment, so we have the leading to nearly a half year and the numbers are increasing to 200. Finally, we have those ongoing trials data was published in Nature Medicine. For the small cell lung patients, also the B7 by 3 ADC have a very dramatically increase of the OR. The object response rate from 25% to 65% is very promising. For the National Phrygian, Casinoma also, the OR was increasing from 25% to nearly about 40%. This is the basic results. So the new drug clinical trial was highly recognized by the international peer. This trial was being an oral presentation in SMO in 2024 in Barcelona, which is selected as the proper paper presentation, and also published in Nature Medicine. Also, we have two Phase III trials of this drug were underway, currently underway. And also, we have the third example. That's what we mentioned earlier. This is a Model III. Model II, also a first in human design. It's EGF and CHOP II ADC. The drug is currently underway. Also have Part II, Part II, Part II is those escalation, Part II expansion. It is International Phase I trial. We have several centers in China. We have three centers in Australia, in Monash Health, Dr. Sophia Frances, and we have two centers in United States. This is the summary, but the results is not published. So in the last, in Part V, I like to show some the establishment achievement of this one word of our center. So the Phase I units of Sui Nhat University Cancer Center is the first Phase I word for anti-cancer drug, which is independently managed by a hospital. Back in 2020, 2014, March, the Phase I units is established, and we have 12 years of heritage. We have a lot of achievements right here, but the numbers are small. We have one apartment from the Department of Clinical Research. We call the CRD, and we have Phase I word. We have also Phase I laboratory for PK analysis, Phase I trial nurses, and we have PI group and the trial pharmacy and the research nurses and statistics teams. Also, we have our own colleague control team. So in our center, the Phase I projects was initiated in the initial stage. We have the research nurses, our own research nurses, and we have several of the staff I, we call clinical Phase I clinical research physician, and we have Phase I nursing team, that's clinical nurses. We have to go through all the protocol and the MISAM SOPs before the initiation. And for the implementation stage, we have Phase I medical and the nursing team as the investigator. We have CRCIA locally to help us to implement all the drug. We have sponsor ethics, sponsor and ethics. to the committee to do the audit. And the process summary, we have a PI and the physician, research physician and the research nurse as a investigation team, and the third party of the audits and the inspection team for the quality control and sponsor to finish the process summary. This is the main process. So for the external integration, we have optimal timing, the position and the teamwork. We are here. We have to have a very close connection with the R&D management department. We often do the, you know, we talk a lot to NEPA, a national medical product administration, maybe once per month, every four weeks, we have a meeting with them to show us our data and what procedure of the face one child on the way. Also at the center of the drug evaluation, of the center of food and drug inspection, we have very close connection with them. Also, we have our research team, a field institution. Most of the time, most of the time, we are at the leading center, we have annually meeting every two or three weeks with all the centers participating in clinical trials to have meetings to, you know, negotiation. And we also have a very position of the partner pharmaceutical company. We have a lot of pharmaceutical company from domestic or internationally. So for another external integration, we have a face one clinical child consortium, annual conference, which is held. The first meeting, annual meeting was held in 2017, the organization, what's the lead is, is the tap into the face one anti-tumer new drug alliance. We have all the pharmaceutical companies, which are in our face one unit and all the top hospital that can help face one child, rejoining to establish this face one union. We have annual meeting every year, and we can come to consensus. So there's external integration, this internal integration, we have collaboration and unity for different departments. Back in our center, our cancer center, the research team was supported from every department. From nursing team, from department of radiology, a GCP pharmacy, ethical, ethnic committee, and also information departments who supports us from the gathering, the patients information, and basic laboratory, and also research nurses, a C&C, a nursing team, and also the department of pathology and laboratory medicines. They all work together to support our research team to perform the face one child smoothly. So we have the collaboration, regulation, support and coordination. We are working very sophisticated, but very smooth of the machine, to efficiently help the patients getting the face one child and find the most suitable drugs. So internal integration, we have a research team development. Also, that's the faculties of our face one unit. We have in US show districts, we have 22 beds, we have nursing team of 40 nurses, members, and we have a lot of research doctors. This is the picture of us. Also, that's the picture. We have to gratitude to the patients, their families, participants, and their clinical trials. This is the achievements of internal integration. From 2014 to until now, there's 12 years of forging head, painting the picture of the clinical research. We can see and figure on the left top, we have almost over 1,000 patients was newly enrolled in face one clinical trials. In 2025, almost 1,600 patients was each year, was newly enrolled in face one clinical trials. And the quality, we have 10 innovative drugs, got successfully approval, for example, like an osmertini and satini, the development map and telemolar pattern. And we have currently ongoing trial, also 165 face one clinical trials, that is innovative drug, current underway. This is the data from 2026, currently 2025, 2023, 2025, we have over 250, ongoing face one studies in our hospital. And the quality successfully passed the feeling as the one of the first batch of the institution of somatic cell clinical research in China. That's the achievements of the 12 years. Also, based on the innovative drug R&D, we have has led over 47 scientific research grants in our face one units, published over 130 papers at first, the corresponding also, of which 25 have impact factors greater than 10. Including cell, nature medicine, cell, and oncology, et cetera. So here's the oral presentation in 2023, 24 in ASCO and ASMO. Here is the major development in 12 years of our face one units. That's all, thank you. (audience applauding) - Thank you very much Professor Ma for very insight for comments. And we'll stop complaining about our workforce and our workload after seeing those numbers. - So the next speaker I'd like to introduce is Associate Professor Ben Tran, who's a medical oncologist at Pedermic Alim Cancer Center in Australia. His research interests include early drug development with a novel focus on novel I/O approaches in GU cancers. He'll be talking to us about T-Cilling Gages in fellow chimneys. Thanks very much Ben. - Cool, great, thanks for having me. (audience applauding) I thought I had only had 20 minutes to have, but I have 30, or maybe 60 Anthony. So I'm just gonna take it slow and we'll just have a chat. So I've been working in T-Cilling Gages for a long time, actually since 2012. Conducted the first study in Solid Tumors around 2014. And it all came, how many fellows in the room? And there are many fellows, a few, a few. So I came back from overseas, back from Toronto, and then I was reading through some papers and I was in GU cancers and early drug development. I read this paper about this novel approach at T-Cilling Gager, targeting PSMA and CD3. And then this mouse model, the cancer went away. And I kind of knew prostate cancer wasn't not responsive to I/O as we knew it. And I thought this is really cool. I want to get myself involved. And so with the support of my colleagues at Royal Melbourne at the time, Jayesh and Mark Rosenthor, went out and started approaching companies. Is Bayer in the room? Is there a Bayer rep here? Is Bay Bay not sponsoring Anthony? So, no. Because they'd bought out this company called MicroMit and they'd developed this T-Cilling Gager. And I said, hey, and I started meeting with them and we started meeting every meeting. So at ASCO, at ESMO, at ACR, the triple meeting, and trying to get them to bring their study into Australia. And they didn't, bastards. But over that year or so, a couple of years, I developed some knowledge because they were willing to share some information under CDA. And with that knowledge, I was then interested in other T-Cilling Gagers that were being developed. And remember, running into a poster at the triple meeting from a small company in Seattle called Emergent. And they developed also a PSMA CD3 T-Cilling Gager. And I had a current engagement. I had a good conversation. And I thought, this is really cool. And I blind called them when I got back to Australia. And I said, hey, I'm that guy, the poster. Do you want to bring your drug to Australia? Let's do the Phase I study. And they did. And we got Anthony involved. And that kind of got me started in developing T-Cilling Gagers in Solar Tumors. So if you're a fellow out there, if you find something that's interesting with the support of your bosses, you might be able to build a career out of it. Or if you call my career career. OK, so these are my disclosures. So what are T-Cilling Gagers? So these are little drugs that try to redirect T-Cells to fight cancer. They're made up of a little component that targets a tumor through biting to a tumor associated antigen. And another part that binds and activates T-Cells normally CD3. But there's more common now to explore other ways of targeting CD3 cells. There are a little bits of-- anybody's combined. And subsequently, they may have a very short half-life, but you can extend their half-life by attaching things to them. The idea is that when you activate a T-Cell in the presence of tumor, it kind of redirects side-of-the-top.com. So that T cell then fights the cancer and gets rid of is the idea There's so many different types of T cell engages being developed at the moment It started out with in the box a that that's the Amazon trademark to bite Which is kind of two parts of an FAB targeting Either both the two the tumour through TAA and the CD3 But as I said they tried to extend the half-life so they attached a larger portion to make it a half-life extended version in B And then indeed you've heard of to bento first I think This is in the reveal melanoma. This is not targeting A tumour target expressed on the Cell surface itself, but actually targeting peptides that are presented by MHC molecules And then there's some more interesting T cell engages the perhaps one of the more interesting ones at the moment It is kind of masking technology This is kind of in the little Diagram and E there where there's masks That come essentially mask the binding domain for CD3 or the T cell engage apart and also the tumour associated antigen part And in doing so it limits activation of the immune system until you get to the tumour micro environment where proteas is kind of cleave these masks So a lot of development in this space But unfortunately a lot of the development has been in hematological cancers To date most approved T cell engages have been in hem cancers Taken in B cells through CD19 CD20 in BCMA. There's only been really three approved drugs in solid tumors You can forget about the one at the bottom and cat a maximab which was given Intrepareitoneally for malignant societies. It's not really used and the other two indications are pretty poor prognosis Indications pretty low hanging for it right yet small cell lung cancer Which is the most hematological or four solid tumors and you have you a female melanoma where there's not much activity at all The first T cell engage are those blin a tumour map, and I think It's important to understand how that was developed because a lot of the learnings that we've developed there We don't want to make the same mistakes and we haven't really made the same mistakes We have learned from it, but it's just a reminder that as we learn things and developing new classes of drugs We should adopt them in the next generation of drugs as well So blin is this CD19 CD3 bite tiny molecule and very short half life and understanding it was a short half life Micro med at the time said well, it's not gonna last so long in a system. Let's give it three times a week And let's give it as a two or two or four-hour infusion It's kind of sounds worse than dialysis or pretty much like dialysis, right? We're used to be anyway and what they found is they couldn't escalate very high And they couldn't escalate very high because patients were getting CRS every time they were getting infusions and also iCans And there were no responses and the drugs seemed dead And then they went back and said look they began to understand what cytokine release syndrome was They understood that it was related to c-max And they said well maybe can we prolong Exposure and reduce c-max by giving the drug through a continuous IV infusion Seems hard to deliver in the clinic, but it's something that they did and it worked it allowed them to achieve high doses and they also implemented step dosing to overcome CRS as well And this allowed them to deliver an effective dose up to 90 mics per meter square per day They had much less CRS much less iCans They utilized steroid rescue for these symptoms They understood that iCans could be detected early with kind of handwriting assessments And they'll either escalate to doses where they could see responses. So when from a dead drug To a very effective and now an approved drug And this is just through understanding the kind of the novel toxicities with which happened With this novel approach but this took 10 years to go from the start of clinical development to the start of the first pivotal study And that's a really long and um steep initially but very prolonged learning curve So micrometry made blinotumab also delved into solid tumors And this is the drug that i was talking to Bayer about for years This was known as AMG212 or Pazotuxysiomab which is a PSMA-CD3 T cell-engager And they learned from the blin experience while blin was still going They said we can't give this thing three times a week um that's not the way to go and we don't really want to commit to a continuous IV infusion That seems miserable So they said let's give this subcutaneously And you can see the waterfall plot of PSA responses on the top right there The subcutaneous dosing of 212 resulted in a lot of PSA responses this was great But they were short-lived they were short-lived because 28 out of 30 patients developed neutralizing antidrogue antibodies So soon after you develop the response the immune system was getting rid of the drug and then your responses were gone So they switched to continuous IV dosing there were less 80As with continuous IV dosing but again this was not not something that could be delivered in the clinic long term But this is a great proof of concept Yes T cell-engager worked in hematological cancers but we can also make them work in solid tumors We can make immunotherapy work for prostate cancer And so leveraging the knowledge from this amgine bought 212 and they developed Amgine 160 later known as acarpatomab This was my ticket But that got expired So I was lucky enough to kind of treat the first patient in the world on this I used my knowledge through that Through my experience in the years prior with other T cell-engagers to say to amgine I'm your man you want me involved in this study I have a lot of experience. I know how to do this now And so yes, this was a half-life extended version of amg 212 And it did lead to responses And it was impressive enough that we started to design the phase three study which Amgine was kind enough to choose me to be a co-chair of The what was I was hoping would be the pivotal practice changing phase three study Unfortunately as we expanded sites beyond those experienced High volume phase one sites We realized that many sites were not as experienced in the managing site of currently syndrome And it became misery patients were getting really really sick intervening and serious was was was late And also at that time we then have realized ADA's were limiting the durability responses and the drug was canned So effective drugs and prostate cancer hard to deliver Due to issues with CRS and durability of response Whilst amgine was developing amg 160 acupatimab They also were developing a very similar drug with exactly the same construct But instead of targeting piece maus targeting DL3 This is um the later known to be telatimab And unlike the drug and prostate cancer this was practice changing And unlike the drug and prostate cancer there were no or very few anti-drug antibodies And CRS was much more manageable So even though the construct was essentially the same except just flipping out your tumor associated an engine's target You were getting a lot Much more tolerable much more durable responses and again as I said a practice changing drug So it's not just the drug it's also the tumor and probably also the patient that contributes to how drugs perform And how tolerable they might be Okay, let's talk about CRS So CRS used to be something I used to be really worried about in the clinic Something I kind of used to set my watch to six hours after dosing to call the ward To make sure the resident was going to give a bit of steroid or maybe some tosy if needed Something I don't stress much about anymore But I guess it just comes with experience the more you see it the more you deal with it the less stress you come The you are about it essentially what cytokine release syndrome is is when you engage T cell engages You induce the release of cytokines mainly IL-6 but also other cytokines like TNFL for another's And this manifests itself as a fever Maybe some rygals and that would be considered a grade one series Sometimes that kind of extra perfusion results in hypertension or hypoxia which would be considered grade two CRS and then the severity can increase This is through manageable I think with early intervention with some paracetamol non steroidals bit of steroids Bit of tosy lismar if you need it But it's also preventable of use in prophylaxis very common now for T cell engages have steroid prophylaxis Sometimes they throw in bit of IV for all prophylaxis The use of tosy lismar as a prophylaxis hasn't really been very successful And it's not a not a great way to develop a drug in my opinion But the biggest advance to mitigate against CRS was this concept of step dosing So what the guys at Bayon and Amjian realized was that CRS was associated with CMax the maximum concentration of the drug one delivered The higher the dose the higher the CMax and therefore the grade of the more severe the CRS And whilst it's poorly understood the introduction of step dosing meant that you could Initially started a low dose in juice less severe CRS And then step up to a high dose and when you went up to that high dose or if you maybe Do three steps and go to a high dose again the CRS you might have experienced if you use that as your nitrodose Was much much less or some very much mitigated and so this allows you to kind of repeat the target dose with the same CMax but with less CRS And whilst it's poorly understood there are some Papers that went about trying to understand how this worked and essentially it may relate to a pool of cytokines where T-selectivation triggers kind of this cascade and release of this pool of cytokines And once you deplete those cytokines when you're dosing with recurrent doses with current drug, there's not much cytokine left to release and therefore you're not getting much CRS. And so this study showed that up to an interval of 28 days with this HER2CD3T cell-engager, you would maintain a depletion of this Paulo cytokines and you would mitigate CRS if your second dose was 174-21 days after the initial dose. And you could do this without impacting the efficacy. Cytokine release was not required for target cell killing. So if you think about it that way, you've got to release your little Paul, you want to get the dose right to release enough Paulo cytokines, not to cause patients to be too sick, but enough Paulo cytokines so that when you can deliver your next dose much higher without any CRS. So that's now adopted as a standard of care and developing T-cell-engagers. And I think it should be adopted from the beginning. Some companies like to go, well let's just try single dose first and then eventually we'll try a second step dose and then eventually we'll try third step dose and that just prolongs dose escalation. I think you commit to three step dosing from the outset and you're going to escalate all steps together to get to the target dose. We've already alluded to, I've already alluded to the fact that maybe the way you administer the drug can also reduce CRS. You know we spoke about continuous IV infusion, dropping your C-max and therefore you mitigating CRS, we spoke about subcutaneous administration. It's really attractive just to whack your little injections, your belly and to fight cancer. But the problem is at least in solar tumors, not in hematological cancer, but in solar tumors and particularly in prostate cancer there is a greater likelihood of immunogenicity. There's a greater likelihood you'll develop ADAs with subcutaneous dosing. It doesn't appear to be all solar tumors. Prostate cancer is definitely a key here, may relate to all the MDCs and other macrophages that are around prostate cancer. But there has been very rare currencies of successful subcutaneous administration of T-cell engages in solar tumors. And the other way to do this is a continuous IV infusion, but that's not attractive. Who wants to do that? One cool thing that the hematologists have done and we're kind of starting to learn from is debulking. So this theory is if you have less target to engage, there's going to be less activation of T-cells and there's less activation of T-cells, there's going to be less CRS. And so the guys from Rochelle developing Glifitemab, which is a CD20 directed CD3 T-cell Engager, they saw a bunch of CRS as expected. But when they used in combination with chemotherapy, they gave our shop to these lymphoma patients for a cycle and through Inglifitemab with cycle 2, the CR8s dropped from 60% down to 10%. So debulking the tumor first meant that there was less CRS patients were tolerating treatment much better. Today in solar tumors we haven't seen that, but that's because in solar tumors to date, or at least what we've reported. That's because in solar tumors today, we've been using this in the late line phase 1 patients where they, you can't really debulk them with anything, their resistance to most therapies. They're very high burden and when you're trying to look for a signal to see of lower tumor burden, it's related to lower CRS, you're just comparing high versus very high tumor burden, not really truly comparing to low tumor burden. Up until something will hopefully present next year. So this is a study that I'm doing with Amgen using Zalaritomy, which is their new T-cell engages targeting, steep one. And in a very aggressive approach, this has been given to people with biochemical recurrence. They have kind of micro-mestatic disease, or maybe it is messtatic, but you can only see it on a PET scan, and they've never had any hormonal therapy. And so what we hope to report in the next year is that when you have low tumor burden, a solar tumor is you do not get CRS, or you get very, very, very little CRS. So if you can't give T-cell engages at a low tumor burden and you don't have any effective therapies to debulk tumor, like they do in hematology, this concept, which I don't really think is long-term feasible, but pretty cool, very interesting scientifically, is maybe you can debulk target. So this was presented at ASER last year. For anybody based radio-conjugates, so radio-nucleides, we sometimes give a cold antibody, which is an antibody that doesn't have a luteusia or titanium attached, to bind to some of the existing target, and then you've followed up with a hot antibody, so you can ensure delivery goes, of the drug goes to the tumor, and less so to normal tissues, right? And so in this study, a rune motor map, which is a HER2 target at T-cell engage, they couldn't like the blin-to-mab experience, they couldn't escalate to get any efficacy, and they'll get any all this toxicity that was mostly on target but off-tumor. So what they said was, why don't we just throw some perceptin in there, trace-2-zumab, bind a bit of the HER2, and then follow up with the rune, and what they were able to do then was they were to say, well, there was a less CRS, because there was a less target of bind, trace-2-zumab bound some of the target already, and then they were able to escalate the dose of rune motor map, enough to get efficacy. Unfortunately, this is not a long-term approach, and I believe that this kind of this compound has been canned. Another way to mitigate CRS with T-cell engage, and we've kind of been exploring as a community over the years, is just peer back on your CD3 activation. Can you reduce your CD3 affinity? Can you attenuate it a little bit? And kind of the most famous company doing this was the company called Tenio Bio, they had a couple of different drugs where the CD3 affinity was wound way down. But what we learned after a year or so is it's really a sheet approach. You know, you wind down your CD3 affinity, you don't get any activation, and you get, you might reduce CRS, but you don't get any efficacy. But maybe there is a sweet spot, you know, so maybe there is a sweet spot, and there's this new drug, well, it's not so new now, it's in phase three, it has rhythmic from J&J, they haven't reported their CD3 affinity. It's a KLK2 CD3 T-cell engage, but theoretically, I think, we all believe that it has a reduced affinity for CD3, and they are getting very little CRS, and they're getting some efficacy. And you compare it to a drug like Zalarita mig, which is kind of, it's competitive out there at the moment in phase three trials. We know that's got higher CD3 affinity, it's more active, but also has more CRS. So can you dial that up and down a little bit to try and find the sweet spot where your drug's going? There's some people say, hey, we haven't got C-cell engages to work in solid tumors yet, while we're dialing it down. So maybe once you get the efficacy there, you can dial it back to make it more deliverable, but there's definitely pros to both approaches, I believe both approaches. One thing which I think is really interesting is this concept of conditional binding. This is where you only bind to CD3 or the tumor within the tumor only. And if you do that, if you can design a drug that only binds, target within the tumor, only you can limit T-selectivation and mitigate CRS. And there's a couple of ways of doing that. You can have these kind of masks, these kind of unmasked within the tumor by kind of tumor-specific proteases, or you can develop drugs that are pH dependent because tumors are slightly more acidic than normal tissue and then in a more acidic environment, maybe the affinity is greater. The coolest drug which I've been lucky to be involved with is, it was a small bite, it could aminex, it had this massive masks around both their domains, both the CD3 and the tumor targeting domain. And we reported their results from their prostate drug, PSMA, targeted CD3. So we've spoken about how PSMA targeted CD3, T-selectivation is a fail at a time and again, well this one looks pretty good. There's way less CRS, the masking works, and there's way more efficacy. When you look at the fine print at really high doses, when you're unmasking really high doses within the tumor, there's going to be unmasked drug that leaks back into the circulation, and then you're going to get some on-target off-tumor effects. But this is, this is how it would mitigate, you just get your dose right. One thing though is if you pick the target correctly, well you pick the right target where you're going to have very minimal off-tumor target expression, you may not need the benefits of masking. With step-go-sing and the target selection, you might not need masking, but for this target, PSMA target masking definitely helps. So on-target off-tumor toxicities have also limited T-selectivation development. So most tumour-associated engines are definitely tumour-associated, they're not tumour-specific. So one of those PSMA drugs, we've had dry mouth, we've had hearing issues, we've had blurred visions, for steep one targeting, we've had some myalgia. And as I said, you can mitigate against these problems by improving your target selection. You can saturate target in normal tissue using this cold antibody approach, or you can use conditional binding, whether that be the masking or the PH activation, or you can have a designer drug that is andgated, which means you are only bind to that target if also this other target is also expressed. And they can kind of improve your selection of binding to tumour only as opposed to normal tissue. So BentaFus has selected a target that is presented by MHC class molecules, and this is very tumour-specific, and you can see here there's very little toxicity outside of the to see a rest. is a very little on target of tumor toxicity. So that's the toxicity dealt with, but we still haven't addressed the fact that C-cell engages have less efficacy in solar tumors compared to hematological cancers. Can I fit in there? But look at that waterfall plot. That's pretty impressive. And the durability in the right, these responses last forever. This is the holy grail for solar tumors, right? Let's get a deep response and let's keep it a response. Teletum ab, which is approved, 40% response rate, not bad, but responses can be short-lived. Zalorid amic in prostate cancer, 24% overall response rate. And you can see the spider plot, things are turning around pretty quickly. So why do we get less efficacy in solar tumors? Why are the hematologists lucky enough to have drugs that work for a long time? For T-cell engages, I think it comes down to target expression. Target expression is much more homogenous in hematological cancers. And they probably have a much more receptive TMEs well, whereas in solar tumors, target expression is heterogeneous. There's an immunosuppressive TME. There's a concept of immune exhaustion and there's development of ADAs as well. But target expression requires it's very different for T-cell engages compared to other drugs. When you have ADCs and radio-unuculates, there's this all this kind of bystander effect with a lutecium. Beta emitter, you're going to kill a lot of cells next door to the cell you're binding to. With ADCs, you're going to get a bystander effect with payload released into the tumor microenvironment. T-celling therapies or T-celling agents don't have that. You might not need the high density expression to ensure a lot of binding, a lot of crossover, a lot of bystander effect, but you do need expression on all cells. Because a single activated T-cells does kill the cancer cell it's attached to. There's no bystander effect with these drugs, or not yet. That's the holy grail. Can we get some epitope spreading, some innate immunity to fight cancer cells that don't express the target? And solid tumors here, this is quickly have greater heterogeneity. In B-cell lymphoma, the number of patients with very low or heterogeneous expression is 12% from this paper. Improstate cancer, depending on how you score it, it can be up to 50% of patients don't express targets efficiently. ADA is another issue. Thankfully, this is not an issue in hem cancers because if you're depleting B-cells, you don't develop antibodies. All right, so this is the way it works, though. So an antigen presenting cell, phagocytosis, the process, the drugs and peptides, peptides are loaded and presented, induces B-cells, differentiated and plasma cells improves ADA's. You'd think that if you're getting ADA's that you may be overcome that by depleting B-cells. So there's a couple of companies have tried to do this. This is the Roche study. They had a CEA, C-cell, Engager, and they saw a whole bunch of ADA's that were not good. And they thought, let's give a CD20 monoclonal antibody to deplete B-cells. And hopefully that can reduce ADA's and we can prove that our drugs are pretty good and maybe we can give it together. It didn't work. It worked a little bit. You do reduce ADA's a little bit, but you don't deplete it completely. So this is not the right approach for developing drugs and solar tumors anyway, but it's interesting that if you get ADA's depleting B-cells, drug-wise is not helpful in solar tumors. But they do limit efficacy and they can limit durability if they are neutralizing. The size of proteins inject a subcontainer to look at an influence by a distribution. If you have a big drug, a big protein, unlike insulin, which is very small, that's going to go through your lymphatic syndrome, an lymphatic system, and generator, an immune response. But also drug structure, epitopes can also drive immunogenicity. I was lucky enough to be involved with this study that Amtrakonduct and they showed that there were certain domains within their CD3 binding domain, and certain epitopes within their CD3 binding domain are also in their P-SMA binding domain that were driving immunogenicity. Having said that, there was the same CD3 epitopes on telatumab and that wasn't driving immunogenicity. So there's definitely something about the tumor and the patient that is causing this. Immune exhaustion is another reason that perhaps T-cell engages don't work as well in solid tumors. In a preclinical experiment, it's shown that if you give T-cell engage around, after round up the round, but at the time you hit the fourth round, they don't kill cancer cells anymore. They're a commonable exhausted. There's this study from Pazer Rittermig, the J&J KOK2 T-cell engage, which showed that if you dose further apart, your immune cells perhaps show signs of less exhaustion. And also, in this myeloma study, if your immune cells are less exhausted coming into receive treatment, you're more likely to benefit from treatment. So what is the best way to determine if your immune cells are exhausted? I think that still remains to be seen, but this is a concept that we're all looking towards better understanding. And perhaps overcoming as well. So can we overcome T-cell exhaustion with post-immolation molecules? These involve targeting 4-1BB or CD28, and the idea is if you combine these with the normal T-cell engage, you can improve durability, enhance anti-tumor activity, and perhaps you can reduce the amount of dosing in need of the T-cell engage. However, as I've said, the whole agrarial here is trying to induce an undodorous immune response, but the immunosuppressive T-me in solid tumors is preventing this in inhibits affected T-cells and suppressor's dendritic cells. Interesting studies and hemysological cancers show that you can induce epitope or antigen spreading to induce an undodorous immune response and create this kind of bystander effect for T-cell engages. Not something we're doing in solid tumors yet, but I think this is the next step to make responses much more durable in patients receiving T-cell engages. So to wrap up, these are active in solid tumors. They're a standard account of a couple of tumor types. I think we're improving the clinical development and improving the constructs that have been developed will minimize toxicity. It's potential is limited by the lack of durability, and I think we invest a lot more work into understanding this and overcoming this will develop the next generation T-cell engages that really transform care. Thanks guys. [APPLAUSE] - Is that? - Yeah. I'd like to invite Professor Mar back up to the stage and we'll take some questions. While the microphone's just moving around, we do have one question from an online audience member for Professor Mar. The question is in particular, you did touch on this, but are there any collaborations with other university centres involved with drug development like Tongli University or is it a more competitive relationship? Are there any collaborators at the university? Oh, China is a very competitive company. [LAUGHTER] Sorry. It's also very competitive in Phase One child. We have several, you know, Phase One units, which cancels a hospital, especially. We are competing just to develop all those promising drugs. Except for Tongji and we have the cancer hospital in Beijing. And in Fudan University Cancer Center and in Hunan Changsha and in Sichuan, in Huazi Medical, there are several, about 10 or 12 cancer centers, which is all very high level, after ability to capability to perform a Phase One child. And always we have those, you know, promising drugs to be considered to whether to perform. So we have to compete and collaborate. If one drug is leading by some PIs in some cancer center, we're all joining and to, you know, promote patients is for the benefit of the patients. Yeah. Thank you. Mo, you go, Jenny. Oh, thank you. I've got a question for you, Shane. A question for Ben. In terms of China and collaboration, you, Shane, do you think there is opportunity for greater East, West, harmonization with drug development, given, you know, the phenomenal progress we're seeing from China, but, you know, there's differences in patient population, tolerance of different therapies. How do you think the field should move forward? So it's more like, you know, we have notes very much of the experience to do in these natural trials. We do, like I said, we have two models of the physiotherapist. One is the natural product to perform. One is the, you know, if you spread of the, you know, the slugs of all the centers in, whether in the United States or Australia or China, for example, like the previously, the, the murk have talked about the drug to develop in the national league. In America, in China, they have to spread all the slugs in, you know, balance league for different, different hands of hospital. Then we can, to, you know, introduce those patients, basically all the patients, the situation, to choose what is the best for the patients. That's for domestic drug. I think we're in a pursuit for the speed of the enrollment and the, the, the, the, the, part of the numbers for the room. So actually we have several of the Vesuvantra, Vesuvantra, Vesuvantra, the sponsor is prospective to be enrolled in 200 and 300 dishes, or how they'll have a year, six months. So it's very, very enthusiastic to ambitious for the pharmaceutical companies to pursue, pursue the Phase One chart. I have no idea what is performing internationally, but I think if the multivision is come from the pharmaceutical company, is the interest is the most in the speed and the core. Before you go, Janie, can I follow up? Is it very frustrating when you're participating in a multinational study, when you're used to just enrolling forwards, you can easily enroll cohorts from your own center, right? So is it frustrating then now that you like participating in multivision studies? We like to participate in multinational facility, not as leading or not leading or participating. Yes, sir. Yeah. We are not, you know, as a matter of fact, a lot of patients are eager to join clinical trials. You know, there's a lot of patients in China. Yeah. And not all of them are insured. Yeah. As a matter of fact, it's lower insure rates and the reimbursement is not too marriage. And the commercial insurance is not very popular in China. So, and a lot of the, you know, economic status of all those patients is not very rich. So they like to know if they're intentionally or domestically, they don't care. They just have to use one treatment after the standard cares. Yeah. Yes, it sounds like there's a lot of like influence and power by sponsors. What I'd like to see is potentially multi-regional investigator that trials across different regions. A question for Ben, given your, I guess, leadership in T-cell engages, I'm seeing some parallels between some of the limitations and solid tumors and that of CAR-T. What do you think, you know, in terms of how we can learn from the T-cell-engager era to inform solid tumor CAR-T development? 100%. There is, you know, that's, for me, there's been a natural progression from T-cell engages to moving into the CAR-T world. The limitations are very similar. It may not be, and perhaps being working CAR-T, that's perhaps why I don't care about C-R-S so much anymore. It's more the H-L-H-O-A-C-H-S. So there are definitely learnings, but still the hematologist way ahead of us. So I think learning from hematologist is also very important, right? So they've been there, don't they? I have a question for you. Go back. You talk about his E-S. Do you have a beer show, the C-I-S? What's your procedure? The standard procedure to treat the patients with C-I-S. Do you have a precaution or a proliferated drug to use? Yes, so might-- Yes, so for me, it's like a panadol, which is paracetamol, and some-- and I use cramadol for rygals. If they get a little-- if they're persistent fever, this hypertension, I throw some steroids at them, hydrochloric, normally about 200. And if that still persists, I throw some tosi. Other people use tosi much earlier, I think. Do you have a larger amount of the steroids? Yeah, he's 200 of hydrochloric. 200. Yeah. Cool. Too. So a question for both of you, but Professor Ma, you mentioned what changed in China, right? Because of the data and tariffy issues that were there before. So what changed, and how is that dealt with? And then how has that been prevented from recurring since then? Yeah. Because it's a good question. Thank you, team. A lot of Chinese doctors do not like willing to talk about that. But I don't think it's a very bad thing. It's like I said, it's a fierce girl in growing pain. Back in those days, 10 years ago, when I was first in part of the business, I can see this very chaos. Like it's a majority of the domestic drugs. For international drug, we are participating in most of the majority back in years for the international drugs. And we can do a very strict of the quality control in our center. But I'm not sure. It's very performing in all the centers in the other cities, at the hospital. But after that, after 2015, and a lot of persecution is being called and have the data retrieval, all these things, after two years of reformation, maybe two regulation is being revised by CFDA. One is the common regression following by the international drugs. How do we conduct an international drug to perform this method, this model to all of the INDs, no methods from domestic or from international? This is the number one. Number two is to encourage the pharmaceutical company in China, the pharmaceutical company, to not do any mid-to-trial, do first-in-class trial. That's the innovation strategy for the CFDA from top to bottom to avoid such off the integrity issue. Because as long as we don't have to go to the mid-to-trial, I've probably got time for one. Oh, if that's OK. So for Ben, we're seeing a lot of-- for example, DLL3, Matala. But then there's also now DLL3 ADCs that look really good. Where do you see the long-term development? Are they going to challenge each other? Do you see potential sequential users of that? Are there some patients who do better on ADC versus TCE? Where do you see things moving? Yeah, I think in the long-term-- CCL engages are harder to start, right? But they get much easier later. And if they're durable, the responses are durable, then it's long-term easy. ADCs are maybe easier to get started. But by the time you've been on it for six, nine months, it's really hard. So I think it depends on the balance between efficacy and toxicity. At the moment, I feel as though TCE linkages could do better from a durability perspective. And also getting a patient onto it. For sick patients, a small cell, it's much easier to just throw in an ADC right seeing three weeks. So that's some limitations. But if subcudocing works for DLL3, that's going to overcome some of that. Thank you. Thank you. One final question, I think, Dimitri. Hi, this is a question for Professor Ma Amt, I'm Dimitri from P1 Medicines. And so a lot of ADCs are using the same payload, right? So there's a lot of ADC trials. And it comes with a challenge in the future. You're running out the actual options for this patient. So biomarkers become more and more relevant now to select the patients right from the beginning. Is there any translational work has been done at your center to address this future challenge or overall in China? Thank you. Yeah, thank you. That's a very good question. As a matter of fact, all ADC trial, we have the T-shirt being collected, not all of the patients are voluntary. Collect the T-shirt for the IHC analysis. But we found that in several of the ADC, especially the membrane marker ADC. For example, like a chop to ADC or B7H3 ADC, there's a membrane marker. Often, FC gamma receptor deficients, they have no ADCC effects, only purely as a membrane marker. The membrane expression of the targets is not relevant to the efficacy. It's a very common especially in membrane marker. So I have read the paper by Andy Anderson's sensor. They have a two or chop to ADC, the TATO-DXT trial. They have discovered the membrane marker and the intercellular expression of B7H3, the ratio which is connected to ADC's efficacy. And we also look into the most physically mechanisms, like the integrated of the drug. And always the sustained time of the target expression in membrane and it's all relevance. But I don't think it's a single factor. That can dramatically affect the efficacy of one drug. So maybe a systemic change of a whole system. Thank you. Please join me in thanking the three speakers for this session. I'd like to invite Mr Thomas Chu to the stage.