Evolution of cell & gene therapy in China: the case for universal CAR-T

Arsalan: Thank you so much, Vivian. Really appreciate your presentation. And now let’s hear from Kai.

Kai: Hello everyone. I’m very glad to be here today and I’m very glad to share my topic about evolution of CAR-T clinical development in China. What are the key areas of focus for current clinical development? And three topics: First, considerations for the clinical application of CAR-T cell therapy. And as we all know, non-Hodgkin’s lymphoma, more and more patients suffer from non-Hodgkin’s lymphoma and (08:53) PMBCL and HGBCL and was common in some types of non-Hodgkin’s lymphoma. Commonly, after, if they relapse or (09.07) first-line chemotherapy, such as (09:12), and then these patients need to receive second-line therapy (09:19) response to (09:23 third-line) chemotherapy. And (09:26) stem cell transplant patient is recommended there. However, there are still some patients not suitable for transplantation. Some patients do not respond to second-line therapy. Maybe CAR-T therapy is a good choice for them.

And before CAR-T therapy, there are some factors to be considered. One is two CAR-T cells are currently approved for patients with relapsed aggressive B-cell lymphoma after second-line or higher systemic therapy. And second, CAR-T cell efficacy may be compromised by the conditions of a patient’s T-cells after multiple chemotherapy treatments. That means if a patient had received more chemotherapy, maybe a lower T-cell function. And third, consideration for the use of CAR-T cell therapy, including previous systemic treatment history and the sequence of treatment, specific disease conditions, patient comorbidities, whether the central nervous system is involved, and the time and the place of diagnosis and treatment. Four, with the advent of other CD19 target therapies, how to sequence CD19 CAR-T cells with other anti-CD19 therapies for relapsed aggressive B-cell lymphoma deserves further exploration and research.

Then, after our consideration of CAR-T therapy, just like (11:18), now CAR-T (11:21). Here is the model of a holistic treating strategy for patients with diffuse large B-cell lymphoma. If a patient relapsed or refractory after first-line chemotherapy, clinical trial is still recommended for these patients. And then, usually they need to receive the salvage therapy. For the whole chemo-sensitive disease, autologous stem cell consolidation is still recommended. However, there are still chemo-refractory disease (12:04) salvage therapy, and who relapse even after autologous stem cell transplantation. Now, CAR-T therapy may be a good choice for these patients.

The topic CAR-T cell therapy is currently a popular therapy in the field of lymphoma treatment and many studies are exploring the application of CAR-T therapy in the second-line treatment of LBCL.

Currently there are a lot of results. Here is the preliminary results of three global Phase 3 studies of CAR-T cell therapy, including ZUMA-7, tisa-cel – Belinda and Transform.

There is a big difference of these three clinical trials, Signal 2 (13:13). One is CD28, and the other two are (13:21). The three global Phase 3 studies show some exciting results in the treatment of the relapsed and refractory B-cell lymphoma. In terms of safety, nearly 90% of patients in both standard therapy and CAR-T cell therapy groups experienced over grade three toxicity, but key differences included cytokine release syndrome and neurotoxicity in each CAR-T cell group, and (14:09). The incidence of grade over three CRS was low in all studies, so all of the three studies, as I said. In addition, in these three studies, there was no significant difference in treatment-related mortality between the different treatment groups. So these three studies are similar, including enrolling adult patients with LBCL who were refractory to first-line therapies.

(15:52) topic: Further development in haematology malignancy. (15:02) three studies have shown exciting results, preliminary results. A question: Will CD19 CAR-T cell therapy replace autologous stem transplantation in B-cell lymphomas? In these three trials, high-risk DLBCL B-cell lymphoma and refractory to first-line therapy (15:35) receive CAR-T cell therapy and salvage therapy. And now we have some good (15:46) preliminary results, maybe CAR-T can replace autologous stem transplantation in the future. We look forward to the final results. However, CAR-T therapy is maybe not an end point and cannot replace autologous stem transplantation in acute lymphoblastic lymphoma. Maybe it’s another story, different story. Because for patients (16:26) who receive CAR-T cell therapy, the incidence of relapse still high, so it’s not unsatisfactory. Stem cell transplant (16:40) still needed for these patients. CAR-T cell therapy is just bridging therapy, different from in B-cell lymphoma.

Now, as the good performance of liso-cel in clinical trial, so you have more opportunity to expand into earlier lines with broader development program. From (17:13), especially for those patients (17:20) who are not suitable for transplantation. (17:25) also multiple myeloma. We look forward to the final results, look forward to good results. Thank you for your attention. Thank you.

Arsalan: Thank you, Kai. Thank you, Kai. Now let’s have Jai wrap up the presentations.

Jai: Thank you (17:53) introduction and thank you (17:57) Novotech and Endpoints News invitation. I am very happy to join today at the webinar and talk about the universal CAR-T. I do believe this is a very hot topic. I’m from the (18:12) company from China, (18:14), and the CMO. Today I’d like to (18:20) and briefly introduce the challenges of allogenic CAR-T in China. As I mentioned, (18:32) CAR-T therapy is already approved by the FDA in China, already approved (18:39) in China. And around one year, around 400 patients treated by this kind of (18:50) therapy. Today, we compare with (18:55) CAR-T therapy and universal CAR-T therapy, where there are some difference and/or the advantage. We’ve got the universal CAR-T (19:10) from a healthy donor. After the manufacture, they spend two weeks, can be treated to a suitable (19:19) patient. However, (19:22) process, and (19:27) universal CAR-T approved by the (19:29).

I would like to briefly introduce the process, the universal CAR-T manufacturing process. Firstly, a healthy donor will be selected and (19:45). And after one day (19:47) the T-cell, spend another day to transduction and gene knock out. Different companies use different strategies. For example, (19:59) we use (20:02) strategy or knock out, and anti-CD22, the antibiotic. After that, they spend around one week or 10 days, (20:15) formulation. So we can use one day to infusion the patient if they are suitable (20:22). That is (20:24) and totally can be (20:26) 100 patients. That will compare with (20:32) CAR-T cell. (20:35) reduce the manufacture process and the cost.

So (20:42) kind of universal CAR-T (20:48). The first one is GvHD. Because the allogeneic CAR-T cell infusion, the antibody, so the host cell, we already checked and treated the immune attack, increasing some (21:04) things. Another key issue is the host versus and graft rejection because the host T-cell (21:16) the allogeneic CAR-T cell (21:23) infusion (21:24).

How to manage the GvHD, different companies use different strategies. The first (21:35) is TCR gene knock out or knock down. Another one is no-gene editing strategy. The first one I briefly introduced, the first strategy is TCR gene knock out or knock down. We can use CRISPR, TALEN, ZFN and ARCUS as strategies to (22:03) TCR knock out. The (22:05) use CRISPR’s technique to knock out (22:11) TCR strategy. Another one is no-gene editing. We can use the virus specific CAR-T and the ᵞᵟ T, and NKT cell, even they use cord blood and CAR-T cell. That will be key in managing the GvHD (22:33). In the (22:36) we use two strategies. One is TCR knock out. Another one, they are trying to use ᵞᵟ T-cell to make the universal CAR-T happen in our (22:51).

Another strategy of managing HvG rejections, here there are three strategies. The first one is immune suppression. We can use the commercially available antibody such as anti-CD52 antibodies, Alemtuzumab. Another one is CD38 antibody, commercially available (23:22) to manage the NK cells in injections. And (23:28) that it will be used to T-cell injections. Another strategy to use (23:33) extensive lymphodepletion, to manage the T-cell and NK cell to injections. Another (23:44) use the T or NK selective depletion (23:51) two strategies. One is Alemtuzumab, we mentioned, our first (23:57) use the anti-CD52 antibody (24:01). Another, to use the NK (24:03) strategy.

Another (24:04) immune (24:05). We can use HLA disruptions for T-cell injections. We also use HLA-E and CD47 overexpression for the NK cell injections. Also we use the NK (24:23) checkpoint, such as (24:26) to manage the (24:31) T-cell injections. (24:35) and use different strategies. Caribou use the heavy, intense (24:42) strategy and the checkpoint in their strategy. Another one is – the last one is HLA matching. And Takeda and another company (24:53). But there is needed more data to support the strategies. I put in here (25:03) strategy is a high risk for infections. And because (25:08) very heavy (25:09) introduce some neutropenia (25:14) cytopenia (25:16). But the second strategy is (25:20) and need more data to support that.

Here, I would like to introduce Bioheng’s universal CAR-T. We are a durable target, CD19 and CD22 as a target. We use second generation and CAR-T construction. We use an anti-virus transductor to the anti CD19 and CD22 CAR to make (26:00) happen. We can find, here we knock out the TCR and we knock out CD22, so there is (26:16) first generation, and the universal CAR-T. We are trying to develop (26:25) B-cell (26:27).

It is using this strategy, we had to use anti-CD52 antibody combined with our (26:45) regimen to the (26:50). We have (26:57) study in China. Here is a study design, is a single-arm, open-label (27:05) centre dose-escalation Phase 1 study. We use two dose levels, one (27:12) and three(27:14) the patient. Pre-conditioning regimen, we use CTX and Fludarabine. I mentioned anti-CD52 antibodies, Alemtuzumab. Here is our patient, the demographics (27:36) patient. (27:39) is 1. They are very heavy at (27:45) treatment refractory and chemo refractory or relapse. All the patients (27:51) relapsed and refractory is the B-all patient.

This data has (28:02) and make the oral presentation in 2020, so I will take this opportunity and briefly introduce the data. (28:21) adverse events of special interest, CRS is (28:28). Each patient has (28:32) CRS, but (28:35) is only 70%. GvHD is zero. Prolonged cytopenia is 50, so half of the patients have (28:45) prolonged cytopenia. And CMV infection reactivations, about one third, and (28:56). Half of the patients, CMV infections reactive (29:03), so in pneumonia we have the one patient happened, and (29:07) 70%. The conclusion in (29:12) no DLT, GvHD, ICANS and added the (29:21) data, a new data, a new (29:23), they happened to (29:26), so (29:29) and CRS recovered within seven days after one dose, and (29:34) managed that. No RCL had been detected. That is (29:42).

In terms of the clinical outcomes, all the six patients received one infusion of the (29:59) and the universal CAR-T. And the (30:02), the CR and the CRi is (30:06 83 around). And the 100th patient achieved the MRD (30:13) on day 28, so follow-up, the median follow-up (30:18) 4.3 months, and three fifths (30:28) patient achieved the CR and the CRi, and they continue to remain MRD negative. Patient 2 (30:37) received the (30:41) after two months. The patient 6 suffered a cardiac arrest on (30:54) after the infusion (30:57).

Here is a summary for the CTA101, is CRISPR/cas9 engineered a universal CAR-T. And Phase 1 data showed the CR and the CRi rate was 83.3% on day 28 after the CTA101 infusion, no DLT, no ICANs, no GvHD, and the safety profile is manageable. The good news is this project (31:37) the NMPA from China agency approved for the IND for (31:45) clinical trial, that is on May 17, so this year. Our companies are working on the (31:56) trial (31:56).

The (32:00) data has (32:02) cancer research. The last slides, we are trying to show that it is (32:11) trial in China. (32:15) and the chemical trial (32:17) data shows around 1000 (32:21) CAR-T trials around the world, and one half are in China, one third in the US. That’s our presentation today, and back to our host, Arsalan.

Arsalan: Thank you very much for such an informative presentation, and now I want to thank all of our presenters for their presentations. Now it’s time to turn to our questions from the audience. Now the first one to Vivian – with so many years and the experience, why do you think China has become the hub for CAR-T cell therapy?

Vivian: Thank you for the question. I think there are several reasons that make China become the hub for CAR-T cell therapy. The first, there is a solid foundation of science in China. And secondly, China has the big patient population which can facilitate recruitment in clinical trial development relatively quickly. And thirdly, the Chinese government encourages studies in the cell therapy area by issuing different guidelines to guide the company to develop the cell therapy product. And fourthly, the investigator-initiated trials are widely conducted in China in the cell therapy area, which accumulate valuable data in different indications. I think those are the reasons to make China the hub for CAR-T cell therapy from my point of view.

Arsalan: Very good. Can you also now share the most common challenges and opportunities for companies that are wanting to invest in cell and gene therapy in China?

Vivian: Yeah. First, let me talk about the opportunity. I think the opportunity is huge. First, the government encouraged research in the cell therapy area. And secondly, the efficacy of cell therapy is very good, impressive, especially in the haematology tumour. And thirdly, as I mentioned before, China has a very big patient population and strong (34:35) needs, so I think all those are the opportunities for those companies who want to develop the cell therapy in China.

Next, let’s talk about the challenges. I think there are still a lot of challenges. Firstly, is how to show the efficacy (34:53 tumour). (34:55) cell therapy has a very good efficacy in the haematology tumour, but how to ensure the efficacy in the solid tumour, that will broaden-----

Arsalan: Vivian, I’m sorry. We’re having some difficulty hearing you. If you could maybe reset your audio, your microphone? Now you’re coming through clear. Perhaps you could speak again your answer.

Vivian: Okay. So repeat again?

Arsalan: Yes, it’s perfect now.

Vivian: Okay. Firstly, let me talk about opportunity. I think the opportunity is huge. There are several reasons. The first is the government encouraged the research in cell therapy. And secondly, the efficacy of cell therapy is very good, is impressive, especially in the haematology of a tumour. And thirdly, as I mentioned before, China has a very big patient population and there is strong (35:54) needs. And I think all those contribute to the opportunities for the cell therapy development in China.

And next, let’s talk about the challenges. I think there are still a lot of challenges. First, we all know that cell therapy has a good efficacy in the haematology tumour, but in the solid tumour the efficacy is still not that good. If it can show a good efficacy in the solid tumour, that will broaden the patient (36:24). And the other challenge is the (36:28) which I believe (36:30) companies’ experiments. And also, the (36:33) for the cell therapy is relatively long. Sometimes it will take patients to wait around three to four weeks. And some patients can not even wait, and they need bridging therapy during that time period, so that’s another challenge. And of course, as Dr Jie Chen mentioned before, in terms of the safety, if we can further lower the side effects, such as CRS, neurotoxicity, GvHD, gene (37:05), that will be (37:06) for the cell therapy.

And lastly, I would like to mention another two points. Firstly is the cost. We know the cost is still very high. And how to ensure the patient is affordable, that is another challenge. Last, but not least is we know there are a lot of trials, cell therapy trials in China, especially for those very hard to target, how to make the sponsor, the company differentiate from those company ahead of them, so that’s another challenge. All those are the challenges I think the companies are experiencing right now. Thanks.

Arsalan: Thank you very much, Vivian. Now, Professor Kai, what do you think is the next biggest impact using CAR-T therapy, Professor?

Kai: Thank you for your good questions. I think (38:01) change the kind of treatment strategy for relapsed and the refractory diffused large B-cell lymphoma, we know CAR-T will be recommended for more patients who receive a second-line treatment regime, in particular, some high-risk refractory diffused large B-cell lymphoma patients. In fact, even (38:27) patients receive the second-line chemotherapy (38:35) not as satisfactory. The classic (38:41) study had already given us the answer. So five-year overall response (38:47) was only about 10%. I don’t think (38:52) we need more evidence, clinical evidence, especially (38:58) clinical trials. And it is particularly expected that in some centres in China such as Beijing, (39:09) Wuhan will be able to participate in, and even lead these multicentre clinical trials, have more opportunities to cooperate with international companies. Thank you.

Arsalan: Now, what are some of the key challenges that are still in clinical development with CAR-T therapy though?

Kai: Thank you for your questions. I think the key challenges mainly is (39:39) therapy of disease guided by precise detection. We need to know who is sensitive or not to CAR-T before the therapy. For example, patients with good T-cell function and a normal immune microenvironment can be directly treated with CAR-T. However, patients whose T-cell function is inhibited can be considered to (40:11). In certain patients we (40:20) can be considered (40:21) to receive universal CAR-T in the future. Thank you.

Arsalan: Thank you. Dr Chen, can you explain the strategies implemented to minimise the hose versus graph projection?

Jie: That’s a very good question. I need to (40:42) the companies working on that to solve the problem. We use the first strategy and intend to (40:52) TCR knock out, so we have used TCR knock out and anti-CD52 knock out to ensure the (41:03) is manageable. Another strategy (41:08), I also use (41:10) we use two strategies and the one platform. That platform will be (41:25) generation and put some of the (41:32) another cytokine and the (41:40) and then our platform. That is our key strategy. I think all the company (41:48) for the different strategies. Thank you.

Arsalan: You’re the Chief Medical Officer at Bioheng. Tell me what you consider to be the most exciting development of what your company is currently doing.

Jie: Thank you for your question. One is (42:06) we are (42:06) universal CAR-T. I mentioned that we are (42:11) manufacture. (42:14) therapy and (42:16). That is very exciting. Another one is to significantly reduce the cost. And (42:24) has already approved the (42:27) very, very expensive, even in China, and the difficulty (42:33). If (42:34) can be reduced either half or (42;40) half of our cost, so (42:43) can benefit on more (42:46) the patient. I’m very excited to use one strategy (42:51) and get the (42:54) approved by the (42:55) so we can cooperate with PPC and Novotech to (42:59).

Another one is CD-7 (43;05). We use (43:07). That will be (43:10) by the FDA by (43:11), so we are trying to develop (43:14) China around the US to (43:20) and the (43:23).

Arsalan: We wish you much luck and fortune with those two studies. Now back to Vivian. What are your thoughts on the future of biotech companies conducting their research in China?

Vivian: Thank you for the question. I think the future of biotech companies that are conducting their research in China is bright. There are several reasons. First, the government supports clinical research in China. For example, the government shortened the approval timeline to 60 working days, and currently this timeline is strictly followed by the government, which makes it reasonable to join the global studies. Secondly, as I mentioned before, China has a very big patient population which can shorten the overall recruitment timeline and the drug development timeline, which I believe is very important for the biotech companies. And also in terms of the development cost, the China cost is relatively low, only about 40-50% compared to the Western countries, so that’s another attraction. And on top of that, I think China has the world’s second largest pharmaceutical market, which I believe is the attraction for most biotech companies. But however, if the biotech companies, if they have no local expertise of China, they can always collaborate with the locals here or local biotech companies to conduct their clinical trials in China. That’s all. Thank you.

Arsalan: Thank you very much. Mr Xue, where has the most significant effect on patients been that we’ve seen using CAR-T therapy, Kai?

Kai: Thank you for your question. (45:16) the most significant effect, I think compared to the traditional treatment is the efficacy is long and is the overall responsibility (45:29) especially for (45:31). And the second is it takes patients less time, which (45:37) one time, so reducing patients’ psychological and physiological burden. Thank you.

Arsalan: And now, is there a specific cancer type that has been the area of focus for universal CAR-T trials? Dr Jie Chen?

Jie: Thank for your question. For the (46:06) Professor Xue Kai mentioned, and the CD-7 or CD-20 and CD-22, the others were (46:16 a good target), so the potential indication will be (46:19), the B-cells and the non-Hodgkin’s lymphoma. Another one is (46:27) target for the (46:30) indication. That is already for the (46:35) and the (46:47). Another target, potential target, (46;41). Also the T-cell and (46:47), so that is our target. We are trying to find some difference, such as the CD and (46:56) and other ones for the solid tumour is another strong (47:05) highly expensive in Asia and even in China, gastric cancer. (47:14) that is potentially the target for developing the CAR-T. Even the (47:23) CAR-T or universal CAR-T. For the (47:27) to target, I think there are several the company are working on (47:35) the potential for the (47:40) and development to universal CAR-T.

Arsalan: Thank you. Vivian, a question for you. Can you elaborate more on government support to encourage biopharma innovation?

Vivian: Thank you for the question. I think the Chinese government (47:59) reforms over the past two years to encourage biopharma innovation. (48:05) they shortened the start-up timeline. As I mentioned before, the (48:10) approval timeline in China right now is only 60 working days. And this was strictly followed by Chinese government, which makes China feasible to join the global study. And secondly, it also encourages simultaneous global drug development. If you have around 15-20% of Chinese patients from the global study and also the Chinese data is in line with the global data, then you have the chance to use this Chinese patient data for your China and global registration purpose. And also, as I mentioned before, the NMPA (48:50) such as (48:52) prior to review and the conditional approval. All these will expedite the drug development in China.

And also, the government issued a lot of drug development guidelines to help the company to give out the products. Last but not least, I would like to mention, in terms of the NDA approval, the NMPA, right now they can do the independent review, no need to wait for other countries (49:23), which make the NDA approval faster. We can see some cases, the drug was approved in China (49:32) after the US approval, sometimes even ahead of the US approval. I think all these other ways the government is using to encourage the biopharma innovation. Thanks.

Arsalan: Back to you, Professor Kai. What has been the impact of cell and gene therapy in China throughout the COVID-19 pandemic?

Kai: Thank you for your question. I don’t think (50:01) attention has been paid to cell and gene therapy by the Chinese government. For example, this month MRNA vaccine (50:13) centre started construction in Shanghai. I don’t (50:19) carried out in some major cities in China, such as Beijing, Shanghai, (50:25), Wuhan and (50:28). Most global patients in (50:30) centre in these cities come from other places. The epidemic of COVID-19 may affect many patients going and choosing the big cities, making them have to be treated at local hospitals, and may also miss the treatment opportunity of better medical resources, especially for some refractory patients who failed in multi-line treatments. But I think it’s only a temporary (51:06), so gradual control of the epidemic situation and the possible (51:13) adjustments will gradually reduce these impacts. After all, the research and development of gene biotherapy has also received (51:27) om China, just as Vivian Gu has mentioned. Thank you.

Arsalan: We have one final question, and it’s for you, Dr Jie Chen. What stage of development are we in for developing a universal CAR-T cell therapy?

Jie: Thank you. Now (51:51) stage is (51:53) get an NMPA approval and NDA approval (52:00). Potentially if everything is (52:05) we can complete our study in one and a half year, Phase 1, and can go to the Phase 2 (52:15) to get approved after three or four years. It’s now in that stage. Another strategy (52:24) is (52:26) the FDA or China agency in the IND in the future.

Arsalan: That’s all the time that we have for today. Thank you to everyone in the audience for tuning in. Thank you again to my esteemed panel for sharing your time and your expertise. And we appreciate Novotech for sponsoring the discussion on Endpoints Webinars. If you’d like to re-watch this show, or to share with your colleagues, a link for on demand viewing will be sent. I’m Arsalan Arif for Endpoints News. Thanks for joining us and we hope to see you at a future Endpoints Webinar. Thank you.