Welcome to The Transplant Sessions brought to you by the Video Journal of Hematological Oncology (VJHemOnc). This exclusive discussion features leading experts Bruce Levine and Christian Chabannon, who debate key updates in transplantation and cell therapy from the ASH 2020 virtual Annual Meeting.
The topics being discussed include graft failure, graft-versus-host disease (GvHD), post-transplant relapse and cellular therapy updates.
“This was the REACH3 study, and the study demonstrated superior clinical efficacy of ruxolitinib compared to all other options for graft-versus-host disease. This was a study presented by Robert Zeiser with many other European core investigators. And ruxolitinib is likely to become an important option, or even standard of care for second-line therapy for patients who are affected with chronic graft-versus-host disease, but other agents are in development. ”
– Christian Chabannon
Post-transplant relapse and immuno-oncology
“Some patients treated with allogeneic hematopoietic stem cell transplantation, will either be refractory or relapse within months after transplant. And a Phase I trial was reported from my institution in Marseille, demonstrating the feasibility of substituting selected and ex vivo activated natural killer cells, donor-derived natural killer cells, to the usual donor lymphocyte infusions, that are typically used in this setting either to treat or to prevent relapse, following a transplantation.”
– Christian Chabannon
“So my myeloma takeaways are, it’s a very crowded field. Key will be durability here, also antigen escape targeting only BCMA. And there will be at least one and probably two FDA approved products in 2021, I believe. But in thinking about the durability and antigen escape, I think we’ll see groups continue to explore combining with gamma-secretase inhibitors, upregulate BCMA, additional targets such as CD19 or SLAMF7, also known as CD319. ”
– Bruce Levine
Cellular therapy landscape and 2021 meetings
“I would just like to stress again that what was absolutely obvious during this 62nd ASH annual meeting, was the rapid growth in numbers, and in diversity around the development of cellular therapies.”
– Christian Chabannon
“I think we’re going to see more and more IPSE CAR-T, CAR-NK development. And look for that next year or this year, I should say, at ASH, December 2021.”
– Bruce Levine
Bruce Levine: Hello, and welcome to the transplant session with VJHemOnc. I’m Bruce Levine from the University of Pennsylvania. My partner in this discussion is Christian Chabannon. We’re going to be highlighting a number of abstracts that caught our eye at the ASH meeting. At this point, I’ll hand it over to Christian, to begin the discussions.
Christian Chabannon: Well, thank you so much Bruce for the introduction. I’m Christian Chabannon working at Aix-Marseille University in Southeastern France, and the Institute Paoli-Calmettes Comprehensive Cancer Center. And as Bruce mentioned, there were a large number of abstracts and presentations during this first virtual edition of the ASH annual meeting, dealing both with what we now call conventional hematopoietic cell transplantation, and the new category of cellular therapy medicinal products, many of them being industry manufactured now. Starting with the hematopoietic cell transplantation, I selected a small number of abstracts mostly in relation to allogeneic hematopoietic cell transplantation. Allogeneic hematopoietic cell transplantation can fail due to post-transplant infections, due to GVHD, or due to tumor relapse, disease relapse. And three abstracts were dealing with the management of chronic graft-versus-host disease, potentially bringing innovative solutions to the treatment of this feared complication of allogeneic cell transplantation.
Christian Chabannon: So, one abstract presented the results of a randomized trial, comparing ruxolitinib which is a JAK inhibitor, with best available therapy in patients with steroid refractory or dependent chronic graft-versus-host disease. This was the REACH3 study, and the study demonstrated superior clinical efficacy of ruxolitinib compared to all other options for graft-versus-host disease. This was a study presented by Robert Zeiser with many other European core investigators. And ruxolitinib is likely to become an important option, or even standard of care for second line therapy for patients who are affected with chronic graft-versus-host disease, but other agents are in development. Another abstract was testing actually another JAK inhibitor, the name is baricitinib. Again, in refractory chronic graft-versus-host disease, phase one, two study, showing that this new agent is well-tolerated, and shows some significant efficacy for patients with severe chronic graft-versus-host disease.
Christian Chabannon: What’s interesting in this abstract is that, most treated patients were actually suffering of chronic graft-versus-host disease for extended period of times, showing that the agents still retain some efficacy in this setting. Slightly different approach, an agent that blocks the CSF-1 receptor pathway. CSF-1 is an important agent, that controls the activity of macrophages that infiltrate tissues during the chronic graft-versus-host disease process. And again, a phase one study of an agent named axatilimab targeting this pathway CSF-1 receptor. Again, showing both safety, and a significant clinical efficacy in the context of severe steroid refractory steroid dependent, chronic graft-versus-host disease. So no firm conclusion maybe except for ruxolitinib, that is already in use at many programs for a significant period of times. But likely, new options in the future to treat this complication of graft-versus-host disease, following allogeneic stem cell transplantation.
Christian Chabannon: And as a complication again is relapse. Some patients treated with allogeneic hematopoietic stem cell transplantation, will either be a refractory or relapse within months after transplant. And a phase one trial was reported from my institution in Marseille, demonstrating the feasibility of substituting selected and ex vivo activated natural killer cells, donor derived natural killer cells, to the usual donor lymphocyte infusions, that are typically used in this setting either to treat or to prevent relapse, following a transplantation. And 16 patients were accrued in this trial. NK cells were manufactured at three dose levels, patients were treated, no safety signal was seen. And as compared to historical controls, these very small cohorts of patients, faired quite fairly. Obviously more trials, more inclusions are needed to confirm efficacy, but this product would qualify as a medicinal product. And that allows me to let Bruce continue with this new category of medicinal products that are made of immune effector cells.
Bruce Levine: Yeah. Thank you, Christian, and let’s continue on the theme of GVHD, and transplant. Just want to highlight an abstract 354, Orca-T a precision Treg-engineered donor product prevents acute GVHD with less immunosuppression, and an early multicenter experience. And this is a study out of Rob Negrin’s group at Stanford. And Orca-T is a CD34-selected Treg graft. It was tested in a single center of phase two, and a multicenter phase one B trial. 50 data from 50 patients was presented, the Orca-T patients versus standard-of-care showed earlier neutrophil and platelet in graph, meant in shorter hospital stay. The acute and chronic GVHD was less with Orca-T. The GVHD relapse-free survival at one year was higher for Orca-T versus standard-of-care. And coming as I do from a manufacturing background, I just want to highlight that the manufacturing is a 24 hour process, 72 hour vein to vein.
Bruce Levine: So, when thinking about scaling of this, and deploying it to larger numbers, that certainly is a consideration. Next, I like to highlight four CAR-T abstracts in myeloma, each of them targeting BCMA. The first is, abstract 131. This is the bluebird bb2121, idecabtagene vicleucel, or ide-cel. And this is the original bluebird product, and updated results from the phase one CRB-401 study was shown for 62 patients, median follow-up 14.7 months, median progression-free survival 8.8 months, overall survival 34.2, overall response rate 75.8, and CR of 38. So, looking good there. This was submitted to the FDA. BLA submitted March, 2020. The [inaudiable] date for FDA approval is March 27th of this year. Next abstract is 130, which is the new and improved bluebird product, 21217. And what this is the BCMA CAR T-cells that are cultured with the PI3-kinase inhibitor.
Bruce Levine: And that enriches for T cells displaying a memory like a phenotype. This is a dose escalation study. 66% of the patients had cytokine release syndrome of any grade, 24% had neurotoxicity responses seen at all dose levels. Median duration of response in 40 patients was 17 months, that was dose dependent. The next BCMA is from J and J, Janssen license from Nanjing legend, the CARTITUDE-1 study. That was presented data from 97 patients. And this is a product term cilta-cel. And a median follow-up here was 8.8 months cytokine release syndrome, and 92 to 95% of the patients, there was a low rate of grade greater than three cytokine release syndrome, median follow-up of 12.4 months. There is 67% stringent complete response rate, overall response rate of 97% plus. So continuing the outstanding results that we’ve seen from that group prior. And then the final one I’ll highlight is abstract 133 from CARSgen, and the Mayo clinic. This is a study Lummicar to the product has CT053. But as they reported treating 24 subjects with an 87% of oral response rate, 79% complete response rate. So quite good. Here, they presented data from patients treated in North America with at least eight weeks of assessment, and a 94% overall response rate. And they say that supports a launch of the phase two study.
Bruce Levine: So my myeloma takeaways are, it’s a very crowded field. Key will be durability here, also antigen escape targeting only BCMA. And there will be at least one and probably two FDA approved products in 2021, I believe. But in thinking about the durability and antigen escape, I think we’ll see groups continue to explore combining with gamma secretase inhibitors, upregulate BCMA, additional targets such as CD19 or SLAMF7, also known as CD319. Leukemia just highlight one abstract, that’s 160, the ALLCAR19 from Autolus, the AUTO1 trial. This is the fast off rate trial. 16 of 19 patients achieved minimal residual disease, complete response. And this is product… This is a event-free survival at six months was 62%, and 76% for those whose products were manufactured using a closed process. And then in lymphoma, abstract 405 is the Kite-Gilead ZUMA-12 study, showed an 85% overall response rate, 74% CR in 27 patients abstract 600. Another Autolus study, this is a dual targeted CAR CD19/22, AUTO3. And showing good results here. Overall response rate of 65%, complete response of 51%. A couple of days ago, we… And one other point about this product, it was combining checkpoint inhibitor pembro. So, just recently, Autolus announced that they’re looking to partner out this dual targeted CAR to focus on their other products.
Bruce Levine: And then, finally in lymphoma abstract 118, lisocabtagene maraleucel, from Juno, BMS overall response rate 84 to 88%. And that’s a mantle cell lymphoma that will be a competitor to Kites, to Corridors. And then, finally, I just want to highlight not a CAR study, but a T cell receptor preclinical study from Intellia that I thought was interesting, because this is a targeted insertion of a high avidity WT1 T cell receptor. And they’re showing preclinical efficacy, and models of AML and ALL. They’re knocking out the T cell receptor alpha and beta genes, and inserting this transgenic T cell receptor into the track locus. And what was really striking, is they’re able to achieve multiple sequential gene, and at some primary human T cells, with up to 99% efficiency, and insertion of the transgenic T cell receptor at 55 to 80% efficiency. So that was really interesting. So a lot more to talk about. We do have a limited time though, and I want to turn it back to Christian, just to close out. And Christian, you have a meeting that you’d like to share with everyone.
Christian Chabannon: Yeah, absolutely. Bruce, thank you. Before I mentioned the upcoming European jointly sponsored by EHA and EBMT CAR-T meetings, the fourth edition that will be fully virtual. I would just like to stress again that what was absolutely obvious during this 62nd ASH annual meeting, was the rapid growth in numbers, and in diversity around the development of cellular therapies. You rightly mentioned that in the field of multiple myeloma, for example, the important point to observe is durability of the responses. And there were several approaches that were shown at ASH, such as the one by a Chinese company that develops a dual BCMA and CD19 CAR-T cell therapy with a very fast manufacturing process. When there is a abstract 178, the medicinal product is developed by Gracell Biotechnologies in Shanghai, and they showed both feasibility safety, and preliminary evidence of efficacy for this new medicinal products.
Christian Chabannon: And very similarly, there was a poster presentations, 1402, showing the feasibility of developing a multi specific off-the-shelf CAR-NK cell therapy, engineered for improved persistence, and improved clinical efficacy. Again, in multiple myeloma, this is an approach developed by Fate Therapeutics in San Diego, and one patient has been treated so far. You can find more on the preclinical evidence of biological activity for this new agent. That said again, because the field is expanding so fast with a huge investment from the biotechnology and pharmaceutical companies. We will hold the third European CAR-T cell meetings, as already mentioned, jointly sponsored by the EBMT and EHA, the European Hematology Associations, early February, 2021. And once again, we will have keynote lecturers from around the world, showcasing the European clinical and pre-clinical activity, trying to first develop this new field, attract young talents. And we will also devote a significant fraction of the presentations at the next EBMT annual meeting in March, virtual again, unfortunately because of COVID-19 pandemic. But we will devote a significant fraction of the EBMT annual meeting to the topic of immune effector cells, and other gene therapies to treat neoplastic and non neoplastic diseases.
Bruce Levine: Yeah, the rapid manufacturing was interesting. I’m glad you highlighted the Fate abstract. I think we’re going to see more and more IPSE CAR-T, CAR-NK development. And look for that next year or this year, I should say, at ASH, December, 2021. And also, I’d like to highlight the international society for cell and gene therapy meeting, that will be May 26th to 28th. It will be virtual again. We had a fantastic platform that was very engaging. Abstract deadline is January 25th, all aspects of cell and gene therapy, research clinical, translational commercialization, regulatory quality ethics. Take a look at isct2021.com for more information. And Christian, it was a great conversation. Glad to be with you today.
Christian Chabannon: I’m glad to be with you too, and I hope that everything goes well. Stay safe, healthy, politically safe, and see you soon.
Explore the latest updates in hematological stem cell transplantation, including expert interviews from major international congresses.
Bruce Levine – Declaration of financial interest due to intellectual property and patents in the field of cell and gene therapy. Consultant: Novartis, Terumo, Lilly Asia Ventures. Scientific Advisory Board: Avectas, Patheon/ThermoFisher Viral Vector Services, Immuneel, Incysus, Ori Biotech, Vycellix. Co-Founder and equity holder: Tmunity Therapeutics. Conflict of interest is managed in accordance with University of Pennsylvania policy and oversight
Christian Chabannon – Speakers bureau & advisory boards: Sanofi SA, Kite / Gilead, Novartis, Celgene / BMS, Janssen, Bellicum Pharmaceuticals, Terumo BCT
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