COSTEM 2021 | Bispecific antibodies vs CAR T-cells for R/R multiple myeloma
Hermann Einsele, MD, FRCP, University of Würzburg, Würzburg, Germany, compares the advantages and disadvantages of bispecific antibodies and chimeric antigen receptor (CAR) T-cells for the treatment of relapsed or refractory (R/R) multiple myeloma. To begin with, Prof. Einsele explains how bispecific antibodies are readily available as an off-the-shelf product whilst CAR T-cells currently need to be manufactured and quality can vary. Although allogeneic CAR T-cells are currently being developed, there are multiple obstacles including immunogenicity and extensive genetic engineering which negatively impact CAR T-cell persistence. Prof. Einsele then discusses the roles of other agents such as immunomodulatory drugs (IMiDs), immune checkpoint inhibitors and tyrosine kinase inhibitors which can be used in combination with CAR T-cells to increase persistence, before he goes on to outline evidence suggesting that bispecific antibodies could be given for shorter time periods. Finally, Prof. Einsele explains how, on the one hand, CAR T-cells can be highly efficacious, with overall response rates (ORR) ranging between 80-100% versus 60% for bispecific antibodies, but, on the other hand, have been associated with more severe cytokine release syndrome (CRS) and neurotoxicity in comparison to bispecific antibodies, and cannot be used to treat elderly patients. This interview took place at the 6th Congress on Controversies in Stem Cell Transplantation and Cellular Therapies (COSTEM), which took place virtually.
Transcript (edited for clarity)
The bispecific antibodies are clearly off-the-shelf products. So, you can actually go to the pharmacy, you can get a precise dosing, you can choose between subcutaneous IV application, you can decide between different application modes, and even further, you can decide about the target. Now, with the CAR T-cells, you have to take what you get, because the CAR T-cell product is highly variable. It depends on the T-cell subset at the time of leukapheresis, it depends on transduction efficacy, and also viability of the CAR T-cells...
The bispecific antibodies are clearly off-the-shelf products. So, you can actually go to the pharmacy, you can get a precise dosing, you can choose between subcutaneous IV application, you can decide between different application modes, and even further, you can decide about the target. Now, with the CAR T-cells, you have to take what you get, because the CAR T-cell product is highly variable. It depends on the T-cell subset at the time of leukapheresis, it depends on transduction efficacy, and also viability of the CAR T-cells. Furthermore, it can take up to 8 weeks from leukapheresis to CAR T-cell infusion, so it’s definitely not an off-the-shelf product with a high variability. I think these are clearly advantages for bispecific antibodies.
Now, we are moving into alloCARs, which probably will help us to get the CAR T-cells more as an off-the-shelf product, but I think there’s still issues about immunogenicity, extensive genetic engineering, which might also have an impact on the persistence and the function of the CAR T-cells. Now if we look at the- so CAR T-cells- one expects that CAR T-cells is a one-shot treatment, but in myeloma, the persistence is rather limited. And so, at the moment, a lot of strategies are involving CAR T-cells plus additional drugs like IMiDs, CELMoDs, immune checkpoint blockers, anti-CD38 antibodies or tyrosine kinase inhibitors to actually improve the persistence of the CAR T-cell. So, for me, for myeloma, the CAR T-cells are not a one-shot treatment.
Now, the BiTEs are kind of considered as an ongoing treatment forever, but here I feel that with the BiTEs, and we have experiences and also from different trials, we know that probably giving BiTEs for a short time period will already induce a maximum response. So, I don’t think that we really need to give BiTEs until progression. And furthermore there’s the issue of retreatment, and I think with the CAR T-cells, at least with the BCMA-directed CAR T-cells, we have some experience that retreatment is not really very effective in contrast, at least, with BiTEs, in other disease settings, like B-ALL, we know that we can retreat the patient very successfully. So, I think there are quite a few arguments in favor of bispecific antibodies when compared to CAR T-cells.
Now, going to the efficacy and toxicity, what we know is that the overall response rate and the complete remission rate is higher with CAR T-cells. So, with CAR T-cells, its overall response rate 80% to 100%, CR rate 40% to 85%, and with bispecifics, the overall response rate is slightly above 60%, and the complete remission rate between 30% and 50%. Also, the progression-free survival that was reported seems to be longer for the CAR T-cells.
But on the other hand, the toxicity is higher with CAR T-cells, more severe cytokine release syndrome, more severe ICANS, and more hemotoxicity and more infections with CAR T-cells when compared to bispecific antibodies. And I think the BiTEs are still in kind of a dose-escalation phase, so maybe also the treatment efficacy will improve with the bispecifics. And last but not least, the elderly patient, there are data that you can treat patients even beyond 80 with bispecific antibodies, which probably is not feasible with CAR T-cells.
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