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IMW 2021 | CAR-T vs bispecifics: the best immune approach to replace ASCT

Hermann Einsele, MD, FRCP, of the University of Würzburg, Würzburg, Germany, shares his thoughts on which method would be most beneficial as a replacement for autologous stem cell transplantation (ASCT) in the treatment of multiple myeloma, chimeric antigen receptor T-cell (CAR-T) therapy or bispecific antibodies (BsAbs). BsAbs are advantageous as they are an off-the-shelf products, accessible to patients, and can be administered in a precise dosage. In contrast to this, CAR-T therapies are not yet available off-the-shelf, require intensive production, and the product is highly variable. Data shows that CAR-T therapy can achieve higher rates of complete response and progression-free survival when compared to BsAbs; however, BsAbs induce less toxicities than CAR-T therapy. Prof. Einsele also describes how CAR-natural killer (CAR-NK) cells or alloCARs could provide an off-the-shelf alternative to CAR-T therapy, commenting on how the genetic modifications used to make alloCARs may impact their immune potential and viability, and reporting that not enough is yet known about the action of CAR-NK cells for them to be a viable option as a replacement for ASCT. This interview took place during the 18th International Myeloma Workshop (IMW 2021) congress.

Transcript (edited for clarity)

I was asked to talk about the replacement of high-dose chemotherapy and autologous stem cell transplantation by immunotherapy. My specific task was to address the role of bispecific antibodies or to balance between bispecific antibodies in CAR T-cells. And one of the major points that I would like to make is that the bispecific antibodies clearly have an advantage because they are off-the-shelf products...

I was asked to talk about the replacement of high-dose chemotherapy and autologous stem cell transplantation by immunotherapy. My specific task was to address the role of bispecific antibodies or to balance between bispecific antibodies in CAR T-cells. And one of the major points that I would like to make is that the bispecific antibodies clearly have an advantage because they are off-the-shelf products. They are available as products that can be used for subcutaneous or IV application that we can do precise dosing, and then the application can be weekly, two weekly, and even three weekly.

And in addition, we can use off-the-shelf products and target different antigens on a myeloma cell-like using BCMA-directed bispecifics, GPRC5D bispecifics, FcRH5 bispecific antibodies. And also maybe in the future CD38-directed BiTEs. In contrast, CAR T-cells are not off-the-shelf products so they require a quite intensive production time. The cell product is highly variable so the T-cell subset composition, the transduction efficacy, the viability of the CAR T-cells all are influencing the final immunotherapeutic product that we use.

So, there is clearly a difference in the availability and the precise dosing, and I see this as an advantage for the bispecific antibodies. It was mentioned, and we have a previous discussion already that maybe CAR-NK cells or alloCARs might actually be a game changer because they could actually be off-the-shelf CAR T-cell products. On the other hand, the extensive genetic modification that has to be used to make alloCARs available might also have an impact on the immunogenicity and maybe also the viability of the alloCARs.

The CAR-NK cells that could also be off-the-shelf CAR cell product. We don’t really know enough about the persistence of these cells about the migration into the tumor tissue. So, I think at the moment we don’t really see or do have enough data to really see that CAR-NK cells or alloCARs can be really used as a kind of replacement of conventional autologous CAR T-cells. Then we have the issue about efficacy and toxicity and the data that are available clearly show that CAR T-cells induce a higher rate of follow or response. A higher rate of CR rates and maybe a longer progression-free survival compared to all the bispecific antibodies that are available in clinical trials, but a lot of them, the bispecifics, they haven’t been really used in the highest dose range. And some of these trials, the MTD hasn’t been really reached yet. So, I think we still see some- we probably see additional improvements in the overall response rate and maybe also in progression-free survival with the bispecifics.

Then there is a question about the application mode. So, CAR T-cells are a kind of one-shot treatment whereas with bispecific it’s a treatment forever. Now, I wouldn’t really confirm this. I think if we look at the CAR T-cell products used for treatment of multiple myeloma, clearly it’s a limited time. We find these cells to persist in the peripheral blood. So, I don’t really see that CAR T-cells are kind of a living drug or at least live for a long time period. And the strategies that are increasingly used, like adding in CELMoDs, adding in IMiDs, adding in antibodies or tyrosine kinase inhibitors and give these for a long time period indicates that obviously this one-short treatment with CAR T-cells in myeloma doesn’t really work. And with bispecifics, it’s very true. It’s very true that there is at the moment, the issue that they are given as a continuous treatment until progression, but from the data that I see from the different trials, I would think that probably a limited time of application then stopping and then re-treatment if a patient is progressing would also be an interesting option.

And about toxicity, it’s clear that at least with a dose range that has been evaluated with CAR T-cells and bispecifics, there is an advantage for the bispecifics that induce a lower rate of CRS and lower decree of CRS and the same applies to neurotoxicity, and also the hematotoxicity is clearly more pronounced with CAR T-cells when compared to bispecific antibodies. So, in summary, I would probably go for the bispecific antibodies to replace autologous stem transplantation.

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