Existing CAR T Cells Show Promise Even as Newer Agents Emerge in Multiple Myeloma

Noopur Raje, MD

Noopur Raje, MD

In recent years, research on the efficacy of CAR (chimeric antigen receptor) T-cell therapy in multiple myeloma has shown deep and durable responses in patients, according to Noopur Raje, MD. Some of the studies have resulted in new CAR T-cell agents introduced to the treatment landscape.

The newer CAR T cells mainly target the B-cell maturation antigen (BCMA); previous research has shown that targeting BCMA is highly effective. The key to making this treatment even more effective may be to administer CAR T-cell agents earlier in the course of disease, explained Raje. This strategy may be especially beneficial for patients with high-risk myeloma. Among higher-risk patients, oncologists are also considering administering CAR T cells at the time of diagnosis to enhance efficacy.

In an interview withTargeted Oncologyat the 24thAnnual International Congress on Hematologic Malignancies, Raje, director, Center for Multiple Myeloma, Massachusetts General Hospital, discussed emerging CAR T-cell therapies in multiple myeloma. She also explained how CAR NK (natural killer) cells differ from other CAR agents.

TARGETED ONCOLOGY: What is the role of CAR T-cell therapy in multiple myeloma?

Raje: We have quite a lot of data now in the space of CAR T cells. We have several different CARs, all targeting BCMA and all showing durable and deep responses in very late stage myeloma patients. There are newer targets that we will be considering and thinking about what we should be doing in terms of how to generate the next generation.

TARGETED ONCOLOGY: What are some of the new targets have emerged in the space?

Raje: The big thing with CARs right now is everyone is targeting BCMA. We have seen fantastic responses with that, so we are looking at moving that earlier on in the disease course, specifically in the high-risk myeloma patients. In these patients, we are looking at bringing up CARs at the time of diagnosis so that patients receive the induction treatment that has high-risk FISH cytogenetics. We would actually consider doing a CAR T-cell therapy here because, in general, the responses and durability of patients in that population are quite low.

In addition to considering the CARs that we have studied previously earlier on [in the disease course], we are looking at other CARs as well. We are looking at CARs that are dual-signaling or dual-targeting, that is, those that target BCMA and APRIL, for example. We are looking at CARs like the CAR from Janssen, which binds to 2 separate BCMAs, and we are seeing very deep responses with that CAR. There are sequential CARs, which are being used at least by investigators in China, where they have used a CD20 CAR followed by the BCMA CAR. There are also several other different strategies for creating CARs. We are already in the space of using off-the-shelf CARs, and we will be opening up the first clinical trials using allogenic CAR T cells directed against BCMA. With this, you do not have to wait for the generation of CARs, and we will be studying those in the context of myeloma.

The other thing that is interesting in the CAR T-cell space which will be presented later on at this meeting are the NK cells. Along with the CARs that we are using today, if we can also target or activate the NK cells, we might be able to get better responses. That is something we will be studying in the future.

TARGETED ONCOLOGY: How are the CAR NK cells different than the other agents?

Raje: The downside of NK cells right now is that they do not live that long. They remain in circulation for about 10 days. The question is, can we use them in combination with something else to get a deep response? Once we get the deep response, we won’t need the NK cells around. NK cells are just a different immune strategy. It’s still a cellular strategy. We have seen nice data which have been presented in leukemia already, and we are working on it in myeloma. We just have to wait and see how this pans out.

TARGETED ONCOLOGY: What are the challenges in using CAR T cells in myeloma?

Raje: The biggest challenge has been getting the CAR T-cell product. As of right now, we are still using the autologous CAR T-cell product. However, the time to generate CARs is approximately 4 weeks or so. That is from when we collect the cells from patients, send them to be generated, then get them back to patients. These are very sick patients who do not have many options, so our biggest challenge is how can we control their disease for the 4 weeks [while the CAR T-cell product is prepared]. Once we start doing CARs earlier on in the disease course, this is not going to be a problem because we will have options to bridge patients to get them to that level.

The other thing that we are thinking of is using off-the-shelf CARs as well, such as allogenic CAR products. Once we have those, there would be no waiting time. That is 1 of the biggest challenges right now.

TARGETED ONCOLOGY: What are the biggest concerns with toxicity?

Raje: We were afraid of going into the CAR T-cell space when we first started. We have been very pleasantly surprised in the context of myeloma. We have not seen a lot of toxicity with these CARs, and that may have to do with the costimulatory domain that we are using. It may also be using T cells that are not very potent, so they do not expand as much.

The 2 big toxicities that you have to worry about with CAR T-cell technology is neurotoxicity and cytokine release syndrome (CRS). I think what has happened, which we have learned from our lymphoma and leukemia colleagues, is that we are pretty good at picking up these toxicities, and we have the antidotes to treat them.

In general, I would say the toxicity of CAR T cells is way better than some of the toxicities of other cellular products, such as autologous stem cell transplant.

TARGETED ONCOLOGY: What are the advantages to using off-the-shelf CAR products?

Raje: The benefit is patients do not have to wait around for the cells to be manufactured. Because it is off-the-shelf, you can keep reusing these cells as well. I do not want to jump too far ahead because we have to first figure out if these are efficacious and make sure they are safe, but we also have to make sure we can continue to give them again to patients. We are using most of these allogenic products from a few donors, and then you have to consider other problems when you are using donor-derived products. I do think there is a lot we can do in the future.

TARGETED ONCOLOGY: What do you hope oncologists take away from your talk at this meeting?

Raje: It’s an exciting space to be in. It’s exciting because, with the first rendition of these CAR T cells that we have for myeloma, we have seen minimal residual disease-negative disease in multiply-relapsed patients. That in itself tells us that this is extremely potent. It is up to us to move this forward in the appropriate patient population and to change the 1-year benefit we have been getting so far in this disease to make this more durable. The sky is the limit, and there is so much we can do in terms of manipulating these to make them more potent and make them more effective, as well as less toxic. It’s a real fun time to be doing this type of work for our patients with myeloma.