Success of CAR T Cells in Blood Cancers Calls for Further Expansion into the Solid Tumor Arena

Michael Bishop, MD

Chimeric antigen receptor (CAR) T cells have shown clinical promise in many cancer types, and according to Michael Bishop, MD, these agents have demonstrated curative ability in some cases.

CAR T-cell therapy has seen the most impact in leukemia and lymphoma, especially in cancers affecting children and adolescents. However, in 2021, the FDA approved the first CAR T-cell therapy for relapsed or refractory (R/R) multiple myeloma. FDA approved CAR T-cell therapies include idecabtagene vicleucel (ide-cel; Abecma) for the treatment of R/R multiple myeloma after 4 or more lines of prior therapy, lisocabtagen maraleucel (Breyanzi) for the treatment of R/R large B-cell lymphoma after 2 or more prior lines of therapy, tisagenlecleucel (Kymriah) for the treatment of R/R diffuse large B-cell lymphoma (DLBCL), and axicabtagene ciloleucel (Yescarta) for the treatment of DLBCL, primary mediastinal B-cell lymphoma, high grade B-cell lymphoma, DLBCL that results from follicular lymphoma (FL), as well as for the treatment of follicular lymphoma.¹

There has been some effort to adapt CAR T cells for solid tumors, but to limited success. According to the National Cancer Institute (NCI), the majority of tumor antigens are inside solid tumor cells, outside of the reach of CAR T cells. Current trials are underway according to the NCI but have not had the same success that has been shown with blood cancers.

“When we think about CAR T cells, we don't hear a whole lot in regard to the application in solid tumors. Solid tumors present their own challenges, but there are CAR T-cell studies out there. The difficulty there is the expression of a surface antigen that's not expressed on normal tissues,” Bishop, professor emeritus of microbiology and immunology at the University of California, San Francisco stated.

In an interview with Targeted Oncology, Bishop, discussed how CAR T cells have reshaped the treatment landscape, the future of their use, and their potential in solid tumors.

TARGETED ONCOLOGY: How have CAR T cells reshaped the treatment landscape in recent years?

BISHOP: I think it’s made a significant impact upon patient care. If we look at the 3 major groups of patients for which CAR T cells are indicated, and particularly the first, the FDA approved agents for non-Hodgkin lymphoma and for pediatric and young adult acute lymphoblastic leukemia (ALL). More recent approvals have been for mantle cell lymphoma (MCL), and now we're awaiting and what we expect to be the first indication for multiple myeloma. Starting with ALL for this pediatric population, CAR T cells have been a game changer. These are unfortunate young people who have median survivals of less than 6 months, and to see these high response rates that enabling them to potentially go on to an allogeneic stem cell transplant and in some cases, be free of disease is totally remarkable. 

In the non-Hodgkin lymphoma setting, we now have 3 products indicated for advanced B-cell non-Hodgkinlymphoma, again with game changers for patients with totally refractory disease. Now there is this therapeutic option that is potentially curative. We're seeing now patients out to 5 years without any further therapy after receiving CAR T cells. 

For MCL, it provides an additional option. There's lots of options for MCL, but the CAR T cell results had very high response rates, and a significant proportion had response rates higher than what we've seen in DLBCL. The long-term data is yet to be determined and rather relative to the impact on their natural history, but there are sustained complete remissions without any further therapy and we just got to see how long those are going to last.

Finally, we are waiting for additional results in other forms of non-Hodgkin lymphoma particularly in indolent lymphoma such as follicular lymphoma (FL). The initial results are extremely encouraging. We now have some initial review in chronic lymphocytic leukemia and small lymphocytic lymphoma. We do consider that to be the initially encouraging results. So, we're going to have these trials available to us within this year. 

Coming back to multiple myeloma, a number of trials that are highly exciting variations on the approaches we already have, in terms of the targets, dual targeting, and the use of different receptors. These results have been exciting in terms of the very high response rates. I think the disappointing aspect of multiple myeloma is that we aren't seeing the sustained remissions that we're observing in leukemias and lymphomas. But we are seeing improvement across protocols over time. So, I think it's an exciting time for patients to have these various options.

The FDA has approved ide-cel for the treatment of multiple myeloma. What do you think the impact of this approval will be?

I think, just from a practical standpoint, this is something that will be readily available to patients. One of the hardest things about the multiple myeloma trials [historically] is it's highly competitive and patients are competing for production slots. Many of these are early phase 1 or phase 2, and so there's no availability. So, all of a sudden having a commercial product available at our own institution, we're always trying to enroll patients on the clinical trials and help move the field forward, but to have a commercially available product that hopefully will be immediately available to a large patient population, is opening an avenue for patients who otherwise don't have really good treatment options. This is going to have a significant clinical impact in the myeloma community.

Can you discuss which malignancies appear to be furthest along? And where do you see the most potential for CAR T cells in the future?

The ones that are furthest along are definitely the non-Hodgkin lymphomas. The only aspect of that is it appears that we're getting complete responses that are sustainable in maybe 40% to 50% of patients. So, there's still significant areas that we can improve upon for this patient population. 

The other area where there's significant opportunity is in ALL because it’s where we've seen success in children. There are also studies being performed in adults, and I think this is where we're all very excited about. There are a number of trials looking at ALL, including the use of allogeneic CAR T cells in this setting.

One area that's been difficult is in acute myeloid leukemia (AML), and the difficulty there is the biology of the disease and finding a target that's not expressed on important normal hematopoietic cells. But there's a number of institutions looking at the use of CAR T cells potentially as a bridge to allogeneic stem cell transplantation as well as using it as a single agent to get patients in remission with the thought that there can be elimination of leukemic cells and yet, maintenance of some normal hematopoiesis. That’s going to be a huge challenge.

The other hematologic malignancy where I think there's tremendous opportunity is in CLL. We have several good agents for CLL, so, it's going to be a little bit of a crowded field. But still, CLL was the first disease where a clinical study was showing the efficacy of CAR T cells, and I still think that for patients with refractory disease or who have toxicities to currently available agents, this potentially could change the natural history of that disease.

If we think about CAR T cells, you don't hear a whole lot in regard to the application in solid tumors. Solid tumors present their own challenges, but there are CAR T cell studies out there. The difficulty there is the expression of a surface antigen that's not expressed on normal tissues. But people have been very creative about co-expression of more than one molecule that might not be expressed on normal tissues and then looking at mutated surface antigens. 

Do you see value for use of CAR T cells in myeloproliferative neoplasms?

The difficulty in myeloproliferative neoplasms is the same problem that is in AML. The difficulties are finding a good target for these and the biology of the disease. It's going to present a tremendous challenge. At this point in time, there's interest in using it in these entities, but finding the proper target is going to be the biggest challenge for their application.

We now have some long-term data and like I'd said, we're actually beginning to believe that many of the CAR T cells have curative potential. We're also seeing the limitations, but those limitations can be overcome. We just need to use new techniques. We've also learned to better manage toxicities, and we would like to see these applied to a broader population of patients. We think that [CAR T-cell therapy] is currently being underutilized, and there's a significant proportion of patients who can benefit.

_REFERENCE:

_{FDA-approved CAR T-cell Therapies. UPMC Hillman Cancer Center. Accessed May 5, 2021. https://bit.ly/3h3NmiB.}

_{CAR T-Cell Therapy Approved by FDA for Mantle Cell Lymphoma. National Cancer Institute. Accessed May 5, 2021. https://bit.ly/3eiZoD8}