Brentjens Highlights BCMA, Next Steps With CAR T-Cell Therapy

Renier J. Brentjens, MD

CD19 has shown great success as a target for chimeric antigen receptor (CAR) T-cell therapy in both acute lymphoblastic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL). Now, the B-cell maturation antigen (BCMA) has emerged as another promising target, according to Renier J. Brentjens, MD, PhD.

In patients with relapsed/refractory multiple myeloma, the BCMA-targeted CAR T-cell therapy bb2121 induced complete remissions (CRs) in 56% of patients. This phase I study of 21 patients demonstrated that bb2121 was well tolerated, and was associated with an objective response rate of 94% and a partial response rate or better of 89%. Following 40 weeks of follow-up, the median progression-free survival (PFS) had not been reached, but the 9-month PFS was 71%.

OncLive: Can you discuss other targets being investigated in addition to CD19 for CAR T-cell therapy?

In an interview with OncLive, Brentjens, an associate professor, and chief of the Cellular Therapeutics Center, Memorial Sloan Kettering Cancer Center, discussed the emergence of BCMA as a target for CAR T-cell therapy and other next steps for the field.Brentjens: There has been a significant amount of success targeting CD19 on B-cell cancers. In fact, there are 2 drugs that are now commercially available, one from Novartis and one from Gilead. Both are targeting tumor cells that express CD19, particularly in children and young adults with ALL, as well as adults with DLBCL. The question is whether this is the end of the road or if these genetically modified CAR T cells are eventually going to be applied to other cancers or other types of targets.

There has been a lot of success with targeting CD19 in the field of hematologic malignancies. There are also some other targets that have already shown some success at this relatively early stage, particularly BCMA. There are currently 5 different institutions and companies that are running clinical trials targeting BCMA in patients with relapsed/refractory multiple myeloma. It would seem, based on the early data, that there is an overlap between what we saw with CD19-targeted therapies in ALL and DLBCL and some of the data that are coming out targeting BCMA. These suggest that BCMA could be the second target that will ultimately get an FDA approval.

Although identifying new targets is important, it is also important to improve the current therapy that we already have. There is work that we do in the laboratory where we provide genes to the T cells that express CAR and allow these T cells to function better when they are infused back into the patient. We already know that many of the patients with certain diseases will not achieve a remission, or will relapse if they do achieve a remission. They sometimes relapse with cancer cells that no longer express the target, which we call immune escape.

The goal was to design the next generation of CAR T cells that can overcome the current limitations of the technology. We call these armored CAR T cells because they are additionally fortified with the cytokine that can be pro-inflammatory, a costimulatory ligand, or even antibodies that can block the checkpoint pathways, such as PD-1/PD-L1. There is a lot of animal data to suggest that these approaches have promise moving forward.

In addition, it is worth noting that this armored CAR technology has been employed to a certain degree. There are groups that are combining different drugs with the CAR T cells, such as different antibodies to checkpoint blockade. At our center, we are targeting CD19 with T cells that have been additionally modified with a costimulatory ligand called 4-1BB ligand. We have an ovarian model where we target MUC16 in patients with relapsed/refractory ovarian cancer that additionally secrete the cytokine IL-12, which is a pro-inflammatory cytokine.

We are anxiously awaiting to see how this technology and additional modifications can improve the persistence, the antitumor efficacy, and the overall survival of the patients we treat.

Can you discuss the success that we have seen with CD19 in hematologic malignancies?

In addition, we have a long catalog of other approaches that we are eager to test in the clinical setting. One important point is that we can do as many mouse models as we want, since they are very informative and important. However, ultimately what dictates what patients are going to receive this are global phase I and II trials that we need to rapidly institute. These will help us determine which additional modifications we should carry forward to the next FDA-approved product. We started our first trial targeting CD19 and we were one of the first to do so with a retroviral vector in 2006 at Memorial Sloan Kettering Cancer Center. We have been investigating this for a while. We initially started by treating patients with chronic lymphocytic leukemia because it gave us a proper window to make the cells under FDA-approved conditions so we can infuse them into the patient and see the outcomes.

While the T cells were well tolerated in that disease, it was only 3 years later when we started treating adults with relapsed/refractory ALL that also express CD19 and we started seeing dramatic responses. Our initial CR rate was 100%. It was gratifying that after we published our first report, the group at the University of Pennsylvania found similar results with a slightly different CAR targeted to CD19 in children with relapsed ALL. That was followed by the National Cancer Institute and the Fred Hutchinson Cancer Center. Those are 4 major centers all using similar technology and demonstrating a similar gratifying, high CR rate in these difficult-to-treat patients.

These studies spurred on the industry to do multicenter studies. Two of those multicenter studies have allowed an FDA approval for a commercialized product. In the case of Novartis, the target was in children and young adults with relapsed/refractory ALL. In the case of KITE/Gilead, it was in the context of relapsed/refractory DLBCL. This is not the end of the CD19 story. These companies, along with others, will continue to do phase II registration trials to obtain an FDA approval, whether it is overlapping in similar diseases or expanding beyond to other B-cell immunologic malignancies.

Berdeja JG, Lin Y, Raje N, et al. Durable clinical responses in heavily pretreated patients with relapsed/refractory multiple myeloma: updated results from a multicenter study of bb2121 anti-BCMA CAR T cell therapy. In: Proceedings from the 59th ASH Annual Meeting and Exposition; December 9-12, 2017; Atlanta, Georgia. Abstract 740.