Eric Smith, MD, PhD, discusses the development of novel CAR T-cell therapies for patients with multiple myeloma.
Eric L. Smith, MD, PhD
The advent of cellular therapy has invigorated the field of multiple myeloma, particularly for patients in the relapsed/refractory setting who have historically had a poor prognosis, according to Eric Smith, MD, PhD. However, he said, there is still more to accomplish regarding chimeric antigen receptor (CAR) T-cell therapy.
“CAR T-cell therapy for myeloma certainly has exciting data to date, but there are ways in the lab that we can modify these T cells further and create an even safer and more effective therapy,” said Smith.
The anti-BCMA CAR T-cell therapy bb2121 has shown impressive data, most notably a median progression-free survival of 11.8 months for patients with relapsed/refractory disease. One of the newer CAR T-cell therapies in development is JCARH125, which is being manufactured by Juno Therapeutics (Celgene) and currently being evaluated in a phase I/II trial (NCT03430011). This product is also targeting BCMA in relapsed/refractory multiple myeloma.
In an interview with OncLive during the 2018 SOHO Annual Meeting, Smith, a medical oncologist at Memorial Sloan Kettering (MSK) Cancer Center, discussed the development of novel CAR T-cell therapies for patients with myeloma.Smith: One of the most exciting advances in recent times for myeloma has been the advent of cellular therapy. We are seeing responses in patients who really have no other options, and a very limited prognosis. The responses so far to date do not seem durable in the majority of patients. I discussed ways to advance CAR T-cell therapy for myeloma with novel CAR T-cell vectors that may hopefully enhance the depth and persistence of responses to CAR T cells for those patients.bb2121 is the most advanced in terms of data that have been presented in the relapsed population and are being treated in US-based clinical trials. I have been involved in the development of JCARH125, which is also progressing in clinical trials now. The results have not been reported.
I spend most of my time in the laboratory where we are making novel CAR T-cell designs that are aimed at increasing the persistence. In some areas, we think we are improving the design, particularly with JCARH125. This is a human-derived CAR T-cell therapy, which may limit the patient's immune response against the CAR T cell. That is something that has been seen in mouse CAR T cells that target CD19 in lymphoma—where the patient’s immune system then recognizes the CAR as foreign. That limits the persistence and potential to give the patient a second dose of therapy.
Other things that we are looking at for the next generation of CAR T-cell therapies include targeting more than 1 target with the same CAR vector. Also, at MSK, we have pioneered what we call "armored CAR T cells." There, we have done gene modification to the T cell, not only encoding for the CAR, but also for a second gene that encodes a protein, which gives the T cells a further advantage to eradicate the myeloma in the immunosuppressive microenvironment.Multiple studies with CD19 and BCMA CAR T cells for myeloma have shown that the expansion and persistence of the gene-modified T cells correlate with deeper and more durable responses. There are a few reasons now why patients are relapsing after CAR T-cell therapy. One of which is because the target antigen gets downregulated or is not expressed in a small population of cells, and those cells end up growing out. For that reason, we are looking at dual targeting.
However, the other reason is that myeloma relapses and still expressing the target. That happens because the T cells are no longer functionally persistent. They may still be there at low levels, but they are not doing their job—they cannot divide and kill anymore. We are looking at ways to further modify the CAR T cells in order to kill and potentially persist at higher levels for longer.We certainly hope for cure. With the CD19-targeted CAR T cells in B-cell acute lymphocytic leukemia and diffuse large B-cell lymphoma, it looks like a substantial number of those patients do turn out to be cured—or at least have very durable remissions. With bb2121, we have not had proof [of cure] yet. However, we are certainly hoping that with that product and others, we will get there.Armored CAR T cells have been pioneered at MSK. It is where we put in a vector that encodes at least 2 genes, the first is the CAR itself, and the second is a gene that gives the T cells another advantage. For example, it may be a proinflammatory cytokine that helps recruit the T cells and make them better killers. It may be a ligand that is expressed on the surface of the cells but interacts with other cells in the myeloma tumor microenvironment. This would be in order to give the T cells an advantage and avoid immune suppression by other cells nearby that are potentially killing them.
The third thing that we have been doing more recently is getting the CAR T cells to secrete an antibody fragment against what is suppressing them, like with PD-1/PD-L1, where checkpoint blockade has shown to be effective in some other malignancies.I do think that the results to date have been very encouraging in these very relapsed/refractory populations, which have been the predominant populations that have been studied. The really exciting thing in myeloma, and potentially in other malignancies as well, will be when we can move some of these therapies up to earlier lines where the disease is a little bit less proliferative a less resistant to treatments. Hopefully there, we will see the kinds of durable responses and potentially cures that we are looking for.
Raje NS, Berdeja JG, Lin Y, et al. bb2121 anti-BCMA CAR T-cell therapy in patients with relapsed/refractory multiple myeloma: Updated results from a multicenter phase I study. J Clin Oncol. 2018;36 (suppl; abstr 8007).