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.
OncLive: What are some of the new developments in CAR T-cell therapy for patients with myeloma that you discussed in your presentation at the 2018 SOHO Annual Meeting?
: 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.
What are some of the products currently in the landscape? Which ones are coming down the pike?
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.
You mentioned persistence of CAR T cells. Could you explain what the challenge is there?
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.