Drawbacks

To date, adverse events seen in BCMA-targeting CAR T-cell trials have been similar to those observed with CD-19 CARs. Among the observed adverse events is cytokine release syndrome (CRS), where the body’s immune system releases a large number of cytokines in response to the treatment. In CD-19 targeting CAR there have also been a number of neurological toxicities observed.

“CD19 experience is a little further ahead than myeloma but, anecdotally, in our experience, there has not been the same degree of toxicity in targeting BCMA in myeloma as reported in some cases with respect to CD19,” Dr Green said. “We are a little more cautious because we have refined the approach and come to a better understanding of how to reduce toxicity in all situations.”

Other Improvements

Dr Green and colleagues are also preparing to start enrollment on a clinical trial testing BCMA-targeting CAR T cells combined with the gamma secretase inhibitor LY3039478.4 Theoretically, LY3039478 may enhance the killing of cancer cells by increasing BCMA expression on multiple myeloma cells, making the targeted BCMA therapy more effective.

“One of the nice things about this therapy is that patients will not need to demonstrate any expression of BCMA on plasma cells to be eligible,” Dr Green said.

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In addition, he noted that testing for myeloma and its precursor diseases is often done by looking for BCMA that has “fallen off” the plasma cells and is circulating in the blood stream.

“This small molecule will increase BCMA expression on the target cells and decrease its circulating level,” Dr Green said. “We think that might be important to make the CAR T cells more effective because the BCMA floating around in circulation could potentially complicate or limit the capacity for CAR T cells to specifically target myeloma cells.”

Where Does CAR Fit?

As trials continue to explore the safety and efficacy of CAR T-cell therapy for patients with myeloma, where this treatment will fit in with the current armamentarium remains a question.

“Right now, we are integrating the therapy in patients after they have seen some of the more traditional treatments that we know to be effective,” Dr Green said. “That is what makes sense from a patient and ethical perspective.”

As the research moves forward though, if CAR T-cell therapy is demonstrated to be well-tolerated and game-changing in terms of long-term outcomes, there will be a strong motivation and rationale for moving CAR T cell therapy earlier in the treatment process, Dr Green said.

Editor’s note: This article has been updated to clarify that tisagenlecleucel (Kymriah) is approved for the treatment of children and young adults with advanced leukemia and adults with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy.

References

  1. 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. Blood. 2017:130:740.
  2. Fan F, Zhao W, Liu J, et al. Durable remissions with BCMA specific chimeric antigen receptor (CAR)-modified T cells in patients with refractory/relapsed multiple myeloma. J Clin Oncol. 2017:35;suppl abstr LBA3001.
  3. NCI Staff. With FDA Approval for Advanced Lymphoma, Second CAR T-Cell Therapy Moves to the Clinic. Published October 25, 2017.
  4. BCMA-specific CAR T-cells combined with gamma secretase inhibitor (LY3039478) to treat relapsed or persistent multiple myeloma. ClinicalTrials.gov Identifier: NCT03502577.