While chimeric antigen receptor (CAR) T-cell (CAR-T) therapies engineered to target the B-cell maturation antigen (BCMA) have produced promising objective response rates in multiple myeloma, many patients eventually relapse. In previous trials, only 8% to 29% of patients experienced a complete response or a very good partial response to the therapy.1

In recent studies in the journal Blood, 2 groups of researchers investigated different strategies that may hold promise in improving efficacy of anti-BCMA CAR-T in multiple myeloma — by boosting the expression of BCMA-expressing tumor cells, or by studying the properties of T cells extracted early in the course of disease progression to evaluate if they can be manufactured into more efficacious CAR-T therapies.

“The durability of the responses is what we’re looking to improve,” Andrew J. Cowan, MD, of the University of Washington, Seattle, told Cancer Therapy Advisor.

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Dr Cowan and his colleagues at the Fred Hutchinson Cancer Research Center in Seattle tested a novel approach that involves gamma secretase (GS) inhibitors (GSI), a class of small-molecule compounds that were initially developed to treat Alzheimer’s disease and later tested for solid tumors, but did not demonstrate clinical promise for those conditions.

A 2015 study, however, revealed an unexpected effect of GSIs that had potential relevance for CAR-T therapies in multiple myeloma.2 In mouse models, GS was shown to cleave BCMA off the surface of plasma cells, releasing soluble BCMA into the blood, while GSIs enhanced surface expression of BCMA on plasma cells by preventing cleavage.

The findings intrigued Dr Cowan’s colleagues, and prompted them to investigate whether GSIs could boost the efficacy of anti-BCMA CAR-T therapies in myeloma by increasing the availability of its target protein. In a study published in September 2019, they found that exposing human myeloma cell lines as well as patient tumor samples to GSIs RO4929097 or LY3039478 in vitro increased surface expression of BCMA and promoted binding of anti-BCMA CAR T-cells to myeloma cells.1 “And in 2 different mouse models, the cancer was more likely to regress for long periods in the mice [that] received the GSI and BCMA CAR-T combination,” Dr Cowan explained.