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Publications of the Week

γ-Secretase Inhibition Increases Efficacy of BCMA-Specific Chimeric Antigen Receptor T Cells in Multiple Myeloma

By October 9, 2019No Comments

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This week we profile a recent publication in Blood from the laboratory of Dr. Stanley Riddell (pictured) at Fred Hutch.

Can you provide a brief overview of your lab’s current research focus?

Dr. Riddell’s lab focuses on establishing the principles for the safe and effective use of T cell immunotherapy to treat cancer. This effort encompasses fundamental studies of T cell differentiation and signaling, the development of preclinical animal models, clinical translation, and novel applications of synthetic biology to enhance therapeutic T cells, modified with specific chimeric antigen receptors (CARs) or T cell receptors (TCRs).

What is the significance of the findings in this publication?

B cell maturation antigen (BCMA) is a validated target for chimeric antigen receptor (CAR) T cell therapy in multiple myeloma. Despite promising objective response rates, most patients relapse, and low BCMA expression on a subset of tumor cells has been suggested as a probable escape mechanism. We developed a strategy to increase antigen density on myeloma cells using small molecule drugs together with BCMA CAR T cell therapy. The small molecule drugs are inhibitors of γ-secretase, an enzyme that cleaves BCMA from the cell surface, thereby reducing antigen density on the tumor cells. Upon treatment with γ-secretase inhibitors (GSIs), myeloma cell lines and patient myeloma cells increased surface BCMA. GSI treatment also increased the recognition of myeloma cells by CAR T cells in vitro. In a mouse model of myeloma, GSI combined with BCMA CAR T cells increased antitumor efficacy and survival as compared to BCMA CAR T cells alone. Moreover, three patients with refractory multiple myeloma who were treated with a GSI showed markedly increased BCMA expression as well as an increase in the percentage of BCMA+ cells, demonstrating that this approach can be used to increase antigen density in heavily pre-treated patients.

What are the next steps for the research?

A first-in-human clinical trial in which a γ-secretase inhibitor is combined with BCMA-specific CAR T cells is currently ongoing at Fred Hutch/SCCA to evaluate whether increased antigen expression leads to improved long-term outcomes.

This work was funded by:

This research was supported by a gift from Bard Richmond; grants from the National Institutes of Health and Multiple Myeloma Opportunities in Research and Education; and research funding from Juno Therapeutics, a Celgene company.

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