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BCMA CAR T Cells Response in Myeloma Improved by Gamma Secretase Inhibitor

May 19, 2020 12:09:00 PM / by Stacy Matthews Branch, DVM, PhD

Hands in hands close up_AdobeStock_294430178-1A clinical trial targeting BCMA CAR-T cells with GSIs shows promising results for patients suffering from multiple myeloma.

Multiple myeloma (MM) is a plasma cell cancer that has affected an estimated 32,110 people in the US in 2019 according to the National Cancer Institute. About a half million people worldwide have this disease. Due to the progressive and mutational nature of MM, it remains difficult to treat successfully. Studies to better understand the mechanisms involved in MM progression are needed to inform what therapeutic approaches would best provide effective treatment for MM.

It is known that the B-cell maturation antigen (BCMA) is a cell surface receptor that is expressed on plasma cells and functions to maintain plasma cell homeostasis. Studies have revealed that gamma-secretase–mediated cleavage sheds BCMA from the plasma cell surface leading to the production of soluble BCMA. Patients with MM have higher concentrations of soluble BCMA and poorer outcomes, possibly due to increased proliferation and survival of MM cells. Therefore, targeting BCMA may represent a promising approach to treat MM.

Treatment with chimeric antigen receptor T cells (CAR-T cells) that target BCMA has shown positive responses; however, relapse occurs in most patients. In animal models, gamma secretase inhibitors (GSI) increase BCMA density on the plasma cell surface and decrease soluble BCMA levels. A clinical trial was conducted in patients with relapsed/refractory MM to determine the effect of GSI on plasma cell expression of BCMA. First, patient T cells were obtained and transduced to create BCMA CAR-T cells. The patients were treated with GSI for 5 days, and a bone marrow aspirate was taken by day 5 of the GSI treatment to measure BCMA expression on the plasma cells. The patients then received immunoablation chemotherapy followed by infusion of the BCMA CAR-T cells and another dosing with GSI.

The researchers observed a 100% overall response rate in patients receiving BCMA CAR-T with GSI treatment, and the patients did not experience relapses by the 20-week follow up period. The results are promising given the high and lasting responses even with lower CAR-T cell doses. A study with more participants comparing BCMA CAR-T alone and with GSI will provide additional valuable information regarding the efficacy of the GSI inclusion approach.

HemaCare’s GMP-compliant bone marrow aspirate facilitates clinical research for life-changing cell-therapy treatments.

Resource:

Gamma Secretase Inhibitor Improves Responses to BCMA CAR T Cells in Myeloma. (2020). Retrieved 14 April 2020, from https://www.targetedonc.com/news/gamma-secretase-inhibitor-improves-responses-to-bcma-car-t-cells-in-myeloma

 

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