Andrew J. Cowan, MD, Discusses the Phase I Clinical Trial of GSI and BCMA CAR T-Cells

Article

The expert explained the rationale for the phase I first-in-human clinical trial evaluating the combination of a gamma-secretase inhibitor and B-cell maturation antigen CAR T-cells in patients with heavily pretreated multiple myeloma.

Andrew J. Cowan, MD, from the University of Washington, spoke about the rationale for the phase I first-in-human clinical trial evaluating the combination of a gamma-secretase inhibitor (GSI) and B-cell maturation antigen (BCMA) CAR T-cells in patients with heavily pretreated multiple myeloma. 

Results from this trial, which were presented at the 61st American Society of Hematology (ASH) Annual Meeting & Exposition, held in Orlando, Florida, from December 7-10, 2019, revealed promising responses. The best overall response rate (ORR) was 100% among 6 evaluable patients who received the GSI JSMD194 and BCMA CAR T-cells. This included 5 exceptional partial responses (PRs) and 1 PR. Additionally, 5 patients achieved minimal residual disease negativity by way of flow cytometry and no patients relapsed as of the data cutoff date of July 15, 2019. 

Transcription:

So, as many are likely aware, one of the more common targets for CAR T-cells in multiple myeloma is a plasma cell surface protein called BCMA. And BCMA is almost routinely expressed on the surface of plasma cells. We know from prior research that there is a cell membrane protein called gamma-secretase that is involved with cleavage of BCMA off of the surface of plasma cells. We have done preclinical work that has shown that using a class of medications called gamma-secretase inhibitors, which were actually originally developed for use in Alzheimer’s dementia, we can block the action of gamma-secretase and increase BCMA expression on the surface of plasma cells and reduce soluble BCMA. And, when given in combination with BCMA CAR T-cells, we hypothesized that this might potentially increase the antitumor efficacy of BCMA CAR T-cells. 

Reference:

Cowan AJ, Pont M, Sather BD, et al. Efficacy and Safety of Fully Human Bcma CAR T Cells in Combination with a Gamma Secretase Inhibitor to Increase Bcma Surface Expression in Patients with Relapsed or Refractory Multiple Myeloma. Presented at: 2019 ASH Annual Meeting and Expo; December 7-10, 2019; Orlando, FL. Poster 204. 

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