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.
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.
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.