Abstract
γ-Secretase inhibitors with BCMA CAR-T therapy improved survival in a multiple myeloma mouse model.
Major Finding: γ-Secretase inhibitors with BCMA CAR-T therapy improved survival in a multiple myeloma mouse model.
Mechanism: γ-Secretase cleaves BCMA on cell surfaces; thus, γ-secretase inhibitors increase BCMA density.
Impact: A clinical trial combining γ-secretase inhibitors with BCMA CAR-T therapy is now under way.
Although chimeric antigen receptor T (CAR-T) cell therapies represent a major advance in the treatment of several cancers, limitations include the fact that cancer cells in some patients may not highly express the target molecules on their surfaces and that relapse may occur with antigen-low disease. Pont and colleagues developed a strategy for the treatment of multiple myeloma with a B-cell maturation antigen (BCMA)–based CAR-T therapy combined with drugs intended to increase the density of BCMA on the surfaces of cancer cells. The experimental drugs are inhibitors of γ-secretase, an enzyme that cleaves BCMA on the cell surface, thus reducing BCMA density. Treatment of myeloma cell lines and patient-derived myeloma cells with γ-secretase inhibitors (GSI) dose-dependently increased the amount of BCMA on the surfaces of the cancer cells and decreased the concentration of the soluble portion of BCMA—which may act as a decoy for BCMA-directed CAR-T cells—that is released upon γ-secretase cleavage. GSI treatment also increased the recognition of cancer cells by CAR-T cells in vitro. These effects were replicated in mice engrafted with multiple myeloma cells. In the same mouse model, by the time all mice receiving BCMA-directed CAR-T cells alone had died due to disease progression, 60% of the mice treated with the CAR-T cells plus a GSI remained alive. Preliminary experiments involving three patients with refractory multiple myeloma revealed that GSI treatment also increased BCMA expression on the surface of the cancer cells by a median of 33-fold and raised the percentage of BCMA+ cancer cells from a median of 27.5% to 99.3%. Based on these results, it may be possible to improve the number of patients who can benefit from this CAR-T therapy and prevent relapse due to low antigen–expressing cells, and the authors have begun a clinical trial combining GSI with BCMA-directed CAR-T cells.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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