Gamma secretase inhibitors (GSIs), initially promising for enhancing BCMA-targeted CAR T-cell therapy in multiple myeloma (MM), exhibit complex and nuanced effects on bone marrow cells, according to a new study. Researchers from the University of Miami and Fred Hutch Translational Science and Therapeutics division found that GSIs induce significant changes in gene expression across various bone marrow cell types, impacting tumor cell survival and immune cell function. These findings suggest both potential benefits and risks associated with GSI use in MM treatment, warranting careful consideration of patient selection and treatment strategies.
Broad Impact on Gene Expression
The study, led by Dr. David Coffey and Dr. Damian Green, involved single-cell RNA sequencing and ATAC sequencing of bone marrow samples from MM patients before and after GSI treatment. The analysis revealed that GSI therapy significantly altered the expression of 567 genes across 20 different cell types. This indicates that the effects of gamma secretase inhibition extend beyond simply increasing tumor cell death. "We have to be careful…there are a lot of off-target effects that we need to be aware of, and that’s really what this study brings to light," said Coffey.
BCMA Modulation and Signaling
GSIs target BCMA, increasing its surface expression on cells, which can enhance the efficacy of BCMA-targeted CAR T-cells. However, the study also found that GSI treatment increased the expression of genes downstream of BCMA that are involved in cell survival and proliferation within MM cells. This suggests that while GSIs can enhance CAR T-cell therapy, they may also inadvertently promote tumor growth if used as a monotherapy. "There should be some caution in [using GSIs as a monotherapy] because there could be some proliferative effects on the tumor cells," Coffey cautioned.
Impact on Monocytes and Immune Response
Interestingly, the researchers observed that GSI treatment decreased the number of non-classical monocytes in the bone marrow. These monocytes promote tumor growth by releasing cytokines that support MM cell survival. When monocytes treated with GSIs were tested for their ability to support tumor growth, they produced significantly fewer cytokines. This suggests that GSIs could provide an additional therapeutic benefit by modulating the immune response and reducing the support that monocytes provide to cancer cells.
Implications of Prior Anti-BCMA Therapy
The study also shed light on the effects of GSIs in patients who had previously received anti-BCMA therapies, a group often excluded from initial clinical trials. The researchers found that in two patients with prior anti-BCMA therapy, the BCMA coding region in the genome was completely deleted. "While GSIs have great potential, if the patient has a deleted BCMA gene, it’s going to have no [BCMA-specific] effect," Coffey explained. This finding underscores the importance of genetically screening patients to ensure their BCMA gene is intact before initiating GSI treatment.
Future Directions
These findings highlight the complex and sometimes contradictory effects of GSIs in the treatment of multiple myeloma. While GSIs can enhance BCMA-targeted therapies and modulate immune responses, they also carry the risk of promoting tumor cell survival and may be ineffective in patients with BCMA gene deletions. Future research will focus on further elucidating the precise molecular effects of GSI treatment on myeloma cells to optimize their use in combination therapies.
