Combining BioXcel‘s BXCL701 with immune checkpoint inhibitors may potentially help treat men with castration-resistant prostate cancer (CRPC), says the Branford, Conn., pharma company.
Dr. Luca Rastelli, BioXCel’s vice-president for oncology research and development, presented the poster, “The synergy between BXCL701, a DPP inhibitor, and immune checkpoint inhibitors discovered using AI and Big Data analytics,” April 3 at the American Association for Cancer Research (AACR) 2017 Annual Meeting in Washington, D.C.
“BXCL701, our first-in-class small molecule immuno-modulator, stimulates a pro-inflammatory, anti-tumor cellular response that is complementary to the one mediated by immune-checkpoints,” Rastelli said in a press release. “In addition, genomic data analysis of patients with CRPC showed that BXCL701 molecular targets are upregulated in patients previously treated with the androgen deprivation therapies enzalutamide or abiraterone. These data support our plan to develop BXCL701 as a monotherapy and in combination with immune-checkpoint inhibitors in advanced CRPC.”
BXCL701 is an immunotherapy with two mechanisms of action: it targets the fibroblast activator protein, which inhibits immuno-suppressive fibroblasts within tumors, and interacts with the tumor blood vessels, helping immune cells enter the tumor tissue. Fibroblasts are connective tissue cells that are often co-opted by cancer cells to help the tumor grow.
BXCL701 also targets DPP8/9 proteins, which reduces the immunosuppressive activity of tumor-infiltrated myeloid-derived suppressor cells.
BioXcel researchers hypothesized that BXCL701 mechnisms of action would make it a promising therapy to combine with immune checkpoint inhibitors. Their data shows that BXCL701 did, in fact, transform the immuno-suppressive tumor microenvironment into an immuno-permissive one, complementing the action of a next-generation of PD-1 inhibitors in a mouse model of colon cancer.
Further findings revealed that CRPC men often have high levels of DDP8 and DDP9, suggesting that this population could be uniquely sensitive to the combination approach.
“These findings show that BXCL701 in combination with an anti-PD1 agent may demonstrate clinical benefit in patients that do not respond to ICI therapy,” said Rastelli. “Moreover, BXCL701 has broad potential to combine with other checkpoint inhibitors and therapeutic modalities including vaccines and cellular therapies.”
Rastelli was invited to discuss the findings at the AACR conference’s “Targeted Immunotherapeutics Interactome: Beyond Checkpoint Inhibitors” session.