BioXcel Therapeutics’ immuno-oncology candidate BXCL701 was shown to enhance the anti-tumor effects of immune checkpoint inhibitors in prostate models, according to an Oct. 5 poster session at the 24th Annual Prostate Cancer Foundation Scientific Retreat in Washington, D.C.
The company reported recent findings from multiple studies showing that BXCL701 — a dipeptidyl peptidases (DPP) inhibitor — could inhibit tumor growth by increasing pro-inflammatory protein levels and immune-cell modulation in a series of cancer models.
The drug achieves this effect by inhibiting DPP8/9 and Fibroblast Activator Protein (FAP), which affect neuroendocrine prostate cancer (NEPC) at different stages of disease progression.
The poster, “Synergy Between [BXCL701], a DPP Inhibitor, and Immune Checkpoint Inhibitors Discovered Using AI and Big Data Analytics,” was presented by Vince O’Neill, chief medical officer of BioXcel, which is based in Branford, Connecticut.
“We had previously identified the tremendous potential of BXCL701 as a tumor inhibitory agent in castration-resistant prostate cancer (CRPC),” O’Neill stated in a press release. “Mechanistic studies suggest that BXCL701 also has potential to induce anti-tumor effect in NEPC, an aggressive tumor type observed in roughly 20-30% of patients treated with androgen inhibitors, Zytiga and Xtandi (ADT).”
O’Neill added that BXCL701 modulates the activity of multiple immune pathways, including stimulator of interferon genes (STING), indoleamine 2,3-dioxygenase (IDO) and the CXCL12/CXCR4 axis, which are known to play a role in the progression of CRPC and NEPC.
“This represents a unique opportunity for advancing the treatment of these patients,” he said. “Our plan is to initiate an open-label proof of concept trial to further understand the clinical activity of BXCL701 as monotherapy and in combination with Keytruda in NEPC patients.”
At an April 2017 presentation during the American Association for Cancer Research (AACR) 2017 Annual Meeting in Washington, the company reported that BXCL701 works in two ways: by targeting the fibroblast activator protein, which inhibits immuno-suppressive fibroblasts within tumor, and by interacting with the tumor blood vessels, helping immune cells enter the tumor tissue.
The candidate’s mechanisms of action could hold promise when combined with immune checkpoint inhibitors, researchers say, as data suggests that BXCL701 was able to transform the immuno-suppressive tumor microenvironment into an immuno-permissive one, complementing the action of a next-generation of PD-1 inhibitors in an animal model of colon cancer.
Because BXCL701 also targets DPP8/9 proteins — which reduce the immunosuppressive activity of tumor-infiltrated myeloid-derived suppressor cells — BXCL701 could also represent a promising approach for men with CRPC who have high levels of DDP8 and DDP9.
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