Abstract LB-077: Dipeptidyl Peptidase Inhibitor BXCL701 synergizes with an OX40-agonist antibody resulting in synergistic anti-tumor response and survival in an animal model of colorectal cancer by bridging the innate and adaptive arms of the immune system
Authors: Agarwal Veena R. , MacDougall John , Bhatia Dimple , Gupta Snigdha , Zagga Zeenia , keshava Nirmal 
Published: August 2019

The oral DPP8/9 and FAP inhibitor BXCL701 in combination with an anti-PD-1 antibody (aPD-1) has demonstrated inhibition of tumor growth as well as up-regulation of immuno-stimulatory cytokines and tumor-infiltrating immune cells in animal models [AACR 2017, ASCO 2018]. In the present study, the primary cytokines/chemokines influenced by BXCL701 administered as a single agent have been explored and provide the rational for an efficacy study of BXCL701 in combination with an OX40-agonist antibody (aOX40). Cytokines/chemokines were evaluated in serum samples from animals in an acute PK/PD study revealing that BXCL701 stimulated several pro-inflammatory factors. The most stimulated cytokine was IL-18 which is known to bridge the innate and adaptive immune systems through induction of IFN-γ and the CD134 (OX40) pathway. (J of Immunol, 2006, 177: 234). Therefore, an in vivo study was conducted by combining BXCL701, aOX40 and aPD-1 in a preclinical model (MC38) of colorectal cancer. Evaluation of tumor size on day 23 compared to vehicle control showed aOX40 and BXCL701 treated animals to have tumor growth inhibition (TGI) of 0.8% (p = 0.97), and 8% (p = 0.61) respectively. Importantly, BXCL701 in combination with aOX40 resulted in synergistic inhibition of 51% (p = 0.001) when compared to vehicle. A 43% TGI (p = 0.006) was observed in animals treated with the combination of aPD-1 and aOX40. Addition of BXCL701 to the double combination of aOX40 and aPD-1 resulted into 59% TGI (p = 0.0005). At study end, BXCL701 demonstrated a significant improvement in the survival of animals when combined with aOX40. The median survival of vehicle treated animals was determined to be 30 days. BXCL701 and aOX40-treated animal groups had median survival of 35 days and 29 days, respectively (BXCL701 vs Vehicle p = 0.0958, aOX40 vs Vehicle p = 0.8560). The median survival of animals treated with combination of BXCL701 and aOX40 was significantly increased to 46 days in comparison to BXCL701 alone (p &lt; 0.0001), while combination of aPD1 and aOX40 treated animals had a median survival of 36 days (aPD-1 and aOX40 vs Vehicle p = 0.0991). The triple combination of BXCL701, aOX40 and aPD1 resulted in the median survival of 46 days (p &lt; 0.0001 vs Vehicle). In conclusion, the inclusion of BXCL701 in the drug combinations was necessary for a survival benefit because while the aOX40 and aPD-1 combination showed a significant TGI on day 23, this did not translate into an overall survival benefit. Therefore, BXCL701 contributed to a clear synergistic anti-tumor and survival response within the combinations. Ostensibly, BXCL701-regulated cytokines are responsible for the observed synergism with anOX40 treatment. The present study suggests the clinical evaluation of BXCL701 in combination with an OX40-agonist in solid tumors.

Citation Format: Veena R. Agarwal, John MacDougall, Dimple Bhatia, Snigdha Gupta, Zeenia Zagga, Nirmal keshava. Dipeptidyl Peptidase Inhibitor BXCL701 synergizes with an OX40-agonist antibody resulting in synergistic anti-tumor response and survival in an animal model of colorectal cancer by bridging the innate and adaptive arms of the immune system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-077.