American Association for Cancer Research (AACR) 2020 Virtual Meeting II – Abstract
STRO-002, An Anti-FolRα ADC, Demonstrates Immune-Modulating Properties and Potentiates PD-L1 Blockade
Millicent Embry*, Sihong Zhou*, Christine Cheng, Janice Yu, Cristina Abrahams, Xiaofan Li, Jeff Hanson, Cuong Tran, Gang Yin, Shamim Ahmad, Krishna Bajjuri, Venita DeAlmeida, Mark Lupher, and Trevor Hallam
* Contributed equally
There is growing evidence that tumor-targeted cytotoxins can also enhance anti-tumor immunity by inducing immunogenic cell death (ICD) in tumor cells and promoting recruitment of immune effector cells. We sought to investigate the immune stimulating potential of STRO-002, an antibody drug conjugate (ADC) composed of an anti-Folate receptor alpha (FolRα) antibody conjugated to a tubulin-targeting hemiasterlin warhead via a cleavable linker. FolRα is a single chain glycosylphosphatidylinositol-anchored membrane receptor glycoprotein with minimal expression in normal tissues. Its overexpression in several cancer indications has been described, including in ovarian, endometrial, non-small cell lung carcinoma (NSCLC), and triple negative breast cancer (TNBC), thus making it an ideal ADC target. We have previously demonstrated potent in vitro and in vivo activity of STRO-002 in several FolRα expressing models. Here we show that the hemiasterlin warhead, SC209, and STRO-002 ADC induced ICD in vitro as evidenced by presentation of cell-surface calreticulin and release of HMGB1 and ATP. As a result of ICD, STRO-002 treated FolRα positive cancer cells induced antigen-dependent monocyte activation, as well as, increased phagocytic activity in PBMCs co-cultured with tumor cells. To determine if these immunogenic properties could improve therapeutic efficacy, we evaluated STRO-002 in combination with the immune checkpoint inhibitor Avelumab (anti-PD-L1) in a mouse syngeneic MC38 model engineered to express human FolRα (MC38-hFolRα). Results showed that STRO-002 and Avelumab alone inhibited tumor growth and could induce complete responses (e.g. no palpable tumors) at low frequency (< 15%), while co-administration of STRO-002 and Avelumab significantly enhanced efficacy leading to complete response in the majority of animals. Furthermore, when animals that initially achieved complete response were re-challenged with MC38-hFolRα cells, they showed durable anti-tumor immunity, indicating formation of immunological memory. Immunohistochemical analysis conducted seven days after treatment revealed a significant increase in tumor-infiltrating cytotoxic CD8+ T cells in animals treated with combination of STRO-002 + Avelumab versus either monotherapy. Cumulatively, these results suggest that STRO-002 synergizes with Avelumab to enhance anti-tumor response by inducing ICD in tumor cells, which in turn, promote T cell recruitment. These data support the rationale for combining STRO-002 with immune checkpoint inhibitors to potentially enhance their clinical efficacy.