Overcoming androgen receptor-mediated prostate cancer resistance to immunotherapy

Metastatic prostate cancer is lethal with limited treatment options. Immunotherapy has significantly improved survival in patients a variety of solid tumors, however, only presented marginal efficacy in metastatic prostate cancer (mPCa) patients. There is a limited understanding of the de novo mechanisms of resistance to immunotherapy in prostate cancer. Thus, there is an unmet need to understand the mechanisms of resistance and to develop effective immunotherapies for mPCa. The activated immune cells kill cancer cells through a common mechanism by secreting a toxic chemical called “Granzymes”. Immune cell itself has a defense mechanism to prevent self-killing. In our preliminary studies, we fond that androgen receptor activation can produce a chemical called “SERPINB9”, which is a known inhibitor for Granzymes. We have initial proof-of-concept data from animal studies showing that prostate tumor cells engineered to express a lot of SERPINB9 are resistant to immunotherapy as compared to the original un-engineered prostate cancer cells that only express low levels of SERPINB9. Furthermore, we found an alternative pathway with an immune stimulatory antibody B10G5 to enable immune cell kill SERPINB9Hi prostate cancer cells independent of Granzyme B-mediated killing. Therefore, in this proposed study, our goal is to understand how androgen receptor activity enhances the expression of SERPINB9 and thus protection of prostate cancer from Granzyme-mediated immune cell killing and evaluate the therapeutic efficacy of B10G5 and co-targeting AR in pre-clinical prostate mouse models. Given that androgen-receptor activity is mostly specific to the prostate cancer, our observation would provide a novel and fundamental mechanism that explains why prostate cancer is resistant to immunotherapy. Given that the antibody B10G5 is currently in IND-enabling study as a first-in-class immunotherapy for all solid tumors, our study will have a significant impact on prostate cancer patients battling hormone-resistant diseases in the very near term, such as 3-5 years of term.