Both targeted therapy and immunotherapy have shown great promise for the treatment of cancer patients, but neither approach results in durable success in the majority of patients. The combination of targeted therapies with immunotherapies has the potential to result in higher, more durable clinical responses and improved survival in patients with metastatic cancer. Besides inducing the release of antigens following tumor destruction, targeted therapies may also reverse the immunosuppressive microenvironment found at the tumor site. In previous studies, we found that BRAF inhibition enhances T-cell infiltration into tumors, partially by downregulating VEGF at the tumor site (CCR, Liu et al 2013). In addition, we have found other combinations in murine models that are effective, such as dasatinib plus anti-OX40 antibody in c-kit positive tumors (Blood, Yang et al 2012). Recently we reported that PTEN loss in tumors results in less infiltration by T-cells, and lower responses to anti-PD1 therapy in advanced melanoma patients (Cancer Discovery, Peng et al 2016). Importantly, this could be overcome in murine models using a combination of PI3K beta inhibitor and anti-PD1, a concept which will be tested in the clinic. We are now utilizing a high throughput screen of more than 1000 compounds to determine which can most effectively enhance the ability of tumor-specific T-cells to kill autologous tumor (poster #341). This screen evaluates tumor death using flow cytometry to detect intratumoral activated caspases 3 and 7, since T-cells kill using a caspase-dependent apoptotic pathway. Positive candidates are then confirmed and tested in murine tumor models. We are also evaluating the molecular basis of immune resistance using a similar in vitro screen as well as an in vivo screen with tumor cells transduced with shRNA libraries. Positive candidates will be tested for expression utilizing our banked samples from responding and non-responding patients who have received tumor-infiltrating lymphocytes (TIL). Using these screens we have thus far determined that the aurora kinase inhibitors, topoisomerase I inhibitors (poster #214), and HSP90 inhibitors (poster #276) enhance T-cell based immunotherapies. We are evaluating the mechanisms of action of these combination therapies. HSP90 inhibitors enhance anti-CTLA4 activity due to a mechanism involving the interferon response genes, for example. We have also found that altering metabolic pathways (eg, inhibiting glycolysis) in tumor cells enhances antitumor immune responses. In summary, we are currently performing high throughput screens to determine the best agents to combine with immunotherapy strategies, as well as molecular determinants of immune resistance.
Citation Format: Weiyi Peng, Rina Mbofung, Leila Williams, Patrick Hwu. Rational combinations of targeted and immunotherapies [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr IA19.
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