Melanoma is a highly aggressive form of skin cancer, whose rates of morbidity and mortality are continuously increasing. The development of immunotherapeutic agents like anti-PDL1 and anti-CTLA4 antibodies has resulted in fundamental advances in the treatment of melanoma. However, long lasting responses are only observed in a small subset of immunotherapy-treated melanoma patients. This shortfall highlights the need for a better understanding of the molecular mechanisms that govern tumor sensitivity or resistance to immunotherapy. To address this need, autologous patient-derived tumor cell lines and tumor infiltrating lymphocytes (TILs) were utilized in an in vitro activated caspase 3-based high-throughput screen, to identify compounds that increase the sensitivity of melanoma cells to T-cell mediated cytotoxicity. The screen consisted of a library of 850 bioactive compounds. One group of compounds that was most able to enhance T-cell killing of melanoma cells was topoisomerase I (Top1) inhibitors including: topotecan, and irinotecan.
Topoisomerases are a family of DNA enzymes, which are involved in unwinding DNA and relieving torsional strain during replication and transcription. Our results indicate that treatment of melanoma tumor cells with a Top1 inhibitor prior to exposure to autologous T cells, produced a synergistic increase in tumor cell death, as measured by intracellular staining of activated caspase 3, and computed using CalcuSyn. We have also recapitulated this finding in an in vivo model, where a better anti-tumor effect was observed in tumor- bearing mice treated with an antibody against the co-inhibitory molecule Programmed Death Ligand 1 (PDL1) in combination with a nanoparticle liposomal formulation of irinotecan, than in cohorts treated with either antibody or drug alone. These findings suggest synergism between Top1 inhibitors and immune-based therapies in the treatment of melanoma.
Genomic and proteomic changes elicited by inhibition of Top1 are now being investigated to identify the molecular factors that mediate the effect of Top1 inhibitors on T cell-mediated killing of melanoma. Our goal is to identify molecular changes mediated by Top1 inhibition in melanoma tumor cells, and/or the tumor microenvironment, that relieves immunosuppression and potentiates the activity of cytotoxic T cell-based immunotherapy.
Understanding how Top1 inhibitors enhance melanoma killing by immunotherapy will allow for the development of predictive biomarkers, and also augment immune-based therapeutic strategies to ensure durable responses in a larger population of melanoma patients. By using melanoma as a model disease system, we can gain valuable insights into the dynamics of cancer immune response that may be applied to other cancers where effective treatment strategies are also lacking.
Citation Format: Jodi A. McKenzie, Rina M. Mbofung, Shruti Malu, Patrick Hwu. Increasing the antitumor efficacy of immunotherapy in melanoma by using topoisomerase I inhibitors. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B152.