Abstract 1617: Systematic evaluation of Cloudman S91 and YUMM1.7 murine melanoma models to immunotherapy and focal radiation
Authors: Urs Sumithra , Germain Derrik , Nelson Olivia , Kucharczyk Lauren , Draper David , Barnes Sheri 
Published: June 2022

In the preclinical setting, the B16-F10 syngeneic melanoma model is commonly used but is highly refractory to most immunomodulators, limiting the applicability of this model. To expand our offerings of melanoma models beyond B16-F10, we have characterized two syngeneic melanoma models - Cloudman S91 and YUMM1.7, for preclinical oncology studies. Our in vivo (immune-oncology and radiation) and in vitro (flow cytometry) analyses establishes that Cloudman S91 is a more responsive model compared to YUMM1.7. The two models were evaluated for their responses to immune modulatory agents and focal radiation. Single agent treatment of established Cloudman S91 tumors with checkpoint inhibitors (CPI) anti-mPD-1 and anti-mPD-L1 resulted in 116% and 41% increase in time to progression (%ITP) respectively. Treatment with anti-mCTLA-4, on the other hand, resulted in over 283% ITP with 20% tumor free survivors (TFS). Contrastingly, YUMM1.7 had no response to checkpoint blockade. These results indicate Cloudman S91 as a more responsive model to checkpoint blockade compared to YUMM1.7. Both models were found to be sensitive to focal beam radiation (RT) delivered using the Small Animal Radiation Research Platform (SARRP; Xstrahl) resulting in dose dependent tumor growth delay in both models. In order to determine if the addition of CPI to RT could improve the outcome, we tested anti-mPD1 in combination with RT at 5Gy. Both models had improved response to combination treatment, with YUMM1.7 showing a 43% ITP and the Cloudman with &gt;350% ITP over untreated controls and 15% and 170% over RT single treatment. Analysis of untreated tumors by flow cytometry shows that both tumor models have a large myeloid population and relatively low lymphoid infiltrate. Changes in immune profiles upon treatment with anti-mPD1 and RT or in combination were further analyzed. Notably, RT treatment alone increased CD8+ T cell infiltration and decreased the M2 macrophage infiltration to the tumors resulting in a less immunosuppressive tumor microenvironment. In the combination groups, this microenvironment enhances the response to immunotherapy as seen in the improvement in activity compared to RT alone. Here we demonstrate the varying responses within the same histotype to similar treatments to help in drug discovery programs. Combination of radiotherapy with immunotherapy offers benefits of modulating immune cells and enhancing the local and potentially abscopal effects of immunotherapy in both the Cloudman S91 and YUMM1.7 melanoma models. These characterizations can be useful in guiding model selection of murine melanoma and can inform rational combination treatment approaches for data driving decisions in drug development.

Citation Format: Sumithra Urs, Derrik Germain, Olivia Nelson, Lauren Kucharczyk, David Draper, Sheri Barnes. Systematic evaluation of Cloudman S91 and YUMM1.7 murine melanoma models to immunotherapy and focal radiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1617.