SITC'16 Abstracts published; here's the Joint MSKCC(Wolchok Lab)/PPHM Abstract #P194...
ABSTRACTS:http://resource-cms.springer.com/springer-cms/rest/v1/content/11027680/data/v1/Volume+4+Supplement+1+PDF+pt+2 I. P194/SITC’16/11-11-16(MSK+PPHM): “Phosphatidylserine Targeting Antibody in Combination with Checkpoint Blockade & Tumor Radiation Therapy Promotes Anti-Cancer Activity in Mouse Melanoma” AUTHORS: Sadna Budhu(MSKCC PRESENTING AUTHOR) 1, Olivier De Henau 2, Roberta Zappasodi 1, Kyle Schlunegger 3, Bruce Freimark 4, Jeff Hutchins 5, Christopher A. Barker 6, Jedd D. Wolchok 7, Taha Merghoub(Memorial Sloan Kettering SENIOR AUTHOR) BACKGROUND: Phosphatidylserine (PS) is a phospholipid that is exposed on the surface of apoptotic cells, some tumor cells and tumor endothelium. PS has been shown to promote anti-inflammatory and immunosuppressive signals in the tumor microenvironment. Antibodies that target PS have been shown to reactivate anti-tumor immunity by repolarizing tumor associated macrophages to a M1-like phenotype, reducing the number of MDSCs in tumors and promote the maturation of dendritic cells into functional APCs. In a B16 melanoma model, targeting PS in combination with immune checkpoint blockade has been shown to have a significantly greater anti-cancer effect than either agent alone. This combination was shown to enhance CD4+ and CD8+ T cell infiltration and activation in the tumors of treated animals. Radiation therapy is an effective focal treatment of primary solid tumors, but is less effective in treating metastatic solid tumors as a monotherapy. There is evidence that radiation induces immunogenic tumor cell death and enhances tumor-specific T cell infiltration in irradiated tumors. In addition, the abscopal effect, a phenomenon in which tumor regression occurs outside the site of radiation therapy, has been observed in both preclinical and clinical trials with the combination of radiation therapy and immunotherapy. METHODS: We examined the effects of combining tumor radiation therapy with an antibody that targets PS (1 N11)[Note: PGN635 (B2GPI-dep.) is Fully-Human Bavituximab=1N11=AT004 (B2GPI-depen.); Genentech studying 89Zr-PGN635 as a Tumor Imaging Agent, “indep. of cancer type”] and an immune checkpoint blockade (anti-PD-1) using the mouse B16 melanoma model. Tumor surface area and overall survival of mice were used to determine efficacy of the combinations. RESULTS: We examined the expression of PS on immune cells infiltrating B16 melanomas. CD11b + myeloid cells expressed the highest levels of PS on their surface whereas T cells and B16 tumor cells express little to no PS. These data suggest that targeting PS in B16 melanoma would induce a pro-inflammatory myeloid tumor microenvironment. We hypothesize that therapies that induce apoptotic cell death on tumor cells would enhance the activity of PS-targeting antibodies. We therefore examined the effects of combining a PS-targeting antibody with local tumor radiation. We found that the PS-targeting antibody synergizes with both anti-PD-1 and radiation therapy to improve anti-cancer activity and overall survival. In addition, the triple combination of the PS-targeting antibody, tumor radiation and anti-PD-1 treatment displayed even greater anti-cancer and survival benefit. CONCLUSIONS: This finding highlights the potential of combining these 3 agents to improve outcome in patients with advanced-stage melanoma and may inform the design of future clinical trials with PS targeting in melanoma and other cancers *end*
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