Antibodies derived from patient tumors augment response to immune checkpoint blockade in cancer 3582

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Abstract Description Background B-cells and Tertiary Lymphoid Structures (TLS) are associated with response to Immune Checkpoint Blockade (ICB) but their functional role remains unexplored. Here, we evaluate the therapeutic efficacy of tumor-derived antibodies in combination with ICB-based regimen. Methods and Results Tumors from ICB-treated melanoma patients were analyzed. Major pathologic response (MPR) was used to evaluate response (R – responder; NR – non-responder). TLS were analyzed on GeoMx which revealed distinct transcriptional states by response (r = 0.88, p < 0.0001). R-TLS were enriched for CD8+ T-cells, NK cells, memory B-cells and NK-cell cytotoxicity pathways (p < 0.05). BCR sequencing of patient specimen (R = 9, NR = 3) yielded 546 unique antibodies. R-BCR had enhanced somatic hypermutation (p = 7.2e-9) and isotype switching (50.1% R vs 32.6% NR). Flow cytometry identified 73 antibodies that bound A375 human melanoma cells. Antibody dependent cell cytotoxicity (ADCC) assay identified 10 melanoma-binding antibodies that induced significant cell death of A375 and BP murine melanoma cells. In vivo experiments identified 4 ADCC+ antibodies that homed to BP tumors with systemic delivery. One clone, RAPC5-7-156, synergized with αPD-L1 to reduce BP tumor growth compared to isotype (p = 0.0003) and α-PD-L1 only (p = 0.005). Conclusion Tumor-derived antibodies are capable of augmenting response to ICB. This presents new opportunities for tumor target discovery and for improving clinical outcomes to ICB. Funding Sources This work is supported by the Mark Foundation for Cancer Research (#AWD00005025 to J. Wargo, K. McBride, T. Cascone, and T. Bruno) and the Adelson Medical Research Foundation (#04-7023433 to J. Wargo). Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

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