Preclinical GEM and GDA Models of Primary and Metastatic Melanoma

Division Of Basic Sciences - Nci

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Abstract

As an essential part of the collaborative program with Dr. Glenn Merlino's laboratory at the NCI, we have previously developed several immunocompetent allograft models for metastatic melanoma that appeared sensitive to immune checkpoint blockade (ICB) with an anti-CTLA-4 antibody. This collaboration included an NCI CRADA to evaluate sensitivity to AstraZeneca's proprietary mouse anti-PD-L1 antibody in the Hgftg;Cdk4R24C/R24C GEM-derived allograft model. This antibody (designated clone 80) is the mouse isotype IgG1 engineered to correspond to durvalumab, carrying the D265A mutation to minimize Fc receptor interaction and tumor cell apoptosis. Consistent with clinical observations for ICB in melanoma, anti-PD-L1 treatment elicited complete and durable response in a subset of melanoma-bearing mice, mirroring the comparable subset of patients with melanoma that respond to the same immunotherapeutic intervention. We have pursued additional internal research into early treatment assessment. We analyzed gene expression profiles, T-cell infiltration, and TCR signatures in regressing tumors compared with tumors exhibiting no response to anti-PD-L1 treatment. Successful anti-PD-L1 antibody treatment response in melanoma required infiltration of CD8-positive T cells, a gene signature of immune activity, and recruitment of a diverse pool of TCR rearrangements with selective increase in productive frequency. TCR blood and tumor sequence data indicated that a positive anti-PD-L1 response in melanoma results in expansion of the TCR CDR3 repertoire to generate a rich TCR set of diverse clonotypes, but analysis of TCRs in blood only does not reflect the true diversity of clones present in responder tumors. The diversified TCR clonotype repertoire we identified in tumors, published in Molecular Cancer Res., proved to be essential for targeting the multitude of neoantigens that are expressed on tumor cells. Moreover, we found that Hgftg;Cdk4R24C/R24C tumors exhibited a recurrent non-uniform response to anti-PD-L1 that will be useful for evaluation of potential combination immunotherapies to increase the number of mice with durable response and prevent relapse.