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. In the recent round of experiments, two GEM-derived allograft models prepared from metastatic lesion sites and featuring clinically relevant aberrations in either BRAF or HGF/MET pathways have been characterized in terms of tumor latency in corresponding GDA allografted animals, severity of primary disease, incidence of metastasis, as well as rate and velocity of tumor recurrence upon surgical resection. These studies enabled to determine characteristic disease timelines in both models thus preparing these preclinical tools for evaluation of melanoma therapeutics in adjuvant and neo-adjuvant settings. Anti-PD-1 efficacy experiments have been completed in both models, as well as a follow-up efficacy experiment with PD-L1 blockade therapy conducted on small early measurable primary tumors in one of the aforementioned models. All studies have been complemented by a full biomarker evaluation and analysis of tumor infiltrating immune system landscapes and alteration thereof by examined immuno-oncology intervention modalities.