Translational studies of metastatic melanoma in the era of immunotherapy - from humanized mouse models to clinical trials

Sammanfattning: Immunotherapy with PD-1 inhibitors has transformed the treatment of met-astatic cutaneous mela- noma, and can lead to complete and durable responses in a proportion of patients. However, in around half of the patients, the treatment has little or no effect. In patients with metastatic uveal melanoma, a rare form of melanoma arising in the eye, effective treatments are lacking altogether. The overall aim of the research on which this thesis is based, is to develop and utilize mouse models to identify new immunotherapies for pa-tients with metastatic melanoma. In paper I we describe the development of a novel immune humanized pa-tient derived xenograph (PDX) model. The PDX is based on sequential transplantation of ex vivo expanded, autologous tumor infiltrating lympho-cytes (TIL), and mirror the treatment effects seen in corresponding pa- tients. In paper II we evaluate the feasibility and preclinical efficacy of chimeric anti-gen receptor (CAR)-T cell therapy in melanoma and find that CAR T cells against HER2 are able to kill human cutaneous and uveal melanoma cells in vitro and in vivo. In paper III we first assess the rationale of combined epi-genetic modulation and PD-1 inhibition in experimental melanoma, and show that the histone deacetylase (HDAC) inhibitor entinostat increases expression of HLA-I and PD-1 on mela- noma cell lines and enhances the effect of a PD-1-inhibitor in vivo. Next, we describe the design and preliminary results of an ongoing phase II trial evaluating the effect of entinostat in combination with pembrolizumab (a PD-1 inhibitor) in patients with metastatic uveal mel-anoma. In conclusion, this thesis shows that i) PDX models can be used to study key aspects of the human antitumoral immunity in melanoma; ii) that HER2 CAR-T cells represent a potential future treatment for metastatic melanoma refractory to other immunotherapies; and iii) that entinostat increases HLA- I expression and potentiates the effect of PD-1 inhibition in melanoma models, and that the same combination can result in clinical efficacy with manageable toxicity in patients with metastatic uveal melanoma.

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