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TMOD-05. EXTRACRANIAL TUMORS INFLUENCE INTRACRANIAL RESPONSE TO IMMUNE CHECKPOINT INHIBITORS IN PRE-CLINICAL MODELS OF MELANOMA BRAIN METASTASIS


 Melanomas frequently spread to the brain, with up to 75% of patients developing brain metastases. Treatment of metastatic melanoma has been revolutionized by the advent of immune checkpoint inhibitors (ICI) targeting PD-1 and CTLA-4. However, responses to ICI within the immune-specialized brain environment are not well understood owing to the lack of immunocompetent animal models for the investigation of intracranial responses to checkpoint blockade. We studied the effect of ICI in a syngeneic mouse model of melanoma brain metastasis with concurrent intracranial and subcutaneous tumors. Either D3UV3 cells, derived from a UVB irradiated clone of D4M.3A melanoma cell line, or vehicle were subcutaneously injected into the flank of C57BL/6 mice. 3 days later, D3UV3 cells tagged with firefly luciferase were implanted into the striatum using stereotactic injection. Mice were then treated with anti-PD-1 antibody, anti-CTLA-4 antibody, a combination of anti-PD-1 and anti-CTLA-4 antibodies, or isotype controls. We observed striking differences in survival between mice with concurrent intracranial and subcutaneous tumors compared to intracranial tumors alone. Mice with intracranial tumors alone experienced no benefit in survival following monotherapy with anti-PD-1 (p=1) or anti-CTLA-4 (p=0.1) compared to isotype-treated mice, and only a slight benefit with combination treatment (p=0.049). In contrast, mice with concurrent tumors experienced a significant increase in overall survival with anti-CTLA-4 monotherapy (p=0.01) and combination anti-CTLA-4 and anti-PD-1 treatment (p=0.01) compared to isotype-treated mice, although treatment with anti-PD-1 alone did not increase survival (p=0.28). These results indicate that the presence of extracranial disease can modulate intracranial immune responses following checkpoint blockade. We have therefore established a pre-clinical model with concurrent intracranial and extracranial tumors to better recapitulate the clinically observed context of brain metastases. We hope this model will lead to a better understanding of the setting in which ICI is effective for patients with melanoma brain metastases.