PACM-04 ONCOLYTIC ADENOVIRUS RGDOX INDUCES SYSTEMIC CD8+ T CELL–MEDIATED IMMUNITY ACROSS INTRACRANIAL MELANOMA METASTASES: RATIONALE FOR A PHASE I TRIAL

Abstract

Amongst solid cancers, melanoma brain metastases (MBM) have the highest likelihood of metastasizing to the brain. The use of immune checkpoint inhibitors (ICI) has emerged as first line therapy; however, intracranial progression and acquired resistance highlight the need for novel immunotherapeutic strategies for this patient population. Oncolytic viral (OV) therapy leverages tumor cell replication machinery to selectively replicate and kill tumor cells while promoting anti-tumor immunity. The oncolytic adenovirus Delta-24-RGDOX (RGDOX) has been shown to function as a TME modulator in both preclinical and clinical settings. Here, we investigated the anti-tumor efficacy of RGDOX combined with ICIs in synchronous extracranial—intracranial (s.c.-i.c.) and intracranial—intracranial (i.c.-i.c.) murine melanoma models (B16F10 and D4M). Using this approach, we inoculated the s.c. (s.c.-i.c. model) or i.c. (i.c.-i.c.) tumor with RGDOX and monitored for viral induced cytotoxicity within the infected tumor while assessing for the simultaneous generation of intracranial antitumor immunity against the uninfected tumor. The combinatorial strategy of RGDOX with PD-1/CTLA-4 inhibition significantly reduced tumor growth within the infected and distant intracranial tumor while also improving survival in tumor bearing mice. Through a series of immune depletion experiments, therapeutic efficacy was determined to be mediated through CD8+ T cells. Additionally, eradication of subcutaneous tumor led to immunologic memory preventing intracranial tumor formation. Immunophenotyping and spatial profiling demonstrated that treatment boosted anti-tumor immunity in both infected and uninfected intracranial tumors through enhanced T-cell activity, and increased infiltration of both dendritic cells and inflammatory macrophages. In contrast, immunosuppressive populations were reduced in both infected tumors and uninfected intracranial tumors following treatment. These findings provide the foundation for our trial—Dose Ranging, Toxicity Seeking, Phase 1 Trial of Oncolytic Adenoviral Therapy for Melanoma Intracranial and Extracranial Metastases (NCT07444606)—and suggest oncolytic viral therapy is a promising therapeutic approach for the generation of antitumor immunity against MBM.