Intratumoral anti-CTLA-4 delivery by an oncolytic Vaccinia virotherapy virus elicits CD8+ T cell immunity and synergizes with anti-PD-1 to reject “cold” tumors

CTLA-4 is a clinically validated antibody target for cancer immunotherapy. Toxicity, which is linked to efficacy in available anti-CTLA-4 regimens has, however, restricted their use and precluded full therapeutic dosing. Here we describe and preclinically characterize a potentially safe and highly efficacious strategy to target CTLA-4. Intratumoral administration of an oncolytic Vaccinia virus, engineered to encode a novel Treg depleting, checkpoint-blocking, anti-CTLA-4 antibody and GM-CSF (VVGM-aCTLA4) achieved tumor-restricted CTLA-4 receptor saturation and Treg-depletion, and regressed diverse tumors spanning inflamed to immunologically ignorant microenvironments. Critically, intratumorally “ignited” antitumor immunity translated into stronger systemic expansion of tumor-specific CD8+ T cells compared with systemic anti-CTLA-4. In a clinically relevant mouse model resistant to systemic immune checkpoint blockade, i.t. VVGM-aCTLA4 synergized with anti-PD-1 to reject “cold” tumors. Based on our established proof-of-concept, a clinical trial evaluating i.t. VVGM-aCTLA4 (BT-001) alone and in combination with anti-PD-1 in metastatic or advanced solid tumors has commenced. CT26 tumours treated with the vaccinia virus mBT-001 expressing anti-CTLA-4 and GM-CSF, the empty vaccinia virus, or untreated.