Enhanced T-Cell Priming and Improved Anti-Tumor Immunity through Lymphatic Delivery of Checkpoint Blockade Immunotherapy

SIMPLE SUMMARY: While checkpoint blockade immunotherapy results in durable, complete responses in some patients, most cancer types are non-responsive and the majority of patients with cancers known to be responsive do not benefit from these therapies. Herein, we show that antigen directed T-cell priming orchestrated through combined vaccination and checkpoint blockade immunotherapy delivered through the lymphatics can improve anti-tumor responses in otherwise non-immunogenic, syngeneic melanoma models. The work presented herein suggests that by directing immune responses within the regional lymph node environment, more patients could potentially benefit from checkpoint blockade immunotherapies. ABSTRACT: An infusion of checkpoint blockade immunotherapy (CBI) has revolutionized cancer treatments for some patients, but the majority of patients experience disappointing responses. Because adaptive immune responses are mounted by the concentrated assembly of antigens, immune cells, and mediators in the secluded and protective environment of draining lymph nodes (dLNs), we hypothesize that lymphatic delivery of CBI (αCTLA-4 and αPD-1) to tumor dLNs (tdLNs) improves anti-tumor responses over intravenous (i.v.) administration, and that vaccination against tumor associated antigen (TAA) further enhances these responses. Mono- and combination CBI were administered i.v. or through image-guided intradermal (i.d.) injection to reach tdLNs in vaccinated and unvaccinated animals bearing either primary or orthotopically metastasizing B16F10 melanoma. Vaccination and boost against TAA, Melan-A, was accomplished with virus-like particles (VLP) directed to tdLNs followed by VLP boost after CBI administration. Lymphatic delivery of CBIs reduced primary tumor size and metastatic tumor burden, alleviated the pro-tumorigenic immune environment, and improved survival over systemic administration of CBIs. Animals receiving CBIs lymphatically exhibited significantly enhanced survival over those receiving therapies administered partially or completely through systemic routes. By combining vaccination and CBI for effective T-cell priming in the protected environment of dLNs, anti-tumor responses may be improved.