Checkpoint inhibitor therapy augments pre-existing T-cell responses to tumor antigens, resulting in tumor control in 20-40% of patients with melanoma and other cancers. As a means to increase the effectiveness of this approach, we developed a dendritic cell (DC)-based vaccine strategy that specifically induces anti-tumor T-cell responses and prevents checkpoint activation. The approach is based on lentiviral vectors that express checkpoint inhibitor and tumor antigen and transduce DCs at high efficiency as a result of virion-packaging of the lentiviral accessory protein Vpx. In addition, the vectors express CD40 ligand (CD40L), a cell surface protein that strongly activates DCs, causing the cells to mature and secrete immunostimulatory cytokines, including TNFα, IL-6, and IL-12, that potentiate T-cell responses. The therapy harnesses the ability of DCs to prime T-cell responses against tumors, resulting in long-term antigen expression and continuous, localized release of checkpoint inhibitor during antigen-presentation. In the lymphocytic choriomeningitis virus (LCMV) mouse model, immunization with DCs transduced with lentiviral vectors that express soluble programmed cell death protein 1 (PD-1), CD40L and LCMV epitopes induced a 10-fold expansion of LCMV-specific CD8 T-cells and protected the mice against high-titer LCMV and a lethal intracranial LCMV challenge. Protection was 100-fold greater than that achieved by vaccination with LCMV peptide epitope-pulsed DCs. The strategy also appeared to cure mice infected with clone 13 LCMV, a chronic form of disease that results from T-cell exhaustion induced by checkpoint activation. In the B16-OVA mouse melanoma model, immunization with DCs transduced with vectors that express soluble PD-1, CD40L and OVA epitopes or a tumor antigen epitope from tyrosinase-related protein (TRP-1) protected mice from tumor formation. DC vaccination post-B16 challenge reduced tumor growth and prolonged survival. Mice immunized four days after intravenous injection of B16 cells showed no evidence of lung melanoma nodules three weeks later. Remarkably, immunization by direct injection of lentiviral vector, a method that obviates the need to harvest patient DCs, proved equally effective as ex vivo DC transduction in suppressing tumor growth. In addition, direct injection resulted in a much longer half-life of transduced cells. These studies demonstrate the ability of this approach to induce antigen-specific responses and overcome CTL exhaustion. Moreover, the lentiviral vector approach provides a means to express tumor neoantigens for the development of personalized immunotherapies that stimulate tumor-specific T-cell responses by clones present at low level or to antigens that the host has not responded.

Citation Format: Takuya Tada, Nathaniel R. Landau, Thomas David Norton. Checkpoint inhibitor vaccine stimulates antitumor T-cells that block tumor growth [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B121.