Abstract 4055: Immune checkpoint DNA vaccines enhance anti-tumor immunity in murine melanoma model

Abstract

Abstract Background: Immune checkpoint blockade has emerged as an important cancer treatment strategy. However, the cost of repeat injections of these antibodies limits its availability to many patients globally. We have been developing DNA vaccines targeting immune checkpoints as a potentially more affordable approach to cancer immunotherapy. We have reported this platform could induce endogenous anti-CTLA-4 antibody and anti-tumor immunity. Here, we tested a DNA vaccine targeting PD-1 for anti-tumor responses. Methods: Murine CTLA-4 or PD-1 DNA sequences were inserted into an expression plasmid, pVAC-1, forming DNA vaccines targeting CTLA-4 or PD-1 respectively. Mouse melanoma models were established by inoculating B16F10 cells in the flank of C57BL/6 mice. The mice were randomized into treatment groups, including vector (control), radiation therapy (RT), or RT plus DNA vaccinations targeting CTLA-4 and/or PD-1. Vaccinations were given weekly via intra-muscular injection of the DNA plasmids in conjunction with electroporation. RT was given in 3 daily fractions of 8 Gy during the second week of vaccination. Serum samples were collected and subjected to ELISA for antibody titers. Tumors were measured twice weekly. Tumor samples were collected and subjected to IHC staining for immune markers. Results: Vaccination with plasmids encoding CTLA-4 (pVAC-1-CTLA-4) and PD-1 (pVAC-1-PD-1) induced endogenous antibodies against CTLA-4 and PD-1, respectively. The antibodies were detected beginning 2 weeks after the first vaccination, reached peak concentrations of 3-15 μg/mL in the following 1-2 weeks, and declined within a week once vaccination stopped. Compared with vector alone, preliminary studies using vaccination with both pVAC-1-CTLA-4 and pVAC-1-PD-1 suggested enhanced B16F10 tumor response without evidence of toxicities such as body weight loss or organ damage. In further preliminary studies, adding of both pVAC-1-CTLA-4 and pVAC-1-PD-1 DNA vaccines to RT resulted in increased CD8+ tumor infiltrating lymphocytes compared to either RT or vaccine alone and suggested enhanced tumor response. Conclusions: Immune checkpoint DNA vaccines induced endogenous specific antibodies, demonstrated a favorable safety profile, and may confer anti-tumor immunity. This DNA vaccine platform holds potential as a cost-effective approach to immunotherapy. Further studies are warranted to compare the effects of these immune checkpoint DNA vaccines with those of exogenous immune checkpoint targeting antibodies. Citation Format: Keng-Hsueh Lan, Raghava Sriramaneni, Justin C. Jagodinsky, Claire Baniel, Amy Erbe-Gurel, Jacquelyn A. Hank, Sung-Hsin Kuo, Keng-Li Lan, Zachary S. Morris. Immune checkpoint DNA vaccines enhance anti-tumor immunity in murine melanoma model [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4055.