Abstract 709: AST-301, a pDNA-based therapeutic cancer vaccine encoding HER2 ICD, improves the efficacy of checkpoint blockade therapy in CD34+ humanized gastric cancer mouse model

Abstract

Abstract PD-1/PD-L1 play a crucial role in modulating immune response and promoting self-tolerance through activating apoptosis of antigen-specific T cells and suppressing apoptosis of regulatory T cells. Although immunotherapy to block this may provide a greater survival benefit for some patients, the therapeutic effect shown in clinical trials is limited by shortage of pre-existing CD8+ T cells infiltrating the tumor. AST-301 is a pDNA-based therapeutic cancer vaccine encoding HER2 ICD sequence. It was effective in eliciting HER2-specific T cells and antibody immunity in the majority of breast and ovarian cancer patients who completed the vaccine regimen and has proven safety as well as long-term immunological memory efficacy of T-cell immune by the phase 1 study (PN 109, NCT00436254). Our previous study has shown that AST-301 has anti-tumor effects by mediating NK cells in human HER2+ gastric cancer cell (NCI-N87) xenograft athymic mice. Here, we aimed to determine whether combined administration of AST-301 can enhance the anti-tumor effect of immune checkpoint inhibitor (ICI) using NCI-N87 xenograft humanized mouse. To confirm the tumor suppressive effect of pembrolizumab (anti-PD-1) treatment combined with AST-301 in the hu-CD34+ hematopoietic stem cell-engrafted NSG mice that formed tumors with NCI-N87, AST-301 (100 μg) and pembrolizumab (5 mg/kg) were administered into mice once a week for a total of 3 times and one booster doses of AST-301 was injected at week 4. Pembrolizumab low dose (5 mg/kg) test group administered with AST-301 had a relatively higher tumor growth inhibition (TGI) effect than the same concentration of Pembrolizumab alone group. TGI effect (%) of G2 (a combination of AST-301 and Pembrolizumab 5 mg/kg), G3 (Pembrolizumab 5 mg/kg), and G4 (Pembrolizumab 10 mg/kg) were 54%, 47%, and 78%, respectively. To evaluate the mechanism underlying the enhanced anti-tumor effect due to the combined administration of AST-301 and pembrolizumab, we measured the ratio of immune cells isolated from spleen and tumor in mice. in G2, the ratio of helper T cells and cytotoxic T cells in splenocytes higher than the vehicle-treated control group (G1), and the ratio of cytotoxic T cells infiltrated the tumor was also detected high in some subjects compared to those in all the other three groups. These results suggest that AST-301 can improve HER2+ gastric cancer treatment outcomes of immune checkpoint blockade therapy by inducing a robust cytotoxic CD8+ T cell response to tumor cells. Currently, we are ongoing study to prove the anti-tumor synergistic effects of the combination of AST-301 and various FDA-approved Antibody Drug Conjugates (ADCs). This effort is focused on narrowing the administration doses to low levels to resolve the safety issue of ADC or ICI, and it will strongly support the diverse applicability of the cancer therapeutic vaccine. Citation Format: Hyo-Hyun Park, Hye-Ran Kim, Jin Kyeong Choi, Jee Hyun Choi, JinHo Kang, Jinback Lim, Hyo Jung Lim, Jong Yeong Lee, Eunkyo Joung, Hun Jung. AST-301, a pDNA-based therapeutic cancer vaccine encoding HER2 ICD, improves the efficacy of checkpoint blockade therapy in CD34+ humanized gastric cancer mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 709.