Abstract 4113: AST-301,a pDNA-based cancer vaccine encoding HER2-ICD, enhances anti-tumor effect of HER2-ADC in a HER2-expressed gastric cancer xenograft model
Authors: Kang Jinho , Park Hyo-Hyun , Choi Jee Hyun , Lim Jinback , Jang Seong-Yong , Kim Min-Ah , Park Myeong-Kyu , Park Yun-Hee , Lim Soyeon , Chung Chul-Woong , Choi Jin Kyeong , Joung Eunkyo , Kim Ashley Yongmin , Jung Hun 
Published: March 2024

Background: In gastric cancer, the HER2 overexpression (6% to 29.5% of gastric cancers) is considered to increase proliferation activity and suppress apoptosis of the cancer cells. However, HER2-targeting therapy in gastric cancer has not been fully evaluated. Currently, new approaches with HER2-tageted antibody-drug conjugates (ADCs) have led to promising results in HER2-related solid tumors. ADCs may have immune-modulating properties and that the payloads delivered by ADCs may induce immunogenic cell death. Based on this rationale, ADC and cancer vaccine combination would be potentially synergistic to improve clinical outcomes. This study was conducted to evaluate an synergistic effect and immune response of the combination of AST-301 and HER2-ADC in HER2-expressed gastric cancer xenograft model. AST-301 phase 1 study (PN109) was completed and phase 2 randomized-control trials (CornerStone-001, CornerStone-003) have been conducted in breast cancer and gastric cancer.

Methods: NCI-N87 cells were mixed with the same amount of matrigel at 1x107 cells to formation tumors in the flanks of athymic BALB/c nude mice. After the tumor size of mice reached 100-200 mm3, all of them were randomly classified into four groups (n=7/group) and drug administration was initiated. AST-301 (100 μg/animal, intradermal injection, mixed with rhuGM-CSF as an immune adjuvant) was administered once a week to a total of fourth. LCB01 (1 mg/kg, intravenous injection) was administered to once. Enhertu (1 or 3 mg/kg, intravenous injection) was administered to twice for four weeks. The relative tumor size and TGI rate at day 25 were key endpoints of efficacy. To evaluate the mechanism underlying the enhanced anti-tumor effect due to the combined administration of AST-301 and HER2-ADCs, immune-cell profiling was also conducted using FACS analysis.

Results: Our previous study has shown that AST-301 has anti-tumor effects in human gastric cancer xenograft athymic BALB/c nude mouse model. It was showed that adding AST-301 to LCB01 or Enhertu inhibited tumor growth based on a TGI rate at days 25; AST-301 combining with LCB01 vs LCB01 mono (52 % vs 43 %), AST-301 combining with Enhertu vs Enhertu mono (42 % vs 24 %).As an explorative endpoint, it was observed that myeloid-derived suppressor cells (MDSCs) elevation was modestly inhibited in tumor site in AST-301 mono or certain combination regimen adding AST-301. It was remarkable (or observed or captured) that MDSCs elevation was inhibited in tumor site in the combination groups of all ADCs with AST-301 compared to normal saline groups.

Conclusion: With combining AST-301 and HER2 ADCs, it was demonstrated that anti-tumor effect was likely synergistic in the athymic mouse model. Phase 2 study of AST-301 in HER2-expressed gastric cancer has been on going (CornerStone-003, NCT 05771584).

Citation Format: Jinho Kang, Hyo-Hyun Park, Jee Hyun Choi, Jinback Lim, Seong-Yong Jang, Min-Ah Kim, Myeong-Kyu Park, Yun-Hee Park, Soyeon Lim, Chul-Woong Chung, Jin Kyeong Choi, Eunkyo Joung, Ashley Yongmin Kim, Hun Jung. AST-301,a pDNA-based cancer vaccine encoding HER2-ICD, enhances anti-tumor effect of HER2-ADC in a HER2-expressed gastric cancer xenograft model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4113.