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.1 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 immunue-modulating properties and that the payloads delivered by ADCs may induce immunogenic cell death.2 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 to formation tumors in the flanks of athymic BALB/c nude mice, Athymic BALB/c nude mouse model (n=7/group) after the tumor size of mice reached 100–200 mm3, and drug administration was initiated. AST-301 (100 ug/animal, intradermal injection, mixed with rhuGM-CSF as an immune adjuvant) was administered once a week to a total of fourth. HER2 ADCs were administered complying to respective dosing schedule. The relative tumor size and tumor growth inhibition (TGI) rate at day 25 were key endpoints of efficacy. To evaluate the immunologic mechanism underlying the enhanced anti-tumor effect, immune-cell profiling was conducted using a FACS analysis.
Results It was showed that adding AST-301 to LCB01 or Kadcyla inhibited a tumor growth based on TGI rate at days 25; AST-301 combining with LCB01 vs LCB01 mono (52% vs 43%), AST-301 combining with Kadcyla vs Kadcyla mono (43% vs 34%). It was also observed or that myeloid-derived suppressor cells (MDSCs) elevation was inhibited in tumor site in the combination groups of all ADCs with AST-301 compared to control group.
Conclusions With combining AST-301 and HER2 ADCs, it was demonstrated that antitumor effects were likely synergistic in athymic mouse model. Immunologically, the combination of AST-301 and HER2 ADCs suppressed the increase of MDSC in the tumor environment. Based on those supporting data, phase 2 study of AST-301 in HER2-expressed gastric cancer has been active (CornerStone-003, NCT#05771584).
Ciesielski M, Szajewski M. The relationship between HER2 overexpression and angiogenesis in gastric cancer. Medicine (Baltimore). 2018 Oct;97(42):e12854.
Rassy E, Rached L, Pistilli B. Antibody drug conjugates targeting HER2: Clinical development in metastatic breast cancer. Breast. 2022 Dec;66:217–226.
Ethics Approval Korea testing & Research institute IRB Approval No. IAC2022–2963
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