HER2-targeted immunotherapies: preclinical evaluation of anti-HER2 vaccine-antibody interactions in vivo and development of a cynomolgus monkey HER2 cellular model

Human epidermal growth factor receptor-2 (HER2) overexpression is observed in approximately 15-20% of breast carcinomas, and it is correlated with poor prognosis. The development of monoclonal antibodies targeting HER2 in combination with chemotherapy has revolutionized HER2+ breast cancer therapy and resulted in significant improvement in patients’ survival. However, monoclonal antibodies do not provide long-term protection due to intrinsic or acquired therapy resistance, and multiple administrations are frequently associated with the emergence of side effects, eventually leading to therapy failure. Collectively, these drawbacks have prompted the need to investigate other approaches against HER2+ breast carcinomas. Pre-clinical evaluation of ES2B-C001, a virus-like particle-based HER2 vaccine, has demonstrated promising therapeutic activity in human HER-2 transgenic mouse models. Now, ES2B-C001 vaccine entered clinical testing. As patients eligible for early clinical trials may still be under anti-HER2 monoclonal antibody treatment plus chemotherapy, I investigated in FVB mice the effects of concomitant administration of the murine trastuzumab precursor 4D5 over vaccine immunogenicity and therapeutic efficacy, to assess the feasibility of their combination could be feasible. Results demonstrated that ES2B-C001 vaccine elicited high and persistent levels of HER2-specific antibodies, regardless of monoclonal antibody co-treatment, thus supporting the feasibility of administering ES2B-C001 in patients receiving trastuzumab, without hampering vaccine activity. The development of new anti-HER2 agents requires preclinical approaches capable of predicting functional cross-reactivity, while minimizing the use of nonhuman primates use. The second aim of this project consisted in the generation of cell lines expressing cynomolgus HER2 and in the evaluation of their sensitivity to anti-HER2 therapeutic agents. The growth of NIH 3T3 cyHER2 cell line was inhibited by trastuzumab and tucatinib, thus demonstrating its suitability for assessing functional inhibition of cynomolgus HER2 in vitro. This model provides a potential tool to refine preclinical testing strategies and to reduce the use of primates in toxicology studies.