Background Keynote-942 (AACR 2023; ASCO 2023) represents the first clinical success of a personalized cancer vaccine. mRNA-4157 is a personalized neoantigen vaccine (Moderna) that, when combined with pembrolizumab, demonstrated prolongation of RFS and DMFS when given as adjuvant therapy for high-risk melanoma following complete resection. These findings demonstrate that the immune system can be successfully primed to target cancer neoantigens for clinical benefit; however, individualized vaccines are costly in time and manufacturing, limiting generalizability.

Methods An alternative approach is to focus on shared antigens that arise across a large frequency of patients, enabling an ‘off-the-shelf’ targeted immunotherapy. Success factors for such an approach include identification of shared (neo)antigens that are: (1) present in large numbers of patients, (2) specific to tumors, and (3) under evolutionary pressure to be retained. Acquired resistance mutations (ARM) fulfill these criteria as they: (1) arise in the majority of patients undergoing targeted therapy, (2) are specific or over-represented in tumors, (3) are retained as a result of the selective pressure from the targeted therapeutic, (4) have clear prognostic value as they drive treatment resistance, and (5) have not been clinically responsive to existing checkpoint inhibitors. Thus, ARMs are ideal as targets for innovative approaches to cancer immunotherapy.

Results Replicate Bioscience has developed a precision immunotherapy (PIO), RBI-1000, targeting ARM in ER+ breast cancer. RBI-1000 is a self-replicating RNA (16,000 bases on a novel alphaviral vector encoded in a lipid nanoparticle) encoding multiple on-target and bypass mutations that arise as patients are on 1L endocrine therapy (e.g., ESR1m+). Immune responses, inclusive of both antibodies and T cells, elicited by RBI-1000 leads to control and elimination of tumor cells expressing ARM in preclinical models. Coupling targeted therapy SOC and PIO (i.e. estrogen blockade and RBI-1000) generates a synthetic immune lethal state for the tumor: if the tumor retains endogenous ESR1, it is subject to the targeted therapy, while if it develops an ARM, it is now eliminated by RBI-1000. RBI-3000, our EGFRm PIO and second oncology therapeutic, targets the known resistance mutations, and primary mutations that are less responsive to tyrosine kinase inhibitor (TKI) therapy and will be administered in combination with SOC TKIs. The coupling of targeted and PIO therapies is anticipated to better address clinical need in the metastatic setting, with chemotherapy replacing surgical resection to address tumor bulk.

Conclusions PIO is a novel approach to cancer immunotherapy that is widely applicable to any cancer with characterized ARM.