Targeting acquired resistance mutations in tumors using self-replicating RNA: A Phase I trial of RBI1000, a srRNA vaccine, as a monotherapy and in combination in endocrine resistant advanced and metastatic breast cancer

Targeting acquired resistance mutations in tumors using self-replicating RNA Despite the recent success of tumor immunotherapies, cancer vaccines have failed to translate into clinical efficacy.

Apart from immunogenicity, selection of successful tumor antigen targets is confounded by clonal heterogeneity and removal of mutated clones via immune editing in both primary tumors and metastatic lesions.

To address these issues, we have designed a novel approach to target acquired resistance mutations using self-replicating RNA (srRNA).

In ER+ breast cancer, acquired resistance mutations develop in the ligand binding domain of the estrogen receptor (ESR1) rendering them insensitive to endocrine therapies.

Even in a heterogenous tumor environment, removal of cells harboring acquired resistance mutations will drive sensitivity of the remaining cells to concurrently administered standard-of-care endocrine therapy.

This creates a lose-lose situation for individual tumor cells due to competing selective pressures: cells without acquired resistance mutations are removed via endocrine therapy, whereas mutated cells are removed by the immune system lengthening the time patients can effectively be on endocrine therapy.

We have demonstrated that this srRNA vaccine can induce robust immune responses to targeted acquired resistance mutations and result in tumor control in mouse models. Based on these results, we will advance this candidate into clinical testing.