Clonal Neoantigen: Emerging "Mechanism-based" Biomarker of Immunotherapy Response

Simple Summary Persistent DNA mutations that affect cellular growth and survival result in the transformation of normal cells into malignant cells. These initiating mutations that involve all of the cancer cells are called clonal mutations. Clonal mutations expressed on the surface provide a distinguishable target for immune cells to identify and grab the cancer. Immune effector cells released to attack cancer by checkpoint inhibitor therapy do not kill the cancer unless they can recognize it. Retrospective data has shown improved survival in patients who receive checkpoint inhibitors and have a high clonal neoantigen profile compared to those who do not. Vigil (R) is a novel immune technology that is designed to increase clonal neoantigen targeting immune effector cells. Recurrence-free survival and overall survival advantage vs. control has been observed with Vigil (R) in a randomized trial. Vigil's ability to increase clonal neoantigen targeting effector cells may be a critical link to achieving more consistent immunotherapy activity.Abstract Clonal mutations represent the initiating molecular defects related to cellular transition of a normal phenotype to a malignant phenotype. Molecular genomic assessment utilizing next generation and whole exome sequencing is now being increasingly applied to biomarker determination to refine the use of targeted immune therapies. Case examples followed by retrospective study assessment have convincingly demonstrated clonal neoantigens provide a relevant predictor of response to checkpoint inhibition. A meta-analysis, by Litchfield et al., of over 1000 cancer patients from 12 landmark trials demonstrated no clinical benefit to checkpoint inhibitor (CPI) therapy in correlation to high subclonal tumor mutational burden (TMB), whereas high clonal TMB was found to be significantly correlated with better overall survival (p = 0.000000029). We discuss the mechanism of clonal vs. subclonal neoantigen targeting relationship to homologous recombination proficient (HRP) profile, evidence of preclinical and clinical benefit related to clonal neoantigens, and review a novel developing therapy called Vigil (R), designed to expand the clonal neoantigen targeting effector cell populations. Vigil (R) is an autologous cellular immunotherapy which is designed to carry the full set of personal clonal neoantigens. Phase 2b results demonstrate a durable recurrence-free survival (RFS) and overall survival (OS) advantage for Vigil (R) in a subset ovarian cancer population with an HRP cancer profile.