Repair Assisted Damage Detection (RADD) as a predictive biomarker for immunotherapy response in ovarian cancer

Abstract

Objective: Genomic instability has been proposed as a predictive biomarker for immunotherapy in ovarian cancer. We tested a method for measuring DNA damage, a direct measure of genomic instability, in ovarian tumors and its ability to predict immunotherapy response to Vigil (gemogenovatucel-T).

Methods: Eighty-two formalin-fixed paraffin-embedded tumors from the VITAL trial (NCT02346747) underwent DNA damage assessment using Repair Assisted Damage Detection (RADD). VITAL tested maintenance Vigil therapy vs. placebo for stage IIIB-IV newly diagnosed ovarian cancer in clinical complete response. DNA lesion levels determined by RADD were scored and assessed against patient survival outcomes, expression of CD39, and gene expression signatures.

Results: A graduated distribution of RADD scores occurred across all 82 ovarian samples. RADD scores were able to predict HR status (p < 0.001). RADD demonstrated a significant Pearson's correlation with suggested Vigil biomarker CD39 (r = 0.473; p < 0.001), specifically within HRP tumors (r = 0.57; p = 0.002). High RADD scores correlated with worse recurrent free survival (RFS) in the placebo arm of the trial (7.9 vs. 14.7 months, high vs. low; p = 0.066). High RADD scores were also predictive of significant RFS over 39.4 months with Vigil compared to placebo (25.1 vs. 11.7 months, p = 0.005) and improved, but not significantly, OS with 38.8 vs. 31.8 months.

Conclusions: RADD revealed DNA repair proficiency without mutation signatures or expression profiling. High DNA damage levels show improved survival for Vigil maintenance therapies and are correlated with immune evasion proteins. The persistence of DNA lesions in the genomic DNA offers a new biomarker for immunotherapy patient stratification.

Keywords: DNA damage; DNA repair; Fluorescence; Homologous recombination proficient; Immunotherapy; Ovarian cancer.