ENTPD1/CD39 as a predictive marker of treatment response to gemogenovatucel-T as maintenance therapy in newly diagnosed ovarian cancer

Abstract

Background Broadened use of predictive molecular and phenotypic profiling amongst oncologists has facilitated optimal integration of targeted- and immuno-therapeutics into clinical care. However, the use of predictive immunomarkers in ovarian cancer (OC) has not consistently translated into clinical benefit. Vigil (gemogenovatucel-T) is a novel plasmid engineered autologous tumor cell immunotherapy designed to knock down the tumor suppressor cytokines, TGFβ1 and TGFβ2, augment local immune function via increased GMCSF expression and enhance presentation of clonal neoantigen epitopes. Methods: All patients enrolled in the VITAL trial (NCT02346747) of maintenance Vigil vs. placebo as front-line therapy with homologous recombination proficient (HRP) stage IIIB-IV newly diagnosed ovarian cancer underwent NanoString gene expression analysis. Tissue was obtained from surgically resected ovarian tumor tissue following surgical debulking. A statistical algorithm was used to analyze the NanoString gene expression data. Results Using the NanoString Statistical Algorithm (NSA), we identify high expression of ENTPD1/CD39 (which functions as the rate-limiting step in the production of the immune suppressor adenosine from ATP to ADP) as a presumptive predictor of response to Vigil versus placebo regardless of HRP status on the basis of relapse free survival (median not achieved vs 8.1 months, p = 0.00007) and overall survival (median not achieved vs 41.4 months, p = 0.013) extension. Conclusion NSA should be considered for application to investigational targeted therapies in order to identify populations most likely to benefit from treatment, in preparation for efficacy conclusive trials.

CD39 and LDHA affects the prognostic role of NLR in metastatic melanoma patients treated with immunotherapy

“…Based on these results, the role of CD39/ ENTPD1 in the negative effect of a high NLR on the oncologic outcomes of patients with advanced melanoma can be speculated. CD39 ( ENTPD1) functions as the rate-limiting step in converting ATP to ADP [ 21 ]. Adenosine inhibits anti-tumor functions mediated by T cells and NK cells [ 22 ].…”

Clonal Neoantigen: Emerging “Mechanism-based” Biomarker of Immunotherapy Response

“…In essence, Vigil ® therapy would create a "hot" tumor microenvironment more supportive of CPI sensitivity. In fact, p53 mutant DNA [196] and ENTPD1 high RNA expression [197] have been identified as relevant immune response biomarkers to Vigil ® sensitivity and may further contribute to the induction of a "hot" tumor microenvironment and greater immune responsiveness to the clonal neoantigens that contain the appropriate epitopes for TCR binding and enabling a robust anti-cancer immune response. As quoted by Riaz et al [25], "even with the brakes off (CPI treatment), the adaptive immune system still must recognize a majority portion (or ideally all) of cancer as foreign in order to facilitate selective elimination of the cancer".…”