Personalized cancer vaccine strategy elicits polyfunctional T cells and demonstrates clinical benefits in ovarian cancer

Ritaparna Ahmed ,David Tarussio ,Johanna Chiffelle ,Lana E Kandalaft ,Emese Zsiros ,Stephanie Tissot ,Petra Baumgartener ,Cheryl Lai-Lai Chiang ,Hajer Fritah Guiren ,Alexandre Harari ,George Coukos ,Christine Goepfert ,János L Tanyi ,Drew A Torigian ,Florian Huber ,Daniel J Powell ,Anne‐Christine Thierry ,Rosemarie Mick ,Anne-Laure Huguenin-Bergenat ,Harvey L Nisenbaum ,Michal Bassani-Sternberg ,Brian J Stevenson

doi:10.1038/s41541-021-00297-5

Abstract

T cells are important for controlling ovarian cancer (OC). We previously demonstrated that combinatorial use of a personalized whole-tumor lysate-pulsed dendritic cell vaccine (OCDC), bevacizumab (Bev), and cyclophosphamide (Cy) elicited neoantigen-specific T cells and prolonged OC survival. Here, we hypothesize that adding acetylsalicylic acid (ASA) and low-dose interleukin (IL)-2 would increase the vaccine efficacy in a recurrent advanced OC phase I trial (NCT01132014). By adding ASA and low-dose IL-2 to the OCDC-Bev-Cy combinatorial regimen, we elicited vaccine-specific T-cell responses that positively correlated with patients’ prolonged time-to-progression and overall survival. In the ID8 ovarian model, animals receiving the same regimen showed prolonged survival, increased tumor-infiltrating perforin-producing T cells, increased neoantigen-specific CD8+ T cells, and reduced endothelial Fas ligand expression and tumor-infiltrating T-regulatory cells. This combinatorial strategy was efficacious and also highlighted the predictive value of the ID8 model for future ovarian trial development.

Highlights

T cells are essential for controlling cancer progression
We investigated if adding acetylsalicylic acid (ASA) and low-dose IL-2 could further enhance antitumor T-cell responses in a phase I trial of 30 platinum-pretreated, immunotherapy-naive recurrent advanced ovarian cancer (OC) patients (NCT01132014)
We presented evidence that the combinatorial use of ASA, low-dose IL-2, OCDC, Bev, and Cy (Cohort C regimen) increased the magnitude as well as the polyfunctional profile of OCDC vaccine-specific CD4+ and CD8+ T cells that were positively correlated with increased time-to-progression and 3-years overall survival (OS) in OC patients

Summary

Introduction

Prior studies in ovarian cancer (OC) patients consistently reported a correlation between CD3+ tumor-infiltrating lymphocytes (TILs) and overall survival (OS)[1,2,3,4]. This observation provides a rationale for using immunotherapies to mobilize endogenous antitumor T cells. Treg cells suppress tumor-specific T cells and contribute to tumor progression[11,12]. Inhibiting VEGF could lead to “normalization” of tumor vasculature, improving oxygen, nutrient, and chemotherapy delivery to increase tumor toxicity and reduce ascites fluid formation[13,14]

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Results

Conclusion