In Vivo Priming of Peritoneal Tumor-Reactive Lymphocytes With a Potent Oncolytic Virus for Adoptive Cell Therapy.

Esther Giehl,David L Bartlett,Hiromichi Kosaka,Congrong Ma,Zuqiang Liu,Zong Sheng Guo,Udai S Kammula,Mathilde Feist,Michael T Lotze

doi:10.3389/fimmu.2021.610042

Abstract

Adoptive cell therapy (ACT) using autologous tumor infiltrating lymphocytes (TIL) achieves durable clinical benefit for patients from whom these cells can be derived in advanced metastatic melanoma but is limited in most solid tumors as a result of immune escape and exclusion. A tumor microenvironment (TME) priming strategy to improve the quantity and quality of TIL represents an important tactic to explore. Oncolytic viruses expressing immune stimulatory cytokines induce a potent inflammatory response that may enhance infiltration and activation of T cells. In this study, we examined the ability of an attenuated oncolytic vaccinia virus expressing IL15/IL15Rα (vvDD-IL15/Rα) to enhance recovery of lavage T cells in peritoneal carcinomatosis (PC). We found that intraperitoneal (IP) vvDD-IL15/Rα treatment of animals bearing PC resulted in a significant increase in cytotoxic function and memory formation in CD8+ T cells in peritoneal fluid. Using tetramers for vaccinia virus B8R antigen and tumor rejection antigen p15E, we found that the expanded population of peritoneal CD8+ T cells are specific for vaccinia or tumor with increased tumor-specificity over time, reinforced with viral clearance. Application of these vvDD-IL15/Rα induced CD8+ T cells in ACT of a lethal model of PC significantly increased survival. In addition, we found in patients with peritoneal metastases from various primary solid tumors that peritoneal T cells could be recovered but were exhausted with infrequent tumor-reactivity. If clinically translatable, vvDD-IL15/Rα in vivo priming would greatly expand the number of patients with advanced metastatic cancers responsive to T cell therapy.

Highlights

Immunotherapy has emerged as one of the most promising, potentially curative new treatment approaches for patients with advanced metastatic cancer [1]
Immunocompetent C57BL/6 mice were injected with 5.0x105 MC38-luc cancer cells into the peritoneal cavity. 9 days later, tumor-bearing mice were treated with 5.0x107 pfu of vvDD, vvDD-IL15/Ra or PBS according to in vivo bioluminescence imaging (Figure 1A)
Correlational analysis with flow cytometry showed that vvDDIL15/Ra treatment resulted in higher percentages of CD8+ T cells expressing IFN-g, granzyme B, and 4-1BB and of CD4+ cells expressing 4-1BB compared to vvDD or PBS treatment (Figures 1I–K)

Summary

Introduction

Immunotherapy has emerged as one of the most promising, potentially curative new treatment approaches for patients with advanced metastatic cancer [1]. TIL therapy is personalized for the patient’s own tumor associated antigens and may limit tumor escape from immune mechanisms by allowing T cell responses to multiple tumor associated antigens [7]. Primary limitations of TIL therapy include the inability to identify effective TIL from non-inflamed tumors, the exhausted phenotype of those expanded cells, their lack of suitable tumor specificity, and the immunosuppressive tumor microenvironment into which they are delivered. Many solid tumors are immune excluded, lack tumorspecific T cell infiltration, and are not approachable by ACT [10]. This limitation can potentially be overcome by local immune treatments that transform non-inflamed tumors and enhance the recovery of tumor-specific T cells for adoptive transfer [11]

Methods

Results

Conclusion