Adoptive T Cell Therapy Is Complemented by Oncolytic Virotherapy with Fusogenic VSV-NDV in Combination Treatment of Murine Melanoma.

Teresa Krabbe,Roland M Schmid,Tanja Groll,Angela M Krackhardt,Jennifer Altomonte,Katja Steiger,Janina Marek

doi:10.3390/cancers13051044

Abstract

Simple SummaryCancer immunotherapy involves the application of strategies aimed at enhancing the body’s immune system to recognize and clear tumor cells. One such immunotherapeutic approach utilizes cytotoxic immune cells (T cells) harvested from the patient, which are expanded and activated, followed by re-infusion to the same patient. This process is termed adoptive cell therapy (ACT). Although effective in a limited setting, efforts are being made to improve these therapies through the development of rationally designed combination treatments. We have developed an approach, whereby tumors are pretreated with a virus, which has oncolytic effects on the tumor cells, in addition to modulating changes in the tumor microenvironment, thereby improving the recruitment of the adoptively transferred cytotoxic T cells and resulting in synergistic therapeutic responses in the tumor. This results in a substantial prolongation of survival, as demonstrated in an immune-competent mouse model of melanoma.Cancer immunotherapies have made major advancements in recent years and are becoming the prevalent treatment options for numerous tumor entities. However, substantial response rates have only been observed in specific subsets of patients since pre-existing factors determine the susceptibility of a tumor to these therapies. The development of approaches that can actively induce an anti-tumor immune response, such as adoptive cell transfer and oncolytic virotherapy, have shown clinical success in the treatment of leukemia and melanoma, respectively. Based on the immune-stimulatory capacity of oncolytic VSV-NDV virotherapy, we envisioned a combination approach to synergize with adoptive T cell transfer, in order to enhance tumor cell killing. Using the immune-competent B16 melanoma model, we demonstrate that combination treatment has beneficial effects on the suppressive microenvironment through upregulation of MHC-I and maintaining low expression levels of PD-L1 on tumor cells. The approach led to additive cytotoxic effects and improved the recruitment of T cells to virus-infected tumor cells in vitro and in vivo. We observed substantial delays in tumor growth and evidence of abscopal effects, as well as prolongation of overall survival time when administered at clinically relevant dosing conditions. Our results indicate that treatment with oncolytic VSV-NDV, combined with adoptive T cell therapy, induces multi-mechanistic and synergistic tumor responses, which supports the further development of this promising translational approach.

Highlights

In recent years, major advances in our understanding of the tumor microenvironment and responses to therapy have led to a shift in the focus of cancer treatments from the reliance on monotherapies targeting tumor cells, to the development of rational combinatorial approaches involving new cancer immunotherapies to optimally support and unleash the endogenous anti-tumor immune response
We have recently reported that human CD8+ central memory T cells could be used as cell carriers to deliver oncolytic vesicular stomatitis virus (VSV) to human acute myeloid leukemia (AML) cells and exert cytotoxic effector functions to result in an effective combinatorial approach in an immune-deficient xenograft model [10]
The first clinical trials combining oncolytic adenovirus and adoptive cell transfer (ACT) are on the way to demonstrate the clinical benefit of this approach and its relevance in patient treatment (NCT03740256, NCT04217473)

Summary

Introduction

Major advances in our understanding of the tumor microenvironment and responses to therapy have led to a shift in the focus of cancer treatments from the reliance on monotherapies targeting tumor cells, to the development of rational combinatorial approaches involving new cancer immunotherapies to optimally support and unleash the endogenous anti-tumor immune response. Finding the right combination will depend on a profound understanding of the immune system, sophisticated bioinformatic analyses, and prediction systems as well as a multitude of well-characterized treatment options. Immunotherapeutic approaches, such as adoptive cell transfer (ACT)

Methods

Results

Discussion

Conclusion