Tumor Membrane Vesicle Vaccine Augments the Efficacy of Anti-PD1 Antibody in Immune Checkpoint Inhibitor-Resistant Squamous Cell Carcinoma Models of Head and Neck Cancer.

Ramireddy Bommireddy,Lei Huang,Yijian Fan,Anita Kumari,Nabil F Saba,Dong M Shin,Janet Kim,Periasamy Selvaraj,Christopher D Pack,Lenore Monterroza,Zhuo G Chen,Shaker J.C Reddy,Sampath Ramachandiran,Luis E Munoz

doi:10.3390/vaccines8020182

Abstract

Immune checkpoint inhibitor (ICI) immunotherapy improved the survival of head and neck squamous cell carcinoma (HNSCC) patients. However, more than 80% of the patients are still resistant to this therapy. To test whether the efficacy of ICI therapy can be improved by vaccine-induced immunity, we investigated the efficacy of a tumor membrane-based vaccine immunotherapy in murine models of HNSCC. The tumors, grown subcutaneously, are used to prepare tumor membrane vesicles (TMVs). TMVs are then incorporated with glycolipid-anchored immunostimulatory molecules GPI-B7-1 and GPI-IL-12 by protein transfer to generate the TMV vaccine. This TMV vaccine inhibited tumor growth and improved the survival of mice challenged with SCCVII tumor cells. The tumor-free mice survived for several months, remained tumor-free, and were protected following a secondary tumor cell challenge, suggesting that the TMV vaccine induced an anti-tumor immune memory response. However, no synergy with anti-PD1 mAb was observed in this model. In contrast, the TMV vaccine was effective in inhibiting MOC1 and MOC2 murine oral cancer models and synergized with anti-PD1 mAb in extending the survival of tumor-bearing mice. These observations suggest that tumor tissue based TMV vaccines can be harnessed to develop an effective personalized immunotherapy for HNSCC that can enhance the efficacy of immune checkpoint inhibitors.

Highlights

Treatment of head and neck squamous cell carcinoma (HNSCC) with immune checkpoint inhibitors (ICIs) has resulted in improved survival of patients with metastatic HNSCC; the majority of patients (>80%) fail this treatment regardless of tumor human papilloma virus (HPV) status or demographic factors [1,2,3,4,5,6]
glycosyl phosphatidylinositol (GPI)-B7-1 and GPI-IL-12 Are Incorporated into tumor membrane vesicles (TMVs) by Protein Transfer
Flow cytometry analysis of protein expression profile of unmodified TMVs showed that TMVs express tumor and immune cell markers such as cancer stem cell markers (CD24 and CD44), co-stimulation (CD80 (B7-1)), immunosuppression (CD47, PD-L1), and innate immune cells (Gr1) (Figure 1A)

Summary

Introduction

Treatment of head and neck squamous cell carcinoma (HNSCC) with immune checkpoint inhibitors (ICIs) has resulted in improved survival of patients with metastatic HNSCC; the majority of patients (>80%) fail this treatment regardless of tumor human papilloma virus (HPV) status or demographic factors [1,2,3,4,5,6]. Many of the previous approaches employed genetically modified allogeneic tumor cell lines or cell lines developed from patients or single tumor antigens or tumor antigen–specific peptides as vaccine sources [11]. These approaches induced anti-tumor immunity in patients, but clinical benefit was not achieved because the tumors might have escaped immune attack due to their heterogeneity, since the vaccines might not have represented all the variations found in the patient’s tumor. These include the use of patient-specific neoepitope peptide vaccines [19,20,21] and whole tumor lysate pulsed dendritic cell (DC) approaches [22,23] This suggests that it is critical to use patient-specific antigens in developing efficacious therapeutic cancer vaccines. We are investigating a tumor membrane vesicle (TMV)-based vaccine immunotherapy approach for HNSCC in syngeneic mouse models

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