Irradiation or temozolomide chemotherapy enhances anti-CD47 treatment of glioblastoma.

Sharareh Gholamin,Irving Weissman,Amato J Giaccia,Rogelio Esparza,Samuel H Cheshier,Osama A Youssef,Suzana Kahn,Maryam Shahin,Edward E Graves,Marjan Rafat,Siddhartha Mitra

doi:10.1177/1753425919876690

Abstract

Irradiation and temozolomide (TMZ) chemotherapy are the current standard treatments for glioblastoma multiforme (GBM), but they are associated with toxicity and limited efficacy. Recently, these standard therapies have been used to enhance immunotherapy against GBM. Immunotherapy using the anti-CD47 (immune checkpoint inhibitor) treatment has shown promise in treating multiple tumor types, including GBM. The goal of this current work was to test whether irradiation or TMZ chemotherapy could enhance anti-CD47 treatment against GBM. Our results showed that irradiation and TMZ each significantly enhanced anti-CD47-mediated phagocytosis of GBM cells in vitro. Furthermore, mice engrafted with human GBM that received anti-CD47 combined with focal irradiation or TMZ treatment showed a significant increase in the survival rate compared to those that received a single treatment. The tumor growth in mice that received both anti-CD47 and irradiation was significantly less than that of groups that received either anti-CD47 or focal irradiation. The results from this study may support future use of anti-CD47 treatment in combination with irradiation or chemotherapy to enhance the therapeutic efficacy of GBM treatment.

Highlights

Glioblastoma multiforme (GBM) is one of the most devastating brain tumors in adults, with an average median survival of 18 mo.[1,2] The current standard treatment consists of maximal safe resection followed by irradiation and chemotherapy with the alkylating oral agent temozolomide (TMZ)
We demonstrate that irradiation or TMZ chemotherapy enhanced anti-CD47 treatment by increasing macrophage-mediated phagocytosis of tumor cell in vitro
GBM cells subjected to irradiation showed significantly higher phagocytosis compared to control

Summary

Introduction

Glioblastoma multiforme (GBM) is one of the most devastating brain tumors in adults, with an average median survival of 18 mo.[1,2] The current standard treatment consists of maximal safe resection followed by irradiation and chemotherapy with the alkylating oral agent temozolomide (TMZ). Despite an initial modest response to irradiation and chemotherapy after surgical removal of the tumor, the recurrent tumor demonstrates resistance to irradiation and chemotherapy, resulting in poor clinical outcomes.[1,3]. Recent advancements in immunotherapy have offered new hope for improving GBM outcomes.

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