Immunotherapy Resistance in Glioblastoma

Elaina J Wang,Alexander F Haddad,Saket Jain,Manish K Aghi,Ramin A Morshed,Angad S Beniwal,Sabraj Gill,Jia-Shu Chen

doi:10.3389/fgene.2021.750675

Elaina J Wang, Alexander F Haddad + Show 6 more

Open Access

https://doi.org/10.3389/fgene.2021.750675

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Abstract

Glioblastoma is the most common malignant primary brain tumor in adults. Despite treatment consisting of surgical resection followed by radiotherapy and adjuvant chemotherapy, survival remains poor at a rate of 26.5% at 2 years. Recent successes in using immunotherapies to treat a number of solid and hematologic cancers have led to a growing interest in harnessing the immune system to target glioblastoma. Several studies have examined the efficacy of various immunotherapies, including checkpoint inhibitors, vaccines, adoptive transfer of lymphocytes, and oncolytic virotherapy in both pre-clinical and clinical settings. However, these therapies have yielded mixed results at best when applied to glioblastoma. While the initial failures of immunotherapy were thought to reflect the immunoprivileged environment of the brain, more recent studies have revealed immune escape mechanisms created by the tumor itself and adaptive resistance acquired in response to therapy. Several of these resistance mechanisms hijack key signaling pathways within the immune system to create a protumoral microenvironment. In this review, we discuss immunotherapies that have been trialed in glioblastoma, mechanisms of tumor resistance, and strategies to sensitize these tumors to immunotherapies. Insights gained from the studies summarized here may help pave the way for novel therapies to overcome barriers that have thus far limited the success of immunotherapy in glioblastoma.

Highlights

Glioblastoma (GBM) is the most common cause of primary brain malignancy, accounting for 27% of all brain tumors and 80% of malignant brain tumors (Ostrom et al, 2015)
This review aims to delineate the multiple avenues of immunotherapy that have been tested in glioblastoma treatment, including checkpoint inhibitors, vaccines, adoptive transfer of effector lymphocytes, and oncolytic virotherapy to stimulate an anti-tumoral immune response
A similar approach was taken in 23 newly diagnosed GBM (ndGBM) patients who underwent maximal resection and received ATV-NDV, an anti-tumor vaccine infected with the Ulster NDV strain; the results demonstrated significantly increased rates of OS-1 (91 versus 45%) and OS-2 (39 versus 11%) compared to the control group (Steiner et al, 2004)

Summary

INTRODUCTION

Glioblastoma (GBM) is the most common cause of primary brain malignancy, accounting for 27% of all brain tumors and 80% of malignant brain tumors (Ostrom et al, 2015). The current standard of care (SOC) for primary GBM is maximally safe surgical resection followed by concurrent radiotherapy and temozolomide (TMZ) for 6 weeks and adjuvant TMZ for 6 months (Fernandes et al, 2017). The recent use of immunotherapies, such as immune checkpoint inhibitors and autologous T cells expressing chimeric antigen receptors (CAR), to successfully treat various solid and hematologic malignancies has led to growing interest in applying similar methods to GBM. An antiprogrammed death-1 (PD-1) antibody, and ipilimumab, an anti-cytotoxic T-lymphocyte associatedprotein 4 (CTLA-4) antibody, have led to improvements in survival when used in stage III and IV

Autologous

Objective response

Replicating

Findings

CONCLUSION