Recent advances and future of immunotherapy for glioblastoma

ABSTRACT

Introduction: Outcome for glioma (GBM) remains dismal despite advances in therapeutic interventions including chemotherapy, radiotherapy and surgical resection. The overall survival benefit observed with immunotherapies in cancers such as melanoma and prostate cancer has fuelled research into evaluating immunotherapies for GBM.

Areas covered: Preclinical studies have brought a wealth of information for improving the prognosis of GBM and multiple clinical studies are evaluating a wide array of immunotherapies for GBM patients. This review highlights advances in the development of immunotherapeutic approaches. We discuss the strategies and outcomes of active and passive immunotherapies for GBM including vaccination strategies, gene therapy, check point blockade and adoptive T cell therapies. We also focus on immunoediting and tumor neoantigens that can impact the efficacy of immunotherapies.

Expert opinion: Encouraging results have been observed with immunotherapeutic strategies; some clinical trials are reaching phase III. Significant progress has been made in unraveling the molecular and genetic heterogeneity of GBM and its implications to disease prognosis. There is now consensus related to the critical need to incorporate tumor heterogeneity into the design of therapeutic approaches. Recent data also indicates that an efficacious treatment strategy will need to be combinatorial and personalized to the tumor genetic signature.

KEYWORDS:

• Glioma
• immunotherapy
• cancer vaccines
• checkpoint blockade
• passive immunotherapy
• gene therapy

Article highlights

• Molecular features of gliomas such as 1p/19q co-deletion, IDH1 mutation, mutation in TERT gene and loss of ATRX are increasingly used in the diagnosis of tumor samples and are predictive of histological sub-type and prognosis.

• GBM TME is highly immunosuppressive because of the presence of cells such as Tregs, MDSCs and TAMs, secretion of IL-10 and TGF-β by GBM cells, differential regulation of HLA molecules on GBM cells and through the expression of T cell suppressive molecules such as CD80 and PDL1. Thus multipronged strategies are needed to overcome the GBM induced immune suppression effectively.

• Immunotherapeutic strategies targeting GBM can be broadly classified as immunomodulatory approaches, active immunotherapy, passive immunotherapy and adoptive immunotherapy using autologous T cells and CAR T cells.

• Immunomodulatory approaches target immunosuppressive checkpoints such as CTLA-4 and PD-1. A clinical trial evaluating Ipilimumab for recurrent and newly diagnosed GBM is currently recruiting patients (NCT02017717). Another immunomodulatory therapy utilizes gene therapy. The conditionally cytotoxic-immune-stimulatory gene therapy approach developed in our laboratory, has proven to be highly efficacious in several rat and mouse intracranial GBM models and is currently being tested in the clinic (NCT01811992).

• Active immunotherapy aims at stimulating innate and adaptive immune responses against tumor-specific antigens. Several known tumor associated antigens such as HER-2, TRP-2, gp100, MAGE-1, IL-13α2, EphA2 and AIM-2, are being targeted in GBM. Neoantigens such as EGFRvIII are increasingly being used to generate tumor specific responses. Mutant IDH1 peptide-derived vaccine PEPIDH1M is being tested in patients with IDH1 positive recurrent grade II glioma (NCT02193347) and the NOA-16 trial is a Phase I trial of IDH1 peptide vaccine for grade III-IV gliomas (NCT02454634).

• Adoptive immunotherapy using autologous T cell transfer and CAR T cells is also being tested. A phase I trial will test the safety and efficacy of using HER2-specific CARs in patients with recurrent GBM (NCT02442297). The Rosenberg group at NCI (NCT01454596) and the University of Pennsylvania/Novartis (NCT02209376) are also currently recruiting participants to test the safety and feasibility of administering T cells expressing anti-EGFRvIII CAR to GBM patients who have had their first recurrence or have residual disease after initial resection.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This work was supported by National Institutes of Health/National Institute of Neurological Disorders & Stroke (NIH/NINDS) Grants [R01-NS094804, R01-NS074387, R21-NS091555, and R37-NS094804] to M.G.C.; NIH/NINDS Grants [R01-NS076991, R01-NS082311, R21-NS084275, and R01-096756] to P.R.L.; Leah’s Happy Hearts, University of Michigan Comprehensive Cancer Center, The ChadTough Foundation, and The Phase One Foundation to both M.G.C. and P.R.L.; the Department of Neurosurgery, University of Michigan School of Medicine; the Michigan Institute for Clinical and Health Research, [NIH 2UL1-TR000433]; University of Michigan Cancer Biology Training Grant, NIH/NCI (National Cancer Institute) [T32-CA009676]; University of Michigan Training in Clinical and Basic Neuroscience, NIH/NINDS [T32-NS007222]; and the University of Michigan Medical Scientist Training Program, NIH/NIGMS (National Institute of General Medicine Sciences) [T32-GM007863].