Single vs. combination immunotherapeutic strategies for glioma

ABSTRACT

Introduction: Malignant gliomas are highly invasive tumors, associated with a dismal survival rate despite standard of care, which includes surgical resection, radiotherapy and chemotherapy with temozolomide (TMZ). Precision immunotherapies or combinations of immunotherapies that target unique tumor-specific features may substantially improve upon existing treatments.

Areas covered: Clinical trials of single immunotherapies have shown therapeutic potential in high-grade glioma patients, and emerging preclinical studies indicate that combinations of immunotherapies may be more effective than monotherapies. In this review, the authors discuss emerging combinations of immunotherapies and compare efficacy of single vs. combined therapies tested in preclinical brain tumor models.

Expert opinion: Malignant gliomas are characterized by a number of factors which may limit the success of single immunotherapies including inter-tumor and intra-tumor heterogeneity, intrinsic resistance to traditional therapies, immunosuppression, and immune selection for tumor cells with low antigenicity. Combination of therapies which target multiple aspects of tumor physiology are likely to be more effective than single therapies. While a limited number of combination immunotherapies are described which are currently being tested in preclinical and clinical studies, the field is expanding at an astounding rate, and endless combinations remain open for exploration.

KEYWORDS:

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

Article Highlights

• Immunotherapy for malignant glioma is complicated by several factors that may limit the therapeutic efficacy of monotherapies: (i) gliomas are characterized by a high degree of inter-tumor and intra-tumor cellular and molecular heterogeneity; (ii) gliomas have been shown to induce immunosuppression through secreted factors, expression of immunosuppressive checkpoints, and infiltration of immunosuppressive cells.

• Use of single arm immunotherapies may induce selection and continued growth of poorly immunogenic tumor cells.

• There are currently several immunotherapies that show promising results in preclinical and clinical studies, including immunosuppressive checkpoint inhibition, immune-stimulatory gene therapy, antitumor vaccination, oncolytic virotherary, passive antibody therapy, and adoptive T cell therapy.

• Combinations of currently available immunotherapies have significant potential to improve efficacy of treatment.

• Combinations of checkpoint inhibitors are currently being tested in GBM patients (NCT02017717, NCT02311920, NCT02794883).

• Preclinical studies utilizing two-arm combination gene therapy, comprising the conditional cytotoxic gene TK and the cytokine Flt3L resulted in tumor-specific immune responses, long term survival and immunological memory in glioma-bearing rats and mice. This combined immune-gene therapy approach is currently being tested in human GBM clinical trials (NCT01811992).

• Combinations involving more than one type of immunotherapeutic approach are also promising strategies. For example, combining DC vaccination with TK/Flt3L gene therapy resulted in 90% long-term survival of rats with large syngeneic brain tumors, a significant increase in survival when compared to either therapy alone.

• Combining therapeutic approaches which induce immunogenic tumor cell death with immunotherapies has also shown promise in preclinical and clinical settings. An ongoing Phase I clinical trial is testing the efficacy of oncolytic virotherapy with an oncolytic herpes simplex virus (oHSV) engineered to express the cytokine IL-12 in patients with recurrent/progressive GBM, anaplastic astrocytoma, or gliosarcoma (NCT02062827).

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Acknowledgments

The authors are thankful for the academic leadership and support received from Dr Karin Muraszko and the Department of Neurosurgery; to A. Collada and S. Napolitan for superb administrative support; to M. Dzaman for outstanding technical assistance; and to Elijah Lowenstein for superb editorial comments.

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 R37-NS094804, R01-NS094804, R01-NS074387, R01-NS057711, R21-NS091555, and R01-NS094804 to MG Castro; NIH/NINDS grants R01-NS061107, R01-NS076991, R01-NS082311, and R21-NS084275 to PR Lowenstein; Leah’s Happy Hearts, University of Michigan Comprehensive Cancer Center, Chad Tough Foundation, and The Phase One Foundation to both MG Castro and PR Lowenstein. It was also supported by the Department of Chemical Engineering, University of Michigan (S01-OD020053); the Department of Neurosurgery, University of Michigan Medical School; the Michigan Institute for Clinical and Health Research (under NIH grant 2UL1-TR000433); University of Michigan Cancer Biology Training Grant, NIH/NCI (National Cancer Institute) grant T32-CA009676; the University of Michigan Training in Clinical and Basic Neuroscience through NIH/NINDS grant T32-NS007222; the University of Michigan Medical Scientist Training Program, and NIH/NIGMS (National Institute of General Medical Sciences) grant T32-GM007863. Finally, the authors are given support by the National Council of Scientific and Technological Research (CONICET, Argentina, PIP 2011-00353 to M Candolfi and a Doctoral Fellowship to AS Asad) and the National Agency for the Promotion of Science and Technology (ANPYCT, Argentina, PICT 2013-0310, PICT 2015-3309 to M Candolfi).