We have only recently begun to understand how cancer metabolism affects antitumor responses and immunotherapy outcomes. Certain immunometabolic targets have been actively pursued in other tumor types, however, glioblastoma research has been slow to exploit the therapeutic vulnerabilities of immunometabolism. In this review, we highlight the pathways that are most relevant to glioblastoma and focus on how these immunometabolic pathways influence tumor growth and immune suppression. We discuss hypoxia, glycolysis, tryptophan metabolism, arginine metabolism, 2-Hydroxyglutarate (2HG) metabolism, adenosine metabolism, and altered phospholipid metabolism, in order to provide an analysis and overview of the field of glioblastoma immunometabolism.

Glioblastoma is the the most common primary brain tumor in adults. Onset of disease is followed by a uniformly lethal prognosis and dismal overall survival. While immunotherapies have revolutionized treatment in other difficult-to-treat cancers, these have failed to demonstrate significant clinical benefit in patients with glioblastoma. Obstacles to success include the heterogeneous tumor microenvironment (TME), the immune-privileged intracranial space, the blood–brain barrier (BBB) and local and systemic immunosuppressions. Monoclonal antibody-based therapies have failed at least in part due to their inability to access the intracranial compartment. Bispecific T-cell engagers are promising antibody fragment-based therapies which can bring T cells close to their target and capture them with a high binding affinity. They can redirect the entire repertoire of T cells against tumor, independent of T-cell receptor specificity. However, the multiple challenges posed by the TME, immune privilege and the BBB suggest that a single agent approach may be insufficient to yield durable, long-lasting antitumor efficacy. In this review, we discuss the mechanism of action of T-cell engagers, their preclinical and clinical developments to date. We also draw comparisons with other classes of multispecific antibodies and potential combinations using these antibody fragment therapies.

Combining Immunotherapy for Glioblastoma patents related to PEP-CMV DC vaccine with tetanus, as well as poliovirus vaccine and D2C7 in the treatment of glioblastoma. JHS has an equity interest in Annias Immunotherapeutics, which has licensed intellectual property from Duke related to the use of the pepCMV vaccine in the treatment of glioblastoma. 18. JS reports research funding to his institution from Bayer, Roche, Bristol Myers Squiib, Abbvie, Astra Zeneca, MSD, AbbVie and Astellas. 19. DB is co-owner of Berry Consultants, LLC, a company that designs adaptive Bayesian clinical trials for pharmaceutical and medical device companies, NIH cooperative groups, patient advocacy groups, and international consortia. 20. GZ reports no conflicts of interest. 21. TFC is a co-inventor on patent 62/819,322 licensed to Katmai Pharmaceuticals and a Member of the board for the 501c3 Global Coalition for Adaptive Research. 22. MPM reports consultant or advisory roles for Zap, Mevion, Karyopharm, Tocagen and Astra-Zeneca; and Board of Directors options from Oncoceutics. 23. SPreports consultant or advisory roles for Syntalogic, the MITRE Corporation, and Omnitura. 24. MW has received research grants from AbbVie, Adastra, BMS, Merck, Sharp & Dohme (MSD), Merck (EMD), Novocure, Quercis, and Roche; and honoraria for lectures or advisory board participation or consulting from AbbVie, BMS, Celgene, MSD, Merck (EMD), Novocure, Orbus, Roche, and Tocagen. 25. ABH reports consultant or advisory roles for Caris Life Sciences and WCG Oncology; royalties on licensed intellectual property from Celldex Therapeutics and DNAtrix; research funding from Celularity, Carthera, Codiak, and Moleculin. 26. MK reports consultant or advisory roles for Janssen,