Immunotherapy Against Gliomas: is the Breakthrough Near?
Immunotherapeutic approaches have been, and continue to be, aggressively investigated in the treatment of infiltrating gliomas. While the results of late-phase clinical studies have been disappointing in this disease space thus far, the success of immunotherapies in other malignancies as well as the incremental gains in our understanding of immune-tumour interactions in gliomas has fuelled a strong continued interest of their evaluation in these tumours. We discuss a range of immunotherapeutic approaches including, but not limited to, vaccines, checkpoint inhibitors, oncolytic viruses, and gene therapies. Potential biomarkers under investigation to help elucidate which patients may respond or not respond to immunotherapeutic regimens are reviewed. Directions for future investigations are also noted.
Compliance with Ethical Standards
RVL, DAW, CMH, AMS are supported by P50CA221747 SPORE for Translational Approaches to Brain Tumours. DAW and RVL are supported by BrainUp grant 2136.
Conflicts of interest
RVL has received honoraria for serving on advisory boards for Monteris and Ziopharm. RVL, CMH, AMS, and FMI have received honoraria as consultants for Abbvie. FMI has received honoraria for consulting for Merck, Novocure, Tocagen, Alexion, and Regeneron. RVL has received support from Roche for travel to present at a meeting. FMI has received travel support to FDA meeting from Merck. FMI has received funding for research support for investigator-initiated trials from Merck, BMS, and Novocure. RVL have received honoraria for medical editing from Medlink Neurolology, medical review of content for EBSCO Publishing, and creating/presenting board review material for American Physician Institute.
- 1.Lukas RV, Mrugala MM. Pivotal therapeutic trials for infiltrating gliomas and how they affect clinical practice. Neuro Oncol Pract. 2017;4(4):209–19.Google Scholar
- 9.Grossman SA, Ellsworth S, Campian J, et al. Survival in patients with severe lymphopenia following treatment with radiation and chemotherapy for newly diagnosed solid tumors. J Natl Compr Cancer Netw. 2015;13(10):1225–31.Google Scholar
- 19.Wu A, Wiesner S, Xiao J, et al. Expression of MHC I and NK ligands on human CD133 + glioma cells: possible targets of immunotherapy. J Neurooncol. 2007;83(2):133.Google Scholar
- 29.Galluzi L, Buque A, Kepp O, Zitvogel L, Kroemer G. Immunological effects of conventional chemotherapy and targeted anticancer agents. Cancer Cell. 2015;28(6):690–714.Google Scholar
- 31.Voloshin T, Yitzhaki OT, Kaynan N, et al. Tumor treating fields (TTFields) plus anti-PD-1 therapy induce immunogenic cell death resulting in enhanced antitumor efficacy. AACR abstract 3665. Cancer Res. 2017;77(13):3665.Google Scholar
- 32.Ladomersky E, Genet M, Zhai L, et al. Improving vaccine efficacy against malignant glioma. Oncoimmulogy. 2016;5(8):e1196311.Google Scholar
- 35.Bloch O, Shi Q, Anderson SK, et al. ATIM-14. Alliance A071101: a phase 2 randomized trial comparing the efficacy of heat shock protein peptide complex-96 (HSPPC-96)vaccine given with bevacizumab versus bevacizumab alone in the treatment of surgically resectable recurrent glioblastoma. Neuro Oncol. 2017;19(suppl_6):vi29.PubMedCentralGoogle Scholar
- 40.Reardon DA, Schuster J, Tran DD, et al. ReACT: Overall survival from a randomized phase II study of rindopepimut (CDX-110) plus bevacizumab in relapsed glioblastoma. J Clin Oncol. 2015;33(15_suppl):2009.Google Scholar
- 42.Platten M, Schilling D, Bunse L, et al. NOA-16: A first-in-man multicenter phase 1 clinical trial of the German Neurooncology Working Group evaluating a mutation-specific peptide vaccine targeting IDHR132H in patients with newly diagnosed malignant astrocytomas ATIM-33. Neuro Oncol. 2018;20(suppl_6):vi8–9.PubMedCentralGoogle Scholar
- 44.Reardon DA OA, Brandes AA, Rieger J, Wick A, Sepulveda J, Phuphanich S, De Sousa P, Ahluwalia MS, Lim M, Vlahovic G, Sampson J. Randomized phase 3 study evaluating the efficacy and safety of nivolumab vs bevacizumab in patients with recurrent glioblastoma: CheckMate 143. Neuro-Oncology. 2017;19(Suppl. 3):iii21.PubMedCentralGoogle Scholar
- 45.Bristol-Meyers Squibb press release. 2019. https://news.bms.com/press-release/corporatefinancial-news/bristol-myers-squibb-announces-phase-3-checkmate-498-study-did. Accessed 9 May 2019.
- 46.Bristol-Meyers Squibb press release. 2019. https://investors.bms.com/iframes/press-releases/press-release-details/2019/Bristol-Myers-Squibb-Provides-Update-on-Phase-3-Opdivo-nivolumab-CheckMate–548-Trial-in-Patients-with-Newly-Diagnosed-MGMT-Methylated-Glioblastoma-Multiforme/default.aspx. Accessed 5 Sept 2019.
- 64.Klapper JA, Downey SG, Smith FO, et al. High-dose interleukin-2 for the treatment of metastatic renal cell carcinoma: a retrospective analysis of response and survival in patients treated in the surgery branch at the National Cancer Institute between 1986 and 2006. Cancer. 2008;113:293–301.PubMedPubMedCentralGoogle Scholar
- 66.Dixit K, Kumthekar P. Gene delivery in neuro-oncology. Curr Oncol Rep. 2017;9(11):69.Google Scholar
- 68.Chiocca EA, Lukas R, Rao G, Barrett JA, Buck JY, Demars N, Smith A, Miao J, Zhou J, Gelb A, Cooper LJN. Evaluation of controlled IL-12 in combination with a PD-1 inhibitor in subjects with recurrent glioblastoma. J Clin Oncol. 2019;37(15 suppl):2020.Google Scholar
- 70.Tocagen reports results of Toca 5 phase 3 trial in recurrent brain cancer. 2019. https://ir.tocagen.com/news-releases/news-release-details/tocagen-reports-results-toca-5-phase-3-trial-recurrent-brain. Accessed 12 Sept 2019.
- 77.Friedman HS, Prados MD, Wen PY, et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol. 2009;27(28):4733–40.Google Scholar
- 79.Vredenurgh JJ, Cloughesy T, Samant M, et al. Corticosteroid use in patients with glioblastoma at first or second relapse treated with bevacizumab in the BRAIN study. Oncologist. 2010;15(12):1329–34.Google Scholar
- 83.Ma Q, Xing C, Long W, Wang HY, Liu Q, Wang RF. Impact of microbiota on central nervous system and neurological diseases: the gut-brain axis. J Neuroinflamm. 2019;16(1):53.Google Scholar