Challenges and strategies for successful clinical development of immune checkpoint inhibitors in glioblastoma

ABSTRACT

Introduction: Glioblastoma (GBM) remains an incurable tumor with median overall survival of 15 months with the best standard of care. Immune checkpoint inhibitors (CPI) have been the forefront of immunotherapy advances for treatment of various solid cancers. However, clinical development of CPI in GBM has been challenging due to factors associated with intracranial tumors such as limited space for an inflammatory response, difficulties with repeated sampling, and low tumor mutation burden and immunosuppressive mechanisms unique to GBM.

Areas covered: Herein, the authors review the clinical development of CPI in GBM, the challenges involved for their successful implementation, and discuss approaches to overcome these challenges.

Expert opinion: Strategies to improve clinical development of CPI in GBM need to carefully address multiple steps that are needed for successful activation and maintenance of tumor-specific immune responses. Multi-modality approaches are needed to achieve this goal and should focus on augmenting tumor T-cell infiltration, activating cytotoxic T-cells, and maintaining their effector function. CPI have been the most successful immunotherapy approach in the treatment of solid cancers and optimization of combinatorial approaches are needed for their successful implementation in GBM.

KEYWORDS:

• Immune checkpoint inhibitors
• immunosuppressive macrophages
• immunotherapy combinations
• GBM immune microenvironment
• tumor mutational load
• tumor infiltrating lymphocytes

Article highlights

• Immune checkpoint inhibitors (CPI) have been at the forefront of immunotherapy advances for the treatment of cancer. However, clinical development of CPI in GBM has been challenging due to several simultaneous immunosuppressive mechanisms in GBM.

• Local immunosuppressive mechanisms in GBM are due to both tumor intrinsic factors and an immunosuppressive microenvironment.

• Tumor intrinsic factors include expression of T-cell inhibitory ligands, activation of immunosuppressive pathways, and impaired antigen presentation.

• GBM immunosuppressive microenvironment is a result of the absence of cytotoxic T-cells, abundance of immunosuppressive macrophages, and presence of various immunosuppressive soluble factors.

• Systemic immunosuppression in GBM is due to circulating immunosuppressive monocytes and macrophages and low T-cell counts in treatment-naïve patients, exacerbated by lymphotoxic effects of radiation and temozolomide.

• CPI pre-clinical and clinical studies highlight the importance of combinatorial immunotherapies targeting more than one of the above mechanisms for successful development of immunotherapy strategies for the treatment of GBM.

• Combinatorial therapy approaches should be implemented in a step-wise fashion and be aimed at increasing tumor mutational load, tumor infiltrating lymphocytes, selecting effective target antigens, activating infiltrative cytotoxic T-cells, and maintaining T-cell effector function.

• Additional challenges in clinical development of CPI in GBM include radiographic assessment of GBM tumors treated with immunotherapy, implementation of CPI into the existing standard of care for GBM, and management of immunotherapy-induced cerebral edema which warrants careful consideration of steroid use in clinical trial designs.

Declaration of interest

J de Groot has received grant/research support from Sanofi, AstraZeneca, EMD-Serono, Eli Lilly and Company, Novartis, Deciphera Pharmaceuticals and Mundipharma. He is also a paid consultant for Celldex, Deciphera Pharmaceuticals, AbbVie, FivePrime Therapeutics Inc, GW Pharma, Carthera, Eli Lilly, Boston Biomedical Inc, Taiho Pharmaceuticals, Kairos Venture Investments, Syneos Health, Monteris, Agios, Mundipharma and Blue Earth Diagnostics. Furthermore, he serves on advisory boards for Genentech, Celldex, Foundation Medicine Inc, Novogen, Deciphera, AstraZeneca, Insys Therapeutics, Kadmon, Merck & Co., Eli Lilly, Novella Clinical and Blue Earth Diagnostics. He also declares other relevant financial or material interests including serving on the Data and Safety Monitoring Board (DSMB) of Novella and VBL Therapeutics. He also serves on an advisory committee for a clinical trial for VBI Vaccines Inc and has stock ownership in Ziopharm Oncology and Gilead Sciences. Finally, his spouse is employed by Ziopharm Oncology. The authors have no other 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 apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript has not been funded.