Checkpoint inhibitor immunotherapy for glioblastoma: current progress, challenges and future outlook

ABSTRACT

Introduction

Despite maximal surgical resection and chemoradiation, glioblastoma (GBM) continues to be associated with significant morbidity and mortality. Novel therapeutic strategies are urgently needed. Given success in treating multiple other forms of cancer, checkpoint inhibitor immunotherapy remains foremost amongst novel therapeutic strategies that are currently under investigation.

Areas covered

Through a systematic review of both published literature and the latest preliminary data available from ongoing clinical studies, we provide an up-to-date discussion on the immune system in the CNS, a detailed mechanistic evaluation of checkpoint biology in the CNS along with evidence for disruption of these pathways in GBM, and a summary of available preclinical and clinical data for checkpoint blockade in GBM. We also include a discussion of novel, emerging targets for checkpoint blockade which may play an important role in GBM immunotherapy.

Expert opinion

Evidence indicates that while clinical success of checkpoint blockade for the treatment of GBM has been limited to date, through improved preclinical models, optimization in the context of standard of care therapies, assay standardization and harmonization, and combinatorial approaches which may include novel targets for checkpoint blockade, checkpoint inhibitor immunotherapy may yield a safe and effective therapeutic option for the treatment of GBM.

KEYWORDS:

• Cancer
• glioma
• immunotherapy
• antibodies
• checkpoint inhibitors
• clinical trials

Article highlights

• Glioblastoma continues to portend a poor prognosis with standards of care that are centered on gross total resection and chemoradiation.

• Contrary to previous belief, the immune system plays an active role in the CNS and further understanding of CNS immunology will allow for more effective anti-cancer therapeutics.

• New strategies centered on immune engagement and anti-tumoral immune responses will be critical to treatment of GBM. Expediated pre-clinical evaluation and advancement to clinical trials will avail new, potentially life-saving therapeutics for patients.

• While checkpoint inhibitor immunotherapy remains promising, there are still challenges to overcome including low mutational burden, loss of neoantigens, resistance, and lymphopenia secondary to bone marrow T cell sequestration.

• Better clinical outcomes may be realized through additional studies utilizing improved preclinical models, strategies to optimize timing of checkpoint inhibitor immunotherapy in the context of other standard of care therapies, and utilization of combinatorial approaches which may include novel targets for checkpoint immunotherapy.

• Through assay standardization and harmonization, more robust and reliable predictive markers of positive clinical outcomes may be determined. This may lead to additional clinical studies with therapeutic regimens tailored to patient populations most likely to benefit.

• Further preclinical and clinical studies are necessary to gain an increased understanding of the safety and efficacy profile of CNS acting immunotherapeutic checkpoint inhibitors, allowing for new and improved therapeutics for the treatment of GBM.

Acknowledgments

Figures 1, 2, and 3 were illustrated specifically for this manuscript by Megan Llewellyn, MSMI. Copyright Duke University. Printed here with permission under a CC-BY 4.0 license.

Declaration of interest

P.C. Gedeon has declared being a co-inventor of patents which belong to Duke University. J.D. Bernstock has declared positions/equity in CITC Ltd and Avidea Technologies and being on the scientific board of advisors for POCKiT Diagnostics. B.D. Choi has declared being a co-inventor of patents which belong to Duke University and General Hospital Corp. He has also received commercial research grants from ACEA Biosciences. J.H. Sampson has declared being a co-inventor of patents which belong to Duke University; receiving commercial research grants from Annias and Istari; holding ownership interest in Annias, Neuronium, Duke University, and Istari; and is on the advisory board of Bristol Myers Squibb, Medicenna, Insera Health and Annais. 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 work was supported by funding from the National Institutes of Health: F30CA196199 (P.C. Gedeon), R01NS085412 (J.H. Sampson), U01NS090284 (J.H. Sampson), R01CA177476 (J.H. Sampson), R01NS086943 (J.H. Sampson), and R01NS099463 (J.H. Sampson). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.