Considerations when treating high-grade pediatric glioma patients with immunotherapy

ABSTRACT

Introduction

Children with high-grade gliomas (pHGGs) represent a clinical population in substantial need of new therapeutic options given the inefficacy and toxicity of current standard-of-care modalities. Although immunotherapy has emerged as a promising modality, it has yet to elicit a significant survival benefit for pHGG patients. While preclinical studies address a variety of underlying challenges, translational clinical trial design and management also need to reflect the most updated progress and lessons from the field.

Areas Covered

The authors will focus our discussion on the design of clinical trials, the management of potential toxicities, immune monitoring, and novel biomarkers. Clinical trial design should integrate appropriate patient populations, novel, and preclinically optimized trial design, and logical treatment combinations, particularly those which synergize with standard of care modalities. However, there are caveats due to the nature of immunotherapy trials, such as patient selection bias, evidenced by the frequent exclusion of patients on high-dose corticosteroids. Robust immune-modulating effects of modern immunotherapy can have toxicities. As such, it is important to understand and manage these, especially in pHGG patients.

Expert Opinion

Adequate integration of these considerations should allow us to effectively gain insights on biological activity, safety, and biomarkers associated with benefits for patients.

KEYWORDS:

• Biological correlates
• clinical trial design
• diffuse intrinsic pontine glioma
• diffuse midline glioma
• high-grade glioma
• immunotherapy
• toxicity

Article highlights

• The authors review and provide insights on key consideration points in immunotherapy of pHGGs

• Clinical trial design should integrate appropriate patient populations, novel, and preclinically optimized trial design, and logical treatment combinations, especially standard of care modalities. There are critical caveats, such as patient selection bias, due to the nature of immunotherapy trials, such as frequent exclusion of patients on high-dose corticosteroids.

• Robust immune-activating/modulating effects of modern immunotherapy can have toxicities. It is important to understand and manage these, especially in patients with pHGG.

• The rapid evolution of immune-biomarker detection should be integrated to provide intra- and inter-trial comparability.

Declaration of interest

H Okada declares consultant fees from Bristol-Myers Squibb as well as royalties as inventor of: the H3.3K27M TCR, IL-13Ra2 (345-353:1A9V) peptide, and EGFRvIII-CAR for which an exclusive licensing agreement has been executed with Tmunity, Inc., Stemline, Inc. and Novartis Pharma, respectively. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this 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 paper was supported by funding from grants from NIH/NINDS (1R35 NS105068), to H Okada, as well as from the V Foundation.