Faculty Bibliography

PURPOSE/OBJECTIVE:Isocitrate dehydrogenase (IDH) mutant gliomas are a distinct glioma molecular subtype for which no effective molecularly-directed therapy exists. Low-grade gliomas, which are 80-90% IDH mutant, have high RNA levels of the cell surface Notch ligand DLL3. We sought to determine DLL3 expression by immunohistochemistry in glioma molecular subtypes and the potential efficacy of an anti-DLL3 antibody drug conjugate (ADC), rovalpituzumab tesirine (Rova-T), in IDH mutant glioma. EXPERIMENTAL DESIGN/METHODS:We evaluated DLL3 expression by RNA using TCGA data and by immunohistochemistry in a discovery set of 63 gliomas and 20 non-tumor brain tissues and a validation set of 62 known IDH wildtype and mutant gliomas using a monoclonal anti-DLL3 antibody. Genotype was determined using a DNA methylation array classifier or by sequencing. The effect of Rova-T on patient-derived endogenous IDH mutant glioma tumorspheres was determined by cell viability assay. RESULTS:Compared to IDH wildtype glioblastoma, IDH mutant gliomas have significantly higher DLL3 RNA (P<1x10-15) and protein by immunohistochemistry (P=0.0014 and P<4.3x10-6 in the discovery and validation set, respectively). DLL3 immunostaining was intense and homogeneous in IDH mutant gliomas, retained in all recurrent tumors, and detected in only 1 of 20 non-tumor brains. Patient-derived IDH mutant glioma tumorspheres overexpressed DLL3 and were potently sensitive to Rova-T in an antigen-dependent manner. CONCLUSIONS:DLL3 is selectively and homogeneously expressed in IDH mutant gliomas and can be targeted with Rova-T in patient-derived IDH mutant glioma tumorspheres. Our findings are potentially immediately translatable and have implications for therapeutic strategies that exploit cell surface tumor-associated antigens.

OBJECTIVE:To investigate the question of whether salvage therapy with the programmed cell death protein 1 (PD-1)-blocking antibodies nivolumab or pembrolizumab with or without bevacizumab offers clinical or survival benefit in patients with recurrent high-grade gliomas (HGGs). METHODS:This was a single-institution retrospective observational study in 31 adult patients who received pembrolizumab (Keytruda) or nivolumab (Opdivo) with or without concurrent bevacizumab for recurrent high-grade glioma. RESULTS:= 0.3). The median survival from date of first anti-PD-1 dose was 6.6 months (95% CI 4.2-9.1). CONCLUSION:Salvage therapy with nivolumab or pembrolizumab with or without bevacizumab does not confer a survival benefit in this heavily pretreated unselected patient population. Until the results of the currently ongoing clinical trials become available, the use of PD-1-blocking antibodies should be considered in selected individuals only. CLASSIFICATION OF EVIDENCE:This retrospective observational study provides Class IV evidence that for patients with recurrent HGGs, salvage therapy with nivolumab or pembrolizumab does not significantly improve survival.

PURPOSE OF REVIEW/OBJECTIVE:More effective therapies for glioblastoma are urgently needed. Immunotherapeutic strategies appear particularly promising and are therefore intensively studied. This article reviews the current understanding of the immunosuppressive glioblastoma microenvironment, discusses the rationale behind various immunotherapies, and outlines the findings of several recently published clinical studies. RECENT FINDINGS/RESULTS:The results of CheckMate-143 indicated that nivolumab is not superior to bevacizumab in patients with recurrent glioblastoma. A first-in man exploratory study evaluating EGFRvIII-specific CAR T cells for patients with newly diagnosed glioblastoma demonstrated overall safety of CAR T cell therapy and effective target recognition. A pilot study evaluating treatment with adoptively transferred CMV-specific T cells combined with a CMV-specific DC vaccine was found to be safe and resulted in increased polyclonality of CMV-specific T cells in vivo. Despite the success of immunotherapies in many cancers, clinical evidence supporting their efficacy for patients with glioblastoma is still lacking. Nevertheless, the recently published studies provide important proof-of-concept in several areas of immunotherapy research. The careful and critical interpretation of these results will enhance our understanding of the opportunities and challenges of immunotherapies for high-grade gliomas and improve the immunotherapeutic strategies investigated in future clinical trials.