Cell-surface antigen profiling of pediatric brain tumors: B7-H3 is consistently expressed and can be targeted via local or systemic CAR T-cell delivery

Abstract

Background Immunotherapy with CAR T-cells is actively being explored for pediatric brain tumors in preclinical models and early phase clinical studies. At present it is unclear which CAR target antigens are consistently expressed across different pediatric brain tumor types. In addition, the extent of HLA class-I expression is unknown, which is critical for tumor recognition by conventional αβTCR T-cells. Methods We profiled 49 low- and high-grade pediatric brain tumor patient-derived orthotopic xenografts (PDOX) by flow analysis for the expression of five CAR targets (B7-H3, GD2, IL13Rα2, EphA2, HER2), and HLA class-I. In addition, we generated B7-H3-CAR T-cells and evaluated their antitumor activity in vitro and in vivo. Results We established an expression hierarchy for the analyzed antigens (B7-H3 = GD2 >> IL13Rα2 > HER2 = EphA2) and demonstrated that antigen expression is heterogenous. All high-grade gliomas expressed HLA class-I, but only 57.1% of other tumor subtypes had detectable expression. We then selected B7-H3 as a target for CAR T-cell therapy. B7-H3-CAR T-cells recognized tumor cells in an antigen-dependent fashion. Local or systemic administration of B7-H3-CAR T-cells induced tumor regression in PDOX and immunocompetent murine glioma models resulting in a significant survival advantage. Conclusions Our study highlights the importance of studying target antigen and HLA class-I expression in PDOX samples for the future design of immunotherapies. In addition, our results support active preclinical and clinical exploration of B7-H3-targeted CAR T-cell therapies for a broad spectrum of pediatric brain tumors.

Immune Checkpoint-Associated Locations of Diffuse Gliomas Comparing Pediatric With Adult Patients Based on Voxel-Wise Analysis

“…The results that DGs with high expression of B7-H3 in adults located in this region might exactly reveal the difference in age and the association between B7-H3 and DGs. As the white matter is indicated to contribute to the malignant behaviors such as the spread of gliomas (38), mature white matter in adults rather than pediatric patients is assumed to be more conducive to this cancerous nature. Moreover, the anterior horn (also known as the frontal horn) of the ventricle is found to frequently affected by adult DGs (Figure 1B).…”

World Cancer Day 2021 - Perspectives in Pediatric and Adult Neuro-Oncology

“…It has been a very exciting time for innovative approaches using several types of therapy that harness the immune system, either alone, in combination or added to standard therapies using chemotherapy or radiation therapy ( 89 , 90 ). These approaches include tumor vaccines ( 91 ), oncolytic viruses ( 92 – 96 ), immune checkpoint inhibitors ( 97 – 99 ) and chimeric antigen receptor ( CAR) T-cells ( 100 – 103 ). Improved clinical outcomes using immune checkpoint inhibitors in patients with biallelic mismatch repair deficiency and high tumor mutation burdens (TMB) have been reported ( 104 ).…”

Targeting Tumor-Associated Antigen: A Promising CAR-T Therapeutic Strategy for Glioblastoma Treatment

“…Developing targeted GBM therapies has increasingly become a research hotspot. Several preclinical and clinical studies on CAR-T immunotherapy for malignant gliomas have yielded positive results ( Ahmed et al, 2017 ; Schneider et al, 2017 ; Thistlethwaite et al, 2017 ; Haydar et al, 2020 ). The therapeutic patterns of CAR-T cells targeting TAAs for GBM treatment are depicted in Figure 4 .…”

“…In 2019, Nehama et al verified that CAR-T targeting B7-H3 release effective factors such as IFN-γ and IL-2 and control the growth of B7-H3 + human GBM cell lines and neurospheres ( Nehama et al, 2019 ). CAR-T targeting B7-H3 has potent antitumor activities in patient-derived orthotopic xenograft and immune-competent animal models ( Haydar et al, 2020 ). Dual CAR-T target antigens exhibit enhanced antitumor activities and improve the heterogeneity and variation of antigens in treating multiple types of solid tumors ( Yang et al, 2020 ).…”