Hg-108multispecific Chimeric Antigen Receptor (car) T-cells Overcome Inter-patient Tumor Heterogeneity and Exhibit Enhanced Antitumor Functionality in the Treatment of Glioblastoma
Year: 2016
Type: article
Abstract: BACKGROUND: Glioblastomas have poor outcomes in children. HER2-specific CAR T-cells kill autologous glioblastoma, but recurrences occur due to antigen escape variants tumor cells that maintain positivity for two other glioma antigens, IL13Rα2 and EphA2. We hypothesized that co-targeting these escape variants will enhance the anti-glioma activity of CAR T-cells. PURPOSE: The intent of this project is to develop trispecific-specific CAR T-cell (triCAR T-cells) for the adoptive immunotherapy of glioblastoma that will overcome inter- and intra-patient heterogeneity. DESIGN/METHODS: We generated and tested the effector functions of patients' triCAR T-cells against autologous glioblastoma cells derived from surgical excision samples. RESULTS: Primary glioblastoma excision samples exhibited varied expression of HER2, IL13Rα2 and EphA2. We generated T-cells trispecific for HER2, IL13Rα2 and EphA2 (triCAR T-cells) by integrating a tricistronic transgene encoding the 3 respective CAR molecules into the T cell genome. Flow cytometry indicated proportionate stable expression of individual CAR molecules on the surface of T-cells. These T-cells show distinct specificity for each of the three glioma antigens evidenced by activation, proliferation, and cytolytic function. Additionally, we used confocal microscopy to examine the T-cell/tumor immunological synapse and discovered microtubule organizing complexes significantly closer to the synapse, indicating a better cytolytic potential of triCAR T-cells. In vitro and in vivo testing in an autologous setup demonstrated enhanced antitumor activity of triCAR T-cells. CONCLUSION: The heterogeneity of glioblastoma justifies targeting multiple glioma antigens simultaneously. We have generated and tested a tri-specific T cell product that exhibits an enhanced anti-glioma efficacy.
Source: Neuro-Oncology
Institution: Baylor College of Medicine
Language: English
Topic: CAR-T cell therapy research
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2431026834