On May 30, 2018 Mustang Bio, Inc. ("Mustang") (NASDAQ:MBIO), a Fortress Biotech (NASDAQ:FBIO) Company focused on the development of novel immunotherapies based on proprietary chimeric antigen receptor engineered T cell (CAR T) technology, reported the publication of preclinical data demonstrating that glioblastoma (GBM)-targeted CD4+ CAR T cells mediate superior antitumor activity over CD8+ CAR T cells (Press release, Mustang Bio, MAY 30, 2018, View Source [SID1234526941]). The results were published in the May 17, 2018, edition of JCI Insight, a peer-reviewed journal of the American Society for Clinical Investigation. Mustang licensed the IL13Rα2‐specific CAR (MB-101) technology used in this preclinical study from the City of Hope National Medical Center ("City of Hope").
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Manuel Litchman, M.D., President and Chief Executive Officer of Mustang, said, "Optimizing T cell potency has the potential to enhance the antitumor efficacy of CAR T therapies in challenging solid tumors, which includes engineering the appropriate composition of CD4+ and CD8+ subsets. This important study conducted by our research partner City of Hope demonstrated the superior antitumor effect of CD4+ over CD8+ T cells in glioblastoma models. Optimizing T cell potency is one of many avenues Mustang is exploring to improve CAR T efficacy, and we look forward to the application of this research in the ongoing Phase 1 trial of our MB-101 IL13Rα2‐specific CAR T therapy in patients with glioblastoma."
Dr. Christine Brown, Heritage Provider Network Professor in Immunotherapy and Associate Director of the T Cell Therapeutics Research Laboratory at City of Hope, said, "This study provides important insight into the differences between CD4+ and CD8+ CAR T cells for maintaining killing potency and resisting exhaustion under conditions of high disease burden. These findings are part of our larger efforts to develop more powerful CAR therapies for the treatment of brain tumors."
In the study, City of Hope investigated the antitumor effect of CD4+ and CD8+ CAR T cells targeting the GBM-associated antigen IL-13 receptor α2 (IL13Rα2) in mouse models. Upon stimulation with IL13Rα2+ GBM cells, the CD8+ CAR T cells exhibited robust short-term effector function but became rapidly exhausted. In comparison, CD4+ CAR T cells persisted after tumor challenge and sustained effector potency.
Mixing with CD4+ CAR T cells failed to improve the effector dysfunction of CD8+ CAR T cells, and CD4+ CAR T cell effector potency was weakened when applied with CD8+ CAR T cells. In orthotopic GBM models, CD4+ outperformed CD8+ CAR T cells, specifically with respect to long-term antitumor response. Maintenance of the CD4+ subset was positively correlated with the recursive killing ability of CAR T cell products derived from GBM patients.