Safety and biological outcomes following a phase 1 trial of GD2-specific CAR-T cells in patients with GD2-positive metastatic melanoma and other solid cancers

• Published in: Journal for immunotherapy of cancer 2024-05, Vol.12 (5), p.e008659
• Main Authors: Gargett, Tessa, Truong, Nga T H, Gardam, Bryan, Yu, Wenbo, Ebert, Lisa M, Johnson, Amy, Yeo, Erica C F, Wittwer, Nicole L, Tapia Rico, Gonzalo, Logan, Jesikah, Sivaloganathan, Purany, Collis, Maria, Ruszkiewicz, Andrew, Brown, Michael P
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antigens; Bone cancer; Cancer therapies; Cells; Chemotherapy; Chimeric antigen receptor - CAR; Colorectal cancer; Combination therapy; Cytotoxicity; Ewings sarcoma; FDA approval; Female; Gangliosides - immunology; Glioma; Humans; Immune Cell Therapies and Immune Cell Engineering; Immunotherapy; Immunotherapy, Adoptive - adverse effects; Immunotherapy, Adoptive - methods; Influenza; Kinases; Lymphocytes; Male; Melanoma; Melanoma - immunology; Melanoma - therapy; Metastasis; Middle Aged; Monoclonal antibodies; Neuroblastoma; Patients; Receptors, Chimeric Antigen - immunology; Solid tumor; T-Lymphocytes - immunology; Treatment Outcome; Tumors
• ISSN: 2051-1426; 2051-1426
• DOI: 10.1136/jitc-2023-008659

BackgroundChimeric antigen receptor (CAR) T cell therapies specific for the CD19 and B-cell maturation antigen have become an approved standard of care worldwide for relapsed and refractory B-cell malignancies. If CAR-T cell therapy for non-hematological malignancies is to achieve the same stage of clinical development, then iterative early-phase clinical testing can add value to the clinical development process for evaluating CAR-T cell products containing different CAR designs and manufactured under differing conditions.MethodsWe conducted a phase 1 trial of third-generation GD2-specific CAR-T cell therapy, which has previously been tested in neuroblastoma patients. In this study, the GD2-CAR-T therapy was evaluated for the first time in metastatic melanoma patients in combination with BRAF/MEK inhibitor therapy, and as a monotherapy in patients with colorectal cancer and a patient with fibromyxoid sarcoma. Feasibility and safety were determined and persistence studies, multiplex cytokine arrays on sera and detailed immune phenotyping of the original CAR-T products, the circulating CAR-T cells, and, in select patients, the tumor-infiltrating CAR-T cells were performed.ResultsWe demonstrate the feasibility of manufacturing CAR-T products at point of care for patients with solid cancer and show that a single intravenous infusion was well tolerated with no dose-limiting toxicities or severe adverse events. In addition, we note significant improvements in CAR-T cell immune phenotype, and expansion when a modified manufacturing procedure was adopted for the latter 6 patients recruited to this 12-patient trial. We also show evidence of CAR-T cell-mediated immune activity and in some patients expanded subsets of circulating myeloid cells after CAR-T cell therapy.ConclusionsThis is the first report of third-generation GD2-targeting CAR-T cells in patients with metastatic melanoma and other solid cancers such as colorectal cancer, showing feasibility, safety and immune activity, but limited clinical effect.Trial registration numberACTRN12613000198729.