Preclinical Efficacy of BCMA-Directed CAR T Cells Incorporating a Novel D Domain Antigen Recognition Domain

• Published in: Molecular cancer therapeutics Vol. 21; no. 7; pp. 1171 - 1183
• Main Authors: Buonato, Janine M., Edwards, Justin P., Zaritskaya, Liubov, Witter, Alexandra R., Gupta, Ankit, LaFleur, David W., Tice, David A., Richman, Laura K., Hilbert, David M.
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 05.07.2022
• Subjects: Animals; B-Cell Maturation Antigen - metabolism; Humans; Immunotherapy, Adoptive; Large Molecule Therapeutics; Mice; Multiple Myeloma - pathology; Receptors, Chimeric Antigen - metabolism; Single-Chain Antibodies - genetics; T-Lymphocytes
• ISSN: 1535-7163; 1538-8514; 1538-8514
• DOI: 10.1158/1535-7163.MCT-21-0552

Chimeric antigen receptor (CAR) T-cell therapies directed against B-cell maturation antigen (BCMA) have shown compelling clinical activity and manageable safety in subjects with relapsed and refractory multiple myeloma (RRMM). Prior reported CAR T cells have mostly used antibody fragments such as humanized or murine single-chain variable fragments or camelid heavy-chain antibody fragments as the antigen recognition motif. Herein, we describe the generation and preclinical evaluation of ddBCMA CAR, which uses a novel BCMA binding domain discovered from our D domain phage display libraries and incorporates a 4-1BB costimulatory motif and CD3-zeta T-cell activation domain. Preclinical in vitro studies of ddBCMA CAR T cells cocultured with BCMA-positive cell lines showed highly potent, dose-dependent measures of cytotoxicity, cytokine production, T-cell degranulation, and T-cell proliferation. In each assay, ddBCMA CAR performed as well as the BCMA-directed scFv-based C11D5.3 CAR. Furthermore, ddBCMA CAR T cells demonstrated in vivo tumor suppression in three disseminated BCMA-expressing tumor models in NSG-immunocompromised mice. On the basis of these promising preclinical data, CART-ddBCMA is being studied in a first-in-human phase I clinical study to assess the safety, pharmacokinetics, immunogenicity, efficacy, and duration of effect for patients with RRMM (NCT04155749).