CD38 as a pan-hematologic target for chimeric antigen receptor T cells

• Published in: Blood advances 2023-08, Vol.7 (16), p.4418-4430
• Main Authors: Glisovic-Aplenc, Tina, Diorio, Caroline, Chukinas, John A., Veliz, Kimberly, Shestova, Olga, Shen, Feng, Nunez-Cruz, Selene, Vincent, Tiffaney L., Miao, Fei, Milone, Michael C., June, Carl H., Teachey, David T., Tasian, Sarah K., Aplenc, Richard, Gill, Saar
• Format: Article
• Language: English
• Subjects: Adult; Animals; Child; Hematologic Neoplasms - metabolism; Hematologic Neoplasms - therapy; Humans; Immunobiology and Immunotherapy; Leukemia, Myeloid, Acute - pathology; Mice; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - therapy; Receptors, Chimeric Antigen - genetics; Receptors, Chimeric Antigen - metabolism; T-Lymphocytes
• ISSN: 2473-9529; 2473-9537; 2473-9537
• DOI: 10.1182/bloodadvances.2022007059

•CART-38 cells are effective against preclinical models of human AML, T-ALL, and MM.•CART-38 cells are at least as effective as current immunotherapies for these diseases. [Display omitted] Many hematologic malignancies are not curable with chemotherapy and require novel therapeutic approaches. Chimeric antigen receptor (CAR) T-cell therapy is 1 such approach that involves the transfer of T cells engineered to express CARs for a specific cell-surface antigen. CD38 is a validated tumor antigen in multiple myeloma (MM) and T-cell acute lymphoblastic leukemia (T-ALL) and is also overexpressed in acute myeloid leukemia (AML). Here, we developed human CD38-redirected T cells (CART-38) as a unified approach to treat 3 different hematologic malignancies that occur across the pediatric-to-adult age spectrum. Importantly, CD38 expression on activated T cells did not impair CART-38 cells expansion or in vitro function. In xenografted mice, CART-38 mediated the rejection of AML, T-ALL, and MM cell lines and primary samples and prolonged survival. In a xenograft model of normal human hematopoiesis, CART-38 resulted in the expected reduction of hematopoietic progenitors, which warrants caution and careful monitoring of this potential toxicity when translating this new immunotherapy into the clinic. Deploying CART-38 against multiple CD38-expressing malignancies is significant because it expands the potential for this novel therapy to affect diverse patient populations.