CD28 costimulation improves expansion and persistence of chimeric antigen receptor–modified T cells in lymphoma patients

• Published in: The Journal of clinical investigation Vol. 121; no. 5; pp. 1822 - 1826
• Main Authors: Savoldo, Barbara, Ramos, Carlos Almeida, Liu, Enli, Mims, Martha P., Keating, Michael J., Carrum, George, Kamble, Rammurti T., Bollard, Catherine M., Gee, Adrian P., Mei, Zhuyong, Liu, Hao, Grilley, Bambi, Rooney, Cliona M., Heslop, Helen E., Brenner, Malcolm K., Dotti, Gianpietro
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.05.2011
• Subjects: Antigens; Antigens, CD19 - metabolism; Biomedical research; Brief Report; Care and treatment; CD28 Antigens - metabolism; Cell receptors; Development and progression; Female; Human subjects; Humans; Immunophenotyping; Immunotherapy; Immunotherapy - methods; Lymphocyte Activation; Lymphocytes; Lymphoma; Lymphoma - metabolism; Lymphoma, B-Cell - metabolism; Lymphoma, Non-Hodgkin - metabolism; Lymphomas; Male; Middle Aged; Patients; Physiological aspects; Positron-Emission Tomography - methods; Protein Structure, Tertiary; Retroviridae - genetics; T cells; T-Lymphocytes - metabolism; Tomography, X-Ray Computed - methods; United States
• ISSN: 0021-9738; 1558-8238; 1558-8238
• DOI: 10.1172/JCI46110

Targeted T cell immunotherapies using engineered T lymphocytes expressing tumor-directed chimeric antigen receptors (CARs) are designed to benefit patients with cancer. Although incorporation of costimulatory endodomains within these CARs increases the proliferation of CAR-redirected T lymphocytes, it has proven difficult to draw definitive conclusions about the specific effects of costimulatory endodomains on the expansion, persistence, and antitumor effectiveness of CAR-redirected T cells in human subjects, owing to the lack of side-by-side comparisons with T cells bearing only a single signaling domain. We therefore designed a study that allowed us to directly measure the consequences of adding a costimulatory endodomain to CAR-redirected T cells. Patients with B cell lymphomas were simultaneously infused with 2 autologous T cell products expressing CARs with the same specificity for the CD19 antigen, present on most B cell malignancies. One CAR encoded both the costimulatory CD28 and the ζ-endodomains, while the other encoded only the ζ-endodomain. CAR+ T cells containing the CD28 endodomain showed strikingly enhanced expansion and persistence compared with CAR+ T cells lacking this endodomain. These results demonstrate the superiority of CARs with dual signal domains and confirm a method of comparing CAR-modified T cells within individual patients, thereby avoiding patient-to-patient variability and accelerating the development of optimal T cell immunotherapies.