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

B Savoldo, CA Ramos, E Liu, MP Mims… - The Journal of …, 2011 - Am Soc Clin Investig
B Savoldo, CA Ramos, E Liu, MP Mims, MJ Keating, G Carrum, RT Kamble, CM Bollard
The Journal of clinical investigation, 2011Am Soc Clin Investig
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 …
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.
The Journal of Clinical Investigation