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


ABSTRACT: 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 ?-endodomains, while the other encoded only the ?-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.

SUBMITTER: Savoldo B 

PROVIDER: S-EPMC3083795 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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

Savoldo Barbara B   Ramos Carlos Almeida CA   Liu Enli E   Mims Martha P MP   Keating Michael J MJ   Carrum George G   Kamble Rammurti T RT   Bollard Catherine M CM   Gee Adrian P AP   Mei Zhuyong Z   Liu Hao H   Grilley Bambi B   Rooney Cliona M CM   Heslop Helen E HE   Brenner Malcolm K MK   Dotti Gianpietro G  

The Journal of clinical investigation 20110411 5


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 h  ...[more]

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