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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 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.
AuthorsBarbara Savoldo, Carlos Almeida Ramos, Enli Liu, Martha P Mims, Michael J Keating, George Carrum, Rammurti T Kamble, Catherine M Bollard, Adrian P Gee, Zhuyong Mei, Hao Liu, Bambi Grilley, Cliona M Rooney, Helen E Heslop, Malcolm K Brenner, Gianpietro Dotti
JournalThe Journal of clinical investigation (J Clin Invest) Vol. 121 Issue 5 Pg. 1822-6 (May 2011) ISSN: 1558-8238 [Electronic] United States
PMID21540550 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Antigens, CD19
  • CD28 Antigens
Topics
  • Antigens, CD19 (metabolism)
  • CD28 Antigens (metabolism)
  • Female
  • Humans
  • Immunophenotyping
  • Immunotherapy (methods)
  • Lymphocyte Activation
  • Lymphoma (metabolism)
  • Lymphoma, B-Cell (metabolism)
  • Lymphoma, Non-Hodgkin (metabolism)
  • Male
  • Middle Aged
  • Positron-Emission Tomography (methods)
  • Protein Structure, Tertiary
  • Retroviridae (genetics)
  • T-Lymphocytes (metabolism)
  • Tomography, X-Ray Computed (methods)

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