CD28 Costimulation Improves Expansion and Persistence of Chimeric Antigen Receptor-Modified T Cells in Lymphoma Patients

J Clin Invest. 2011 May;121(5):1822-6. doi: 10.1172/JCI46110. Epub 2011 Apr 11.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 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

Substances

  • Antigens, CD19
  • CD28 Antigens