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CD28 costimulation improves expansion and persistence of chimeric antigen receptor–modified T cells in lymphoma patients
Barbara Savoldo, … , Malcolm K. Brenner, Gianpietro Dotti
Barbara Savoldo, … , Malcolm K. Brenner, Gianpietro Dotti
Published April 11, 2011
Citation Information: J Clin Invest. 2011;121(5):1822-1826. https://doi.org/10.1172/JCI46110.
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Brief Report Immunology Article has an altmetric score of 28

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

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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.

Authors

Barbara 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

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Figure 1

Transduction efficiency and phenotypic/function profile of T cell lines.

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Transduction efficiency and phenotypic/function profile of T cell lines....
(A) FACS and Q-PCR analyses showing transduction efficiency with CAR.CD19ζ and CAR.CD19-28ζ vectors (left). Bars indicate mean values for peripheral blood samples from 6 patients (Supplemental Table 1). Each symbol represents an individual cell line. Representative histograms of T cells transduced with CAR.CD19ζ and CAR.CD19-28ζ vectors from patients number 1 and number 5 are also presented (right). Numbers represent the percentage of CAR+ cells. (B) Results of a 4-hour 51Cr-release assay at an effector/tumor cell (E/T) ratio of 20:1. Target cells were Raji (CD19+, CD80+, CD86–), a Burkitt lymphoma cell line; HLDM-2 (CD19–, CD80+, CD86+), a Hodgkin lymphoma cell line; and K562 (CD19–, CD80–, CD86–), an erythroid leukemia cell line that is susceptible to natural killer cell activity. Both CAR.CD19ζ+ and CAR.CD19-28ζ+ T cells specifically targeted CD19+ tumors. Data are mean ± SD for the 6 T cell lines. (C) Phenotypic composition of CAR.CD19ζ+ or CAR.CD19-28ζ+ T cells. These products contained both CD8+ and CD4+ CAR-expressing T cells that are predominantly CD45RO+CD62L+, with a fraction of them expressing CD28. Each symbol represents an individual cell line, and horizontal bars denote mean group values.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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