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

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.

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 2

In vivo expansion and persistence of infused CAR.CD19ζ+ versus CAR.CD19-28ζ+ T cell lines as assessed by Q-PCR in peripheral blood.

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In vivo expansion and persistence of infused CAR.CD19ζ+ versus CAR.CD19-...
Data points represent critical postinfusion intervals after the first or second infusion of modified T cells. Patients number 1, number 3, and number 5, who had stable disease or clinical benefit at 6 weeks after the first T cell infusion, received a second infusion of CAR-modified T lymphocytes. Patient number 1 received only CAR.CD19-28ζ+ T cells (2 × 107 cells/m2, the same as for the first infusion), because this was the only product available. Patient number 3 received both CAR.CD19-28ζ+ and CAR.CD19ζ+ T cells, but the cell dose was 60% of their first dose (1 × 108 cells/m2). Patient number 5 received both CAR.CD19-28ζ+ and CAR.CD19ζ+ T cells at the same dose administered during their first infusion (2 × 108 cells/m2). Open arrows indicate the time of T cell infusion, and dashed arrows indicate the time when chemotherapy was initiated for disease progression. Pre, before the first infusion; Pre II, before the second infusion.