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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

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 3

Detection of CAR+ T cells in a skin tumor biopsy.

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Detection of CAR+ T cells in a skin tumor biopsy.
   
(A) Immunohistoche...
(A) Immunohistochemical examination (diaminobenzidine with hematoxylin counterstaining) of a punch biopsy of a lymphoma skin lesion from patient number 5 at 2 weeks after T cell infusion showed that tumor cells were CD20+ (shown), CD10+, BCL2+, and BCL6+, consistent with involvement by follicular lymphoma with large cell transformation. Scattered CD3+ CD8+ cells infiltrated the tumor. Of note, the infused CAR.CD19-28ζ+ product consisted of 85% CD8+ cells. Scale bar: 100 μm. (B) FACS analysis of a cell suspension obtained from a fragment of the tumor biopsy. Viable cells represented approximately 45% of the preparation. The far left panel shows the gate on CD45+ cells, which represented 12% of the viable cells. The middle panel shows the CD3+ lymphocytes infiltrating the tumor, which accounted for 6.7% of CD45+ cells (0.8% of all viable cells). The far right panel illustrates that 20% of the gated CD3+ lymphocytes cells coexpressed the CAR, as assessed by the Fc-Cy5 monoclonal antibody, which binds to the IgG1-CH2CH3 spacer region of the CD19-specific CARs (~0.16% of all viable cells). SSC, side scatter.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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