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.
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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 |
Journal | The Journal of clinical investigation
(J Clin Invest)
Vol. 121
Issue 5
Pg. 1822-6
(May 2011)
ISSN: 1558-8238 [Electronic] United States |
PMID | 21540550
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Antigens, CD19
- CD28 Antigens
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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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