CD28 costimulation improves expansion and persistence of chimeric antigen receptor–modified T cells in lymphoma patients
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,...
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| Published in | The Journal of clinical investigation Vol. 121; no. 5; pp. 1822 - 1826 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
American Society for Clinical Investigation
01.05.2011
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| Subjects | |
| Online Access | Get full text |
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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. |
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| AbstractList | 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. 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.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. 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. |
| Audience | Academic |
| Author | Liu, Hao Rooney, Cliona M. Brenner, Malcolm K. Gee, Adrian P. Heslop, Helen E. Mims, Martha P. Savoldo, Barbara Ramos, Carlos Almeida Liu, Enli Dotti, Gianpietro Kamble, Rammurti T. Mei, Zhuyong Bollard, Catherine M. Grilley, Bambi Carrum, George Keating, Michael J. |
| AuthorAffiliation | 1 Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, USA. 2 Department of Pediatrics, Texas Children’s Hospital, Houston, Texas, USA. 3 Department of Medicine, Baylor College of Medicine, Houston, Texas, USA. 4 The Methodist Hospital, Houston, Texas, USA. 5 The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. 6 Biostatistics Core of the Dan L. Duncan Cancer Center, Houston, Texas, USA. 7 Department of Virology and 8 Department of Immunology, Baylor College of Medicine, Houston, Texas, USA |
| AuthorAffiliation_xml | – name: 1 Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, USA. 2 Department of Pediatrics, Texas Children’s Hospital, Houston, Texas, USA. 3 Department of Medicine, Baylor College of Medicine, Houston, Texas, USA. 4 The Methodist Hospital, Houston, Texas, USA. 5 The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. 6 Biostatistics Core of the Dan L. Duncan Cancer Center, Houston, Texas, USA. 7 Department of Virology and 8 Department of Immunology, Baylor College of Medicine, Houston, Texas, USA |
| Author_xml | – sequence: 1 givenname: Barbara surname: Savoldo fullname: Savoldo, Barbara – sequence: 2 givenname: Carlos Almeida surname: Ramos fullname: Ramos, Carlos Almeida – sequence: 3 givenname: Enli surname: Liu fullname: Liu, Enli – sequence: 4 givenname: Martha P. surname: Mims fullname: Mims, Martha P. – sequence: 5 givenname: Michael J. surname: Keating fullname: Keating, Michael J. – sequence: 6 givenname: George surname: Carrum fullname: Carrum, George – sequence: 7 givenname: Rammurti T. surname: Kamble fullname: Kamble, Rammurti T. – sequence: 8 givenname: Catherine M. surname: Bollard fullname: Bollard, Catherine M. – sequence: 9 givenname: Adrian P. surname: Gee fullname: Gee, Adrian P. – sequence: 10 givenname: Zhuyong surname: Mei fullname: Mei, Zhuyong – sequence: 11 givenname: Hao surname: Liu fullname: Liu, Hao – sequence: 12 givenname: Bambi surname: Grilley fullname: Grilley, Bambi – sequence: 13 givenname: Cliona M. surname: Rooney fullname: Rooney, Cliona M. – sequence: 14 givenname: Helen E. surname: Heslop fullname: Heslop, Helen E. – sequence: 15 givenname: Malcolm K. surname: Brenner fullname: Brenner, Malcolm K. – sequence: 16 givenname: Gianpietro surname: Dotti fullname: Dotti, Gianpietro |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/21540550$$D View this record in MEDLINE/PubMed |
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| Title | CD28 costimulation improves expansion and persistence of chimeric antigen receptor–modified T cells in lymphoma patients |
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