Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor
Open accessAbstract
Purpose: T cells can be genetically modified to express an anti-CD19 chimeric antigen receptor (CAR). We assessed the safety and efficacy of administering autologous anti-CD19 CAR T cells to patients with advanced CD19 + B-cell malignancies. Patients and Methods: We treated 15 patients with advanced B-cell malignancies. Nine patients had diffuse large B-cell lymphoma (DLBCL), two had indolent lymphomas, and four had chronic lymphocytic leukemia. Patients received a conditioning chemotherapy regimen of cyclophosphamide and fludarabine followed by a single infusion of anti-CD19 CAR T cells. Results: Of 15 patients, eight achieved complete remissions (CRs), four achieved partial remissions, one had stable lymphoma, and two were not evaluable for response. CRs were obtained by four of seven evaluable patients with chemotherapy-refractory DLBCL; three of these four CRs are ongoing, with durations ranging from 9 to 22 months. Acute toxicities including fever, hypotension, delirium, and other neurologic toxicities occurred in some patients after infusion of anti-CD19 CAR T cells; these toxicities resolved within 3 weeks after cell infusion. One patient died suddenly as a result of an unknown cause 16 days after cell infusion. CAR T cells were detected in the blood of patients at peak levels, ranging from nine to 777 CAR-positive T cells/μL. Conclusion: This is the first report to our knowledge of successful treatment of DLBCL with anti-CD19 CAR T cells. These results demonstrate the feasibility and effectiveness of treating chemotherapy-refractory B-cell malignancies with anti-CD19 CAR T cells. The numerous remissions obtained provide strong support for further development of this approach.
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Most clinical protocols and all commercially approved therapies have relied on viral vectors to deliver CAR transgenes into T cells.
“Further, most clinical protocols, and all the commercially approved therapies, have relied on viral vectors to deliver CAR transgenes into T cells (9-14,24-26).”
From Scalable Manufacturing of CAR T Cells for Cancer Immunotherapy (2021) · cites this paper as [13]
The Preparation of Anti-CD19 CAR T Cells and Ex Vivo Assays section (page unavailable) says this clinical study used a gammaretroviral vector encoding the CAR, supporting it as an example of viral-vector delivery. The paper does not establish that most clinical protocols used viral vectors or that all commercially approved therapies did. (LLM, conf=0.86)
Experimental — accuracy not yet measuredAll approved CAR T-cell products are second-generation CARs that incorporate CD28 or CD137 (4-1BB) co-stimulatory signals.
“All approved CAR T-cell products are second-generation CARs that incorporate CD28 or CD137 (4-1BB) co-stimulatory signals, which are essential for eliciting effector and memory cell expansion and persistence and a clinically relevant immune response (9-15).”
From Scalable Manufacturing of CAR T Cells for Cancer Immunotherapy (2021) · cites this paper as [13]
The ‘Anti-CD19 CAR T Cells Generated From PBMCs of Heavily Treated Patients’ section states that the CAR used in this study contained a CD28 costimulatory moiety. The paper does not establish that all approved CAR T-cell products are second-generation CARs or that they use either CD28 or CD137; it describes this study’s construct, not the approved-product class. (LLM, conf=0.87)
Experimental — accuracy not yet measuredMost CAR T cell trials to date have used autologous peripheral blood and apheresis as the main cell sources for manufacturing.
“First, most CAR T cell trials to date have used autologous peripheral blood and apheresis as the main cell sources for manufacturing (9-18,21,22).”
From Scalable Manufacturing of CAR T Cells for Cancer Immunotherapy (2021) · cites this paper as [13]
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- Authors
- Kochenderfer, J. N., Dudley, M. E., Kassim, S. H., Somerville, R. P. T., Carpenter, R. O., Stetler-Stevenson, M., Yang, J. C., Phan, G. Q., Hughes, M. S., Sherry, R. M., Raffeld, M., Feldman, S., Lu, L., Li, Y. F., Ngo, L. T., Goy, A., Feldman, T., Spaner, D. E., Wang, M. L., Chen, C. C., Kranick, S. M., Nath, A., Nathan, D.-A. N., Morton, K. E., Toomey, M. A., & Rosenberg, S. A.
- Affiliations
- National Institutes of Health (US)
- James N. Kochenderfer, Mark E. Dudley, Sadik H. Kassim, Robert P.T. Somerville, Robert O. Carpenter, Maryalice Stetler-Stevenson, James C. Yang, Q. Phan, Marybeth S. Hughes, Richard M. Sherry, Mark Raffeld, Steven Feldman, Lily Lu, Yong F. Li, Lien T. Ngo, Debbie-Ann N. Nathan, Kathleen E. Morton, Mary Ann Toomey, and Steven A. Rosenberg, National Cancer Institute; Clara C. Chen, Clinical Center, National Institutes of Health (NIH); Sarah M. Kranick and Avindra Nath, National Institutes of Neurologic...
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2015-02-20
- Volume
- 33
- Issue
- 6
- Pages
- 540-549
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- PMC
- PMC4322257
- OpenAlex
- W2170513194
- Cited by
- 1,595
- References
- 2
- Citations by year
- 2026: 25 · 2025: 68 · 2024: 95 · 2023: 88 · 2022: 99 · 2021: 147 · 2020: 179 · 2019: 203 · 2018: 214 · 2017: 201 · 2016: 158 · 2015: 108 · 2014: 6 · 2012: 1
- FWCI
- 76.17
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Oncology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Health and Human Services (HHSN261200800001E)
- National Institutes of Health (Contract No. HHSN261200800001E., #HHSN261200800001E, HHSN261200800001C)
- Kite Pharma
- National Cancer Institute (No. HHSN261200800001E, Contract No.,HHSN261200800001E, HHSN261200800001E))
- NIH Clinical Center (HHSN261200800001E)
- Topics
- Health Sciences › Medicine › Oncology › CAR-T cell therapy research
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- diffuse large B-cell lymphoma, indolent B-cell lymphoma, chronic lymphocytic leukemia, anti-CD19 chimeric antigen receptor, CAR T-cell therapy, autologous T cells, chemotherapy-refractory lymphoma, complete remission, neurotoxicity, CAR T cell persistence
- MeSH terms
- Adult, Aged, Antineoplastic Combined Chemotherapy Protocols, Combined Modality Therapy, Cyclophosphamide, Female, Humans, Male, Middle Aged, Receptors, Antigen, T-Cell, T-Lymphocytes, Vidarabine, Immunotherapy, Adoptive, Lymphoma, B-Cell, Lymphoma, Large B-Cell, Diffuse, Antigens, CD19, Transplantation Conditioning
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