Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma
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BACKGROUND: In a phase 1 trial, axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, showed efficacy in patients with refractory large B-cell lymphoma after the failure of conventional therapy. METHODS: anti-CD19 CAR T cells per kilogram of body weight after receiving a conditioning regimen of low-dose cyclophosphamide and fludarabine. The primary end point was the rate of objective response (calculated as the combined rates of complete response and partial response). Secondary end points included overall survival, safety, and biomarker assessments. RESULTS: Among the 111 patients who were enrolled, axi-cel was successfully manufactured for 110 (99%) and administered to 101 (91%). The objective response rate was 82%, and the complete response rate was 54%.With a median follow-up of 15.4 months, 42% of the patients continued to have a response, with 40% continuing to have a complete response. The overall rate of survival at 18 months was 52%. The most common adverse events of grade 3 or higher during treatment were neutropenia (in 78% of the patients), anemia (in 43%), and thrombocytopenia (in 38%). Grade 3 or higher cytokine release syndrome and neurologic events occurred in 13% and 28% of the patients, respectively. Three of the patients died during treatment. Higher CAR T-cell levels in blood were associated with response. CONCLUSIONS: In this multicenter study, patients with refractory large B-cell lymphoma who received CAR T-cell therapy with axi-cel had high levels of durable response, with a safety profile that included myelosuppression, the cytokine release syndrome, and neurologic events. (Funded by Kite Pharma and the Leukemia and Lymphoma Society Therapy Acceleration Program; ZUMA-1 ClinicalTrials.gov number, NCT02348216 .).
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CAR T-cells elicited complete responses in 32-67% of lymphoma patients and showed better complete response rates in patients with leukemia.
“These CAR T-cells were able to elicit complete responses (CR) in 32-67% of lymphoma patients and showed better CR rates in patients with leukemia (16-19).”
From Scalable Manufacturing of CAR T Cells for Cancer Immunotherapy (2021) · cites this paper as [16]
The Results > Efficacy section reports a 54% complete response rate in 101 patients with refractory large B-cell lymphoma, which falls within the cited 32–67% range. This paper does not establish that range across lymphoma patients or report better complete response rates in patients with leukemia. (LLM, conf=0.88)
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 [16]
The ZUMA-1 trial reported an overall response rate of 82%, with an ongoing response in 39%, at a median follow-up of 27 months.
“the ZUMA-1 trial that reported an overall response rate of 82%, with an ongoing response in 39%, at a median follow-up of 27 months.”
From Tumor interferon signaling and suppressive myeloid cells are associated with CAR T-cell failure in large B-cell lymphoma (2021) · cites this paper as [2]
Identified factors that affect the efficacy of CAR T-cell therapy include the quality of circulating T cells used for manufacturing, homeostatic cytokine levels at the end of lymphodepleting chemotherapy, and CAR T-cell expansion.
“Identified factors that affect the efficacy of CAR T-cell therapy include the quality of circulating T cells used for manufacturing, homeostatic cytokine levels at the end of lymphodepleting (LD) chemotherapy, and CAR T-cell expansion.”
From Tumor interferon signaling and suppressive myeloid cells are associated with CAR T-cell failure in large B-cell lymphoma (2021) · cites this paper as [2]
Chronic IFN signaling mediates immunosuppression and resistance to radiation and immune checkpoint inhibitor therapy in solid tumors.
“Recently, the Minn group elucidated how chronic IFN signaling mediates immunosuppression and resistance to radiation and immune checkpoint inhibitor therapy in solid tumors.2,24,54”
From Tumor interferon signaling and suppressive myeloid cells are associated with CAR T-cell failure in large B-cell lymphoma (2021) · cites this paper as [2]
In the pivotal ZUMA-1 trial, the degree of early axi-cel expansion in the peripheral blood associated with a DR.
“In the pivotal ZUMA-1 trial, the degree of early axi-cel expansion in the peripheral blood associated with a DR.”
From Tumor interferon signaling and suppressive myeloid cells are associated with CAR T-cell failure in large B-cell lymphoma (2021) · cites this paper as [2]
One part of this program is to increase tumor expression of multiple T-cell ligands that lead to exhaustion of T cells infiltrating the TME.
“One part of this program is to increase tumor expression of multiple T-cell ligands that lead to exhaustion of T cells infiltrating the TME.”
From Tumor interferon signaling and suppressive myeloid cells are associated with CAR T-cell failure in large B-cell lymphoma (2021) · cites this paper as [2]
When tumors express a gene signature (ISG.RS) consisting of genes coordinately activated by multiple types of IFN, a multigenic therapy resistance program is activated.
“When tumors express a gene signature (ISG.RS) consisting of genes coordinately activated by multiple types of IFN, a multigenic therapy resistance program is activated.”
From Tumor interferon signaling and suppressive myeloid cells are associated with CAR T-cell failure in large B-cell lymphoma (2021) · cites this paper as [2]
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- Authors
- Neelapu, S. S., Locke, F. L., Bartlett, N. L., Lekakis, L. J., Miklos, D. B., Jacobson, C. A., Braunschweig, I., Oluwole, O. O., Siddiqi, T., Lin, Y., Timmerman, J. M., Stiff, P. J., Friedberg, J. W., Flinn, I. W., Goy, A., Hill, B. T., Smith, M. R., Deol, A., Farooq, U., McSweeney, P., Munoz, J., Avivi, I., Castro, J. E., Westin, J. R., Chavez, J. C., Ghobadi, A., Komanduri, K. V., Levy, R., Jacobsen, E. D., Witzig, T. E., Reagan, P., Bot, A., Rossi, J., Navale, L., Jiang, Y., Aycock, J., Elias, M., Chang, D., Wiezorek, J., & Go, W. Y.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Montefiore Medical Center (US)
- City Of Hope National Medical Center (US)
- Mayo Clinic (US)
- Loyola University Medical Center (US)
- Hackensack University Medical Center (US)
- Cleveland Clinic (US)
- University of Iowa (US)
- ORCID
- Neelapu, Sattva S.
- Locke, Frederick L.
- Bartlett, Nancy L.
- Lekakis, Lazaros J.
- Miklos, David B.
- Jacobson, Caron A.
- Braunschweig, Ira
- Oluwole, Olalekan O.
- Siddiqi, Tanya
- Lin, Yi
- Timmerman, John M.
- Stiff, Patrick J.
- Friedberg, Jonathan W.
- Flinn, Ian W.
- Goy, Andre
- Hill, Brian T.
- Smith, Mitchell R.
- Deol, Abhinav
- Farooq, Umar
- Munoz, Javier
- Avivi, Irit
- Castro, Januario E.
- Westin, Jason R.
- Ghobadi, Armin
- Komanduri, Krishna V.
- Levy, Ronald
- Jacobsen, Eric D.
- Witzig, Thomas E.
- Reagan, Patrick
- Bot, Adrian
- Rossi, John
- Jiang, Yizhou
- Elias, Meg
- Chang, David
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2017-12-28
- Volume
- 377
- Issue
- 26
- Pages
- 2531-2544
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC5882485
- OpenAlex
- W2773804840
- Cited by
- 6,030
- References
- 35
- Citations by year
- 2026: 569 · 2025: 737 · 2024: 766 · 2023: 772 · 2022: 877 · 2021: 842 · 2020: 697 · 2019: 482 · 2018: 262 · 2017: 4 · 2016: 2 · 2013: 2 · 2012: 2
- FWCI
- 173.07
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Wayne State University
- Cleveland Clinic
- Barbara Ann Karmanos Cancer Institute
- Tel Aviv University
- Kite Pharma
- Roy J. and Lucille A. Carver College of Medicine, University of Iowa
- National Cancer Institute (K23CA201594, P30CA016672)
- 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
- axicabtagene ciloleucel, CAR T-cell therapy, large B-cell lymphoma, refractory lymphoma, anti-CD19 chimeric antigen receptor, autologous T cells, conditioning regimen, objective response rate, complete response, overall survival, neutropenia, cytokine release syndrome, neurological events, myelosuppression
- MeSH terms
- Adult, Aged, Female, Humans, Interleukins, Male, Middle Aged, Nervous System Diseases, Neutropenia, Receptors, Antigen, T-Cell, T-Lymphocytes, Biomarkers, Survival Rate, Immunotherapy, Adoptive, Lymphoma, Large B-Cell, Diffuse, Disease-Free Survival, Antigens, CD19, Young Adult
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