Chimeric Antigen Receptor–Modified T Cells for Acute Lymphoid Leukemia
Open accessAbstract
Chimeric antigen receptor-modified T cells with specificity for CD19 have shown promise in the treatment of chronic lymphocytic leukemia (CLL). It remains to be established whether chimeric antigen receptor T cells have clinical activity in acute lymphoblastic leukemia (ALL). Two children with relapsed and refractory pre-B-cell ALL received infusions of T cells transduced with anti-CD19 antibody and a T-cell signaling molecule (CTL019 chimeric antigen receptor T cells), at a dose of 1.4×10(6) to 1.2×10(7) CTL019 cells per kilogram of body weight. In both patients, CTL019 T cells expanded to a level that was more than 1000 times as high as the initial engraftment level, and the cells were identified in bone marrow. In addition, the chimeric antigen receptor T cells were observed in the cerebrospinal fluid (CSF), where they persisted at high levels for at least 6 months. Eight grade 3 or 4 adverse events were noted. The cytokine-release syndrome and B-cell aplasia developed in both patients. In one child, the cytokine-release syndrome was severe; cytokine blockade with etanercept and tocilizumab was effective in reversing the syndrome and did not prevent expansion of chimeric antigen receptor T cells or reduce antileukemic efficacy. Complete remission was observed in both patients and is ongoing in one patient at 11 months after treatment. The other patient had a relapse, with blast cells that no longer expressed CD19, approximately 2 months after treatment. Chimeric antigen receptor-modified T cells are capable of killing even aggressive, treatment-refractory acute leukemia cells in vivo. The emergence of tumor cells that no longer express the target indicates a need to target other molecules in addition to CD19 in some patients with ALL.
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All 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 [9]
The paper states that the CTL019 receptor includes a CD137 (4-1BB) signaling domain, and the Results report substantial expansion of CTL019 cells in two children. It does not establish that all approved CAR T-cell products are second-generation CARs or that they all incorporate CD28 or CD137; the Methods describe this as a phase 1 trial, not a survey of approved products. No page numbers are available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredMost 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 [9]
The Methods describe this clinical protocol as using a lentiviral vector, and the Abstract says CTL019 was expressed using lentiviral-vector technology. This supports the paper as an example of a clinical protocol using a viral vector, but it does not establish that most protocols or all commercially approved therapies use viral vectors. (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 [9]
Incorporation of a dominant-negative, cytoplasmically truncated TβRII receptor within T cells attenuated immunosuppression by TGF-β.
“With refinements in T cell engineering, incorporation of a dominant-negative, cytoplasmically truncated TβRII receptor within T cells attenuated immunosuppression by TGF-β377.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [377]
Nearly all patients with cytokine storm are febrile.
“Nearly all patients with cytokine storm are febrile”
From Cytokine storm (2020) · cites this paper as [8]
Fever in cytokine storm may be high grade in severe cases.
“the fever may be high grade in severe cases”
From Cytokine storm (2020) · cites this paper as [8]
Highly elevated serum interleukin-6 levels are found in CAR T-cell therapy-induced cytokine storm and several other cytokine storm disorders.
“Highly elevated serum interleukin-6 levels are found in CAR T-cell therapy–induced cytokine storm and several other cytokine storm disorders.”
From Cytokine storm (2020) · cites this paper as [8]
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- Authors
- Grupp, S. A., Kalos, M., Barrett, D., Aplenc, R., Porter, D. L., Rheingold, S. R., Teachey, D. T., Chew, A., Hauck, B., Wright, J. F., Milone, M. C., Levine, B. L., & June, C. H.
- Affiliations
- Children's Hospital of Philadelphia (US)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2013-04-18
- Volume
- 368
- Issue
- 16
- Pages
- 1509-1518
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC4058440
- OpenAlex
- W2105400883
- Cited by
- 3,509
- References
- 26
- Citations by year
- 2026: 105 · 2025: 169 · 2024: 198 · 2023: 237 · 2022: 260 · 2021: 290 · 2020: 339 · 2019: 318 · 2018: 299 · 2017: 320 · 2016: 311 · 2015: 294 · 2014: 229 · 2013: 129 · 2012: 6
- FWCI
- 172.01
- Type
- journal article
- Language
- en
- Update notices
- correction (2016-03-10)
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA165206, R01CA102646, R01CA116660, P30CA016520)
- Topics
- Health Sciences › Medicine › Oncology › CAR-T cell therapy research
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Acute Lymphoblastic Leukemia research
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- chimeric antigen receptor T cells, acute lymphoblastic leukemia, B-cell precursor acute lymphoblastic leukemia, CD19, tisagenlecleucel, relapsed/refractory leukemia, cytokine release syndrome, B-cell aplasia, etanercept, tocilizumab, complete remission
- MeSH terms
- Child, Chimera, Female, Humans, Immunotherapy, Receptors, Antigen, T-Cell, Remission Induction, T-Lymphocytes, Antigens, CD19, Precursor Cell Lymphoblastic Leukemia-Lymphoma
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