Chimeric Antigen Receptor–Modified T Cells for Acute Lymphoid Leukemia

By Stephan A. Grupp, M. Kalos, D. Barrett, R. Aplenc, David L. Porter, S. Rheingold, D. Teachey, A. Chew, B. Hauck, J. F. Wright and 3 more. New England Journal of Medicine, 2013

3,219 citations recorded by the source corpus.

Summary 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 1.4×106 to 1.2×107 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 anti-leukemic 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.

Subfields: Oncology, Public Health, Environmental and Occupational Health

View Paper: https://www.semanticscholar.org/paper/8d0ad14eed4d2aa2759708802d97a349afe54394

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In Oncology

In Public Health, Environmental and Occupational Health

James J. Collins

Citations in the corpus

Molecular remission of infant B-ALL after infusion of universal TALEN gene-edited CAR T cells (2017, background): “In heavily treated cancer patients, and especially in infants, it is not always possible to manufacture an effective therapeutic product (9).”
Distinct Signaling of Coreceptors Regulates Specific Metabolism Pathways and Impacts Memory Development in CAR T Cells. (2016, positive): “Among several proposed strategies, the use of CARs has shown potent effects in augmenting the immune response to cancers, particularly B cell malignancies (Brentjens et al., 2013; Grupp et al., 2013; Kalos et al., 380 Immunity 44, 380–390, February 16, 2016 ª2016 Elsevier Inc. 2011).”
CD22-CAR T Cells Induce Remissions in CD19-CAR Naïve and Resistant B-ALL (2017, neutral): “12,44 In a recent report of 50 patients rendered into remission with CD19-CAR therapy, with a median follow-up of 10.6 months, 40% of patients had relapsed, and loss of the CD19 target accounted for 65% of the total relapses.”
Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia (2018, neutral): “Any grade 3 or 4 adverse event 19 (25) 33 (44) 8 (11) 4 (6)”
Toxicities of chimeric antigen receptor T cells: recognition and management. (2016, neutral): “If the tumorassociated antigen towhich theCAR is targeted is expressed on normal tissues, those tissuesmaybedamaged, as is the casewithnormalB cells being depleted by anti-CD19 CAR T cells.8,16,31 CAR T cells may damage normal tissues by unexpectedly cross-reacting with a protein that is not express”
Engineering T cells with Customized Therapeutic Response Programs Using Synthetic Notch Receptors (2016, neutral): “Particular subresponses can contribute to toxic side effects (Barrett et al., 2014b; Brentjens et al., 2013; Grupp et al., 2013; Porter et al., 2011), which in some cases can be as dangerous as the disease itself (Davila et al.”