TY - JOUR
T1 - Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors
AU - Liu, Enli
AU - Marin, David
AU - Banerjee, Pinaki
AU - MacApinlac, Homer A.
AU - Thompson, Philip
AU - Basar, Rafet
AU - Kerbauy, Lucila Nassif
AU - Overman, Bethany
AU - Thall, Peter
AU - Kaplan, Mecit
AU - Nandivada, Vandana
AU - Kaur, Indresh
AU - Cortes, Ana Nunez
AU - Cao, Kai
AU - Daher, May
AU - Hosing, Chitra
AU - Cohen, Evan N.
AU - Kebriaei, Partow
AU - Mehta, Rohtesh
AU - Neelapu, Sattva
AU - Nieto, Yago
AU - Wang, Michael
AU - Wierda, William
AU - Keating, Michael
AU - Champlin, Richard
AU - Shpall, Elizabeth J.
AU - Rezvani, Katayoun
N1 - Funding Information:
Supported by a grant from the M.D. Anderson Cancer Center CLL and Lymphoma Moonshot, by grants (1 R01 CA211044-01, 5 P01CA148600-03, and P50CA100632-16) from the National Institutes of Health (NIH), and by a grant (CA016672) to the M.D. Anderson Cancer Center from the NIH.
Publisher Copyright:
Copyright © 2020 Massachusetts Medical Society.
PY - 2020/2/6
Y1 - 2020/2/6
N2 - BACKGROUND Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has shown remarkable clinical efficacy in B-cell cancers. However, CAR T cells can induce substantial toxic effects, and the manufacture of the cells is complex. Natural killer (NK) cells that have been modified to express an anti-CD19 CAR have the potential to overcome these limitations. METHODS In this phase 1 and 2 trial, we administered HLA-mismatched anti-CD19 CAR-NK cells derived from cord blood to 11 patients with relapsed or refractory CD19- positive cancers (non-Hodgkin's lymphoma or chronic lymphocytic leukemia [CLL]). NK cells were transduced with a retroviral vector expressing genes that encode anti-CD19 CAR, interleukin-15, and inducible caspase 9 as a safety switch. The cells were expanded ex vivo and administered in a single infusion at one of three doses (1×105, 1×106, or 1×107 CAR-NK cells per kilogram of body weight) after lymphodepleting chemotherapy. RESULTS The administration of CAR-NK cells was not associated with the development of cytokine release syndrome, neurotoxicity, or graft-versus-host disease, and there was no increase in the levels of inflammatory cytokines, including interleukin-6, over baseline. The maximum tolerated dose was not reached. Of the 11 patients who were treated, 8 (73%) had a response; of these patients, 7 (4 with lymphoma and 3 with CLL) had a complete remission, and 1 had remission of the Richter's transformation component but had persistent CLL. Responses were rapid and seen within 30 days after infusion at all dose levels. The infused CAR-NK cells expanded and persisted at low levels for at least 12 months. CONCLUSIONS Among 11 patients with relapsed or refractory CD19-positive cancers, a majority had a response to treatment with CAR-NK cells without the development of major toxic effects. (Funded by the M.D. Anderson Cancer Center CLL and Lymphoma Moonshot and the National Institutes of Health; ClinicalTrials.gov number, NCT03056339.)
AB - BACKGROUND Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has shown remarkable clinical efficacy in B-cell cancers. However, CAR T cells can induce substantial toxic effects, and the manufacture of the cells is complex. Natural killer (NK) cells that have been modified to express an anti-CD19 CAR have the potential to overcome these limitations. METHODS In this phase 1 and 2 trial, we administered HLA-mismatched anti-CD19 CAR-NK cells derived from cord blood to 11 patients with relapsed or refractory CD19- positive cancers (non-Hodgkin's lymphoma or chronic lymphocytic leukemia [CLL]). NK cells were transduced with a retroviral vector expressing genes that encode anti-CD19 CAR, interleukin-15, and inducible caspase 9 as a safety switch. The cells were expanded ex vivo and administered in a single infusion at one of three doses (1×105, 1×106, or 1×107 CAR-NK cells per kilogram of body weight) after lymphodepleting chemotherapy. RESULTS The administration of CAR-NK cells was not associated with the development of cytokine release syndrome, neurotoxicity, or graft-versus-host disease, and there was no increase in the levels of inflammatory cytokines, including interleukin-6, over baseline. The maximum tolerated dose was not reached. Of the 11 patients who were treated, 8 (73%) had a response; of these patients, 7 (4 with lymphoma and 3 with CLL) had a complete remission, and 1 had remission of the Richter's transformation component but had persistent CLL. Responses were rapid and seen within 30 days after infusion at all dose levels. The infused CAR-NK cells expanded and persisted at low levels for at least 12 months. CONCLUSIONS Among 11 patients with relapsed or refractory CD19-positive cancers, a majority had a response to treatment with CAR-NK cells without the development of major toxic effects. (Funded by the M.D. Anderson Cancer Center CLL and Lymphoma Moonshot and the National Institutes of Health; ClinicalTrials.gov number, NCT03056339.)
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U2 - 10.1056/NEJMoa1910607
DO - 10.1056/NEJMoa1910607
M3 - Article
C2 - 32023374
AN - SCOPUS:85079036488
SN - 0028-4793
VL - 382
SP - 545
EP - 553
JO - New England Journal of Medicine
JF - New England Journal of Medicine
IS - 6
ER -