Use of CAR-Transduced Natural Killer Cells in CD19-Positive Lymphoid Tumors.

Abstract

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.).

• Authors: Enli Liu, David Marin, Pinaki Banerjee, Homer A Macapinlac, Philip Thompson, Rafet Basar, Lucila Nassif Kerbauy, Bethany Overman, Peter Thall, Mecit Kaplan, Vandana Nandivada, Indresh Kaur, Ana Nunez Cortes, Kai Cao, May Daher, Chitra Hosing, Evan N Cohen, Partow Kebriaei, Rohtesh Mehta, Sattva Neelapu, Yago Nieto, Michael Wang, William Wierda, Michael Keating, Richard Champlin, Elizabeth J Shpall, Katayoun Rezvani
• Journal: The New England journal of medicine (N Engl J Med) Vol. 382 Issue 6 Pg. 545-553 (02 06 2020) ISSN: 1533-4406 [Electronic] United States
• PMID: 32023374 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2020 Massachusetts Medical Society.

Chemical References

• Antigens, CD19
• Receptors, Chimeric Antigen

Topics

• Aged
• Allografts
• Antigens, CD19
• Cell- and Tissue-Based Therapy
• Female
• Fetal Blood
• Genetic Vectors
• Humans
• Killer Cells, Natural (immunology, transplantation)
• Leukemia, Lymphocytic, Chronic, B-Cell (immunology, therapy)
• Lymphoma, Non-Hodgkin (immunology, therapy)
• Male
• Middle Aged
• Receptors, Chimeric Antigen (antagonists & inhibitors)
• Remission Induction (methods)
• Retroviridae (genetics)
• Transplantation Conditioning