Chimeric antigen receptor-engineered natural killer cells for cancer immunotherapy

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Abstract

Natural killer (NK) cells are a critical component of the innate immune system. Chimeric antigen receptors (CARs) re-direct NK cells toward tumor cells carrying corresponding antigens, creating major opportunities in the fight against cancer. CAR NK cells have the potential for use as universal CAR cells without the need for human leukocyte antigen matching or prior exposure to tumor-associated antigens. Exciting data from recent clinical trials have renewed interest in the field of cancer immunotherapy due to the potential of CAR NK cells in the production of “off-the-shelf” anti-cancer immunotherapeutic products. Here, we provide an up-to-date comprehensive overview of the recent advancements in key areas of CAR NK cell research and identify under-investigated research areas. We summarize improvements in CAR design and structure, advantages and disadvantages of using CAR NK cells as an alternative to CAR T cell therapy, and list sources to obtain NK cells. In addition, we provide a list of tumor-associated antigens targeted by CAR NK cells and detail challenges in expanding and transducing NK cells for CAR production. We additionally discuss barriers to effective treatment and suggest solutions to improve CAR NK cell function, proliferation, persistence, therapeutic effectiveness, and safety in solid and liquid tumors.

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Most cited references 226

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Chimeric antigen receptor T cells for sustained remissions in leukemia.

Shannon Maude, Noelle Frey, Pamela Shaw … (2014)

Relapsed acute lymphoblastic leukemia (ALL) is difficult to treat despite the availability of aggressive therapies. Chimeric antigen receptor-modified T cells targeting CD19 may overcome many limitations of conventional therapies and induce remission in patients with refractory disease. We infused autologous T cells transduced with a CD19-directed chimeric antigen receptor (CTL019) lentiviral vector in patients with relapsed or refractory ALL at doses of 0.76×10(6) to 20.6×10(6) CTL019 cells per kilogram of body weight. Patients were monitored for a response, toxic effects, and the expansion and persistence of circulating CTL019 T cells. A total of 30 children and adults received CTL019. Complete remission was achieved in 27 patients (90%), including 2 patients with blinatumomab-refractory disease and 15 who had undergone stem-cell transplantation. CTL019 cells proliferated in vivo and were detectable in the blood, bone marrow, and cerebrospinal fluid of patients who had a response. Sustained remission was achieved with a 6-month event-free survival rate of 67% (95% confidence interval [CI], 51 to 88) and an overall survival rate of 78% (95% CI, 65 to 95). At 6 months, the probability that a patient would have persistence of CTL019 was 68% (95% CI, 50 to 92) and the probability that a patient would have relapse-free B-cell aplasia was 73% (95% CI, 57 to 94). All the patients had the cytokine-release syndrome. Severe cytokine-release syndrome, which developed in 27% of the patients, was associated with a higher disease burden before infusion and was effectively treated with the anti-interleukin-6 receptor antibody tocilizumab. Chimeric antigen receptor-modified T-cell therapy against CD19 was effective in treating relapsed and refractory ALL. CTL019 was associated with a high remission rate, even among patients for whom stem-cell transplantation had failed, and durable remissions up to 24 months were observed. (Funded by Novartis and others; CART19 ClinicalTrials.gov numbers, NCT01626495 and NCT01029366.).

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

Enli Liu, David Marin, Pinaki B. Banerjee … (2020)

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. 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 (1×10 5 , 1×10 6 , or 1×10 7 CAR-NK cells per kilogram of body weight) after lymphodepleting chemotherapy. 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. 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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Current concepts in the diagnosis and management of cytokine release syndrome.

Daniel Lee, Rebecca Ellis Gardner, David Porter … (2014)

As immune-based therapies for cancer become potent, more effective, and more widely available, optimal management of their unique toxicities becomes increasingly important. Cytokine release syndrome (CRS) is a potentially life-threatening toxicity that has been observed following administration of natural and bispecific antibodies and, more recently, following adoptive T-cell therapies for cancer. CRS is associated with elevated circulating levels of several cytokines including interleukin (IL)-6 and interferon γ, and uncontrolled studies demonstrate that immunosuppression using tocilizumab, an anti-IL-6 receptor antibody, with or without corticosteroids, can reverse the syndrome. However, because early and aggressive immunosuppression could limit the efficacy of the immunotherapy, current approaches seek to limit administration of immunosuppressive therapy to patients at risk for life-threatening consequences of the syndrome. This report presents a novel system to grade the severity of CRS in individual patients and a treatment algorithm for management of CRS based on severity. The goal of our approach is to maximize the chance for therapeutic benefit from the immunotherapy while minimizing the risk for life threatening complications of CRS.

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Author and article information

Contributors

Jianhua Yu: Jiayu@coh.org

Journal

Journal ID (nlm-ta): J Hematol Oncol

Journal ID (iso-abbrev): J Hematol Oncol

Title: Journal of Hematology & Oncology

Publisher: BioMed Central (London )

ISSN (Electronic): 1756-8722

Publication date (Electronic): 7 December 2020

Publication date PMC-release: 7 December 2020

Publication date Collection: 2020

Volume: 13

Electronic Location Identifier: 168

Affiliations

[1 ]GRID grid.261331.4, ISNI 0000 0001 2285 7943, The Ohio State University Comprehensive Cancer Center, ; Columbus, OH 43210 USA

[2 ]GRID grid.410425.6, ISNI 0000 0004 0421 8357, Department of Hematology and Hematopoietic Cell Transplantation, , City of Hope National Medical Center, ; 1500 E. Duarte Road, KCRB, Bldg. 158, 3rd Floor, Room 3017, Los Angeles, CA 91010 USA

[3 ]GRID grid.410425.6, ISNI 0000 0004 0421 8357, Hematologic Malignancies and Stem Cell Transplantation Institute, , City of Hope National Medical Center, ; Los Angeles, CA 91010 USA

[4 ]GRID grid.410425.6, ISNI 0000 0004 0421 8357, Department of Immuno-Oncology, , City of Hope Beckman Research Institute, ; Los Angeles, CA 91010 USA

[5 ]GRID grid.410425.6, ISNI 0000 0004 0421 8357, City of Hope Comprehensive Cancer Center and Beckman Research Institute, ; Los Angeles, CA 91010 USA

Article

Publisher ID: 998

DOI: 10.1186/s13045-020-00998-9

PMC ID: 7720606

PubMed ID: 33287875

SO-VID: cf07be74-8cd8-4892-be57-7c731bb2133c

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 16 September 2020

Date accepted : 12 November 2020

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;

Award ID: AI129582

Award ID: CA247550

Award ID: NS106170

Award ID: CA223400

Award ID: CA210087

Award ID: CA068458

Award ID: CA163205

Award Recipient : Michael A. Caligiuri Jianhua Yu

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: chimeric antigen receptor,natural killer cells,t cells,cancer immunotherapy

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: chimeric antigen receptor, natural killer cells, t cells, cancer immunotherapy

Chimeric antigen receptor-engineered natural killer cells for cancer immunotherapy

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Abstract

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Cancer Immunotherapy

Most cited references 226

Chimeric antigen receptor T cells for sustained remissions in leukemia.

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

Current concepts in the diagnosis and management of cytokine release syndrome.

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