Efficacy of chimeric antigen receptor engineered natural killer cells in the treatment of hematologic malignancies: a systematic review and meta-analysis of preclinical studies

Donald J Bastin; Marisa K Kilgour; Risa Shorr; Elham Sabri; Aurélien Delluc; Michele Ardolino; Scott McComb; Seung-Hwan Lee; David Allan; Tim Ramsay; Alissa Visram

doi:10.1016/j.jcyt.2024.11.004

Efficacy of chimeric antigen receptor engineered natural killer cells in the treatment of hematologic malignancies: a systematic review and meta-analysis of preclinical studies

Cytotherapy. 2024 Nov 23:S1465-3249(24)00928-9. doi: 10.1016/j.jcyt.2024.11.004. Online ahead of print.

Authors

Donald J Bastin¹, Marisa K Kilgour², Risa Shorr³, Elham Sabri⁴, Aurélien Delluc⁵, Michele Ardolino⁶, Scott McComb⁷, Seung-Hwan Lee⁸, David Allan⁵, Tim Ramsay⁹, Alissa Visram¹⁰

Affiliations

¹ Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
² Cancer Research, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
³ Learning Services, The Ottawa Hospital, Ottawa, Ontario, Canada.
⁴ Methods Centre, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
⁵ Department of Medicine (Hematology), The Ottawa Hospital, Ottawa, Ontario, Canada.
⁶ Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada; Cancer Research, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada; CI3, University of Ottawa, Ottawa, Ontario, Canada.
⁷ Human Health Therapeutics Research Center, National Research Council, Ottawa, Ontario, Canada.
⁸ Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
⁹ Methods Centre, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada.
¹⁰ Department of Medicine (Hematology), The Ottawa Hospital, Ottawa, Ontario, Canada. Electronic address: alisvisram@toh.ca.

PMID: 39692673
DOI: 10.1016/j.jcyt.2024.11.004

Abstract

Background: Chimeric antigen receptor (CAR) engineered NK cells (CAR-NK) are a novel approach to the immunotherapy of hematologic malignancies which seeks to overcome some of the challenges faced by CAR-T cells (CAR-T). With few published clinical studies, preclinical studies can identify strategies to accelerate clinical translation. We conducted a systematic review on the preclinical in vivo use of CAR-NK for the treatment of hematologic malignancies to assess these therapies in a holistic and unbiased manner.

Methods: Our protocol was registered with PROSPERO (ID: CRD42023438375). We performed a search of OVID MEDLINE, OVID Embase, and Embase for animal studies employing human CAR-NK cells in the treatment of hematologic malignancies. Screening of studies for eligibility criteria was performed in duplicate. Our primary outcomes were survival and reduction in tumor volume. Data extraction from individual experiments was performed by one reviewer using Digitizeit^TM software and verified by a second reviewer. Meta-analysis and subgroup analyses were performed using Comprehensive Meta-Analysis^TM software. Information for descriptive outcomes was extracted in duplicate by two independent reviewers. Risk of bias was assessed using the SYRCLE Risk of Bias Tool for Animal Studies.

Results: A total of 34 papers met eligibility criteria. Overall, CD19 was the most common antigen targeted however there was substantial diversity in antigenic targets, source material for generating CAR-NK cells, and NK cell modifications. Mice treated with CAR-NK therapy survived significantly longer than untreated mice (median survival ratio of 1.18, 95% CI: 1.10-1.27, P < 0.001), and mice treated with nonengineered NK cells (median survival ratio 1.13, 95% CI: 1.03-1.23, P < 0.001). Similarly, treatment with CAR-NK significantly reduced the tumor burden when compared to untreated mice (ratio of mean tumor volume 0.23, 95% CI: 0.17-0.32, P < 0.001) or mice treated with nonengineered NK cells (ratio of mean tumor volume 0.37, 95% CI: 0.28-0.51, P < 0.001). Subgroup analysis showed that cotreatment with IL-15 reduced tumor volume but did not increase survival. In general, CAR-NK cell persistence was short but was increased by IL-15.

Conclusions: CAR-NK shows promise for the treatment of hematologic malignancies in preclinical models.

Keywords: CAR-NK; acute leukemia; cell therapy; hematologic malignancy; immunotherapy; lymphoma; multiple myeloma; preclinical systematic review.