CAR-NK cell therapy for hematological malignancies: recent updates from ASH 2022
Journal of Hematology & Oncology volume 16, Article number: 35 (2023)
Chimeric antigen receptor (CAR)-NK cell therapy has the advantages of a low incidence of side effects and a low cost. However, the clinical outcomes are not satisfactory due to limited antitumor effects and a limited proliferative capacity. Recently, progress in CAR-NK cell therapy has been made in NK cell engineering, target design and combination with other agents to treat relapsed or refractory hematological malignancies, especially acute myeloid leukemia and multiple myeloma. This correspondence summarizes the preclinical and clinical updates for universal CAR-NK cell therapy reported at the ASH 2022 annual meeting.
To the editor:
Chimeric antigen receptor (CAR)-T cell therapy has substantially improved the outcomes of patients with hematological malignancies. However, insufficient autologous T cells, an extensive manufacturing time, severe side effects and a high price have restricted the clinical use of CAR-T cells . CAR-NK cell therapy could be a universal, well tolerated and affordable treatment . This report summarized the latest updates at the ASH 2022 annual meeting on the methods to improve the efficacy of CAR-NK cells.
A new CAR screening platform was established to select an appropriate CAR transmembrane domain and endo-domain from 44 CAR constructs containing NK cell activating receptors, cytokine receptors and integrins to match NK cells through coculture target cell killing assays. The selected structure was tested in several cell lines, including SUP-B15, MOLT-4, and Raji, with different binding antigens and showed improved (more than 20%) antitumor efficacy in all killing assays compared with the reported NKG2D-2B4-CD3ζ CAR structure (Abstract 1983) . FT555 is a GRPC5D CAR-NK cell derived from iPSCs expressing hnCD16 (> 90%) and IL15RF (> 90%) with CD38 knocked out. Combination of FT555 and anti-CD38 mAb (daratumumab) showed a prolonged persistence compared with CAR-NK cells alone in a multiple myeloma (MM) mouse model (Abstract 1992) . Another study also exhibited the improved anti-tumor efficacy of BCMA/GRPC5D dual CAR-NK cells in MM model (Abstract 3283) . Downregulating immune checkpoint receptor natural killer group 2A (NKG2A) with CRISPR/Cas9 to disrupt the immunosuppression mediated by the tumor microenvironment was shown to significantly improve the antileukemia efficacy of CD33 CAR NK cells in killing assays and AML mouse model (Abstract 1991) . The combination of a Trispecific killer engager (TriKE) capable of binding to the CD16 Fc receptor with IL-15 stimulation and CD33-binding domains and α3 MICA/B CAR-NK cells-controlled leukemia, while progression was observed in α3 MICA/B CAR-NK cells alone under stress (effector: target ratio of 0.25:1) in vitro (Abstract 4623) .
In a preclinical study, CD123 CAR-NK cells (5-day OS: 100%) also showed less acute toxicity than CD123 CAR-T cells (5-day OS: 0%) in a mouse model engrafted with human hematopoietic cells, while the antileukemia efficacy was comparable in acute myeloid leukemia (AML) mouse models (Abstract 3279) . Another CAR NK cell therapy for AML showed that CD33/FLT3 CAR-NK cells have exhibited promising antileukemia efficacy (> 90% killing of leukemia cells) in animal models, and the addition of endomucin-inhibiting CARs protected ~ 42% of primary healthy human HSCs and HPCs from cytotoxicity in in vitro assays (Abstract 1978) .
Hematopoietic stem cell-derived lymphoid progenitors with Bcl11b inhibition directly differentiate into NK cells rather than T cells, which contributes to the production of stable CAR-NK cells (Abstract 1220)  (Table 1).
A Chinese team presented the initial results of a phase I clinical trial of human umbilical cord-derived CD33 CAR-NK cells for patients with relapsed or refractory AML (Table 2). In 10 evaluated patients, only one patient developed grade 2 cytokine release syndrome (CRS), and no higher-grade CRS occurred. There were no instances of Immune effector cell-associated neurotoxicity syndrome (ICANS) of any grade. All patients with grade 3–4 bone marrow suppression recovered within one month. Regarding antileukemia efficacy, 60% (6/10) of the patients achieved a complete response (CR) 28 days after CAR-NK cell infusion (Abstract 3317) . Another phase I trial of induced pluripotent stem cell (iPSC)-derived B-cell maturation antigen (BCMA) CAR-NK cells is being conducted for MM (Table 2). Neither CRS nor ICANS was observed in 9 patients who received CAR-NK cell infusion (3 received daratumumab as a combination therapeutic agent). One patient treated with 300 million BCMA CAR-NK cells as a monotherapy achieved a very good partial response (VGPR). Two patients achieved a response after 100 million BCMA CAR-NK cells infusion and daratumumab (Abstract 2004) .
Expansion condition, transduction efficiency, and anti-tumor efficacy are the most significant obstacles for CAR-NK cell therapy. In the future, genetically modified methods, preconditioning regimen, cell dose, and combined immunotherapies or hematopoietic stem cell transplant need to be optimized to improve CAR-NK cell therapy, which requires more study to promote the clinical translation of CAR-NK cells.
Availability of data and materials
Chimeric antigen receptor
Cytokine release syndrome
Immune effector cell-associated neurotoxicity syndrome
Acute myeloid leukemia
Natural killer group 2A
Trispecific killer engager
Induced pluripotent stem cell
Very good partial response
Lamers-Kok N, Panella D, Georgoudaki A-M, Liu H, Özkazanc D, Kučerová L, et al. Natural killer cells in clinical development as non-engineered, engineered, and combination therapies. J Hematol Oncol. 2022;15:164.
Wang X, Yang X, Yuan X, Wang W, Wang Y. Chimeric antigen receptor-engineered NK cells: new weapons of cancer immunotherapy with great potential. Exp Hematol Oncol. 2022;11:85.
Swanson L, Lyon K, Tadros W, Loreti M, Babin T, Blair B, et al. Development of next-generation NK cell optimized chimeric antigen receptors (CARs) for iPSC-derived NK cell therapies targeting both solid and liquid tumors. Blood. 2022;140(Supplement 1):4540–1.
Reiser J, Chan SR, Mathavan K, Sillitti D, Mottershead C, Mattson B, et al. FT555: off-the-shelf CAR-NK cell therapy co-targeting GPRC5D and CD38 for the treatment of multiple myeloma. Blood. 2022;140(Supplement 1):4560–1.
Cao Z, Yang C, Wang Y, Wang C, Wang Q, Ye G, et al. Allogeneic CAR-NK cell therapy targeting both BCMA and GPRC5D for the treatment of multiple myeloma. Blood. 2022;140(Supplement 1):7378.
Albinger N, Bexte T, Buchinger L, Wendel P, Al-Ajami A, Gessner A, et al. CRISPR/Cas9 gene editing of immune checkpoint receptor NKG2A improves the efficacy of primary CD33-CAR-NK cells against AML. Blood. 2022;140(Supplement 1):4558–9.
Davis Z, Cichocki F, Felices M, Wang H, Hinderlie P, Juckett M, et al. A novel dual-antigen targeting approach enables off-the-shelf CAR NK cells to effectively recognize and eliminate the heterogenous population associated with AML. Blood. 2022;140(Supplement 1):10288–9.
Caruso S, De Angelis B, Del Bufalo F, Ciccone R, Donsante S, Volpe G, et al. Safe and effective off-the-shelf immunotherapy based on CAR.CD123-NK cells for the treatment of acute myeloid leukaemia. J Hematol Oncol. 2022;15:163.
Garrison B, Deng H, Yucel G, Frankel NW, Gordley R, Hung M, et al. Senti-202, a selective, off-the-shelf, preclinical CAR-NK cell therapy with CD33 and/or FLT3 activating CAR, healthy cell protection from endomucin (EMCN) inhibitory CAR and calibrated release IL-15 for hematologic malignancies including AML. Blood. 2022;140(Supplement 1):4531–2.
Baatz F, Herbst J, Meyer J, Schambach A, Maetzig T, Hust M, et al. Bcl11b-edited lymphoid progenitors for the generation of CAR-engineered natural killer-like cells with potent anti-leukemic activity. Blood. 2022;140(Supplement 1):2862–3.
Huang R, Wen Q, Wang X, Yan H, Ma Y, Mai-Hong W, et al. Off-the-shelf CD33 CAR-NK cell therapy for relapse/refractory AML: first-in-human. Phase I Trial Blood. 2022;140(Supplement 1):7450–1.
Dhakal B, Berdeja JG, Gregory T, Ly T, Bickers C, Zong X, et al. Interim Phase I clinical data of FT576 as monotherapy and in combination with daratumumab in subjects with relapsed/refractory multiple myeloma. Blood. 2022;140(Supplement 1):4586–7.
This manuscript was funded by the National Key R&D Program of China (2022YFA1103300), the Key Project of The National Clinical Research Center for Hematological Diseases (2020ZKZC02), the Chongqing Natural Science Foundation Innovation Group Science Fund (cstc2021jcyj-cxttX0001), and the Special project for talent construction at Xinqiao Hospital (2022XKRC001).
Ethics approval and consent to participate
Consent for publication
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Huang, R., Wen, Q. & Zhang, X. CAR-NK cell therapy for hematological malignancies: recent updates from ASH 2022. J Hematol Oncol 16, 35 (2023). https://doi.org/10.1186/s13045-023-01435-3