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Updated: Jun 20, 2026
Natural Killer NK and CAR-NK Cell Expansion Method using Membrane Bound-IL-21-Modified B Cell Line
Published on: February 8, 2022
NKG2D-CAR-transduced natural killer cells efficiently target multiple myeloma
Alejandra Leivas1,2, Antonio Valeri1,2, Laura Córdoba1,2
1H12O-CNIO Haematological Malignancies Clinical Research Unit, Spanish National Cancer Research Centre, Madrid, Spain.
Abstract:
CAR-T-cell therapy against MM currently shows promising results, but usually with serious toxicities. CAR-NK cells may exert less toxicity when redirected against resistant myeloma cells. CARs can be designed through the use of receptors, such as NKG2D, which recognizes a wide range of ligands to provide broad target specificity. Here, we test this approach by analyzing the antitumor activity of activated and expanded NK cells (NKAE) and CD45RA- T cells from MM patients that were engineered to express an NKG2D-based CAR. NKAE cells were cultured with irradiated Clone9.mbIL21 cells. Then, cells were transduced with an NKG2D-4-1BB-CD3z-CAR. CAR-NKAE cells exhibited no evidence of genetic abnormalities. Although memory T cells were more stably transduced, CAR-NKAE cells exhibited greater in vitro cytotoxicity against MM cells, while showing minimal activity against healthy cells. In vivo, CAR-NKAE cells mediated highly efficient abrogation of MM growth, and 25% of the treated mice remained disease free. Overall, these results demonstrate that it is feasible to modify autologous NKAE cells from MM patients to safely express a NKG2D-CAR. Additionally, autologous CAR-NKAE cells display enhanced antimyeloma activity demonstrating that they could be an effective strategy against MM supporting the development of NKG2D-CAR-NK-cell therapy for MM.
Insights
Chimeric antigen receptor (CAR)-NK cells engineered with NKG2D show potent anti-myeloma activity with reduced toxicity compared to CAR-T cells. This CAR-NK cell therapy offers a promising new strategy for treating multiple myeloma.
Area of Science:
- Immunotherapy
- Cellular therapy
- Oncology
Background:
- CAR-T-cell therapy for multiple myeloma (MM) shows promise but is associated with significant toxicities.
- CAR-NK cells present a potentially safer alternative, especially against resistant myeloma cells.
- NKG2D-based CARs offer broad target specificity by recognizing diverse ligands.
Purpose of the Study:
- To evaluate the antitumor activity and safety of NKG2D-based CAR-engineered NK cells (CAR-NKAE) from MM patients.
- To compare the efficacy of CAR-NKAE cells with CAR-engineered T cells.
- To assess the potential of CAR-NKAE cells as a novel therapeutic strategy for MM.
Main Methods:
- Activated and expanded NK (NKAE) cells and CD45RA- T cells from MM patients were engineered with an NKG2D-4-1BB-CD3z-CAR.
- In vitro cytotoxicity assays were performed against MM cells and healthy cells.
- In vivo studies were conducted to assess the therapeutic efficacy in MM models.
- Genetic stability of CAR-NKAE cells was analyzed.
Main Results:
- CAR-NKAE cells demonstrated potent in vitro cytotoxicity against MM cells with minimal impact on healthy cells.
- In vivo studies showed highly efficient abrogation of MM growth, with 25% of treated mice remaining disease-free.
- CAR-NKAE cells exhibited no genetic abnormalities and were feasible to engineer from autologous patient cells.
- While memory T cells showed more stable transduction, CAR-NKAE cells displayed superior anti-myeloma activity.
Conclusions:
- Autologous NKG2D-CAR-NKAE cells can be safely engineered from MM patients.
- CAR-NKAE cells exhibit enhanced anti-myeloma activity and potential for reduced toxicity.
- NKG2D-CAR-NK-cell therapy represents a viable and effective strategy for treating multiple myeloma.
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