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Updated: Jun 7, 2025
Natural Killer NK and CAR-NK Cell Expansion Method using Membrane Bound-IL-21-Modified B Cell Line
Published on: February 8, 2022
Combinatorial immunotherapy of anti-MCAM CAR-modified expanded natural killer cells and NKTR-255 against
Wen Luo1,2, Aliza Gardenswartz1, Hai Hoang1
1Department of Pediatrics, New York Medical College, Valhalla, NY 10595, USA.
Abstract:
Pediatric patients with recurrent metastatic neuroblastoma (NB) have a dismal 5-year survival. Novel therapeutic approaches are urgently needed. The melanoma cell adhesion molecule (MCAM/CD146/MUC18) is expressed in a variety of pediatric solid tumors, including NB, and constitutes a novel target for immunotherapy. Here, we developed a chimeric antigen receptor (CAR) expressing natural killer (NK) cell-targeting MCAM by non-viral electroporation of CAR mRNA into ex vivo expanded NK cells. Expression of anti-MCAM CAR significantly enhanced NK cell cytotoxic activity compared to mock NK cells against MCAMhigh but not MCAMlow/knockout NB cells in vitro. Anti-MCAM-CAR-NK cell treatment significantly decreased tumor growth and prolonged animal survival in an NB xenograft mouse model. NKTR-255, a polymer-conjugated recombinant human interleukin-15 agonist, significantly stimulated NK cell proliferation and expansion and further enhanced the in vitro cytotoxic activity and in vivo anti-tumor efficacy of anti-MCAM-CAR-NK cells against NB. Our preclinical studies demonstrate that ex vivo expanded and modified anti-MCAM-CAR-NK cells alone and/or in combination with NKTR-255 are promising novel alternative therapeutic approaches to targeting MCAMhigh malignant NB.
Insights
Chimeric antigen receptor (CAR) natural killer (NK) cells targeting melanoma cell adhesion molecule (MCAM) show promise for treating neuroblastoma (NB). Combination therapy with NKTR-255 further enhanced anti-tumor efficacy in preclinical models.
Area of Science:
- Immunotherapy
- Oncology
- Cell Biology
Background:
- Recurrent metastatic neuroblastoma (NB) has poor survival rates, necessitating novel treatments.
- Melanoma cell adhesion molecule (MCAM/CD146/MUC18) is a potential therapeutic target in NB.
- Current immunotherapies for NB require further development.
Purpose of the Study:
- To develop and evaluate chimeric antigen receptor (CAR) natural killer (NK) cells targeting MCAM for NB treatment.
- To assess the efficacy of anti-MCAM CAR-NK cells alone and in combination with NKTR-255.
- To investigate the potential of MCAM as a target for pediatric solid tumor immunotherapy.
Main Methods:
- Non-viral mRNA electroporation was used to engineer NK cells with anti-MCAM CAR.
- In vitro cytotoxicity assays were performed using MCAM-expressing NB cell lines.
- In vivo efficacy was evaluated in an NB xenograft mouse model.
- NKTR-255, an IL-15 agonist, was used to enhance NK cell activity.
Main Results:
- Anti-MCAM CAR-NK cells exhibited enhanced cytotoxic activity against MCAM-high NB cells in vitro.
- Treatment with anti-MCAM CAR-NK cells reduced tumor growth and improved survival in a mouse model.
- NKTR-255 significantly boosted NK cell proliferation, expansion, and anti-tumor effects.
- Combination therapy demonstrated superior in vitro and in vivo anti-NB efficacy.
Conclusions:
- Ex vivo expanded and modified anti-MCAM CAR-NK cells are a promising therapeutic strategy for MCAM-high NB.
- Combination with NKTR-255 can further enhance the efficacy of CAR-NK cell therapy for NB.
- These findings support the development of MCAM-targeted CAR-NK cell immunotherapy for pediatric neuroblastoma.
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