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Circumventing Ewing sarcoma tumor microenvironment resistance by IL1RAP CAR-modified TGFβ1-imprinted natural killer

Wen Luo1,2, Hai-Feng Zhang3, Wei Li4

  • 1Pediatrics, New York Medical College, Valhalla, NY, USA mitchell_cairo@nymc.edu wen_luo@nymc.edu.

Journal for Immunotherapy of Cancer
|July 3, 2026
PubMed
Abstract

Insights

This study developed a novel immunotherapy combining engineered Natural Killer (NK) cells, an IL-15 agonist, and an anti-GD2 antibody to effectively treat refractory Ewing sarcoma (ES). The triple combination demonstrated superior efficacy in preclinical models, offering a promising new strategy for patients with limited options.

Area of Science:

  • Immunotherapy
  • Oncology
  • Cellular Therapy

Background:

  • Metastatic/relapsed/refractory Ewing sarcoma (ES) has a poor prognosis.
  • Natural Killer (NK) cells show cytotoxicity against ES but face tumor microenvironment (TME)-mediated resistance.
  • Current strategies aim to overcome ES resistance to NK cells through combinatorial approaches.

Purpose of the Study:

  • To develop a combinatorial immunotherapy to overcome ES resistance to NK cells.
  • To enhance NK cell tumor targeting, circumvent immunosuppression, and improve cytotoxicity and persistence.
  • To evaluate the efficacy of a novel approach combining chimeric antigen receptor (CAR)-NK cells, an IL-15 agonist (NKTR-255), and an anti-GD2 antibody (dinutuximab).

Main Methods:

  • Peripheral blood mononuclear cells were expanded into NK and TGFβ1-imprinted NK (imNK) cells.
  • Anti-IL1RAP-CAR mRNA was electroporated into NK or imNK cells.
  • In vitro cytotoxicity assays and in vivo xenograft mouse models were used to assess combinatorial therapy efficacy.
  • Single-cell RNA sequencing and mass cytometry analyzed treatment mechanisms.

Main Results:

  • Anti-IL1RAP-CAR-NK cells enhanced NK cytotoxicity and reduced tumor growth/metastasis in vitro and in vivo.
  • TGFβ1-imprinting improved CAR-NK cell cytotoxicity, tumor infiltration, and animal survival.
  • The triple combination (CAR-imNK cells, NKTR-255, dinutuximab) showed superior antitumor efficacy against IL1RAP+GD2+ ES.
  • Mechanistic studies revealed increased ES cell apoptosis and altered TME immune cell infiltration.

Conclusions:

  • Combinatorial innate immunotherapy using TGFβ1-imprinted IL1RAP-CAR-NK cells, an IL-15 agonist, and an anti-GD2 antibody is a promising strategy for metastatic/relapsed/refractory ES.
  • Preclinical data support this approach as a novel therapeutic option for difficult-to-treat ES.
  • Further investigation into this combination therapy is warranted.
Keywords:
Bone CancerChimeric antigen receptor - CARCombination therapyImmunotherapyNatural killer - NK

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