CAR memory-like NK cells targeting the membrane proximal domain of mesothelin demonstrate promising activity in ovarian cancer

Sep 21, 2026

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Epithelial ovarian cancer (EOC) remains among the deadliest gynecological cancers, with limited long-term benefit from current cytoreductive surgery and platinum-based chemotherapy due to relapse and treatment resistance. Cytokine-induced memory-like (CIML) natural killer (NK) cells show promising preclinical and early-phase activity. This study reports that CIML NK cells deliver superior antitumor responses across EOC cell lines, increasing activation receptors while modulating cell-cycle/proliferation and inhibitory gene expression. CAR engineering with a mesothelin (MSLN) membrane-proximal target further enhances activity against MSLN-expressing tumors and patient-derived xenografts. CAR arming substantially reduces CIML NK dysfunction in patient ascites and reveals transcriptomic shifts in metabolism and tonic signaling, while adoptive transfer suppresses tumor growth and prevents metastatic spread in xenograft mice.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages17

Reading Time43 min

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Introduction

Cytokine-induced memory-like NK cells and EOC challenges

CAR-based immunotherapy rationale

NK cell advantages and limitations

IMMUNOLOGY CAR memory–like NK cells targeting the membrane proximal domain of mesothelin demonstrate promising activity in ovarian cancer Mubin Tarannum1, Khanhlinh Dinh1†, Juliana Vergara1†, Grace Birch1, Yasmin Z. Abdulhamid1, Isabel E. Kaplan1, Oyku Ay1, Andreia Maia1, Owen Beaver1, Michal Sheffer1, Roman Shapiro1, Alaa KassimAli1, Han Dong2, James Dongjoo Ham3, Eden Bobilev1, Sydney James4, Amy B. Cameron4, Quang-De Nguyen4, Suthakar Ganapathy5, Chayapatou Chayawatto5, John Koreth1, Cloud P. Paweletz5, Prafulla C. Gokhale5, David A. Barbie5,6, Ursula A. Matulonis7, Robert J. Soiffer1, Jerome Ritz1, Rebecca L. Porter7, Jianzhu Chen3, Rizwan Romee1* Epithelial ovarian cancer (EOC) remains one of the most lethal gynecological cancers. Cytokine-induced memory– like (CIML) natural killer (NK) cells have shown promising results in preclinical and early-phase clinical trials. In the current study, CIML NK cells demonstrated superior antitumor responses against a panel of EOC cell lines, increased expression of activation receptors, and up-regulation of genes involved in cell cycle/proliferation and downregulation of inhibitory/suppressive genes. CIML NK cells transduced with a chimeric antigen receptor (CAR) targeting the membrane-proximal domain of mesothelin (MSLN) further improved the antitumor responses against MSLN-expressing EOC cells and patient-derived xenograft tumor cells. CAR armingof the CIML NK cells subtanstially reduced their dysfunction in patient-derived ascites fluid with transcriptomic changes related to altered metabolism and tonic signaling as potential mechanisms. Lastly, the adoptive transfer of MSLN-CAR CIML NK cells demonstrated remarkable inhibition of tumor growth and prevented metastatic spread in xenograft mice, supporting their potential as an effective therapeutic strategy in EOC. copyright © 2024 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. no claim to original U.S. Government Works. distributed under a creative commons Attribution noncommercial license 4.0 (cc BY-nc) . INTRODUCTION Epithelial ovarian cancer (EOC) is the fifth leading cause of cancerrelated mortality in women with most patients presenting with advanced disease at the time of diagnosis ( 1). The 5-year survival in all stages is ~ 50%, which decreases to ~30% for patients with advanced disease ( 1) . The combination of cytoreductive surgery and platinum-based chemotherapy induces remission in ~80% of women, yet most will relapse and succumb to therapy-resistant disease (2, 3) . Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of hematological and certain solid malignancies (4, 5). Although the presence of tumor-infiltrating lymphocytes has been associated with improved progression-free and overall survival in high-grade serous ovarian carcinoma (HGSOC) (6, 7), single-agent ICIs and in combination with chemotherapies, antiangiogenic agents and poly(adenosine diphosphate–ribose) polymerase inhibitors have only shown a modest response (8–11) . Thus, novel immunotherapeutic strategies are urgently needed to improve survival in EOC. Chimeric antigen receptor (CAR) T cell immunotherapies have remarkably improved the treatment of hematological malignancies, 1division of Transplantation and cellular Therapies, dana-Farber cancer institute, harvard Medical School, Boston, MA, USA. 2department of cancer immunology and virology, dana-Farber cancer institute, harvard Medical School, Boston, MA, USA. 3Koch institute for integrative cancer Research and department of Biology, Massachusetts institute of Technology, cambridge, MA, USA. 4lurie Family imaging center, center for Biomedical imaging in Oncology, dana Farber cancer institute, Boston, MA, USA. 5Belfer center for Applied cancer Science, dana-Farber cancer institute, harvard Medical School, Boston, MA, USA. 6division of Thoracic Oncology, dana-Farber cancer institute, harvard Medical School,

FAQs

Why is epithelial ovarian cancer (EOC) difficult to treat with current therapies?

Despite remission in many patients after cytoreductive surgery and platinum-based chemotherapy, most patients relapse and eventually succumb to therapy-resistant disease. Survival is modest, particularly in advanced stages.

What makes cytokine-induced memory-like (CIML) NK cells promising?

CIML NK cells are generated by brief cytokine stimulation and show increased IFN-γ production, a reduced threshold for secondary activation, massive expansion, and prolonged persistence. These properties address key limitations of conventional NK cell approaches.

How does adding a mesothelin (MSLN) CAR affect CIML NK cell function?

MSLN-targeting CAR-modified CIML NK cells improve antitumor responses against MSLN-expressing EOC cells and patient-derived xenograft tumor cells. CAR arming also reduces dysfunction in patient-derived ascites fluid and supports strong tumor growth inhibition with reduced metastatic spread in xenograft mice.

Sep 21, 2026

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