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Intratumoral NK cell delivery combined with neutralization of the NKG2A pathway as treatment for solid cancer

Genes & Immunity (2024)Cite this article

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Natural killer (NK) cells are innate lymphocytes capable of eliminating transformed and virally infected cells in an antigen-independent manner. Due to their potent cytolytic activity, NK cell-based therapies have been explored for cancer treatment, but NK cell-dependent tumor-evasion and intrinsic immunoregulatory mechanisms have conceivably limited their efficacy, and consequently, constrained their implementation in the clinic. In addition, in solid tumors, reduced trafficking into tumors and poor infiltration rates may account for lack of objective therapeutic responses. Therefore, new therapeutic strategies to circumvent NK-cell dysfunction and fully exploit their cytotoxic potential are needed [1].

NK-cell functions are tightly regulated by a delicate balance of activating and inhibitory receptors. Among the inhibitory receptors responsible for NK-cell control is NKG2A, also expressed on some T lymphocytes. Notably, NKG2A expression is upregulated on NK and T cells upon activation, making activated cells more susceptible to NKG2A-mediated immunosuppression. Preclinical studies demonstrated superior NK- and T-cell activity following NKG2A neutralization [2, 3], paving the way for the entrance of the first-in-class IgG4 humanized neutralizing NKG2A antibody (monalizumab) into clinical trials, primarily for solid tumors, with 12 clinical trials completed (NCT02643550, NCT03794544, NCT03822351) or ongoing (NCT02671435, NCT03801902, NCT03833440, NCT04307329, NCT04590963, NCT05061550, NCT05221840, NCT05903092, NCT06152523). Unfortunately, although systemic administration of monalizumab has an excellent safety profile, in monotherapy fails to show efficacy [4]. Better results, however, have been obtained when monalizumab was combined with cetuximab (NCT02643550, NCT04590963), trastuzumab (NCT04307329) or inhibitory checkpoint blockade therapy (ICB: NCT02671435, NCT03794544, NCT03801902, NCT03822351, NCT03833440, NCT05061550, NCT05221840, NCT05903092, NCT06152523) [1, 2, 4, 5].

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Fig. 1: Immunological response of intratumoral delivery of NK cells and NKG2A neutralizing mAbs.

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Acknowledgements

This work was supported by the PID2020-112892RB-100 funded by MCIN/ AEI/10.13039/501100011033, PDC2021-121769-C21 grant funded by MCIN/ AEI/10.13039/501100011033 and The European Union Next GenerationEU/ PRTR, the Fundación La Caixa (HR21-0083), the AACR-AstraZeneca career development award for physician-scientist in honor of Jose Baselga, Partners of Choice Network AstraZeneca (AZ PoC) and the Fundació La Marató TV3 (488/C/2019) and Fundación FERO. MA was supported by a Spanish Association Against Cancer’s Investigator grant (INVES19041ALVA) and currently receives “Ayudas Ramon y Cajal” (RYC2021-033381) from the MCIN/ AEI/10.13039/501100011033. IM, CE, and MA are part of to the Spanish Cancer Immunotherapy Network REINCA (RED2022-134831-T).

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Authors and Affiliations

  1. Program for Immunology and Immunotherapy, CIMA. Universidad de Navarra, Pamplona, Spain

    Ignacio Melero, Carmen Molina & Maite Alvarez

  2. Navarra Institute for Health Research (IdiSNA), Pamplona, Spain

    Ignacio Melero, Carmen Molina & Maite Alvarez

  3. Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain

    Ignacio Melero

  4. Departments of Immunology and Oncology, Clínica Universidad de Navarra, Pamplona, Spain

    Ignacio Melero

  5. Red de Inmunoterapia del Cáncer (REINCA), Madrid, Spain

    Ignacio Melero, Cristina Eguizabal & Maite Alvarez

  6. Cell Therapy, Stem Cells and Tissue Group, Biobizkaia Health Research Institute, Barakaldo, Spain

    Cristina Eguizabal & Maite Alvarez

  7. Advanced Therapies Unit, Basque Center for Blood Transfusion and Human Tissues, Osakidetza, Galdakao, Spain

    Cristina Eguizabal & Maite Alvarez

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Contributions

IM and MA wrote the manuscript. CM and CE assisted with the preparation of the manuscript. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Ignacio Melero or Maite Alvarez.

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Competing interests

CM and CE declare no competing interests. IM reports receiving commercial research grants from AstraZeneca, BMS, Highlight Therapeutics, Alligator, Pfizer Genmab and Roche; has received speakers bureau honoraria from MSD; and is a consultant or advisory board member for BMS, Roche, AstraZeneca, Genmab, Pharmamar, F-Star, Bioncotech, Bayer, Numab, Pieris, Gossamer, Alligator and Merck Serono. MA reports receiving commercial research grants from Highlight Therapeutics and Pharmamar.

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Melero, I., Molina, C., Eguizabal, C. et al. Intratumoral NK cell delivery combined with neutralization of the NKG2A pathway as treatment for solid cancer. Genes Immun (2024). https://doi.org/10.1038/s41435-024-00267-6

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