Reverse Translation Identifies the Synergistic Role of Immune Checkpoint Blockade and IL15 to Enhance Immunotherapy of Ovarian Cancer

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Immune checkpoint blockade (ICB) has changed the standard of care for many patients with cancer, yet no ICB is approved for ovarian cancer. We hypothesized that maintenance therapy with an IL15 “superagonist” (N-803) and ICB in combination could induce potent immune activation in ovarian cancer. Using flow cytometry, cytometry by time of flight analysis, and cytotoxicity assays, we analyzed patient samples from women with advanced epithelial ovarian cancer treated with N-803 for indications of PD-1/PD-L1 upregulation with this treatment. In addition, ICB and N-803 were evaluated in preclinical studies to determine the functional impact of combination therapy on natural killer (NK) cells in vitro and in vivo. We observed that N-803 stimulated initial NK-cell expansion in patient samples; however, proliferation was not sustained beyond 2 weeks despite continued treatment. This result was reverse translated back to the laboratory to determine the functional relevance of this finding. The addition of ICB with an antibody-dependent cellular cytotoxicity IgG1 antibody against PD-L1 (avelumab) or an IgG4 antibody against PD-1 (pembrolizumab) enhanced N-803 induced NK-cell function in vitro. Using models of human ovarian cancer and NK-cell adoptive transfer in mice, we showed enhanced antitumor control with N-803 and ICB, as well as a combination effect that enhanced NK-cell persistence and expansion in vivo. This work suggests that PD-1/PD-L1 blockade combined with IL15 signaling may overcome resistance to cytokine therapy in ovarian cancer.

Original languageEnglish (US)
Pages (from-to)674-686
Number of pages13
JournalCancer Immunology Research
Issue number5
StatePublished - May 1 2023

Bibliographical note

Funding Information:
Research in this publication was supported by the American Cancer Society (RSG-14-151-01-CCE), the Minnesota Ovarian Cancer Alliance, the Department of Defense (OC190344), The Randy Shaver Cancer Research and Community Fund, the Hematology Research Training Program T32 (2T32HL007062), and the National Cancer Institute (R35 CA197292, P01 CA111412).

Funding Information:
M. Felices reports personal fees from GT BioPharma outside the submitted work. J.S. Miller reports grants and personal fees from Fate Therapeutics, GT Biopharma, Vycellix; personal fees and other support from ONK Therapeutics; and other support from Wugen outside the submitted work. M.A. Geller reports grants from Department of Defense, American Cancer Society, NCI, Minnesota Ovarian Cancer Alliance, and Randy Shaver Cancer Research and Community Fund during the conduct of the study; other support from Fate Therapeutics, HCW Biologics, Sanofi, and Merck outside the submitted work. No disclosures were reported by the other authors.

Publisher Copyright:
© 2023 The Authors; Published by the American Association for Cancer Research.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.


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