{
  "abstract": "Background Platinum resistant ovarian cancer (PROC) remains a lethal disease with few effective treatments. Immune checkpoint inhibitors (ICI) are minimally active 1–5 with no FDA approvals, necessitating novel immotherapy strategies. Natural killer (NK) cells can kill tumor cells without prior sensitization or significant toxicity, but poor expansion and persistence has limited clinical translation.6–9 Cytokine-induced memory-like (CIML) NK cells, generated by brief priming with IL-12, IL-15, and IL-18, exhibit enhanced proliferation, survival, and tumor control in ovarian cancer (OC) models.10–13 CIML-NK cells show promising early results and persistence across several cancers, including a 67% objective response rate (ORR) in rel/ref AML from allogeneic donors.12 14 We hypothesized that intraperitoneally-delivered (i.p.) autologous CIML-NK cells following lymphodepleting chemotherapy (LDC) and followed by low-dose IL-2 would be safe, tolerable and induce anti-tumor responses in patients with PROC.Methods This is a Phase 1b investigator-initiated study with primary objectives to determine safety, tolerability and maximum tolerated dose (MTD) of autologous i.p. CIML-NK cells in patients with PROC; secondary objectives include clinical efficacy measures including ORR, clinical benefit rate, PFS and duration of response. Defining expansion, persistence and immunologic function of CIML-NK cells in blood, peritoneal fluid and pre- and on-treatment tumor biopsies are translational objectives.Eligible patients have PROC treated with ≥1 prior line of platinum-based chemotherapy and measurable disease confined to the abdominopelvic cavity, adequate organ function, ECOG performance status ≤1, and suitable for peritoneal catheter insertion. Patients undergo apheresis on day -7 and LDC with fludarabine (25 mg/m2, days -6 through -2) and cyclophosphamide (50 mg/kg, days -5, -4) (figure 1). During LDC, autogologous CIML NK cells are generated via T cell depletion, NK cell purification, and 12-16-hour incubation with IL-12/IL-15/IL-18, followed by 6-day culture in IL-2-supplemented media to allow patient to receive LDC. CIML-NK cells meeting release criteria are infused i.p. followed by 106 IU/m2 IL-2 s.q. every other day for 5 doses. A 3+3 dose-descalation design is used with two dose levels of CIML-NK cells: 5-10x106 cells/kg and 1-2x106 cells/kg. The DLT observation period is 60 days following infusion. An expansion cohort of 6 patients will be treated at the CIML-NK cell MTD.Results Autologous CIML-NK products of sufficient cell number following 6-day culture and administration through a peritoneal dialysis catheter was achieved in the first two patients enrolled. I.p. administration resulted in no adverse events.Conclusions This study continues to enroll patients at the Dana-Farber Cancer Institute ( NCT06321484).Acknowledgements Product manufacturing performed at DFCI’s Cell Manipulation Core Facility. Support from DFCI’s Immune Effector Cell Program has been invaluable. The authors are deeply grateful for funding support from PHASE ONE Foundation and from Pan-Mass Challenge Team Ovarian Cancer.References Disis ML, Taylor MH, Kelly K, et al. Efficacy and safety of avelumab for patients with recurrent or refractory ovarian cancer: phase 1b results from the JAVELIN solid tumor trial. JAMA Oncol. 03 2019;5(3):393–401. doi:10.1001/jamaoncol.2018.6258Matulonis UA, Shapira-Frommer R, Santin AD, et al. Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: results from the phase II KEYNOTE-100 study. Ann Oncol. 07 2019;30(7):1080–1087. doi:10.1093/annonc/mdz135Moore KN, Bookman M, Sehouli J, et al. Atezolizumab, bevacizumab, and chemotherapy for newly diagnosed stage III or IV ovarian cancer: placebo-controlled randomized phase III trial (IMagyn050/GOG 3015/ENGOT-OV39). J Clin Oncol. Jun 2021;39(17):1842–1855. doi:10.1200/JCO.21.00306Hamanishi J, Takeshima N, Katsumata N, et al. Nivolumab versus gemcitabine or pegylated liposomal doxorubicin for patients with platinum-resistant ovarian cancer: open-label, randomized trial in Japan (NINJA). J Clin Oncol. Sep 02 2021:JCO2100334. doi:10.1200/JCO.21.00334Porter RL, Matulonis UA. Checkpoint blockade: not yet NINJA status in ovarian cancer. J Clin Oncol. Sep 16 2021:JCO2101886. doi:10.1200/JCO.21.01886Geller MA, Cooley SA, Wallet M, et al. APOLLO: a phase I study of adaptive memory natural killer (NK) cells in recurrent ovarian cancer. Journal of Clinical Oncology. 2020/05/20;38(15_suppl):6044-6044. doi:10.1200/JCO.2020.38.15_suppl.6044Geller MA, Cooley S, Judson PL, et al. A phase II study of allogeneic natural killer cell therapy to treat patients with recurrent ovarian and breast cancer. Cytotherapy Jan 2011;13(1):98-107. doi:10.3109/14653249.2010.515582Hoogstad-van Evert JS, Bekkers R, Ottevanger N, Jansen JH, Massuger L, Dolstra H. Harnessing natural killer cells for the treatment of ovarian cancer. Gynecol Oncol. Apr 5 2020;doi:10.1016/j.ygyno.2020.03.020Kaur K, Sanghu J, Memarzadeh S, Jewett A. Exploring the potential of natural killer cell-based immunotherapy in targeting high-grade serous ovarian carcinomas. Vaccines (Basel). Jun 18 2024;12(6)doi:10.3390/vaccines12060677Romee R, Schneider SE, Leong JW, et al. Cytokine activation induces human memory-like NK cells. Blood. Dec 6 2012;120(24):4751–60. doi:10.1182/blood-2012-04-419283Romee R, Leong JW, Fehniger TA. Utilizing cytokines to function-enable human NK cells for the immunotherapy of cancer. Scientifica (Cairo). 2014;2014:205796. doi:10.1155/2014/205796Romee R, Rosario M, Berrien-Elliott MM, et al. Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia. Sci Transl Med. Sep 21 2016;8(357):357ra123. doi:10.1126/scitranslmed.aaf2341Leong JW, Chase JM, Romee R, et al. Preactivation with IL-12, IL-15, and IL-18 induces CD25 and a functional high-affinity IL-2 receptor on human cytokine-induced memory-like natural killer cells. Biol Blood Marrow Transplant. Apr 2014;20(4):463–73. doi:10.1016/j.bbmt.2014.01.006Shapiro RM, Birch GC, Hu G, et al. Expansion, persistence, and efficacy of donor memory-like NK cells infused for post-transplant relapse. J Clin Invest. Mar 29 2022. doi:10.1172/JCI154334Ethics Approval The Dana-Farber/Harvard Cancer Center institutional review board approved the study (IRB No. 23-493), and participants gave written informed consent before taking part.Abstract 547 Figure 1Trial schema",
  "authors": [
    {
      "affiliations": [
        "Dana-Farber Cancer Institute, Boston, MA, USA"
      ],
      "name": "Rebecca L Porter"
    },
    {
      "affiliations": [
        "Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA"
      ],
      "name": "Nabihah Tayob"
    },
    {
      "affiliations": [
        "Dana-Farber Cancer Institute, Boston, MA, USA"
      ],
      "name": "Mubin Tarannum"
    },
    {
      "affiliations": [
        "Dana-Farber Cancer Institute, Boston, MA, USA"
      ],
      "name": "Grace Birch"
    },
    {
      "affiliations": [
        "Dana-Farber Cancer Institute, Boston, MA, USA"
      ],
      "name": "Maily Nguyen"
    },
    {
      "affiliations": [
        "Dana-Farber Cancer Institute, Boston, MA, USA"
      ],
      "name": "Casey Welch"
    },
    {
      "affiliations": [
        "Dana-Farber Cancer Institute, Boston, MA, USA"
      ],
      "name": "Jordan Weiss"
    },
    {
      "affiliations": [
        "Dana-Farber Cancer Institute, Boston, MA, USA"
      ],
      "name": "Joyce Liu"
    },
    {
      "affiliations": [
        "Dana-Farber Cancer Institute, Boston, MA, USA"
      ],
      "name": "Ursula Matulonis"
    },
    {
      "affiliations": [
        "Dana-Farber Cancer Institute, Boston, MA, USA"
      ],
      "name": "Panagiotis Konstantinopoulos"
    },
    {
      "affiliations": [
        "Dana-Farber Cancer Institute, Boston, MA, USA"
      ],
      "name": "Jerome Ritz"
    },
    {
      "affiliations": [
        "Dana-Farber Cancer Institute, Boston, MA, USA"
      ],
      "name": "Sarah Nikiforow"
    },
    {
      "affiliations": [
        "Dana-Farber Cancer Institute, Boston, MA, USA"
      ],
      "name": "Rizwan Romee"
    }
  ],
  "title": "547 A phase 1b study of intraperitoneal cytokine-induced memory-like (CIML) natural killer (NK) cell therapy in platinum resistant ovarian cancer",
  "uid": "1a382ad2-1da7-52ae-8a37-5c4988513aad"
}