During the last 2 decades I have had continuous NCI-funding in the areas of natural killer (NK) cell biology, development of immunotherapies and hematopoietic cell transplantation (HCT) for hematologic malignancies and acute myeloid leukemia (AML). My team, who pioneered adoptive transfer of NK cells, has the largest world experience having infused >200 haploidentical NK cell products to treat patients with hematologic and solid tumor malignancies. Recently we described a new paradigm in human NK cell biology by identifying a unique functional phenotype in NK cells induced by cytomegalovirus (CMV). These long-lived, highly differentiated NKG2C+/CD27+ cells, which we call adaptive NK cells are educated and enriched for the expression of self-inhibitory killer-cell immunoglobulin-like receptors (KIR). They represent the human equivalent of the memory-like Ly49H+ NK cells described in CMV-infected mice. Further, we identified expanded NK cell subsets selectively lacking the proximal signaling molecules Fc?R1?, EAT-2 and SYK individually or in combination. Importantly, they are epigenetically primed for enhanced cytokine production and survival, and mediate potent antibody-dependent cellular cytotoxicity (ADCC) through CD16. The overarching goal of this Outstanding Investigator Award is to develop strategies to enhance the anti-tumor activity of endogenous NK cells in patients with solid tumor malignancies. The objective is to develop off the shelf reagents to activate NK cells, overcome inhibitory receptor signaling, and target them to specific tumor antigens. My group has developed several novel NK cell targeting agents, including bi-specific killer engagers (BiKEs), created by fusing scFv anti-CD16 with scFv for tumor antigens and IL-15/IL-15R?-Fc complexes targeted to tumor antigens developed with an industry partner. In this proposal, we will evaluate the therapeutic potential for these agents using several strategies. First, epidemiologic genetic studies in patients with solid tumors will define the relationship between CMV and human papillomavirus (HPV) exposure, the development of virally-induced adaptive NK cells and the risk of cancer development and response to standard therapies. Second, we will evaluate a novel solid tumor antigen, RHAMM, expressed both on tumors and in the cancerized microenvironment. Third, we will use a novel xenogeneic model we will test the anti-tumor efficacy of adaptive NK cells targeted to RHAMM with our unique agents. Fourth, after preclinical evaluations, we will conduct phase I clinical trials of the optimal agents to treat sold tumor malignancies and will test the role of viral vaccines in inducing or enhancing adaptive NK cell function. Lastly, I will build on my long track record of mentorship to use these investigations as a platform to train future translational scientists. The innovative studies proposed here are well supported by preliminary data and represent an emerging area of considerable excitement in NK cell biology. The successful development of therapies to harness innate adaptive NK cells to target solid tumors will have a substantial impact the field of cancer immunotherapy.

Public Health Relevance

My research group reported that infection with the common cytomegalovirus (CMV) induces a population of natural killer (NK) cells with potent immune and anti-tumor function. These special cells, which we named 'adaptive' NK cells, produce inflammatory cytokines and kill tumor cells through Fc receptors that can be triggered by cancer-specific therapeutic antibodies. The concept of CMV-induced 'adaptive' NK cells is new and little is known about these cells in humans. Our goal is to develop strategies to enhance and exploit these cells to treat solid tumor malignancies. We will study samples from cohorts of solid tumor patients to evaluate the role of CMV and human papilloma virus (HPV) in the risk of developing cancer and in the response to therapy. We will study a new cancer target called RHAMM which is expressed both on tumor cells and in the tumor microenvironment. We will test novel agents to target NK cells to RHAMM, first in a unique mouse model, and then in a phase I clinical trial. We have established an expert team and we will use this innovative translational research to promote mentoring and train future scientists.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Unknown (R35)
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Special Emphasis Panel (ZCA1)
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Welch, Anthony R
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University of Minnesota Twin Cities
Internal Medicine/Medicine
Schools of Medicine
United States
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Sarhan, Dhifaf; Hippen, Keli L; Lemire, Amanda et al. (2018) Adaptive NK Cells Resist Regulatory T-cell Suppression Driven by IL37. Cancer Immunol Res 6:766-775
Oh, Felix; Todhunter, Deborah; Taras, Elizabeth et al. (2018) Targeting EGFR and uPAR on human rhabdomyosarcoma, osteosarcoma, and ovarian adenocarcinoma with a bispecific ligand-directed toxin. Clin Pharmacol 10:113-121
de Witte, Moniek A; Sarhan, Dhifaf; Davis, Zachary et al. (2018) Early Reconstitution of NK and ?? T Cells and Its Implication for the Design of Post-Transplant Immunotherapy. Biol Blood Marrow Transplant 24:1152-1162
Cichocki, Frank; Wu, Cheng-Ying; Zhang, Bin et al. (2018) ARID5B regulates metabolic programming in human adaptive NK cells. J Exp Med 215:2379-2395
Felices, Martin; Lenvik, Alexander J; McElmurry, Ron et al. (2018) Continuous treatment with IL-15 exhausts human NK cells via a metabolic defect. JCI Insight 3:
de Witte, Moniek A; Kuball, Jürgen; Miller, Jeffrey S (2017) NK Cells and ??T Cells for Relapse Protection After Allogeneic Hematopoietic Cell Transplantation (HCT). Curr Stem Cell Rep 3:301-311
Uppendahl, Locke D; Dahl, Carly M; Miller, Jeffrey S et al. (2017) Natural Killer Cell-Based Immunotherapy in Gynecologic Malignancy: A Review. Front Immunol 8:1825
Cichocki, Frank; Valamehr, Bahram; Bjordahl, Ryan et al. (2017) GSK3 Inhibition Drives Maturation of NK Cells and Enhances Their Antitumor Activity. Cancer Res 77:5664-5675
Schmohl, Jörg U; Felices, Martin; Oh, Felix et al. (2017) Engineering of Anti-CD133 Trispecific Molecule Capable of Inducing NK Expansion and Driving Antibody-Dependent Cell-Mediated Cytotoxicity. Cancer Res Treat 49:1140-1152
Felices, M; Chu, S; Kodal, B et al. (2017) IL-15 super-agonist (ALT-803) enhances natural killer (NK) cell function against ovarian cancer. Gynecol Oncol 145:453-461

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