Natural killer (NK) cells are cytotoxic lymphocytes of the innate immune system that are capable of killing virally infected and/or cancerous cells. Nearly 20 years ago, NK cell-mediated immunotherapy emerged as a safe and effective treatment approach for patients with advanced-stage leukaemia. Subsequently, the field of NK cell-based cancer therapy has grown exponentially and currently constitutes a major area of immunotherapy innovation. In general, the development of NK cell-directed therapies has two main focal points: optimizing the source of therapeutic NK cells for adoptive transfer and enhancing NK cell cytotoxicity and persistence in vivo. A wide variety of sources of therapeutic NK cells are currently being tested clinically, including haploidentical NK cells, umbilical cord blood NK cells, stem cell-derived NK cells, NK cell lines, adaptive NK cells, cytokine-induced memory-like NK cells and chimeric antigen receptor NK cells. A plethora of methods to augment the cytotoxicity and longevity of NK cells are also under clinical investigation, including cytokine-based agents, NK cell-engager molecules and immune-checkpoint inhibitors. In this Review, we highlight the variety of ways in which diverse NK cell products and their auxiliary therapeutics are being leveraged to target human cancers. We also identify future avenues for NK cell therapy research.
Natural killer (NK) cell-based therapies are emerging as safe and efficacious treatments for some cancers.
Generally, the two main considerations relating to NK cell therapies are the choice of NK cell source and the method of in vivo enhancement of NK cell function; determining approaches to optimize both of these aspects is of high clinical interest.
Therapeutic NK cells include haploidentical NK cells, chimeric antigen receptor NK cells, stem cell-derived NK cells, umbilical cord blood NK cells, NK cell lines, adaptive NK cells and cytokine-induced memory-like NK cells.
Auxiliary methods for enhancing the therapeutic activity of NK cells in vivo include cytokine-based agents, NK cell-engager molecules (such as TriKEs, ROCK engagers, NKCEs and TriNKETs) and immune-checkpoint inhibitors.
Potential advantages that NK cell therapies have over T cell therapies include more manageable safety profiles and fewer graft restrictions (for example, no requirement for autologous cells, providing opportunities for off-the-shelf products).
NK cell therapies remain subject to important immunosuppressive barriers in the tumour microenvironment; the future success of these therapies will require a better understanding of how these suppressive factors operate and how they can be overcome.
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Herberman, R. B., Nunn, M. E., Holden, H. T. & Lavrin, D. H. Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic and allogeneic tumors. II. Characterization of effector cells. Int. J. Cancer 16, 230–239 (1975).
Kiessling, R., Klein, E. & Wigzell, H. “Natural” killer cells in the mouse. I. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Specificity and distribution according to genotype. Eur. J. Immunol. 5, 112–117 (1975).
Colonna, M. Innate lymphoid cells: diversity, plasticity, and unique functions in immunity. Immunity 48, 1104–1117 (2018).
Scoville, S. D., Freud, A. G. & Caligiuri, M. A. Modeling human natural killer cell development in the era of innate lymphoid cells. Front. Immunol. 8, 360 (2017).
Male, V. et al. Immature NK cells, capable of producing IL-22, are present in human uterine mucosa. J. Immunol. 185, 3913–3918 (2010).
Cichocki, F., Grzywacz, B. & Miller, J. S. Human NK cell development: one road or many? Front. Immunol. 10, 2078 (2019).
Melsen, J. E., Lugthart, G., Lankester, A. C. & Schilham, M. W. Human circulating and tissue-resident CD56bright natural killer cell populations. Front. Immunol. 7, 262 (2016).
Wagner, J. A. et al. CD56bright NK cells exhibit potent antitumor responses following IL-15 priming. J. Clin. Invest. 127, 4042–4058 (2017).
Lanier, L. L., Le, A. M., Civin, C. I., Loken, M. R. & Phillips, J. H. The relationship of CD16 (Leu-11) and Leu-19 (NKH-1) antigen expression on human peripheral blood NK cells and cytotoxic T lymphocytes. J. Immunol. 136, 4480–4486 (1986).
Prager, I. et al. NK cells switch from granzyme B to death receptor-mediated cytotoxicity during serial killing. J. Exp. Med. 216, 2113–2127 (2019).
Bryceson, Y. T., March, M. E., Ljunggren, H.-G. & Long, E. O. Activation, coactivation, and costimulation of resting human natural killer cells. Immunol. Rev. 214, 73–91 (2006).
Romee, R. et al. NK cell CD16 surface expression and function is regulated by a disintegrin and metalloprotease-17 (ADAM17). Blood 121, 3599–3608 (2013).
Barrow, A. D., Martin, C. J. & Colonna, M. The natural cytotoxicity receptors in health and disease. Front. Immunol. 10, 909 (2019).
Zingoni, A. et al. NKG2D and its ligands: “one for all, all for one”. Front. Immunol. 9, 476 (2018).
Schlums, H. et al. Cytomegalovirus infection drives adaptive epigenetic diversification of NK cells with altered signaling and effector function. Immunity 42, 443–456 (2015).
Long, E. O. Negative signaling by inhibitory receptors: the NK cell paradigm. Immunol. Rev. 224, 70–84 (2008).
Parham, P., Norman, P. J., Abi-Rached, L. & Guethlein, L. A. Human-specific evolution of killer cell immunoglobulin-like receptor recognition of major histocompatibility complex class I molecules. Phil. Trans. R. Soc. B 367, 800–811 (2012).
Bernardini, G., Antonangeli, F., Bonanni, V. & Santoni, A. Dysregulation of chemokine/chemokine receptor axes and NK cell tissue localization during diseases. Front. Immunol. 7, 402 (2016).
Kärre, K. NK cells, MHC class I molecules and the missing self. Scand. J. Immunol. 55, 221–228 (2002).
Weng, W.-K. & Levy, R. Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma. J. Clin. Oncol. 21, 3940–3947 (2003).
Varchetta, S. et al. Elements related to heterogeneity of antibody-dependent cell cytotoxicity in patients under trastuzumab therapy for primary operable breast cancer overexpressing Her2. Cancer Res. 67, 11991–11999 (2007).
Castro, F., Cardoso, A. P., Gonçalves, R. M., Serre, K. & Oliveira, M. J. Interferon-gamma at the crossroads of tumor immune surveillance or evasion. Front. Immunol. 9, 847 (2018).
Vitale, M., Cantoni, C., Pietra, G., Mingari, M. C. & Moretta, L. Effect of tumor cells and tumor microenvironment on NK-cell function. Eur. J. Immunol. 44, 1582–1592 (2014).
Molgora, M. et al. The yin-yang of the interaction between myelomonocytic cells and NK cells. Scand. J. Immunol. 88, e12705 (2018).
Batlle, E. & Massagué, J. Transforming growth factor-β signaling in immunity and cancer. Immunity 50, 924–940 (2019).
Zaiatz-Bittencourt, V., Finlay, D. K. & Gardiner, C. M. Canonical TGF-β signaling pathway represses human NK cell metabolism. J. Immunol. 200, 3934–3941 (2018).
Viel, S. et al. TGF-β inhibits the activation and functions of NK cells by repressing the mTOR pathway. Sci. Signal. 9, ra19 (2016).
Otegbeye, F. et al. Inhibiting TGF-beta signaling preserves the function of highly activated, in vitro expanded natural killer cells in AML and colon cancer models. PLoS One 13, e0191358 (2018).
Ravi, R. et al. Bifunctional immune checkpoint-targeted antibody-ligand traps that simultaneously disable TGFβ enhance the efficacy of cancer immunotherapy. Nat. Commun. 9, 741 (2018).
Knudson, K. M. et al. M7824, a novel bifunctional anti-PD-L1/TGFβ Trap fusion protein, promotes anti-tumor efficacy as monotherapy and in combination with vaccine. Oncoimmunology 7, e1426519 (2018).
Terrén, I., Orrantia, A., Vitallé, J., Zenarruzabeitia, O. & Borrego, F. NK cell metabolism and tumor microenvironment. Front. Immunol. 10, 2278 (2019).
Parodi, M. et al. Hypoxia modifies the transcriptome of human NK cells, modulates their immunoregulatory profile, and influences NK cell subset migration. Front. Immunol. 9, 2358 (2018).
Doubrovina, E. S. et al. Evasion from NK cell immunity by MHC class I chain-related molecules expressing colon adenocarcinoma. J. Immunol. 171, 6891–6899 (2003).
Wu, J. D. et al. Prevalent expression of the immunostimulatory MHC class I chain-related molecule is counteracted by shedding in prostate cancer. J. Clin. Invest. 114, 560–568 (2004).
Raulet, D. H., Gasser, S., Gowen, B. G., Deng, W. & Jung, H. Regulation of ligands for the NKG2D activating receptor. Annu. Rev. Immunol. 31, 413–441 (2013).
Ferrari de Andrade, L. et al. Antibody-mediated inhibition of MICA and MICB shedding promotes NK cell-driven tumor immunity. Science 359, 1537–1542 (2018).
Bufler, P. et al. A complex of the IL-1 homologue IL-1F7b and IL-18-binding protein reduces IL-18 activity. Proc. Natl Acad. Sci. USA 99, 13723–13728 (2002).
Sarhan, D. et al. Adaptive NK cells resist regulatory T-cell suppression driven by IL37. Cancer Immunol. Res. 6, 766–775 (2018).
Molgora, M. et al. IL-1R8 is a checkpoint in NK cells regulating anti-tumour and anti-viral activity. Nature 551, 110–114 (2017).
Delconte, R. B. et al. CIS is a potent checkpoint in NK cell-mediated tumor immunity. Nat. Immunol. 17, 816–824 (2016).
Veluchamy, J. P. et al. The rise of allogeneic natural killer cells as a platform for cancer immunotherapy: recent innovations and future developments. Front. Immunol. 8, 631 (2017).
Parkhurst, M. R., Riley, J. P., Dudley, M. E. & Rosenberg, S. A. Adoptive transfer of autologous natural killer cells leads to high levels of circulating natural killer cells but does not mediate tumor regression. Clin. Cancer Res. 17, 6287–6297 (2011).
Henig, I. & Zuckerman, T. Hematopoietic stem cell transplantation—50 years of evolution and future perspectives. Rambam Maimonides Med. J. 5, e0028 (2014).
Luznik, L. et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol. Blood Marrow Transpl. 14, 641–650 (2008).
Ruggeri, L. et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 295, 2097–2100 (2002).
Miller, J. S. et al. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Blood 105, 3051–3057 (2005).
Bachanova, V. et al. Clearance of acute myeloid leukemia by haploidentical natural killer cells is improved using IL-2 diphtheria toxin fusion protein. Blood 123, 3855–3863 (2014).
Mills, C. D. & North, R. J. Expression of passively transferred immunity against an established tumor depends on generation of cytolytic T cells in recipient. Inhibition suppressor T cells. J. Exp. Med. 157, 1448–1460 (1983).
Sorror, M. L. et al. Comparing morbidity and mortality of HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative and myeloablative conditioning: influence of pretransplantation comorbidities. Blood 104, 961–968 (2004).
Dalle, J.-H. et al. Characterization of cord blood natural killer cells: implications for transplantation and neonatal infections. Pediatric Res. 57, 649–655 (2005).
Luevano, M. et al. The unique profile of cord blood natural killer cells balances incomplete maturation and effective killing function upon activation. Hum. Immunol. 73, 248–257 (2012).
Tanaka, H. et al. Analysis of natural killer (NK) cell activity and adhesion molecules on NK cells from umbilical cord blood. Eur. J. Haematol. 71, 29–38 (2003).
Spanholtz, J. et al. Clinical-grade generation of active NK cells from cord blood hematopoietic progenitor cells for immunotherapy using a closed-system culture process. PLoS One 6, e20740 (2011).
Arai, S. et al. Infusion of the allogeneic cell line NK-92 in patients with advanced renal cell cancer or melanoma: a phase I trial. Cytotherapy 10, 625–632 (2008).
Gong, J. H., Maki, G. & Klingemann, H. G. Characterization of a human cell line (NK-92) with phenotypical and functional characteristics of activated natural killer cells. Leukemia 8, 652–658 (1994).
Suck, G. et al. NK-92: an ‘off-the-shelf therapeutic’ for adoptive natural killer cell-based cancer immunotherapy. Cancer Immunol. Immunother. 65, 485–492 (2016).
Jochems, C. et al. An NK cell line (haNK) expressing high levels of granzyme and engineered to express the high affinity CD16 allele. Oncotarget 7, 86359–86373 (2016).
Knorr, D. A. et al. Clinical-scale derivation of natural killer cells from human pluripotent stem cells for cancer therapy. Stem Cells Transl Med. 2, 274–283 (2013).
Woll, P. S. et al. Human embryonic stem cells differentiate into a homogeneous population of natural killer cells with potent in vivo antitumor activity. Blood 113, 6094–6101 (2009).
Hermanson, D. L. et al. Induced pluripotent stem cell-derived natural killer cells for treatment of ovarian cancer. Stem Cells 34, 93–101 (2016).
Nagai, Y. et al. CD38 knockout primary NK cells to prevent fratricide and boost daratumumab activity [abstract]. Blood 134 (Suppl. 1), 870 (2019).
Schuster, S. J. et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N. Engl. J. Med. 380, 45–56 (2019).
Maude, S. L. et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N. Engl. J. Med. 378, 439–448 (2018).
Neelapu, S. S. et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N. Engl. J. Med. 377, 2531–2544 (2017).
Shah, N. N. & Fry, T. J. Mechanisms of resistance to CAR T cell therapy. Nat. Rev. Clin. Oncol. 16, 372–385 (2019).
[No authors listed] Natural killer cells for cancer immunotherapy: a new CAR is catching up. EBioMedicine 39, 1–2 (2019).
Liu, E. et al. Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity. Leukemia 32, 520–531 (2018).
Liu, E. et al. Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. N. Engl. J. Med. 382, 545–553 (2020).
Carlsten, M. & Childs, R. W. Genetic manipulation of NK cells for cancer immunotherapy: techniques and clinical implications. Front. Immunol. 6, 266 (2015).
Li, Y., Hermanson, D. L., Moriarity, B. S. & Kaufman, D. S. Human iPSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity. Cell Stem Cell 23, 181–192.e5 (2018).
Fujisaki, H. et al. Expansion of highly cytotoxic human natural killer cells for cancer cell therapy. Cancer Res. 69, 4010–4017 (2009).
Denman, C. J. et al. Membrane-bound IL-21 promotes sustained ex vivo proliferation of human natural killer cells. PLoS ONE 7, e30264 (2012).
Ojo, E. O. et al. Membrane bound IL-21 based NK cell feeder cells drive robust expansion and metabolic activation of NK cells. Sci. Rep. 9, 1–12 (2019).
Paust, S., Blish, C. A. & Reeves, R. K. Redefining memory: building the case for adaptive NK cells. J. Virol. 91, e00169-17 (2017).
Rölle, A., Meyer, M., Calderazzo, S., Jäger, D. & Momburg, F. Distinct HLA-E peptide complexes modify antibody-driven effector functions of adaptive NK cells. Cell Rep. 24, 1967–1976.e4 (2018).
Cichocki, F. et al. CD56dimCD57+NKG2C+NK cell expansion is associated with reduced leukemia relapse after reduced intensity HCT. Leukemia 30, 456–463 (2016).
Cichocki, F. et al. GSK3 inhibition drives maturation of NK cells and enhances their antitumor activity. Cancer Res. 77, 5664–5675 (2017).
Berrien-Elliott, M. M., Wagner, J. A. & Fehniger, T. A. Human cytokine-induced memory-like (CIML) NK cells. J. Innate Immun. 7, 563–571 (2015).
Romee, R. et al. Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia. Sci. Transl Med. 8, 357ra123 (2016).
Williams, R. et al. Role of recipient CD8+ T cell exhaustion in the rejection of adoptively transferred haploidentical NK cells. Blood 128, 503 (2016).
Grimm, E. A., Mazumder, A., Zhang, H. Z. & Rosenberg, S. A. Lymphokine-activated killer cell phenomenon. Lysis of natural killer-resistant fresh solid tumor cells by interleukin 2- activated autologous human peripheral blood lymphocytes. J. Exp. Med. 155, 1823–1841 (1982).
Lotze, M. T. et al. Lysis of fresh and cultured autologous tumor by human lymphocytes cultured in T-cell growth factor. Cancer Res. 41, 4420–4425 (1981).
Mule, J. J., Shu, S., Schwarz, S. L. & Rosenberg, S. A. Adoptive immunotherapy of established pulmonary metastases with LAK cells and recombinant interleukin-2. Science 225, 1487–1489 (1984).
Rosenberg, S. A., Mulé, J. J., Spiess, P. J., Reichert, C. M. & Schwarz, S. L. Regression of established pulmonary metastases and subcutaneous tumor mediated by the systemic administration of high-dose recombinant interleukin 2. J. Exp. Med. 161, 1169–1188 (1985).
Lotze, M. T., Line, B. R., Mathisen, D. J. & Rosenberg, S. A. The in vivo distribution of autologous human and murine lymphoid cells grown in T cell growth factor (TCGF): implications for the adoptive immunotherapy of tumors. J. Immunol. 125, 1487–1493 (1980).
Rosenberg, S. A. et al. Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N. Engl. J. Med. 313, 1485–1492 (1985).
Phillips, J. H., Gemlo, B. T., Myers, W. W., Rayner, A. A. & Lanier, L. L. In vivo and in vitro activation of natural killer cells in advanced cancer patients undergoing combined recombinant interleukin-2 and LAK cell therapy. J. Clin. Oncol. 5, 1933–1941 (1987).
Hercend, T. et al. Characterization of natural killer cells with antileukemia activity following allogeneic bone marrow transplantation. Blood 67, 722–728 (1986).
Burns, L. J. et al. IL-2-based immunotherapy after autologous transplantation for lymphoma and breast cancer induces immune activation and cytokine release: a phase I/II trial. Bone Marrow Transpl. 32, 177–186 (2003).
Miller, J. S., Prosper, F. & McCullar, V. Natural killer (NK) cells are functionally abnormal and NK cell progenitors are diminished in granulocyte colony-stimulating factor-mobilized peripheral blood progenitor cell collection. Blood 90, 3098–3105 (1997).
Soiffer, R. J., Murray, C., Gonin, R. & Ritz, J. Effect of low-dose interleukin-2 on disease relapse after T-cell depleted allogeneic bone marrow transplantation. Blood 84, 964–971 (1994).
Smith, K. A. Interleukin-2: inception, impact, and implications. Science 240, 1169–1176 (1988).
Rosenberg, S. A. et al. A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone. N. Engl. J. Med. 316, 889–897 (1987).
Shah, M. H. et al. A phase I study of ultra low dose interleukin-2 and stem cell factor in patients with HIV infection or HIV and cancer. Clin. Cancer Res. 12, 3993–3996 (2006).
Zorn, E. et al. IL-2 regulates FOXP3 expression in human CD4+CD25+ regulatory T cells through a STAT-dependent mechanism and induces the expansion of these cells in vivo. Blood 108, 1571–1579 (2006).
Hirakawa, M. et al. Low-dose IL-2 selectively activates subsets of CD4+ Tregs and NK cells. JCI Insight 1, e89278 (2016).
Malek, T. R. The biology of interleukin-2. Annu. Rev. Immunol. 26, 453–479 (2008).
Grabstein, K. H. et al. Cloning of a T cell growth factor that interacts with the beta chain of the interleukin-2 receptor. Science 264, 965–968 (1994).
Carson, W. E. et al. Interleukin (IL) 15 is a novel cytokine that activates human natural killer cells via components of the IL-2 receptor. J. Exp. Med. 180, 1395–1403 (1994).
Dubois, S., Mariner, J., Waldmann, T. A. & Tagaya, Y. IL-15Rα recycles and presents IL-15 in trans to neighboring cells. Immunity 17, 537–547 (2002).
Bergamaschi, C. et al. Circulating IL-15 exists as heterodimeric complex with soluble IL-15Rα in human and mouse serum. Blood 120, e1–e8 (2012).
Kobayashi, H. et al. Role of trans-cellular IL-15 presentation in the activation of NK cell-mediated killing, which leads to enhanced tumor immunosurveillance. Blood 105, 721–727 (2005).
Tang, F. et al. Activity of recombinant human interleukin-15 against tumor recurrence and metastasis in mice. Cell Mol. Immunol. 5, 189–196 (2008).
Klebanoff, C. A. et al. IL-15 enhances the in vivo antitumor activity of tumor-reactive CD8+ T cells. Proc. Natl Acad. Sci. USA 101, 1969–1974 (2004).
Cheever, M. A. Twelve immunotherapy drugs that could cure cancers. Immunol. Rev. 222, 357–368 (2008).
Conlon, K. C. et al. Redistribution, hyperproliferation, activation of natural killer cells and CD8 T cells, and cytokine production during first-in-human clinical trial of recombinant human interleukin-15 in patients with cancer. J. Clin. Oncol. 33, 74–82 (2015).
Miller, J. S. et al. A first-in-human phase I study of subcutaneous outpatient recombinant human IL15 (rhIL15) in adults with advanced solid tumors. Clin. Cancer Res. 24, 1525–1535 (2018).
Cooley, S. et al. First-in-human trial of rhIL-15 and haploidentical natural killer cell therapy for advanced acute myeloid leukemia. Blood Adv. 3, 1970–1980 (2019).
Xu, W. et al. Efficacy and mechanism-of-action of a novel superagonist interleukin-15: interleukin-15 receptor αSu/Fc fusion complex in syngeneic murine models of multiple myeloma. Cancer Res. 73, 3075–3086 (2013).
Kim, P. S. et al. IL-15 superagonist/IL-15RαSushi-Fc fusion complex (IL-15SA/IL-15RαSu-Fc; ALT-803) markedly enhances specific subpopulations of NK and memory CD8+ T cells, and mediates potent anti-tumor activity against murine breast and colon carcinomas. Oncotarget 7, 16130–16145 (2016).
Wrangle, J. M. et al. ALT-803, an IL-15 superagonist, in combination with nivolumab in patients with metastatic non-small cell lung cancer: a non-randomised, open-label, phase 1b trial. Lancet Oncol. 19, 694–704 (2018).
Fehniger, T. A. et al. First-in-human phase I combination of the IL-15 receptor super agonist complex ALT-803 with a therapeutic (anti-CD20) monoclonal antibody (mAb) for patients with relapsed or refractory indolent non-Hodgkin lymphoma (iNHL) [abstract]. Cancer Res. 78 (Suppl. 13), CT146 (2018).
Melaiu, O., Lucarini, V., Cifaldi, L. & Fruci, D. Influence of the tumor microenvironment on NK cell function in solid tumors. Front. Immunol. 10, 3038 (2020).
Vallera, D. A. et al. IL15 trispecific killer engagers (TriKE) make natural killer cells specific to CD33+ targets while also inducing persistence, in vivo expansion, and enhanced function. Clin. Cancer Res. 22, 3440–3450 (2016).
Sarhan, D. et al. 161533 TriKE stimulates NK-cell function to overcome myeloid-derived suppressor cells in MDS. Blood Adv. 2, 1459–1469 (2018).
Gauthier, L. et al. Multifunctional natural killer cell engagers targeting nkp46 trigger protective tumor immunity. Cell 177, 1701–1713.e16 (2019).
Genetic Engineering & Biotechnology News. Merck & Co. partners with Dragonfly on NK-based cancer immunotherapies. GEN https://www.genengnews.com/news/merck-co-partners-with-dragonfly-on-nk-based-cancer-immunotherapies (2018).
André, P. et al. Anti-NKG2A mAb is a checkpoint inhibitor that promotes anti-tumor immunity by unleashing both T and NK cells. Cell 175, 1731–1743.e13 (2018).
Romagné, F. et al. Preclinical characterization of 1-7F9, a novel human anti-KIR receptor therapeutic antibody that augments natural killer-mediated killing of tumor cells. Blood 114, 2667–2677 (2009).
Benson, D. M. et al. IPH2101, a novel anti-inhibitory KIR antibody, and lenalidomide combine to enhance the natural killer cell versus multiple myeloma effect. Blood 118, 6387–6391 (2011).
Korde, N. et al. A phase II trial of pan-KIR2D blockade with IPH2101 in smoldering multiple myeloma. Haematologica 99, e81–e83 (2014).
Carlsten, M. et al. Checkpoint inhibition of KIR2D with the monoclonal antibody IPH2101 induces contraction and hyporesponsiveness of NK cells in patients with myeloma. Clin. Cancer Res. 22, 5211–5222 (2016).
Vey, N. et al. A phase 1 trial of the anti-inhibitory KIR mAb IPH2101 for AML in complete remission. Blood 120, 4317–4323 (2012).
Armand, P. et al. A phase 1b study of dual PD-1 and CTLA-4 or KIR blockade in patients with relapsed/refractory lymphoid malignancies. Leukemia https://doi.org/10.1038/s41375-020-0939-1 (2020).
Bristol Myers Squibb. Interim phase 1/2 data show encouraging clinical benefit for lirilumab in combination with Opdivo (nivolumab) in patients with advanced platinum refractory squamous cell carcinoma of the head and neck. BMS https://news.bms.com/press-release/bristolmyers/interim-phase-12-data-show-encouraging-clinical-benefit-lirilumab-combina (2016).
Bevelacqua, V. et al. Nectin like-5 overexpression correlates with the malignant phenotype in cutaneous melanoma. Oncotarget 3, 882–892 (2012).
Gao, J., Zheng, Q., Xin, N., Wang, W. & Zhao, C. CD155, an onco-immunologic molecule in human tumors. Cancer Sci. 108, 1934–1938 (2017).
Zhang, Q. et al. Blockade of the checkpoint receptor TIGIT prevents NK cell exhaustion and elicits potent anti-tumor immunity. Nat. Immunol. 19, 723–732 (2018).
Sun, H. et al. Human CD96 correlates to natural killer cell exhaustion and predicts the prognosis of human hepatocellular carcinoma. Hepatology 70, 168–183 (2019).
Blake, S. J. et al. Suppression of metastases using a new lymphocyte checkpoint target for cancer immunotherapy. Cancer Discov. 6, 446–459 (2016).
Dong, W. et al. The mechanism of anti-PD-L1 antibody efficacy against PD-L1 negative tumors identifies NK cells expressing PD-L1 as a cytolytic effector. Cancer Discov. 9, 1422–1437 (2019).
Juliá, E. P., Amante, A., Pampena, M. B., Mordoh, J. & Levy, E. M. Avelumab, an IgG1 anti-PD-L1 immune checkpoint inhibitor, triggers NK cell-mediated cytotoxicity and cytokine production against triple negative breast cancer cells. Front. Immunol. 9, 2140 (2018).
Benson, D. M. Jr et al. The PD-1/PD-L1 axis modulates the natural killer cell versus multiple myeloma effect: a therapeutic target for CT-011, a novel monoclonal anti-PD-1 antibody. Blood 116, 2286–2294 (2010).
Beldi-Ferchiou, A. et al. PD-1 mediates functional exhaustion of activated NK cells in patients with Kaposi sarcoma. Oncotarget 7, 72961–72977 (2016).
Pesce, S. et al. Identification of a subset of human natural killer cells expressing high levels of programmed death 1: a phenotypic and functional characterization. J. Allergy Clin. Immunol. 139, 335–346.e3 (2017).
Li, Y. et al. Prognostic impact of programed cell death-1 (PD-1) and PD-ligand 1 (PD-L1) expression in cancer cells and tumor infiltrating lymphocytes in colorectal cancer. Mol. Cancer 15, 55 (2016).
Vari, F. et al. Immune evasion via PD-1/PD-L1 on NK-cells and monocyte/macrophages is more prominent in Hodgkin lymphoma than DLBCL. Blood 131, 1809–1819 (2018).
Hsu, J. et al. Contribution of NK cells to immunotherapy mediated by PD-1/PD-L1 blockade. J. Clin. Invest. 128, 4654–4668 (2018).
Liu, Y. et al. Increased expression of programmed cell death protein 1 on NK cells inhibits NK-cell-mediated anti-tumor function and indicates poor prognosis in digestive cancers. Oncogene 36, 6143–6153 (2017).
Türeci, Ö., Schmitt, H., Fadle, N., Pfreundschuh, M. & Sahin, U. Molecular definition of a novel human galectin which is immunogenic in patients with Hodgkin’s disease. J. Biol. Chem. 272, 6416–6422 (1997).
Folgiero, V. et al. TIM-3/Gal-9 interaction induces IFNγ-dependent IDO1 expression in acute myeloid leukemia blast cells. J. Hematol. Oncol. 8, 36 (2015).
Xu, L. et al. Increased Tim-3 expression in peripheral NK cells predicts a poorer prognosis and Tim-3 blockade improves NK cell-mediated cytotoxicity in human lung adenocarcinoma. Int. Immunopharmacol. 29, 635–641 (2015).
da Silva, I. P. et al. Reversal of NK cell exhaustion in advanced melanoma by Tim-3 blockade. Cancer Immunol. Res. 2, 410–422 (2014).
Triebel, F. et al. LAG-3, a novel lymphocyte activation gene closely related to CD4. J. Exp. Med. 171, 1393–1405 (1990).
Baixeras, E. et al. Characterization of the lymphocyte activation gene 3-encoded protein. A new ligand for human leukocyte antigen class II antigens. J. Exp. Med. 176, 327–337 (1992).
Huard, B., Prigent, P., Tournier, M., Bruniquel, D. & Triebel, F. CD4/major histocompatibility complex class II interaction analyzed with CD4- and lymphocyte activation gene-3 (LAG-3)-Ig fusion proteins. Eur. J. Immunol. 25, 2718–2721 (1995).
Khan, M., Arooj, S. & Wang, H. NK cell-based immune checkpoint inhibition. Front. Immunol. 11, 167 (2020).
Workman, C. J. & Vignali, D. A. A. Negative regulation of T cell homeostasis by lymphocyte activation gene-3 (CD223). J. Immunol. 174, 688–695 (2005).
Woo, S.-R. et al. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res. 72, 917–927 (2012).
Blackburn, S. D. et al. Coregulation of CD8+ T cell exhaustion during chronic viral infection by multiple inhibitory receptors. Nat. Immunol. 10, 29–37 (2009).
Maçon-Lemaître, L. & Triebel, F. The negative regulatory function of the lymphocyte-activation gene-3 co-receptor (CD223) on human T cells. Immunology 115, 170–178 (2005).
Huard, B., Tournier, M. & Triebel, F. LAG-3 does not define a specific mode of natural killing in human. Immunol. Lett. 61, 109–112 (1998).
Taborda, N. A. et al. Short communication: low expression of activation and inhibitory molecules on NK cells and CD4+ T cells is associated with viral control. AIDS Res. Hum. Retroviruses 31, 636–640 (2015).
Miyazaki, T., Dierich, A., Benoist, C. & Mathis, D. Independent modes of natural killing distinguished in mice lacking Lag3. Science 272, 405–408 (1996).
J.S.M. consults for and holds stock in Fate Therapeutics and GT Biopharma. These competing interests have been reviewed and managed by the University of Minnesota in accordance with its conflict of interest policy. J.A.M. declares no competing interests.
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Myers, J.A., Miller, J.S. Exploring the NK cell platform for cancer immunotherapy. Nat Rev Clin Oncol (2020). https://doi.org/10.1038/s41571-020-0426-7