IMMUNE NETWORK

The Korean Association of Immunobiologists (대한면역학회)
권호 표지
DOI QR코드

DOI QR Code

Current Developments in NK Cell Engagers for Cancer Immunotherapy: Focus on CD16A and NKp46

  • Min Hwa Shin (Immune Research Institute, Seegene Medical Foundation) ;
  • Eunha Oh (Immune Research Institute, Seegene Medical Foundation) ;
  • Dohsik Minn (Immune Research Institute, Seegene Medical Foundation)
  • Received : 2024.06.08
  • Accepted : 2024.08.12
  • Published : 2024.10.31
Download PDF
⟨ Previous Next ⟩

Abstract

NK cells are specialized immune effector cells crucial for triggering immune responses against aberrant cells. Although recent advancements have concentrated on creating or releasing T-cell responses specific to tumor Ags, the clinical advantages of this approach have been limited to certain groups of patients and tumor types. This emphasizes the need for alternative strategies. One pioneering approach involves broadening and enhancing anti-tumor immune responses by targeting innate immunity. Consequently, the advent of bi-, tri-, and multi-specific Abs has facilitated the advancement of targeted cancer immunotherapies by redirecting immune effector cells to eradicate tumor cells. These Abs enable the simultaneous binding of surface Ags on tumor cells and the activation of receptors on innate immune cells, such as NK cells, with the ability to facilitate Ab-dependent cellular cytotoxicity to enhance their immunotherapeutic effectiveness in patients with solid tumors. Here, we review the recent advances in NK cell engagers (NKCEs) focusing on NK cellactivating receptors CD16A and NKp46. In addition, we provide an overview of the ongoing clinical trials investigating the safety, efficacy, and potential of NKCEs.

Keywords

References

  1. Jin S, Sun Y, Liang X, Gu X, Ning J, Xu Y, Chen S, Pan L. Emerging new therapeutic antibody derivatives for cancer treatment. Signal Transduct Target Ther 2022;7:39.
  2. Zahavi D, Weiner L. Monoclonal antibodies in cancer therapy. Antibodies (Basel) 2020;9:34.
  3. Moon D, Tae N, Park Y, Lee SW, Kim DH. Development of bispecific antibody for cancer immunotherapy: focus on t cell engaging antibody. Immune Netw 2022;22:e4.
  4. Brinkmann U, Kontermann RE. The making of bispecific antibodies. MAbs 2017;9:182-212.
  5. Zhang M, Lam KP, Xu S. Natural killer cell engagers (NKCEs): a new frontier in cancer immunotherapy. Front Immunol 2023;14:1207276.
  6. Tapia-Galisteo A, Alvarez-Vallina L, Sanz L. Bi- and trispecific immune cell engagers for immunotherapy of hematological malignancies. J Hematol Oncol 2023;16:83.
  7. Gauthier L, Virone-Oddos A, Beninga J, Rossi B, Nicolazzi C, Amara C, Blanchard-Alvarez A, Gourdin N, Courta J, Basset A, et al. Control of acute myeloid leukemia by a trifunctional NKp46-CD16a-NK cell engager targeting CD123. Nat Biotechnol 2023;41:1296-1306.
  8. Colomar-Carando N, Gauthier L, Merli P, Loiacono F, Canevali P, Falco M, Galaverna F, Rossi B, Bosco F, Caratini M, et al. Exploiting natural killer cell engagers to control pediatric B-cell precursor acute lymphoblastic leukemia. Cancer Immunol Res 2022;10:291-302.
  9. Coenon L, Villalba M. From CD16a biology to antibody-dependent cell-mediated cytotoxicity improvement. Front Immunol 2022;13:913215.
  10. Pinto S, Pahl J, Schottelius A, Carter PJ, Koch J. Reimagining antibody-dependent cellular cytotoxicity in cancer: the potential of natural killer cell engagers. Trends Immunol 2022;43:932-946.
  11. Grillo-Lopez AJ, White CA, Dallaire BK, Varns CL, Shen CD, Wei A, Leonard JE, McClure A, Weaver R, Cairelli S, et al. Rituximab: the first monoclonal antibody approved for the treatment of lymphoma. Curr Pharm Biotechnol 2000;1:1-9.
  12. Abdeldaim DT, Schindowski K. Fc-engineered therapeutic antibodies: Recent advances and future directions. Pharmaceutics 2023;15:2402.
  13. Kang TH, Jung ST. Boosting therapeutic potency of antibodies by taming Fc domain functions. Exp Mol Med 2019;51:1-9.
  14. Mellor JD, Brown MP, Irving HR, Zalcberg JR, Dobrovic A. A critical review of the role of Fc gamma receptor polymorphisms in the response to monoclonal antibodies in cancer. J Hematol Oncol 2013;6:1.
  15. Harwardt J, Carrara SC, Bogen JP, Schoenfeld K, Grzeschik J, Hock B, Kolmar H. Generation of a symmetrical trispecific NK cell engager based on a two-in-one antibody. Front Immunol 2023;14:1170042.
  16. Innate Pharma [Internet]. Available at https://www.innate-pharma.com/ [accessed on 21 May 2024].
  17. Affimed [Internet]. Available at https://www.affimed.com/ [accessed on 21 May 2024].
  18. Shin MH, Kim J, Lim SA, Kim J, Kim SJ, Lee KM. NK cell-based immunotherapies in cancer. Immune Netw 2020;20:e14.
  19. Li Y, Basar R, Wang G, Liu E, Moyes JS, Li L, Kerbauy LN, Uprety N, Fathi M, Rezvan A, et al. KIR-based inhibitory CARs overcome CAR-NK cell trogocytosis-mediated fratricide and tumor escape. Nat Med 2022;28:2133-2144.
  20. Wu SY, Fu T, Jiang YZ, Shao ZM. Natural killer cells in cancer biology and therapy. Mol Cancer 2020;19:120.
  21. de Jonge K, Ebering A, Nassiri S, Maby-El Hajjami H, Ouertatani-Sakouhi H, Baumgaertner P, Speiser DE. Circulating CD56bright NK cells inversely correlate with survival of melanoma patients. Sci Rep 2019;9:4487.
  22. Liu S, Galat V, Galat Y, Lee YK, Wainwright D, Wu J. NK cell-based cancer immunotherapy: from basic biology to clinical development. J Hematol Oncol 2021;14:7.
  23. Laskowski TJ, Biederstadt A, Rezvani K. Natural killer cells in antitumour adoptive cell immunotherapy. Nat Rev Cancer 2022;22:557-575.
  24. Melaiu O, Lucarini V, Cifaldi L, Fruci D. Influence of the tumor microenvironment on NK cell function in solid tumors. Front Immunol 2020;10:3038.
  25. Shin MH, Oh E, Kim Y, Nam DH, Jeon SY, Yu JH, Minn D. Recent advances in car-based solid tumor immunotherapy. Cells 2023;12:1606.
  26. Lamers-Kok N, Panella D, Georgoudaki AM, Liu H, Ozkazanc D, Kucerova L, Duru AD, Spanholtz J, Raimo M. Natural killer cells in clinical development as non-engineered, engineered, and combination therapies. J Hematol Oncol 2022;15:164.
  27. Paolini R, Molfetta R. Dysregulation of DNAM-1-mediated NK cell anti-cancer responses in the tumor microenvironment. Cancers (Basel) 2023;15:4616.
  28. Barrow AD, Martin CJ, Colonna M. The natural cytotoxicity receptors in health and disease. Front Immunol 2019;10:909.
  29. Sivori S, Vacca P, Del Zotto G, Munari E, Mingari MC, Moretta L. Human NK cells: surface receptors, inhibitory checkpoints, and translational applications. Cell Mol Immunol 2019;16:430-441.
  30. Luczo JM, Ronzulli SL, Tompkins SM. Influenza a virus hemagglutinin and other pathogen glycoprotein interactions with NK cell natural cytotoxicity receptors NKp46, NKp44, and NKp30. Viruses 2021;13:156.
  31. Medjouel Khlifi H, Guia S, Vivier E, Narni-Mancinelli E. Role of the ITAM-bearing receptors expressed by natural killer cells in cancer. Front Immunol 2022;13:898745.
  32. Parodi M, Favoreel H, Candiano G, Gaggero S, Sivori S, Mingari MC, Moretta L, Vitale M, Cantoni C. NKp44-NKp44 ligand interactions in the regulation of natural killer cells and other innate lymphoid cells in humans. Front Immunol 2019;10:719.
  33. Khan M, Arooj S, Wang H. NK cell-based immune checkpoint inhibition. Front Immunol 2020;11:167.
  34. Li F, Liu S. Focusing on NK cells and ADCC: a promising immunotherapy approach in targeted therapy for HER2-positive breast cancer. Front Immunol 2022;13:1083462.
  35. Yu Y. The function of NK cells in tumor metastasis and NK cell-based immunotherapy. Cancers (Basel) 2023;15:2323.
  36. Demaria O, Gauthier L, Debroas G, Vivier E. Natural killer cell engagers in cancer immunotherapy: next generation of immuno-oncology treatments. Eur J Immunol 2021;51:1934-1942.
  37. Whalen KA, Rakhra K, Mehta NK, Steinle A, Michaelson JS, Baeuerle PA. Engaging natural killer cells for cancer therapy via NKG2D, CD16A and other receptors. MAbs 2023;15:2208697.
  38. Dixon KJ, Wu J, Walcheck B. Engineering anti-tumor monoclonal antibodies and fc receptors to enhance ADCC by human NK cells. Cancers (Basel) 2021;13:312.
  39. Gogesch P, Dudek S, van Zandbergen G, Waibler Z, Anzaghe M. The role of fc receptors on the effectiveness of therapeutic monoclonal antibodies. Int J Mol Sci 2021;22:8947.
  40. Vishwasrao P, Hui SK, Smith DL, Khairnar V. Role of NK cells in cancer and immunotherapy. Onco 2021;1:158-175.
  41. Lian G, Mak TS, Yu X, Lan HY. Challenges and recent advances in NK cell-targeted immunotherapies in solid tumors. Int J Mol Sci 2021;23:164.
  42. Myers JA, Miller JS. Exploring the NK cell platform for cancer immunotherapy. Nat Rev Clin Oncol 2021;18:85-100.
  43. Gauthier L, Morel A, Anceriz N, Rossi B, Blanchard-Alvarez A, Grondin G, Trichard S, Cesari C, Sapet M, Bosco F, et al. Multifunctional natural killer cell engagers targeting NKp46 trigger protective tumor immunity. Cell 2019;177:1701-1713.e16.
  44. Rossi F, Fredericks N, Snowden A, Allegrezza MJ, Moreno-Nieves UY. Next generation natural killer cells for cancer immunotherapy. Front Immunol 2022;13:886429.
  45. Portale F, Di Mitri D. NK cells in cancer: mechanisms of dysfunction and therapeutic potential. Int J Mol Sci 2023;24:9521.
  46. Zhou Y, Cheng L, Liu L, Li X. NK cells are never alone: crosstalk and communication in tumour microenvironments. Mol Cancer 2023;22:34.
  47. Davis ZB, Vallera DA, Miller JS, Felices M. Natural killer cells unleashed: Checkpoint receptor blockade and BiKE/TriKE utilization in NK-mediated anti-tumor immunotherapy. Semin Immunol 2017;31:64-75.
  48. Zamai L, Del Zotto G, Buccella F, Gabrielli S, Canonico B, Artico M, Ortolani C, Papa S. Understanding the synergy of NKp46 and co-activating signals in various NK cell subpopulations: paving the way for more successful NK-cell-based immunotherapy. Cells 2020;9:753.
  49. Page A, Chuvin N, Valladeau-Guilemond J, Depil S. Development of NK cell-based cancer immunotherapies through receptor engineering. Cell Mol Immunol 2024;21:315-331.
  50. Stenger TD, Miller JS. Therapeutic approaches to enhance natural killer cell cytotoxicity. Front Immunol 2024;15:1356666.
  51. Kerbauy LN, Marin ND, Kaplan M, Banerjee PP, Berrien-Elliott MM, Becker-Hapak M, Basar R, Foster M, Garcia Melo L, Neal CC, et al. Combining afm13, a bispecific CD30/CD16 antibody, with cytokine-activated blood and cord blood-derived NK cells facilitates car-like responses against CD30+ malignancies. Clin Cancer Res 2021;27:3744-3756.
  52. ClinicalTrials.gov [Internet]. Available at https://clinicaltrials.gov/ [accessed on 21 May 2024].
  53. Rothe A, Sasse S, Topp MS, Eichenauer DA, Hummel H, Reiners KS, Dietlein M, Kuhnert G, Kessler J, Buerkle C, et al. A phase 1 study of the bispecific anti-CD30/CD16A antibody construct AFM13 in patients with relapsed or refractory Hodgkin lymphoma. Blood 2015;125:4024-4031.
  54. Wu J, Fu J, Zhang M, Liu D. AFM13: a first-in-class tetravalent bispecific anti-CD30/CD16A antibody for NK cell-mediated immunotherapy. J Hematol Oncol 2015;8:96.
  55. Reiners KS, Kessler J, Sauer M, Rothe A, Hansen HP, Reusch U, Hucke C, Kohl U, Durkop H, Engert A, et al. Rescue of impaired NK cell activity in Hodgkin lymphoma with bispecific antibodies in vitro and in patients. Mol Ther 2013;21:895-903.
  56. Bartlett NL, Herrera AF, Domingo-Domenech E, Mehta A, Forero-Torres A, Garcia-Sanz R, Armand P, Devata S, Izquierdo AR, Lossos IS, et al. A phase 1b study of AFM13 in combination with pembrolizumab in patients with relapsed or refractory Hodgkin lymphoma. Blood 2020;136:2401-2409.
  57. Sawas A, Chen PH, Lipschitz M, Rodig S, Vlad G. Clinical and biological evaluation of the novel CD30/CD16a tetravalent bispecific antibody (AFM13) in relapsed or refractory CD30-positive lymphoma with cutaneous presentation: a biomarker phase Ib/IIa study (NCT03192202). Blood 2020;136:25-26.
  58. Nieto Y, Banerjee P, Kaur I, Bassett R, Kerbauy L, Basar R, Kaplan M, Griffin L, Esqueda D, Ganesh C, et al. Abstract CT003: innate cell engager (ICE®) AFM13 combined with preactivated and expanded cord blood (CB)-derived NK cells for patients with refractory/relapsed CD30+ lymphoma. Cancer Res 2022;82:CT003.
  59. Wingert S, Reusch U, Knackmuss S, Kluge M, Damrat M, Pahl J, Schniegler-Mattox U, Mueller T, Fucek I, Ellwanger K, et al. Preclinical evaluation of AFM24, a novel CD16A-specific innate immune cell engager targeting EGFR-positive tumors. MAbs 2021;13:1950264.
  60. Gadea OS, Garralda E, Lopez JS, Awad MM, Thomas JS, Tiu CD, Morales-Espinosa D, Raab C, Rehbein B, Hintzen G, et al. A phase 1/2a open label, multicenter study to assess the safety, tolerability, pharmacokinetics, and efficacy of AFM24 in patients with advanced solid cancers: study design and rationale. J Clin Oncol 2022;40:TPS2672.
  61. El-Khoueiry AB, Rivas D, Lee SH, Thomas JS, Kim YJ, Cervantes A, Saavedra O, Shim BY, Kohlhas L, Hintzen G, et al. Leveraging innate immunity with AFM24, a novel CD16a and epidermal growth factor receptor (EGFR) bispecific innate cell engager: interim results for the non-small cell lung cancer (NSCLC) cohort. J Clin Oncol 2023;41:2533.
  62. El-Khoueiry AB, Olson D, Thomas JS, Pearson AT, Rubel J, Pourang DY, Hui L, Ravenstijn P, Lutkewitz S, Hintzen G, et al. AFM24 in combination with autologous NK cells (SNK01) in patients with advanced/metastatic epidermal growth factor receptor (EGFR) expressing solid tumors: initial results from the phase 1 dose-escalation study. JCO Global Oncology 2023;9:26.
  63. Nkgen Biotech [Internet]. Available at https://nkgenbiotech.com/ [accessed on 21 May 2024].
  64. Gadea OS, Christenson E, El-Khoueiry AB, Cervantes A, Raab C, Gaertner U, Pietzko K, Hintzen G, Ravenstijn P, Morales-Espinosa D, et al. AFM24 in combination with atezolizumab in patients with advanced EGFR-expressing solid tumors: phase 1/2a study design and rationale. J Clin Oncol 2022;40:TPS2673.
  65. Atezolizumab [Internet]. Available at https://www.cancer.gov/about-cancer/treatment/drugs/atezolizumab [accessed on 21 May 2024].
  66. Kim HR, Saavedra O, Cervantes A, Lugowska IA, Oberoi A, El-Khoueiry AB, Thomas JS, Rogowski W, Lopez JS, Shim BY, et al. Preliminary results from the phase 2 study of AFM24 in combination with atezolizumab in patients with EGFR wild-type (EGFR-WT) non-small cell lung cancer (NSCLC). J Clin Oncol 2024;42:2522.
  67. Dragonfly Therapeutics [Internet]. Available at https://www.dragonflytx.com/ [accessed on 21 May 2024].
  68. Safran H, Cassier PA, Vicier C, Forget F, Gomez-Roca CA, Penel N, Campone M, Romano E, Valerin JB, Jerusalem GH, et al. Phase 1/2 study of DF1001, a novel tri-specific, NK cell engager therapy targeting HER2, in patients with advanced solid tumors: phase 1 DF1001 monotherapy dose-escalation results. J Clin Oncol 2023;41:2508.
  69. Vallera DA, Felices M, McElmurry R, McCullar V, Zhou X, Schmohl JU, Zhang B, Lenvik AJ, Panoskaltsis-Mortari A, Verneris MR, 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 2016;22:3440-3450.
  70. Felices M, Warlick E, Juckett M, Weisdorf D, Vallera D, Miller S, Wangen R, Lewis D, Knox J, Schroeder M, et al. 444 GTB-3550 tri-specific killer engager TriKE™ drives NK cells expansion and cytotoxicity in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) patients. J Immunother Cancer 2021;9:A473.
  71. Cai H, Kakiuchi-Kiyota S, Hendricks R, Zhong S, Liu L, Adedeji AO, Chan P, Schutten MM, Kamath AV, Ovacik MA. Nonclinical pharmacokinetics, pharmacodynamics, and translational model of RO7297089, a novel anti-BCMA/CD16A bispecific tetravalent antibody for the treatment of multiple myeloma. AAPS J 2022;24:100.
  72. Plesner T, Harrison SJ, Quach H, Lee C, Bryant A, Vangsted A, Estell J, Delforge M, Offner F, Twomey P, et al. Phase I study of safety and pharmacokinetics of RO7297089, an anti-BCMA/CD16a bispecific antibody, in patients with relapsed, refractory multiple myeloma. Clin Hematol Int 2023;5:43-51.
  73. Plesner T, Harrison SJ, Quach H, Lee CH, Bryant A, Vangsted AJ, Estell J, Delforge M, Offner F, Twomey P, et al. A phase I study of RO7297089, a B-cell maturation antigen (BCMA)-CD16a bispecific antibody in patients with relapsed/refractory multiple myeloma (RRMM). Blood 2021;138:2755.
  74. Arulanandam A, Lin L, Chang HM, Cerutti M, Choblet S, Gao P, Rath A, Bensussan A, Kadouche J, Teper D, et al. Derivation and preclinical characterization of CYT-303, a novel NKp46-NK cell engager targeting GPC3. Cells 2023;12:996.
  75. Stein AS, Jongen-Lavrencic M, Garciaz S, Huls GA, Maiti A, Boissel N, De Botton S, Fleming S, Zwaan CM, de Leeuw DC, et al. A first-in-human study of CD123 NK cell engager SAR443579 in relapsed or refractory acute myeloid leukemia, B-cell acute lymphoblastic leukemia, or high-risk myelodysplasia. J Clin Oncol 2023;41:7005.
  76. Ciulean SI, Uhlig J, Eichenberg T, Fischer J, Albers M, Breunig C, Schmollinger J, Pahl J, Fucek I, Bach C, et al. 329 Redirecting NK cell cytotoxicity by innate cell engagers: a differentiated and innovative approach compared to CAR-NK cells. J Immunother Cancer 2023;11:A376.
  77. Pawlowski KD, Duffy JT, Tiwari A, Zannikou M, Balyasnikova IV. Bi-specific killer cell engager enhances NK cell activity against interleukin-13 receptor alpha-2 positive gliomas. Cells 2023;12:1716.
  78. Khoshtinat Nikkhoi S, Yang G, Owji H, Grizotte-Lake M, Cohen RI, Gil Gonzalez L, Massumi M, Hatefi A. Bispecific immune cell engager enhances the anticancer activity of CD16+ NK cells and macrophages in vitro, and eliminates cancer metastasis in NK humanized NOG mice. J Immunother Cancer 2024;12:e008295.