Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The use of supercytokines, immunocytokines, engager cytokines, and other synthetic cytokines in immunotherapy

Cellular & Molecular Immunology volume 19, pages 192–209 (2022)Cite this article

Subjects

Abstract

Cytokines exert powerful immunomodulatory effects that are critical to physiology and pathology in humans. The application of natural cytokines in clinical studies has not been clearly established, and there are often problems associated with toxicity or lack of efficacy. The key reasons can be attributed to the pleiotropy of cytokine receptors and undesired activation of off-target cells. With a deeper understanding of the structural principles and functional signals of cytokine-receptor interactions, artificial modification of cytokine signaling through protein engineering and synthetic immunology has become an increasingly feasible and powerful approach. Engineered cytokines are designed to selectively target cells. Herein, the theoretical and experimental evidence of cytokine engineering is reviewed, and the “supercytokines” resulting from structural enhancement and the “immunocytokines” generated by antibody fusion are described. Finally, the “engager cytokines” formed by the crosslinking of cytokines and bispecific immune engagers and other synthetic cytokines formed by nonnatural analogs are also discussed.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Mizui M. Natural and modified IL-2 for the treatment of cancer and autoimmune diseases. Clin Immunol. 2019;206:63–70.

    Article  CAS  PubMed  Google Scholar 

  2. Han KP, Zhu X, Liu B, Jeng E, Kong L, Yovandich JL, et al. IL-15:IL-15 receptor alpha superagonist complex: high-level co-expression in recombinant mammalian cells, purification and characterization. Cytokine. 2011;56:804–10.

  3. Glassman CR, Mathiharan YK, Jude KM, Su L, Panova O, Lupardus PJ, et al. Structural basis for IL-12 and IL-23 receptor sharing reveals a gateway for shaping actions on T versus NK cells. Cell. 2021;184:983–99.e924.

    Article  CAS  PubMed  Google Scholar 

  4. Spangler JB, Moraga I, Mendoza JL, Garcia KC. Insights into cytokine-receptor interactions from cytokine engineering. Annu Rev Immunol. 2015;33:139–67.

    Article  CAS  PubMed  Google Scholar 

  5. Abbas AK, Trotta E, R Simeonov D, Marson A, Bluestone JA. Revisiting IL-2: biology and therapeutic prospects. Sci Immunol. 2018;3:eaat1482.

  6. Carnemolla B, Borsi L, Balza E, Castellani P, Meazza R, Berndt A, et al. Enhancement of the antitumor properties of interleukin-2 by its targeted delivery to the tumor blood vessel extracellular matrix. Blood. 2002;99:1659–65.

    Article  PubMed  Google Scholar 

  7. Gillies SD, Lan Y, Williams S, Carr F, Forman S, Raubitschek A, et al. An anti-CD20-IL-2 immunocytokine is highly efficacious in a SCID mouse model of established human B lymphoma. Blood. 2005;105:3972–8.

    Article  CAS  PubMed  Google Scholar 

  8. Murer P, Neri D. Antibody-cytokine fusion proteins: a novel class of biopharmaceuticals for the therapy of cancer and of chronic inflammation. N. Biotechnol. 2019;52:42–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. May MB, Glode A. Blinatumomab: a novel, bispecific, T-cell engaging antibody. Am J Health-Syst Pharm: AJHP. 2016;73:e6–13.

    Article  PubMed  Google Scholar 

  10. Taniguchi T, Matsui H, Fujita T, Takaoka C, Kashima N, Yoshimoto R, et al. Structure and expression of a cloned Cdna for human interleukin-2. Nature. 1983;302:305–10.

    Article  CAS  PubMed  Google Scholar 

  11. Rosenberg SA. IL-2: the first effective immunotherapy for human cancer. J Immunol. 2014;192:5451–8.

    Article  CAS  PubMed  Google Scholar 

  12. Rosenberg SA, Lotze MT, Muul LM, Leitman S, Chang AE, Ettinghausen SE, 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. 1985;313:1485–92.

    Article  CAS  PubMed  Google Scholar 

  13. Kammula US, White DE, Rosenberg SA. Trends in the safety of high dose bolus interleukin-2 administration in patients with metastatic cancer. Cancer. 1998;83:797–805.

    Article  CAS  PubMed  Google Scholar 

  14. Sim GC, Radvanyi L. The IL-2 cytokine family in cancer immunotherapy. Cytokine growth factor Rev. 2014;25:377–90.

    Article  CAS  PubMed  Google Scholar 

  15. Wang X, Rickert M, Garcia KC. Structure of the quaternary complex of interleukin-2 with its alpha, beta, and gamma c receptors. Science. 2005;310:1159–63.

    Article  CAS  PubMed  Google Scholar 

  16. Spolski R, Li P, Leonard WJ. Biology and regulation of IL-2: from molecular mechanisms to human therapy. Nat Rev Immunol. 2018;18:648–59.

    Article  CAS  PubMed  Google Scholar 

  17. Shanafelt AB, Lin Y, Shanafelt MC, Forte CP, Dubois-Stringfellow N, Carter C, et al. A T-cell-selective interleukin 2 mutein exhibits potent antitumor activity and is well tolerated in vivo. Nat Biotechnol. 2000;18:1197–202.

    Article  CAS  PubMed  Google Scholar 

  18. Margolin K, Atkins MB, Dutcher JP, Ernstoff MS, Smith JW, Clark JI, et al. Phase I trial of BAY 50-4798, an interleukin-2-specific agonist in advanced melanoma and renal cancer. Clin Cancer Res. 2007;13:3312–9.

    Article  CAS  PubMed  Google Scholar 

  19. Levin AM, Bates DL, Ring AM, Krieg C, Lin JT, Su L, et al. Exploiting a natural conformational switch to engineer an interleukin-2 ‘superkine’. Nature. 2012;484:529–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. O’Shea JJ, Paul WE. Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells. Science. 2010;327:1098–102.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Kelly-Welch AE, Hanson EM, Boothby MR, Keegan AD. Interleukin-4 and interleukin-13 signaling connections maps. Science. 2003;300:1527–8.

    Article  CAS  PubMed  Google Scholar 

  22. Junttila IS, Creusot RJ, Moraga I, Bates DL, Wong MT, Alonso MN, et al. Redirecting cell-type specific cytokine responses with engineered interleukin-4 superkines. Nat Chem Biol. 2012;8:990–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Zhang L, Ying Y, Chen S, Arnold PR, Tian F, Minze LJ, et al. The transcription factor RelB restrains group 2 innate lymphoid cells and type 2 immune pathology in vivo. Cell Mol Immunol. 2021;18:230–42.

    Article  CAS  PubMed  Google Scholar 

  24. Gurram RK, Zhu J. Orchestration between ILC2s and Th2 cells in shaping type 2 immune responses. Cell Mol Immunol. 2019;16:225–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Yin Y, Boesteanu AC, Binder ZA, Xu C, Reid RA, Rodriguez JL, et al. Checkpoint blockade reverses anergy in IL-13Rα2 humanized scFv-based CAR T cells to treat murine and canine gliomas. Mol Ther oncolytics. 2018;11:20–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Junttila IS. Tuning the cytokine responses: an update on interleukin (IL)-4 and IL-13 receptor complexes. Front Immunol. 2018;9:888.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Wang L, Liu Z, Wang L, Wu Q, Li X, Xie D, et al. Spatial distribution of IL4 controls iNKT cell-DC crosstalk in tumors. Cell Mol Immunol. 2020;17:496–506.

    Article  CAS  PubMed  Google Scholar 

  28. Ring AM, Lin JX, Feng D, Mitra S, Rickert M, Bowman GR, et al. Mechanistic and structural insight into the functional dichotomy between IL-2 and IL-15. Nat Immunol. 2012;13:1187–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Pettit DK, Bonnert TP, Eisenman J, Srinivasan S, Paxton R, Beers C, et al. Structure-function studies of interleukin 15 using site-specific mutagenesis, polyethylene glycol conjugation, and homology modeling. J Biol Chem. 1997;272:2312–8.

    Article  CAS  PubMed  Google Scholar 

  30. Ferrari-Lacraz S, Zheng XX, Kim YS, Li Y, Maslinski W, Li XC, et al. An antagonist IL-15/Fc protein prevents costimulation blockade-resistant rejection. J Immunol. 2001;167:3478–85.

    Article  CAS  PubMed  Google Scholar 

  31. Ferrari-Lacraz S, Zanelli E, Neuberg M, Donskoy E, Kim YS, Zheng XX, et al. Targeting IL-15 receptor-bearing cells with an antagonist mutant IL-15/Fc protein prevents disease development and progression in murine collagen-induced arthritis. J Immunol. 2004;173:5818–26.

    Article  CAS  PubMed  Google Scholar 

  32. Zhou T, Damsky W, Weizman OE, McGeary MK, Hartmann KP, Rosen CE, et al. IL-18BP is a secreted immune checkpoint and barrier to IL-18 immunotherapy. Nature. 2020;583:609–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Jaitin DA, Roisman LC, Jaks E, Gavutis M, Piehler J, Van der Heyden J, et al. Inquiring into the differential action of interferons (IFNs): an IFN-alpha2 mutant with enhanced affinity to IFNAR1 is functionally similar to IFN-beta. Mol Cell Biol. 2006;26:1888–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Thomas C, Moraga I, Levin D, Krutzik PO, Podoplelova Y, Trejo A, et al. Structural linkage between ligand discrimination and receptor activation by type I interferons. Cell. 2011;146:621–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Brideau-Andersen AD, Huang X, Sun SC, Chen TT, Stark D, Sas IJ, et al. Directed evolution of gene-shuffled IFN-alpha molecules with activity profiles tailored for treatment of chronic viral diseases. Proc Natl Acad Sci USA. 2007;104:8269–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Levin D, Schneider WM, Hoffmann HH, Yarden G, Busetto AG, Manor O, et al. Multifaceted activities of type I interferon are revealed by a receptor antagonist. Sci Signal. 2014;7:ra50.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Saxton RA, Tsutsumi N, Su LL, Abhiraman GC, Mohan K, Henneberg LT, et al. Structure-based decoupling of the pro- and anti-inflammatory functions of interleukin-10. Science. 2021;371:eabc8433.

  38. Gorby C, Sotolongo Bellón J, Wilmes S, Warda W, Pohler E, Fyfe PK, et al. Engineered IL-10 variants elicit potent immunomodulatory effects at low ligand doses. Sci Signal. 2020;13:eabc0653.

  39. Vazquez-Lombardi R, Loetsch C, Zinkl D, Jackson J, Schofield P, Deenick EK, et al. Potent antitumour activity of interleukin-2-Fc fusion proteins requires Fc-mediated depletion of regulatory T-cells. Nat Commun. 2017;8:15373.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Charych DH, Hoch U, Langowski JL, Lee SR, Addepalli MK, Kirk PB, et al. NKTR-214, an engineered cytokine with biased IL2 receptor binding, increased tumor exposure, and marked efficacy in mouse tumor models. Clin Cancer Res. 2016;22:680–90.

    Article  CAS  PubMed  Google Scholar 

  41. To MD, Merchant F, Merchant N. MDNA11 is a long-acting IL-2 superkine that potentiates durable immune response in mouse tumor models and non-human primates. J Clin Oncol. 2021;39:e14546.

    Article  Google Scholar 

  42. Burrack KS, Huggins MA, Taras E, Dougherty P, Henzler CM, Yang R, et al. Interleukin-15 complex treatment protects mice from cerebral malaria by inducing interleukin-10-producing natural killer cells. Immunity. 2018;48:760–72.e764.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Huntington ND, Legrand N, Alves NL, Jaron B, Weijer K, Plet A, et al. IL-15 trans-presentation promotes human NK cell development and differentiation in vivo. J Exp Med. 2009;206:25–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Mortier E, Quéméner A, Vusio P, Lorenzen I, Boublik Y, Grötzinger J, et al. Soluble interleukin-15 receptor alpha (IL-15R alpha)-sushi as a selective and potent agonist of IL-15 action through IL-15R beta/gamma. Hyperagonist IL-15 x IL-15R alpha fusion proteins. J Biol Chem. 2006;281:1612–9.

    Article  CAS  PubMed  Google Scholar 

  45. Rubinstein MP, Kovar M, Purton JF, Cho JH, Boyman O, Surh CD, et al. Converting IL-15 to a superagonist by binding to soluble IL-15R{alpha}. Proc Natl Acad Sci USA. 2006;103:9166–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Guo Y, Luan L, Rabacal W, Bohannon JK, Fensterheim BA, Hernandez A, et al. IL-15 superagonist-mediated immunotoxicity: role of NK cells and IFN-γ. J Immunol. 2015;195:2353–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Dubois S, Patel HJ, Zhang M, Waldmann TA, Müller JR. Preassociation of IL-15 with IL-15R alpha-IgG1-Fc enhances its activity on proliferation of NK and CD8+/CD44high T cells and its antitumor action. J Immunol. 2008;180:2099–106.

    Article  CAS  PubMed  Google Scholar 

  48. Xu W, Jones M, Liu B, Zhu X, Johnson CB, Edwards AC, 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. 2013;73:3075–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Wong HC, Jeng EK, Rhode PR. The IL-15-based superagonist ALT-803 promotes the antigen-independent conversion of memory CD8(+) T cells into innate-like effector cells with antitumor activity. Oncoimmunology. 2013;2:e26442.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Guo Y, Luan L, Patil NK, Sherwood ER. Immunobiology of the IL-15/IL-15Rα complex as an antitumor and antiviral agent. Cytokine Growth Factor Rev. 2017;38:10–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Redman JM, Steinberg SM, Gulley JL. Quick efficacy seeking trial (QuEST1): a novel combination immunotherapy study designed for rapid clinical signal assessment metastatic castration-resistant prostate cancer. J Immunother Cancer. 2018;6:91.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Wrangle JM, Velcheti V, Patel MR, Garrett-Mayer E, Hill EG, Ravenel JG, 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. 2018;19:694–704.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Baldo BA. Side effects of cytokines approved for therapy. Drug Saf. 2014;37:921–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Dolman CS, Mueller BM, Lode HN, Xiang R, Gillies SD, Reisfeld RA. Suppression of human prostate carcinoma metastases in severe combined immunodeficient mice by interleukin 2 immunocytokine therapy. Clin Cancer Res. 1998;4:2551–7.

    CAS  PubMed  Google Scholar 

  55. Sabzevari H, Gillies SD, Mueller BM, Pancook JD, Reisfeld RA. A recombinant antibody-interleukin 2 fusion protein suppresses growth of hepatic human neuroblastoma metastases in severe combined immunodeficiency mice. Proc Natl Acad Sci USA. 1994;91:9626–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Gillies SD, Reilly EB, Lo KM, Reisfeld RA. Antibody-targeted interleukin 2 stimulates T-cell killing of autologous tumor cells. Proc Natl Acad Sci USA. 1992;89:1428–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Albertini MR, Yang RK, Ranheim EA, Hank JA, Zuleger CL, Weber S, et al. Pilot trial of the hu14.18-IL2 immunocytokine in patients with completely resectable recurrent stage III or stage IV melanoma. Cancer Immunol, immunotherapy: CII. 2018;67:1647–58.

    Article  CAS  PubMed  Google Scholar 

  58. Klein C, Waldhauer I, Nicolini VG, Freimoser-Grundschober A, Nayak T, Vugts DJ, et al. Cergutuzumab amunaleukin (CEA-IL2v), a CEA-targeted IL-2 variant-based immunocytokine for combination cancer immunotherapy: overcoming limitations of aldesleukin and conventional IL-2-based immunocytokines. Oncoimmunology. 2017;6:e1277306.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Ribba B, Boetsch C, Nayak T, Grimm HP, Charo J, Evers S, et al. Prediction of the optimal dosing regimen using a mathematical model of tumor uptake for immunocytokine-based cancer immunotherapy. Clin Cancer Res. 2018;24:3325–33.

    Article  CAS  PubMed  Google Scholar 

  60. Herter S, Morra L, Schlenker R, Sulcova J, Fahrni L, Waldhauer I, et al. A novel three-dimensional heterotypic spheroid model for the assessment of the activity of cancer immunotherapy agents. Cancer Immunol, Immunotherapy: CII. 2017;66:129–40.

    Article  CAS  PubMed  Google Scholar 

  61. Bachanova V, Lansigan F, Quick DP, Vlock D, Gillies S, Nakamura R. Remission induction in a phase I/II study of an anti-CD20-interleukin-2 immunocytokine DI-Leu16-IL2 in patients with relapsed B-cell lymphoma. Blood. 2015;126:1533.

    Article  Google Scholar 

  62. Bootz F, Neri D. Immunocytokines: a novel class of products for the treatment of chronic inflammation and autoimmune conditions. Drug Discov Today. 2016;21:180–9.

    Article  CAS  PubMed  Google Scholar 

  63. Schliemann C, Palumbo A, Zuberbühler K, Villa A, Kaspar M, Trachsel E, et al. Complete eradication of human B-cell lymphoma xenografts using rituximab in combination with the immunocytokine L19-IL2. Blood. 2009;113:2275–83.

    Article  CAS  PubMed  Google Scholar 

  64. Wagner K, Schulz P, Scholz A, Wiedenmann B, Menrad A. The targeted immunocytokine L19-IL2 efficiently inhibits the growth of orthotopic pancreatic cancer. Clin Cancer Res. 2008;14:4951–60.

    Article  CAS  PubMed  Google Scholar 

  65. Danielli R, Patuzzo R, Di Giacomo AM, Gallino G, Maurichi A, Di Florio A, et al. Intralesional administration of L19-IL2/L19-TNF in stage III or stage IVM1a melanoma patients: results of a phase II study. Cancer Immunol, Immunotherapy: CII. 2015;64:999–1009.

    Article  CAS  PubMed  Google Scholar 

  66. Sun Z, Ren Z, Yang K, Liu Z, Cao S, Deng S, et al. A next-generation tumor-targeting IL-2 preferentially promotes tumor-infiltrating CD8(+) T-cell response and effective tumor control. Nat Commun. 2019;10:3874.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Balkwill F. Tumour necrosis factor and cancer. Nat Rev Cancer. 2009;9:361–71.

    Article  CAS  PubMed  Google Scholar 

  68. Gamm H, Lindemann A, Mertelsmann R, Herrmann F. Phase I trial of recombinant human tumour necrosis factor alpha in patients with advanced malignancy. Eur J Cancer. 1991;27:856–63.

    Article  CAS  PubMed  Google Scholar 

  69. van Horssen R, Ten Hagen TL, Eggermont AM. TNF-alpha in cancer treatment: molecular insights, antitumor effects, and clinical utility. Oncologist. 2006;11:397–408.

    Article  PubMed  Google Scholar 

  70. Balza E, Mortara L, Sassi F, Monteghirfo S, Carnemolla B, Castellani P, et al. Targeted delivery of tumor necrosis factor-alpha to tumor vessels induces a therapeutic T cell-mediated immune response that protects the host against syngeneic tumors of different histologic origin. Clin Cancer Res. 2006;12:2575–82.

    Article  CAS  PubMed  Google Scholar 

  71. Borsi L, Balza E, Carnemolla B, Sassi F, Castellani P, Berndt A, et al. Selective targeted delivery of TNFalpha to tumor blood vessels. Blood. 2003;102:4384–92.

    Article  CAS  PubMed  Google Scholar 

  72. Weiss T, Puca E, Silginer M, Hemmerle T, Pazahr S, Bink A, et al. Immunocytokines are a promising immunotherapeutic approach against glioblastoma. Sci Transl Med. 2020;12:eabb2311.

  73. Spitaleri G, Berardi R, Pierantoni C, De Pas T, Noberasco C, Libbra C, et al. Phase I/II study of the tumour-targeting human monoclonal antibody-cytokine fusion protein L19-TNF in patients with advanced solid tumours. J Cancer Res Clin Oncol. 2013;139:447–55.

    Article  CAS  PubMed  Google Scholar 

  74. Papadia F, Basso V, Patuzzo R, Maurichi A, Di Florio A, Zardi L, et al. Isolated limb perfusion with the tumor-targeting human monoclonal antibody-cytokine fusion protein L19-TNF plus melphalan and mild hyperthermia in patients with locally advanced extremity melanoma. J Surg Oncol. 2013;107:173–9.

    Article  CAS  PubMed  Google Scholar 

  75. Morillon YM 2nd, Su Z, Schlom J, Greiner JW. Temporal changes within the (bladder) tumor microenvironment that accompany the therapeutic effects of the immunocytokine NHS-IL12. J Immunother Cancer. 2019;7:150.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Halin C, Gafner V, Villani ME, Borsi L, Berndt A, Kosmehl H, et al. Synergistic therapeutic effects of a tumor targeting antibody fragment, fused to interleukin 12 and to tumor necrosis factor alpha. Cancer Res. 2003;63:3202–10.

    CAS  PubMed  Google Scholar 

  77. Pasche N, Wulhfard S, Pretto F, Carugati E, Neri D. The antibody-based delivery of interleukin-12 to the tumor neovasculature eradicates murine models of cancer in combination with paclitaxel. Clin Cancer Res. 2012;18:4092–103.

    Article  CAS  PubMed  Google Scholar 

  78. Heuser C, Diehl V, Abken H, Hombach A. Anti-CD30-IL-12 antibody-cytokine fusion protein that induces IFN-gamma secretion of T cells and NK cell-mediated lysis of Hodgkin’s lymphoma-derived tumor cells. Int J Cancer. 2003;106:545–52.

    Article  CAS  PubMed  Google Scholar 

  79. Xu C, Zhang Y, Rolfe PA, Hernández VM, Guzman W, Kradjian G, et al. Combination therapy with NHS-muIL12 and avelumab (anti-PD-L1) enhances antitumor efficacy in preclinical cancer models. Clin Cancer Res. 2017;23:5869–80.

    Article  CAS  PubMed  Google Scholar 

  80. Asadullah K, Sterry W, Volk HD. Interleukin-10 therapy-review of a new approach. Pharmacol Rev. 2003;55:241–69.

    Article  CAS  PubMed  Google Scholar 

  81. Berman RM, Suzuki T, Tahara H, Robbins PD, Narula SK, Lotze MT. Systemic administration of cellular IL-10 induces an effective, specific, and long-lived immune response against established tumors in mice. J Immunol. 1996;157:231–8.

    Article  CAS  PubMed  Google Scholar 

  82. Emmerich J, Mumm JB, Chan IH, LaFace D, Truong H, McClanahan T, et al. IL-10 directly activates and expands tumor-resident CD8(+) T cells without de novo infiltration from secondary lymphoid organs. Cancer Res. 2012;72:3570–81.

    Article  CAS  PubMed  Google Scholar 

  83. Mumm JB, Emmerich J, Zhang X, Chan I, Wu L, Mauze S, et al. IL-10 elicits IFNγ-dependent tumor immune surveillance. Cancer Cell. 2011;20:781–96.

    Article  CAS  PubMed  Google Scholar 

  84. Lauw FN, Pajkrt D, Hack CE, Kurimoto M, van Deventer SJ, van der Poll T. Proinflammatory effects of IL-10 during human endotoxemia. J Immunol. 2000;165:2783–9.

    Article  CAS  PubMed  Google Scholar 

  85. Qiao J, Liu Z, Dong C, Luan Y, Zhang A, Moore C, et al. Targeting tumors with IL-10 prevents dendritic cell-mediated CD8(+) T cell apoptosis. Cancer Cell. 2019;35:901–15.e904.

    Article  CAS  PubMed  Google Scholar 

  86. Zeng R, Spolski R, Finkelstein SE, Oh S, Kovanen PE, Hinrichs CS, et al. Synergy of IL-21 and IL-15 in regulating CD8+ T cell expansion and function. J Exp Med. 2005;201:139–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Moroz A, Eppolito C, Li Q, Tao J, Clegg CH, Shrikant PA. IL-21 enhances and sustains CD8+ T cell responses to achieve durable tumor immunity: comparative evaluation of IL-2, IL-15, and IL-21. J Immunol. 2004;173:900–9.

    Article  CAS  PubMed  Google Scholar 

  88. Li Y, Cong Y, Jia M, He Q, Zhong H, Zhao Y, et al. Targeting IL-21 to tumor-reactive T cells enhances memory T cell responses and anti-PD-1 antibody therapy. Nat Commun. 2021;12:951.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Deng S, Sun Z, Qiao J, Liang Y, Liu L, Dong C, et al. Targeting tumors with IL-21 reshapes the tumor microenvironment by proliferating PD-1intTim-3-CD8+ T cells. JCI Insight. 2020;5:e132000.

  90. Shen S, Sckisel G, Sahoo A, Lalani A, Otter DD, Pearson J, et al. Engineered IL-21 cytokine muteins fused to anti-PD-1 antibodies can improve CD8+ T cell function and anti-tumor immunity. Front Immunol. 2020;11:832.

    Article  PubMed  PubMed Central  Google Scholar 

  91. Knudson KM, Hicks KC, Ozawa Y, Schlom J, Gameiro SR. Functional and mechanistic advantage of the use of a bifunctional anti-PD-L1/IL-15 superagonist. J Immunother Cancer. 2020;8:e000493.

  92. Spitzer MH, Carmi Y, Reticker-Flynn NE, Kwek SS, Madhireddy D, Martins MM, et al. Systemic immunity is required for effective cancer immunotherapy. Cell. 2017;168:487–502.e415.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Chen S, Huang Q, Liu J, Xing J, Zhang N, Liu Y, et al. A targeted IL-15 fusion protein with potent anti-tumor activity. Cancer Biol Ther. 2015;16:1415–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. De Luca R, Neri D. Potentiation of PD-L1 blockade with a potency-matched dual cytokine-antibody fusion protein leads to cancer eradication in BALB/c-derived tumors but not in other mouse strains. Cancer Immunol, Immunotherapy: CII. 2018;67:1381–91.

    Article  PubMed  Google Scholar 

  95. Schwager K, Hemmerle T, Aebischer D, Neri D. The immunocytokine L19-IL2 eradicates cancer when used in combination with CTLA-4 blockade or with L19-TNF. J investig Dermatol. 2013;133:751–8.

    Article  CAS  PubMed  Google Scholar 

  96. Goebeler ME, Bargou RC. T cell-engaging therapies - BiTEs and beyond. Nat Rev Clin Oncol. 2020;17:418–34.

    Article  PubMed  Google Scholar 

  97. Dreier T, Baeuerle PA, Fichtner I, Grün M, Schlereth B, Lorenczewski G, et al. T cell costimulus-independent and very efficacious inhibition of tumor growth in mice bearing subcutaneous or leukemic human B cell lymphoma xenografts by a CD19-/CD3- bispecific single-chain antibody construct. J Immunol. 2003;170:4397–402.

    Article  CAS  PubMed  Google Scholar 

  98. Löffler A, Gruen M, Wuchter C, Schriever F, Kufer P, Dreier T, et al. Efficient elimination of chronic lymphocytic leukaemia B cells by autologous T cells with a bispecific anti-CD19/anti-CD3 single-chain antibody construct. Leukemia. 2003;17:900–9.

    Article  PubMed  Google Scholar 

  99. Bargou R, Leo E, Zugmaier G, Klinger M, Goebeler M, Knop S, et al. Tumor regression in cancer patients by very low doses of a T cell-engaging antibody. Science. 2008;321:974–7.

    Article  CAS  PubMed  Google Scholar 

  100. Labrijn AF, Janmaat ML, Reichert JM, Parren P. Bispecific antibodies: a mechanistic review of the pipeline. Nat Rev Drug Discov. 2019;18:585–608.

    Article  CAS  PubMed  Google Scholar 

  101. Topp MS, Gökbuget N, Stein AS, Zugmaier G, O'Brien S, Bargou RC, et al. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol. 2015;16:57–66.

    Article  CAS  PubMed  Google Scholar 

  102. Barrett DM, Teachey DT, Grupp SA. Toxicity management for patients receiving novel T-cell engaging therapies. Curr Opin pediatrics. 2014;26:43–9.

    Article  CAS  Google Scholar 

  103. Morvan MG, Lanier LL. NK cells and cancer: you can teach innate cells new tricks. Nat Rev Cancer. 2016;16:7–19.

    Article  CAS  PubMed  Google Scholar 

  104. Hodgins JJ, Khan ST, Park MM, Auer RC, Ardolino M. Killers 2.0: NK cell therapies at the forefront of cancer control. J Clin Investig. 2019;129:3499–510.

    Article  PubMed  PubMed Central  Google Scholar 

  105. Wiernik A, Foley B, Zhang B, Verneris MR, Warlick E, Gleason MK, et al. Targeting natural killer cells to acute myeloid leukemia in vitro with a CD16 x 33 bispecific killer cell engager and ADAM17 inhibition. Clin Cancer Res. 2013;19:3844–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Gleason MK, Ross JA, Warlick ED, Lund TC, Verneris MR, Wiernik A, et al. CD16xCD33 bispecific killer cell engager (BiKE) activates NK cells against primary MDS and MDSC CD33+ targets. Blood. 2014;123:3016–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Vallera DA, Felices M, McElmurry R, McCullar V, Zhou X, Schmohl JU, 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;22:3440–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Sarhan D, Brandt L, Felices M, Guldevall K, Lenvik T, Hinderlie P, et al. 161533 TriKE stimulates NK-cell function to overcome myeloid-derived suppressor cells in MDS. Blood Adv. 2018;2:1459–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Schmohl JU, Felices M, Oh F, Lenvik AJ, Lebeau AM, Panyam J, et al. Engineering of anti-CD133 trispecific molecule capable of inducing NK expansion and driving antibody-dependent cell-mediated cytotoxicity. Cancer Res Treat. 2017;49:1140–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Cheng Y, Zheng X, Wang X, Chen Y, Wei H, Sun R, et al. Trispecific killer engager 161519 enhances natural killer cell function and provides anti-tumor activity against CD19-positive cancers. Cancer Biol Med. 2020;17:1026–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Felices M, Kodal B, Hinderlie P, Kaminski MF, Cooley S, Weisdorf DJ, et al. Novel CD19-targeted TriKE restores NK cell function and proliferative capacity in CLL. Blood Adv. 2019;3:897–907.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Moraga I, Spangler JB, Mendoza JL, Gakovic M, Wehrman TS, Krutzik P, et al. Synthekines are surrogate cytokine and growth factor agonists that compel signaling through non-natural receptor dimers. eLife. 2017;6:e22882.

  113. Scheller J, Engelowski E, Moll JM, Floss DM. Immunoreceptor engineering and synthetic cytokine signaling for therapeutics. Trends Immunol. 2019;40:258–72.

    Article  CAS  PubMed  Google Scholar 

  114. Silva DA, Yu S, Ulge UY, Spangler JB, Jude KM, Labão-Almeida C, et al. De novo design of potent and selective mimics of IL-2 and IL-15. Nature. 2019;565:186–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Findeisen M, Allen TL, Henstridge DC, Kammoun H, Brandon AE, Baggio LL, et al. Treatment of type 2 diabetes with the designer cytokine IC7Fc. Nature. 2019;574:63–8.

    Article  CAS  PubMed  Google Scholar 

  116. Rafei M, Berchiche YA, Birman E, Boivin MN, Young YK, Wu JH, et al. An engineered GM-CSF-CCL2 fusokine is a potent inhibitor of CCR2-driven inflammation as demonstrated in a murine model of inflammatory arthritis. J Immunol. 2009;183:1759–66.

    Article  CAS  PubMed  Google Scholar 

  117. Stagg J, Wu JH, Bouganim N, Galipeau J. Granulocyte-macrophage colony-stimulating factor and interleukin-2 fusion cDNA for cancer gene immunotherapy. Cancer Res. 2004;64:8795–9.

    Article  CAS  PubMed  Google Scholar 

  118. Burgess AW, Metcalf D. Serum half-life and organ distribution of radiolabeled colony stimulating factor in mice. Exp Hematol. 1977;5:456–64.

    CAS  PubMed  Google Scholar 

  119. Penafuerte C, Bautista-Lopez N, Boulassel MR, Routy JP, Galipeau J. The human ortholog of granulocyte macrophage colony-stimulating factor and interleukin-2 fusion protein induces potent ex vivo natural killer cell activation and maturation. Cancer Res. 2009;69:9020–8.

    Article  CAS  PubMed  Google Scholar 

  120. Deng J, Yuan S, Pennati A, Murphy J, Wu JH, Lawson D, et al. Engineered fusokine GIFT4 licenses the ability of B cells to trigger a tumoricidal T-cell response. Cancer Res. 2014;74:4133–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Kwong B, Gai SA, Elkhader J, Wittrup KD, Irvine DJ. Localized immunotherapy via liposome-anchored Anti-CD137 + IL-2 prevents lethal toxicity and elicits local and systemic antitumor immunity. Cancer Res. 2013;73:1547–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Zhang Y, Li N, Suh H, Irvine DJ. Nanoparticle anchoring targets immune agonists to tumors enabling anti-cancer immunity without systemic toxicity. Nat Commun. 2018;9:6.

    Article  PubMed  PubMed Central  Google Scholar 

  123. Kih M, Lee EJ, Lee NK, Kim YK, Lee KE, Jeong C, et al. Designed trimer-mimetic TNF superfamily ligands on self-assembling nanocages. Biomaterials. 2018;180:67–77.

    Article  CAS  PubMed  Google Scholar 

  124. Robert M, Miossec P. Reactivation of latent tuberculosis with TNF inhibitors: critical role of the beta 2 chain of the IL-12 receptor. Cell Mol Immunol. 2021;18:1644–51.

  125. Zhang X, Smith SM, Wang X, Zhao B, Wu L, Hu X. Three paralogous clusters of the miR-17~92 family of microRNAs restrain IL-12-mediated immune defense. Cell Mol Immunol. 2021;18:1751–60.

  126. Melero I, Mazzolini G, Narvaiza I, Qian C, Chen L, Prieto J. IL-12 gene therapy for cancer: in synergy with other immunotherapies. Trends Immunol. 2001;22:113–5.

    Article  CAS  PubMed  Google Scholar 

  127. Duffy MR, Parker AL, Bradshaw AC, Baker AH. Manipulation of adenovirus interactions with host factors for gene therapy applications. Nanomed. 2012;7:271–88.

    Article  CAS  Google Scholar 

  128. Liu X, Gao X, Zheng S, Wang B, Li Y, Zhao C, et al. Modified nanoparticle mediated IL-12 immunogene therapy for colon cancer. Nanomed: Nanotechnol, Biol, Med. 2017;13:1993–2004.

    Article  CAS  Google Scholar 

  129. Shum T, Omer B, Tashiro H, Kruse RL, Wagner DL, Parikh K, et al. Constitutive signaling from an engineered IL7 receptor promotes durable tumor elimination by tumor-redirected T cells. Cancer Discov. 2017;7:1238–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Shochat C, Tal N, Bandapalli OR, Palmi C, Ganmore I, te Kronnie G, et al. Gain-of-function mutations in interleukin-7 receptor-α (IL7R) in childhood acute lymphoblastic leukemias. J Exp Med. 2011;208:901–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Geering B, Fussenegger M. Synthetic immunology: modulating the human immune system. Trends Biotechnol. 2015;33:65–79.

    Article  CAS  PubMed  Google Scholar 

  132. Pegram HJ, Lee JC, Hayman EG, Imperato GH, Tedder TF, Sadelain M, et al. Tumor-targeted T cells modified to secrete IL-12 eradicate systemic tumors without need for prior conditioning. Blood. 2012;119:4133–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Kalos M, June CH. Adoptive T cell transfer for cancer immunotherapy in the era of synthetic biology. Immunity. 2013;39:49–60.

    Article  CAS  PubMed  Google Scholar 

  134. Rosenberg SA, Restifo NP. Adoptive cell transfer as personalized immunotherapy for human cancer. Science. 2015;348:62–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Yee C, Thompson JA, Byrd D, Riddell SR, Roche P, Celis E, et al. Adoptive T cell therapy using antigen-specific CD8+ T cell clones for the treatment of patients with metastatic melanoma: in vivo persistence, migration, and antitumor effect of transferred T cells. Proc Natl Acad Sci USA. 2002;99:16168–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Sockolosky JT, Trotta E, Parisi G, Picton L, Su LL, Le AC, et al. Selective targeting of engineered T cells using orthogonal IL-2 cytokine-receptor complexes. Science. 2018;359:1037–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. 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;16:430–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Li H, Er Saw P, Song E. Challenges and strategies for next-generation bispecific antibody-based antitumor therapeutics. Cell Mol Immunol. 2020;17:451–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Sun H, Sun C, Xiao W, Sun R. Tissue-resident lymphocytes: from adaptive to innate immunity. Cell Mol Immunol. 2019;16:205–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Cheng M, Chen Y, Xiao W, Sun R, Tian Z. NK cell-based immunotherapy for malignant diseases. Cell Mol Immunol. 2013;10:230–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Habif G, Crinier A, André P, Vivier E, Narni-Mancinelli E. Targeting natural killer cells in solid tumors. Cell Mol Immunol. 2019;16:415–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Wu C, Wu M, Liang M, Xiong S, Dong C. A novel oncolytic virus engineered with PD-L1 scFv effectively inhibits tumor growth in a mouse model. Cell Mol Immunol. 2019;16:780–2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Varadé J, Magadán S, González-Fernández Á. Human immunology and immunotherapy: main achievements and challenges. Cell Mol Immunol. 2021;18:805–28.

    Article  PubMed  Google Scholar 

  144. He Y, Hwang S, Ahmed YA, Feng D, Li N, Ribeiro M, et al. Immunopathobiology and therapeutic targets related to cytokines in liver diseases. Cell Mol Immunol. 2021;18:18–37.

    Article  CAS  PubMed  Google Scholar 

  145. Nakao S, Arai Y, Tasaki M, Yamashita M, Murakami R, Kawase T, et al. Intratumoral expression of IL-7 and IL-12 using an oncolytic virus increases systemic sensitivity to immune checkpoint blockade. Sci Transl Med. 2020;12:eaax7992.

  146. Kowalsky SJ, Liu Z, Feist M, Berkey SE, Ma C, Ravindranathan R, et al. Superagonist IL-15-armed oncolytic virus elicits potent antitumor immunity and therapy that are enhanced with PD-1 blockade. Mol Ther: J Am Soc Gene Ther. 2018;26:2476–86.

    Article  CAS  Google Scholar 

  147. Joshi BH, Leland P, Asher A, Prayson RA, Varricchio F, Puri RK. In situ expression of interleukin-4 (IL-4) receptors in human brain tumors and cytotoxicity of a recombinant IL-4 cytotoxin in primary glioblastoma cell cultures. Cancer Res. 2001;61:8058–61.

    CAS  PubMed  Google Scholar 

  148. Achrol AA, Manish; Bankiewicz, Krystof; Bexon, Martin; Bisdas, Sotirios; Brem, Steven; Brenner, et al. Intratumoral delivery of MDNA55, an interleukin-4 receptor targeted immunotherapy, by MRI-guided convective delivery for the treatment of recurrent glioblastoma: 2018; https://digitalcommons.psjhealth.org/other_pubs/47.

  149. Eisenberg SP, Evans RJ, Arend WP, Verderber E, Brewer MT, Hannum CH, et al. Primary structure and functional expression from complementary DNA of a human interleukin-1 receptor antagonist. Nature. 1990;343:341–6.

    Article  CAS  PubMed  Google Scholar 

  150. Eloseily EM, Weiser P, Crayne CB, Haines H, Mannion ML, Stoll ML, et al. Benefit of anakinra in treating pediatric secondary hemophagocytic lymphohistiocytosis. Arthritis Rheumatol. 2020;72:326–34.

    Article  CAS  PubMed  Google Scholar 

  151. Mezzaroma E, Toldo S, Farkas D, Seropian IM, Van Tassell BW, Salloum FN, et al. The inflammasome promotes adverse cardiac remodeling following acute myocardial infarction in the mouse. Proc Natl Acad Sci USA. 2011;108:19725–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Mann DL. Inflammatory mediators and the failing heart: past, present, and the foreseeable future. Circulation Res. 2002;91:988–98.

    Article  CAS  PubMed  Google Scholar 

  153. Lan Y, Zhang D, Xu C, Hance KW, Marelli B, Qi J, et al. Enhanced preclinical antitumor activity of M7824, a bifunctional fusion protein simultaneously targeting PD-L1 and TGF-β. Sci Transl Med. 2018;10:eaan5488.

  154. Paz-Ares L, Kim TM, Vicente D, Felip E, Lee DH, Lee KH, et al. Bintrafusp Alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in second-line treatment of patients with NSCLC: results from an expansion cohort of a phase 1 trial. J Thorac Oncol. 2020;15:1210–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the Shenzhen Institute of Synthetic Biology Scientific Research Program (ZTXM20214003), Natural Science Foundation of China (82122055, 81872318), and Natural Science Foundation of Anhui Province (2108085J13).

Author information

Authors and Affiliations

  1. CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China

    Xiaohu Zheng, Jiacheng Bi, Yingying Huang & Zhigang Tian

  2. Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, 518055, Shenzhen, China

    Xiaohu Zheng, Jiacheng Bi, Yingying Huang & Zhigang Tian

  3. Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, 230027, Hefei, China

    Xiaohu Zheng, Yaqi Wu & Zhigang Tian

  4. Hefei TG ImmunoPharma Corporation Limited, Hefei, China

    Xiaohu Zheng, Ying Cheng, Yangyang Li, Yuwei Wu, Guoshuai Cao & Zhigang Tian

Authors
  1. Xiaohu Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yaqi Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jiacheng Bi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yingying Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ying Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yangyang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yuwei Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Guoshuai Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Zhigang Tian
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Z.T. and X.Z. conceived and conducted the project. Z.T. and X.Z. supervised the project. Yaqi. W., Z.T., J.B., Y.H, Y.C., Y.L., Yuwei. W., G.C., and X.Z. wrote the paper.

Corresponding authors

Correspondence to Xiaohu Zheng or Zhigang Tian.

Ethics declarations

Competing interests

The authors declare no competing interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zheng, X., Wu, Y., Bi, J. et al. The use of supercytokines, immunocytokines, engager cytokines, and other synthetic cytokines in immunotherapy. Cell Mol Immunol 19, 192–209 (2022). https://doi.org/10.1038/s41423-021-00786-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41423-021-00786-6

Keywords

This article is cited by

Search

Advanced search

Quick links