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Advancements of Common Gamma-Chain Family Cytokines in Cancer Immunotherapy

  • Received : 2022.01.03
  • Accepted : 2022.02.15
  • Published : 2022.02.28
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Abstract

The approval of immunotherapies such as checkpoint inhibitors (CPIs), adoptive cell therapies and cancer vaccines has revolutionized the way cancer treatment is approached. While immunotherapies have improved clinical outcome in a variety of tumor types, some cancers have proven harder to combat using single agents, underscoring the need for multi-targeted immunotherapy approaches. Efficacy of CPIs and cancer vaccines requires patients to have a competent immune system with adequate cell numbers while the efficacy of adoptive cellular therapy is limited by the expansion and persistence of cells after infusion. A promising strategy to overcome these challenges is combination treatment with common gamma-chain cytokines. Gamma-chain cytokines play a critical role in the survival, proliferation, differentiation and function of multiple immune cell types, including CD8 T-cells and NK cells, which are at the center of the anti-tumor response. While the short halflife of recombinant cytokines initially limited their application in the clinic, advancements in protein engineering have led to the development of several next-generation drug candidates with dramatically increased half-life and bioactivity. When combining these cytokines with other immunotherapies, strong evidence of synergy has been observed in preclinical and clinical cancer settings. This promising data has led to the initiation of 70 ongoing clinical trials including IL-2, IL-7, IL-15 and IL-21. This review summarizes the recent advancements of common gamma-chain cytokines and their potential as a cancer immunotherapy.

Keywords

References

  1. Meyers DE, Banerji S. Biomarkers of immune checkpoint inhibitor efficacy in cancer. Curr Oncol 2020;27:S106-S114. https://doi.org/10.3747/co.27.5549
  2. McLellan AD, Ali Hosseini Rad SM. Chimeric antigen receptor T cell persistence and memory cell formation. Immunol Cell Biol 2019;97:664-674. https://doi.org/10.1111/imcb.12254
  3. Bowen WS, Svrivastava AK, Batra L, Barsoumian H, Shirwan H. Current challenges for cancer vaccine adjuvant development. Expert Rev Vaccines 2018;17:207-215. https://doi.org/10.1080/14760584.2018.1434000
  4. Lin JX, Leonard WJ. The common cytokine receptor γ chain family of cytokines. Cold Spring Harb Perspect Biol 2018;10:a028449.
  5. Raeber ME, Zurbuchen Y, Impellizzieri D, Boyman O. The role of cytokines in T-cell memory in health and disease. Immunol Rev 2018;283:176-193. https://doi.org/10.1111/imr.12644
  6. Leonard WJ, Lin JX, O'Shea JJ. The γc family of cytokines: basic biology to therapeutic ramifications. Immunity 2019;50:832-850. https://doi.org/10.1016/j.immuni.2019.03.028
  7. Waldmann TA. The multi-subunit interleukin-2 receptor. Annu Rev Biochem 1989;58:875-911. https://doi.org/10.1146/annurev.bi.58.070189.004303
  8. Xue D, Hsu E, Fu YX, Peng H. Next-generation cytokines for cancer immunotherapy. Antib Ther 2021;4:123-133. https://doi.org/10.1093/abt/tbab014
  9. Fyfe G, Fisher RI, Rosenberg SA, Sznol M, Parkinson DR, Louie AC. Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol 1995;13:688-696. https://doi.org/10.1200/JCO.1995.13.3.688
  10. Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, Abrams J, Sznol M, Parkinson D, Hawkins M, et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol 1999;17:2105-2116. https://doi.org/10.1200/JCO.1999.17.7.2105
  11. Fisher RI, Rosenberg SA, Fyfe G. Long-term survival update for high-dose recombinant interleukin-2 in patients with renal cell carcinoma. Cancer J Sci Am 2000;6 Suppl 1:S55-S57.
  12. Clinigen. Proleukin® (aldesleukin) [Internet]. Available at https://proleukin.com/ [accessed on 30 December 2021].
  13. Kolb HC, Finn MG, Sharpless KB. Click chemistry: diverse chemical function from a few good reactions. Angew Chem Int Ed Engl 2001;40:2004-2021. https://doi.org/10.1002/1521-3773(20010601)40:11<2004::AID-ANIE2004>3.0.CO;2-5
  14. Ptacin JL, Caffaro CE, Ma L, San Jose Gall KM, Aerni HR, Acuff NV, Herman RW, Pavlova Y, Pena MJ, Chen DB, et al. An engineered IL-2 reprogrammed for anti-tumor therapy using a semi-synthetic organism. Nat Commun 2021;12:4785.
  15. Milla ME, Ptacin JL, Ma L, Caffar CE, Aerni HR, San Jose KM, Pena MJ, Herman RW, Pavlova Y, Chen DB, et al. 1225P - THOR-707, a novel not-alpha IL-2, promotes all key immune system anti-tumoral actions of IL-2 without eliciting vascular leak syndrome (VLS). Ann Oncol 2019;30:v501.
  16. Filip Janku RA, Abdul-Karim R, Azad A, Bendell J, Falchook G, Gan HK, Tan T, Wang JS, Chee CE, Ma L, et al. Abstract LB041: THOR-707 (SAR444245), a novel not-alpha IL-2 as monotherapy and in combination with pembrolizumab in advanced/metastatic solid tumors: interim results from HAMMER, an open-label, multicenter phase 1/2 study. Cancer Res 2021;81:LB041.
  17. Charych DH, Hoch U, Langowski JL, Lee SR, Addepalli MK, Kirk PB, Sheng D, Liu X, Sims PW, VanderVeen LA, 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;22:680-690. https://doi.org/10.1158/1078-0432.CCR-15-1631
  18. Bentebibel SE, Hurwitz ME, Bernatchez C, Haymaker C, Hudgens CW, Kluger HM, Tetzlaff MT, Tagliaferri MA, Zalevsky J, Hoch U, et al. A first-in-human study and biomarker analysis of NKTR-214, a novel IL2Rβγ-biased cytokine, in patients with advanced or metastatic solid tumors. Cancer Discov 2019;9:711-721. https://doi.org/10.1158/2159-8290.CD-18-1495
  19. Lopes JE, Fisher JL, Flick HL, Wang C, Sun L, Ernstoff MS, Alvarez JC, Losey HC. ALKS 4230: a novel engineered IL-2 fusion protein with an improved cellular selectivity profile for cancer immunotherapy. J Immunother Cancer 2020;8:e000673.
  20. Lopes JE, Sun L, Flick HL, Murphy EA, Losey HC. Pharmacokinetics and pharmacodynamic effects of nemvaleukin alfa, a selective agonist of the intermediate-affinity IL-2 receptor, in cynomolgus monkeys. J Pharmacol Exp Ther 2021;379:203-210. https://doi.org/10.1124/jpet.121.000612
  21. Castellani P, Viale G, Dorcaratto A, Nicolo G, Kaczmarek J, Querze G, Zardi L. The fibronectin isoform containing the ED-B oncofetal domain: a marker of angiogenesis. Int J Cancer 1994;59:612-618. https://doi.org/10.1002/ijc.2910590507
  22. Lieverse RI, Marcus D, van der Wiel AM, Van Limbergen EJ, Theys J, Yaromina A, Lambin P, Dubois LJ. Human fibronectin extra domain B as a biomarker for targeted therapy in cancer. Mol Oncol 2020;14:1555-1568. https://doi.org/10.1002/1878-0261.12705
  23. Johannsen M, Spitaleri G, Curigliano G, Roigas J, Weikert S, Kempkensteffen C, Roemer A, Kloeters C, Rogalla P, Pecher G, et al. The tumour-targeting human L19-IL2 immunocytokine: preclinical safety studies, phase I clinical trial in patients with solid tumours and expansion into patients with advanced renal cell carcinoma. Eur J Cancer 2010;46:2926-2935.  https://doi.org/10.1016/j.ejca.2010.07.033
  24. Ongaro T, Gouyou B, Stringhini M, Corbellari R, Neri D, Villa A. A novel format for recombinant antibody-interleukin-2 fusion proteins exhibits superior tumor-targeting properties in vivo. Oncotarget 2020;11:3698-3711. https://doi.org/10.18632/oncotarget.27726
  25. Osenga KL, Hank JA, Albertini MR, Gan J, Sternberg AG, Eickhoff J, Seeger RC, Matthay KK, Reynolds CP, Twist C, et al. A phase I clinical trial of the hu14.18-IL2 (EMD 273063) as a treatment for children with refractory or recurrent neuroblastoma and melanoma: a study of the Children's Oncology Group. Clin Cancer Res 2006;12:1750-1759.
  26. Albertini MR, Hank JA, Gadbaw B, Kostlevy J, Haldeman J, Schalch H, Gan J, Kim K, Eickhoff J, Gillies SD, et al. Phase II trial of hu14.18-IL2 for patients with metastatic melanoma. Cancer Immunol Immunother 2012;61:2261-2271. https://doi.org/10.1007/s00262-012-1286-5
  27. Shusterman S, London WB, Gillies SD, Hank JA, Voss SD, Seeger RC, Reynolds CP, Kimball J, Albertini MR, Wagner B, et al. Antitumor activity of hu14.18-IL2 in patients with relapsed/refractory neuroblastoma: a Children's Oncology Group (COG) phase II study. J Clin Oncol 2010;28:4969-4975. https://doi.org/10.1200/JCO.2009.27.8861
  28. Albertini MR, Yang RK, Ranheim EA, Hank JA, Zuleger CL, Weber S, Neuman H, Hartig G, Weigel T, Mahvi D, et al. Pilot trial of the hu14.18-IL2 immunocytokine in patients with completely resectable recurrent stage III or stage IV melanoma. Cancer Immunol Immunother 2018;67:1647-1658. https://doi.org/10.1007/s00262-018-2223-z
  29. Sharma P, Retz M, Siefker-Radtke A, Baron A, Necchi A, Bedke J, Plimack ER, Vaena D, Grimm MO, Bracarda S, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol 2017;18:312-322. https://doi.org/10.1016/S1470-2045(17)30065-7
  30. Huddart RA, Siefker-Radtke AO, Balar AV, Bilen MA, Powles T, Bamias A, Castellano D, Khalil MF, Van Der Heijden MS, Koshkin VS, et al. PIVOT-10: Phase II study of bempegaldesleukin plus nivolumab in cisplatin-ineligible advanced urothelial cancer. Future Oncol 2021;17:137-149. https://doi.org/10.2217/fon-2020-0795
  31. Waldhauer I, Gonzalez-Nicolini V, Freimoser-Grundschober A, Nayak TK, Fahrni L, Hosse RJ, Gerrits D, Geven EJ, Sam J, Lang S, et al. Simlukafusp alfa (FAP-IL2v) immunocytokine is a versatile combination partner for cancer immunotherapy. MAbs 2021;13:1913791.
  32. Italiano A, Verlingue L, Prenen H, Guerra EM, Tosi D, Perets R, Lugowska I, Moiseenko V, Gumus M, Arslan C, et al. Clinical activity and safety of simlukafusp alfa, an engineered interleukin-2 variant targeted to fibroblast activation protein-α, combined with atezolizumab in patients with recurrent or metastatic cervical cancer. J Clin Oncol 2021;39 15_suppl:5510.
  33. Pyo KH, Koh YJ, Synn CB, Kim JH, Byeon Y, Jo HN, Kim YS, Lee W, Kim DH, Lee S, et al. Abstract 1826: Comprehensive preclinical study on GI-101, a novel CD80-IgG4-IL2 variant protein, as a therapeutic antibody candidate with bispecific immuno-oncology target. Cancer Res 2021;81:1826.
  34. Pyo KH, Koh YJ, Synn CB, Park JC, Kim JH, Byeon Y, Kim SE, Lee JM, Jo HN, Lee W, et al. Abstract 6529: GI101, A novel CD80-IgG4-IL2 variant bispecific protein, inhibits tumor growth and induces anti-tumor immune response in multiple preclinical models. Cancer Res 2020;80:6529.
  35. Cho BC, Shin SJ, Lee JL, Shim BY, Park HS, Yun N, Ham M, Koh YJ, Jang MH. 470 A phase 1/2, open-label, dose escalation and expansion study of GI-101 as a single agent and in combination with a pembrolizumab, lenvatinib or local RT in advanced solid tumors (KEYNOTE-B59). J Immunother Cancer 2021;9 Suppl 2:A499.
  36. Mahmoudpour SH, Jankowski M, Valerio L, Becker C, Espinola-Klein C, Konstantinides S, Quitzau K, Barco S. Safety of low-dose subcutaneous recombinant interleukin-2: systematic review and meta-analysis of randomized controlled trials. Sci Rep 2019;9:7145.
  37. Khammari A, Nguyen JM, Leccia MT, Guillot B, Saiagh S, Pandolfino MC, Knol AC, Quereux G, Chiffolettau A, Labarriere N, et al. Tumor infiltrating lymphocytes as adjuvant treatment in stage III melanoma patients with only one invaded lymph node after complete resection: results from a multicentre, randomized clinical phase III trial. Cancer Immunol Immunother 2020;69:1663-1672.  https://doi.org/10.1007/s00262-020-02572-1
  38. Nguyen LT, Saibil SD, Sotov V, Le MX, Khoja L, Ghazarian D, Bonilla L, Majeed H, Hogg D, Joshua AM, et al. Phase II clinical trial of adoptive cell therapy for patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and low-dose interleukin-2. Cancer Immunol Immunother 2019;68:773-785. https://doi.org/10.1007/s00262-019-02307-x
  39. Dreno B, Khammari A, Fortun A, Vignard V, Saiagh S, Beauvais T, Jouand N, Bercegay S, Simon S, Lang F, et al. Phase I/II clinical trial of adoptive cell transfer of sorted specific T cells for metastatic melanoma patients. Cancer Immunol Immunother 2021;70:3015-3030. https://doi.org/10.1007/s00262-021-02961-0
  40. Parisi G, Saco JD, Salazar FB, Tsoi J, Krystofinski P, Puig-Saus C, Zhang R, Zhou J, Cheung-Lau GC, Garcia AJ, et al. Persistence of adoptively transferred T cells with a kinetically engineered IL-2 receptor agonist. Nat Commun 2020;11:660.
  41. Camisaschi C, Filipazzi P, Tazzari M, Casati C, Beretta V, Pilla L, Patuzzo R, Maurichi A, Cova A, Maio M, et al. Effects of cyclophosphamide and IL-2 on regulatory CD4+ T cell frequency and function in melanoma patients vaccinated with HLA-class I peptides: impact on the antigen-specific T cell response. Cancer Immunol Immunother 2013;62:897-908. https://doi.org/10.1007/s00262-013-1397-7
  42. Filipazzi P, Pilla L, Mariani L, Patuzzo R, Castelli C, Camisaschi C, Maurichi A, Cova A, Rigamonti G, Giardino F, et al. Limited induction of tumor cross-reactive T cells without a measurable clinical benefit in early melanoma patients vaccinated with human leukocyte antigen class I-modified peptides. Clin Cancer Res 2012;18:6485-6496. https://doi.org/10.1158/1078-0432.CCR-12-1516
  43. Rahma OE, Hamilton JM, Wojtowicz M, Dakheel O, Bernstein S, Liewehr DJ, Steinberg SM, Khleif SN. The immunological and clinical effects of mutated ras peptide vaccine in combination with IL-2, GM-CSF, or both in patients with solid tumors. J Transl Med 2014;12:55.
  44. Baek S, Kim YM, Kim SB, Kim CS, Kwon SW, Kim Y, Kim H, Lee H. Therapeutic DC vaccination with IL-2 as a consolidation therapy for ovarian cancer patients: a phase I/II trial. Cell Mol Immunol 2015;12:87-95. https://doi.org/10.1038/cmi.2014.40
  45. Tanyi JL, Chiang CL, Chiffelle J, Thierry AC, Baumgartener P, Huber F, Goepfert C, Tarussio D, Tissot S, Torigian DA, et al. Personalized cancer vaccine strategy elicits polyfunctional T cells and demonstrates clinical benefits in ovarian cancer. NPJ Vaccines 2021;6:36.
  46. Mazzucchelli R, Durum SK. Interleukin-7 receptor expression: intelligent design. Nat Rev Immunol 2007;7:144-154. https://doi.org/10.1038/nri2023
  47. Pulliam SR, Uzhachenko RV, Adunyah SE, Shanker A. Common gamma chain cytokines in combinatorial immune strategies against cancer. Immunol Lett 2016;169:61-72. https://doi.org/10.1016/j.imlet.2015.11.007
  48. Onder L, Narang P, Scandella E, Chai Q, Iolyeva M, Hoorweg K, Halin C, Richie E, Kaye P, Westermann J, et al. IL-7-producing stromal cells are critical for lymph node remodeling. Blood 2012;120:4675-4683. https://doi.org/10.1182/blood-2012-03-416859
  49. Zaunders JJ, Levy Y, Seddiki N. Exploiting differential expression of the IL-7 receptor on memory T cells to modulate immune responses. Cytokine Growth Factor Rev 2014;25:391-401. https://doi.org/10.1016/j.cytogfr.2014.07.012
  50. Sportes C, Babb RR, Krumlauf MC, Hakim FT, Steinberg SM, Chow CK, Brown MR, Fleisher TA, Noel P, Maric I, et al. Phase I study of recombinant human interleukin-7 administration in subjects with refractory malignancy. Clin Cancer Res 2010;16:727-735. https://doi.org/10.1158/1078-0432.CCR-09-1303
  51. Perales MA, Goldberg JD, Yuan J, Koehne G, Lechner L, Papadopoulos EB, Young JW, Jakubowski AA, Zaidi B, Gallardo H, et al. Recombinant human interleukin-7 (CYT107) promotes T-cell recovery after allogeneic stem cell transplantation. Blood 2012;120:4882-4891. https://doi.org/10.1182/blood-2012-06-437236
  52. Tredan O, Menetrier-Caux C, Ray-Coquard I, Garin G, Cropet C, Verronese E, Bachelot T, Rebattu P, Heudel PE, Cassier P, et al. ELYPSE-7: a randomized placebo-controlled phase IIa trial with CYT107 exploring the restoration of CD4+ lymphocyte count in lymphopenic metastatic breast cancer patients. Ann Oncol 2015;26:1353-1362. https://doi.org/10.1093/annonc/mdv173
  53. Lee SW, Choi D, Heo M, Shin EC, Park SH, Kim SJ, Oh YK, Lee BH, Yang SH, Sung YC, et al. hIL-7-hyFc, a long-acting IL-7, increased absolute lymphocyte count in healthy subjects. Clin Transl Sci 2020;13:1161-1169.  https://doi.org/10.1111/cts.12800
  54. Kim JH, Kim YM, Choi D, Jo SB, Park HW, Hong SW, Park S, Kim S, Moon S, You G, et al. Hybrid Fcfused interleukin-7 induces an inflamed tumor microenvironment and improves the efficacy of cancer immunotherapy. Clin Transl Immunology 2020;9:e1168.
  55. Heo M, Kim TW. P425 Phase 1b study of GX-I7, a long-acting interleukin-7, evaluating the safety, pharmacokinetics and pharmacodynamics profiles in patients with advanced solid cancers. In: Proceedings of the Society for Immunotherapy of Cancer (SITC) 2019; 6-10 November 2019; National Harbor, MD, USA. Milwaukee, WI: SITC; 2019. p.282.
  56. Campian JL, Ghosh S, Kapoor V, Yan R, Thotala S, Jash A, Hu T, Mahadevan A, Rifai K, Page L, et al. Long-acting recombinant human interleukin-7, NT-I7, increases cytotoxic CD8+  T cells and enhances survival in mouse glioma models. Clin Cancer Res 2022;clincanres.0947.2021.
  57. Zhou A, Rettig M, Foltz J, Luo J, Butt O, Avvaru C, Katumba R, Kim A, Dunn G, Abraham C, et al. 396 NT-I7, a long-acting interleukin-7, promotes expansion of CD8 T cells and NK cells and immune activation in patients with newly diagnosed high-grade gliomas after chemoradiation. J Immunother Cancer 2021;9 Suppl 2:A428.
  58. Sohn J, Im YH. 322 Efficacy and safety of GX-I7 plus pembrolizumab for heavily pretreated patients with metastatic triple negative breast cancer: The Phase 1b/2 KEYNOTE-899 Study. J Immunother Cancer 2020;8 Suppl 3:A197-A198. https://doi.org/10.1136/jitc-2020-SITC2020.0322
  59. Kim R, Barve M, Mamdani H, Johnson M, Lee BH, Ferrando-Martinez S, Chaney M, Fan J, Le N, Naing A. 404 Initial biomarker and clinical data of a phase 2a study of NT-I7, a long-acting interleukin-7, plus pembrolizumab: cohort of subjects with checkpoint inhibitor-naive advanced MSS-colorectal cancer. J Immunother Cancer 2021;9 Suppl 2:A435.
  60. Naing A, Kim R, Barve M, Johnson M, Lee BH, Ferrando-Martinez S, Pant S, Wolff R, Haymaker C, Chaney M, et al. 408 Preliminary biomarker and clinical ata of a phase 2a study of NT-I7, a long-acting interleukin-7, plus pembrolizumab: cohort of subjects with checkpoint inhibitor-naive advanced pancreatic cancer. J Immunother Cancer 2021;9 Suppl 2:A439. CROSSREF
  61. Stock S, Schmitt M, Sellner L. Optimizing manufacturing protocols of chimeric antigen receptor T cells for improved anticancer immunotherapy. Int J Mol Sci 2019;20:6223.
  62. Adachi K, Kano Y, Nagai T, Okuyama N, Sakoda Y, Tamada K. IL-7 and CCL19 expression in CAR-T cells improves immune cell infiltration and CAR-T cell survival in the tumor. Nat Biotechnol 2018;36:346-351. https://doi.org/10.1038/nbt.4086
  63. He C, Zhou Y, Li Z, Farooq MA, Ajmal I, Zhang H, Zhang L, Tao L, Yao J, Du B, et al. Co-expression of IL-7 improves NKG2D-based CAR T cell therapy on prostate cancer by enhancing the expansion and inhibiting the apoptosis and exhaustion. Cancers (Basel) 2020;12:1969.
  64. Luo H, Su J, Sun R, Sun Y, Wang Y, Dong Y, Shi B, Jiang H, Li Z. Coexpression of IL7 and CCL21 increases efficacy of CAR-T cells in solid tumors without requiring preconditioned lymphodepletion. Clin Cancer Res 2020;26:5494-5505. https://doi.org/10.1158/1078-0432.CCR-20-0777
  65. Pang N, Shi J, Qin L, Chen A, Tang Y, Yang H, Huang Y, Wu Q, Li X, He B, et al. IL-7 and CCL19-secreting CAR-T cell therapy for tumors with positive glypican-3 or mesothelin. J Hematol Oncol 2021;14:118.
  66. Ding ZC, Habtetsion T, Cao Y, Li T, Liu C, Kuczma M, Chen T, Hao Z, Bryan L, Munn DH, et al. Adjuvant IL-7 potentiates adoptive T cell therapy by amplifying and sustaining polyfunctional antitumor CD4+ T cells. Sci Rep 2017;7:12168.
  67. Kim MY, Jayasinghe R, Staser KW, Devenport JM, O'Neal J, Kennerly KM, Carter AJ, Ritchey JK, Gao F, Lee BH, et al. A long-acting interleukin-7, rhIL-7-hyFc, enhances CAR T cell expansion, persistence and anti-tumor activity. Nat Commun 2022.
  68. Choi YW, Kang MC, Seo YB, Namkoong H, Park Y, Choi DH, Suh YS, Lee SW, Sung YC, Jin HT. Intravaginal administration of Fc-fused IL7 suppresses the cervicovaginal tumor by recruiting HPV DNA vaccine-induced CD8 T cells. Clin Cancer Res 2016;22:5898-5908.  https://doi.org/10.1158/1078-0432.CCR-16-0423
  69. Gu YZ, Fan CW, Lu R, Shao B, Sang YX, Huang QR, Li X, Meng WT, Mo XM, Wei YQ. Forced co-expression of IL-21 and IL-7 in whole-cell cancer vaccines promotes antitumor immunity. Sci Rep 2016;6:32351.
  70. Merchant MS, Bernstein D, Amoako M, Baird K, Fleisher TA, Morre M, Steinberg SM, Sabatino M, Stroncek DF, Venkatasan AM, et al. Adjuvant immunotherapy to improve outcome in high-risk pediatric sarcomas. Clin Cancer Res 2016;22:3182-3191. https://doi.org/10.1158/1078-0432.CCR-15-2550
  71. Pachynski RK, Morishima C, Szmulewitz R, Harshman L, Appleman L, Monk P, Bitting RL, Kucuk O, Millard F, Seigne JD, et al. IL-7 expands lymphocyte populations and enhances immune responses to sipuleucel-T in patients with metastatic castration-resistant prostate cancer (mCRPC). J Immunother Cancer 2021;9:e002903.
  72. Isvoranu G, Surcel M, Munteanu AN, Bratu OG, Ionita-Radu F, Neagu MT, Chiritoiu-Butnaru M. Therapeutic potential of interleukin-15 in cancer (review). Exp Ther Med 2021;22:675.
  73. Waldmann TA. The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design. Nat Rev Immunol 2006;6:595-601. https://doi.org/10.1038/nri1901
  74. Bergamaschi C, Rosati M, Jalah R, Valentin A, Kulkarni V, Alicea C, Zhang GM, Patel V, Felber BK, Pavlakis GN. Intracellular interaction of interleukin-15 with its receptor alpha during production leads to mutual stabilization and increased bioactivity. J Biol Chem 2008;283:4189-4199. https://doi.org/10.1074/jbc.M705725200
  75. Waickman AT, Ligons DL, Hwang S, Park JY, Lazarevic V, Sato N, Hong C, Park JH. CD4 effector T cell differentiation is controlled by IL-15 that is expressed and presented in trans. Cytokine 2017;99:266-274. https://doi.org/10.1016/j.cyto.2017.08.004
  76. Conlon KC, Lugli E, Welles HC, Rosenberg SA, Fojo AT, Morris JC, Fleisher TA, Dubois SP, Perera LP, Stewart DM, 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 2015;33:74-82. https://doi.org/10.1200/JCO.2014.57.3329
  77. Miller JS, Morishima C, McNeel DG, Patel MR, Kohrt HE, Thompson JA, Sondel PM, Wakelee HA, Disis ML, Kaiser JC, 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 2018;24:1525-1535. https://doi.org/10.1158/1078-0432.CCR-17-2451
  78. Liu B, Kong L, Han K, Hong H, Marcus WD, Chen X, Jeng EK, Alter S, Zhu X, Rubinstein MP, et al. A novel fusion of ALT-803 (interleukin (IL)-15 superagonist) with an antibody demonstrates antigen-specific antitumor responses. J Biol Chem 2016;291:23869-23881. https://doi.org/10.1074/jbc.M116.733600
  79. Romee R, Cooley S, Berrien-Elliott MM, Westervelt P, Verneris MR, Wagner JE, Weisdorf DJ, Blazar BR, Ustun C, DeFor TE, et al. First-in-human phase 1 clinical study of the IL-15 superagonist complex ALT-803 to treat relapse after transplantation. Blood 2018;131:2515-2527. https://doi.org/10.1182/blood-2017-12-823757
  80. Kim PS, Kwilas AR, Xu W, Alter S, Jeng EK, Wong HC, Schlom J, Hodge JW. 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 2016;7:16130-16145. https://doi.org/10.18632/oncotarget.7470
  81. Margolin K, Morishima C, Velcheti V, Miller JS, Lee SM, Silk AW, Holtan SG, Lacroix AM, Fling SP, Kaiser JC, et al. Phase I trial of ALT-803, a novel recombinant IL15 complex, in patients with advanced solid tumors. Clin Cancer Res 2018;24:5552-5561. https://doi.org/10.1158/1078-0432.CCR-18-0945
  82. Knudson KM, Hodge JW, Schlom J, Gameiro SR. Rationale for IL-15 superagonists in cancer immunotherapy. Expert Opin Biol Ther 2020;20:705-709. https://doi.org/10.1080/14712598.2020.1738379
  83. Miyazaki T, Kuo P, Maiti M, Obalapur P, Addepalli M, Rubas W, Sims P, Zhang P, Marcondes MQ, Madakamutil L, et al. Pharmacokinetic and pharmacodynamic study of NKTR-255, a polymer-conjugated human IL-15, in cynomolgus monkey. Blood 2018;132:2952. 
  84. Wrangle JM, Velcheti V, Patel MR, Garrett-Mayer E, Hill EG, Ravenel JG, Miller JS, Farhad M, Anderton K, Lindsey K, 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. https://doi.org/10.1016/S1470-2045(18)30148-7
  85. 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.
  86. Desbois M, Le Vu P, Coutzac C, Marcheteau E, Beal C, Terme M, Gey A, Morisseau S, Teppaz G, Boselli L, et al. IL-15 trans-signaling with the superagonist RLI promotes effector/memory CD8+ T cell responses and enhances antitumor activity of PD-1 antagonists. J Immunol 2016;197:168-178. https://doi.org/10.4049/jimmunol.1600019
  87. Perez-Martinez A, Fernandez L, Valentin J, Martinez-Romera I, Corral MD, Ramirez M, Abad L, Santamaria S, Gonzalez-Vicent M, Sirvent S, et al. A phase I/II trial of interleukin-15--stimulated natural killer cell infusion after haplo-identical stem cell transplantation for pediatric refractory solid tumors. Cytotherapy 2015;17:1594-1603. https://doi.org/10.1016/j.jcyt.2015.07.011
  88. Shah NN, Baird K, Delbrook CP, Fleisher TA, Kohler ME, Rampertaap S, Lemberg K, Hurley CK, Kleiner DE, Merchant MS, et al. Acute GVHD in patients receiving IL-15/4-1BBL activated NK cells following T-cell-depleted stem cell transplantation. Blood 2015;125:784-792. https://doi.org/10.1182/blood-2014-07-592881
  89. Giuffrida L, Sek K, Henderson MA, House IG, Lai J, Chen AX, Todd KL, Petley EV, Mardiana S, Todorovski I, et al. IL-15 preconditioning augments CAR T Cell responses to checkpoint blockade for improved treatment of solid tumors. Mol Ther 2020;28:2379-2393. https://doi.org/10.1016/j.ymthe.2020.07.018
  90. Liu E, Marin D, Banerjee P, Macapinlac HA, Thompson P, Basar R, Nassif Kerbauy L, Overman B, Thall P, Kaplan M, et al. Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. N Engl J Med 2020;382:545-553. https://doi.org/10.1056/NEJMoa1910607
  91. Heczey A, Courtney AN, Montalbano A, Robinson S, Liu K, Li M, Ghatwai N, Dakhova O, Liu B, Raveh-Sadka T, et al. Anti-GD2 CAR-NKT cells in patients with relapsed or refractory neuroblastoma: an interim analysis. Nat Med 2020;26:1686-1690. https://doi.org/10.1038/s41591-020-1074-2
  92. Fabian KP, Padget MR, Donahue RN, Solocinski K, Robbins Y, Allen CT, Lee JH, Rabizadeh S, SoonShiong P, Schlom J, et al. PD-L1 targeting high-affinity NK (t-haNK) cells induce direct antitumor effects and target suppressive MDSC populations. J Immunother Cancer 2020;8:e000450.
  93. Chu Y, Nayyar G, Kham Su N, Rosenblum JM, Soon-Shiong P, Lee J, Safrit JT, Barth M, Lee D, Cairo MS. Novel cytokine-antibody fusion protein, N-820, to enhance the functions of ex vivo expanded natural killer cells against Burkitt lymphoma. J Immunother Cancer 2020;8:e001238.
  94. Rosser CJ, Tikhonenkov S, Nix JW, Chan OT, Ianculescu I, Reddy S, Soon-Shiong P. Safety, tolerability, and long-term clinical outcomes of an IL-15 analogue (N-803) admixed with Bacillus Calmette-Guerin (BCG) for the treatment of bladder cancer. OncoImmunology 2021;10:1912885.
  95. Do-Thi VA, Lee H, Jeong HJ, Lee JO, Kim YS. Protective and therapeutic effects of an IL-15:IL-15Rα-secreting cell-based cancer vaccine using a baculovirus system. Cancers (Basel) 2021;13:4039.
  96. Kim DH, Kim HY, Lee WW. Induction of unique STAT heterodimers by IL-21 provokes IL-1RI expression on CD8+ T cells, resulting in enhanced IL-1β dependent effector function. Immune Netw 2021;21:e33.
  97. Davis MR, Zhu Z, Hansen DM, Bai Q, Fang Y. The role of IL-21 in immunity and cancer. Cancer Lett 2015;358:107-114. https://doi.org/10.1016/j.canlet.2014.12.047
  98. Davis ID, Skrumsager BK, Cebon J, Nicholaou T, Barlow JW, Moller NP, Skak K, Lundsgaard D, Frederiksen KS, Thygesen P, et al. An open-label, two-arm, phase I trial of recombinant human interleukin-21 in patients with metastatic melanoma. Clin Cancer Res 2007;13:3630-3636. https://doi.org/10.1158/1078-0432.CCR-07-0410
  99. Petrella TM, Mihalcioiu C, Monzon J, McWhirter E, Belanger K, Savage KJ, Song X, Hamid O, Cheng T, Davis M, et al. Final efficacy results of a randomized phase II study of recombinant interleukin-21 compared to dacarbazine in patients with recurrent or metastatic melanoma. J Oncol Res Treat 2019;4:10001322019. 
  100. Thompson JA, Curti BD, Redman BG, Bhatia S, Weber JS, Agarwala SS, Sievers EL, Hughes SD, DeVries TA, Hausman DF. Phase I study of recombinant interleukin-21 in patients with metastatic melanoma and renal cell carcinoma. J Clin Oncol 2008;26:2034-2039. https://doi.org/10.1200/JCO.2007.14.5193
  101. Bhatt S, Parvin S, Zhang Y, Cho HM, Kunkalla K, Vega F, Timmerman JM, Shin SU, Rosenblatt JD, Lossos IS. Anti-CD20-interleukin-21 fusokine targets malignant B cells via direct apoptosis and NK-cell-dependent cytotoxicity. Blood 2017;129:2246-2256. https://doi.org/10.1182/blood-2016-09-738211
  102. Liu H, Wang R, An D, Liu H, Ye F, Li B, Zhang J, Liu P, Zhang X, Yao S, et al. An engineered IL-21 with half-life extension enhances anti-tumor immunity as a monotherapy or in combination with PD-1 or TIGIT blockade. Int Immunopharmacol 2021;101:108307.
  103. Williams P, Rafei M, Bouchentouf M, Raven J, Yuan S, Cuerquis J, Forner KA, Birman E, Galipeau J. A fusion of GMCSF and IL-21 initiates hypersignaling through the IL-21Ralpha chain with immune activating and tumoricidal effects in vivo. Mol Ther 2010;18:1293-1301. https://doi.org/10.1038/mt.2010.49
  104. Uricoli B, Birnbaum LA, Do P, Kelvin JM, Jain J, Costanza E, Chyong A, Porter CC, Rafiq S, Dreaden EC. Engineered cytokines for cancer and autoimmune disease immunotherapy. Adv Healthc Mater 2021;10:e2002214.
  105. Deng S, Sun Z, Qiao J, Liang Y, Liu L, Dong C, Shen A, Wang Y, Tang H, Fu YX, et al. Targeting tumors with IL-21 reshapes the tumor microenvironment by proliferating PD-1intTim-3-CD8+ T cells. JCI Insight 2020;5:e132000.
  106. Lewis KE, Selby MJ, Masters G, Valle J, Dito G, Curtis WR, Garcia R, Mink KA, Waggie KS, Holdren MS, et al. Interleukin-21 combined with PD-1 or CTLA-4 blockade enhances antitumor immunity in mouse tumor models. Oncoimmunology 2017;7:e1377873.
  107. Seo H, Kim BS, Bae EA, Min BS, Han YD, Shin SJ, Kang CY. IL21 therapy combined with PD-1 and Tim-3 blockade provides enhanced NK cell antitumor activity against MHC class I-deficient tumors. Cancer Immunol Res 2018;6:685-695. https://doi.org/10.1158/2326-6066.CIR-17-0708
  108. Li Y, Cong Y, Jia M, He Q, Zhong H, Zhao Y, Li H, Yan M, You J, Liu J, 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.
  109. Chapuis AG, Ragnarsson GB, Nguyen HN, Chaney CN, Pufnock JS, Schmitt TM, Duerkopp N, Roberts IM, Pogosov GL, Ho WY, et al. Transferred WT1-reactive CD8+ T cells can mediate antileukemic activity and persist in post-transplant patients. Sci Transl Med 2013;5:174ra27.
  110. Chapuis AG, Lee SM, Thompson JA, Roberts IM, Margolin KA, Bhatia S, Sloan HL, Lai I, Wagener F, Shibuya K, et al. Combined IL-21-primed polyclonal CTL plus CTLA4 blockade controls refractory metastatic melanoma in a patient. J Exp Med 2016;213:1133-1139. https://doi.org/10.1084/jem.20152021
  111. Peng J, Ye L, Li T, Zhu Q, Guo J, Xiao K, Wei Y. Irradiated bladder cancer cells expressing both GM-CSF and IL-21 versus either GM-CSF or IL-21 alone as tumor vaccine in a mouse xenograft model. BioMed Res Int 2019;2019:8262989.
  112. He X, Wang J, Zhao F, Chen D, Chen J, Zhang H, Yang C, Liu Y, Dou J. ESAT-6-gpi DNA vaccine augmented the specific antitumour efficacy induced by the tumour vaccine B16F10-ESAT-6-gpi/IL-21 in a mouse model. Scand J Immunol 2013;78:69-78. https://doi.org/10.1111/sji.12074
  113. Kefaloyianni E. Soluble forms of cytokine and growth factor receptors: mechanisms of generation and modes of action in the regulation of local and systemic inflammation. FEBS Lett 2022. doi: 10.1002/1873-3468.14305.
  114. Do-Thi VA, Lee JO, Lee H, Kim YS. Crosstalk between the producers and immune targets of IL-9. Immune Netw 2020;20:e45.
  115. Li Z, Chen L, Qin Z. Paradoxical roles of IL-4 in tumor immunity. Cell Mol Immunol 2009;6:415-422. https://doi.org/10.1038/cmi.2009.53
  116. Wan J, Wu Y, Ji X, Huang L, Cai W, Su Z, Wang S, Xu H. IL-9 and IL-9-producing cells in tumor immunity. Cell Commun Signal 2020;18:50.