Intravenous injection of a novel viral immunotherapy encoding human interleukin-7 in nonhuman primates is safe and increases absolute lymphocyte count

References

• Chen D, Tang T-X, Deng H, Yang X-P, Tang Z-H. Interleukin-7 biology and its effects on immune cells: mediator of generation, differentiation, survival, and homeostasis. Front Immunol. 2021;12:1. doi:10.3389/fimmu.2021.747324.
   Web of Science ®Google Scholar
• Barata JT, Durum SK, Seddon B. Flip the coin: iL-7 and IL-7R in health and disease. Nat Immunol. 2019;20(12):1584–10. doi:10.1038/s41590-019-0479-x.
   PubMed Web of Science ®Google Scholar
• Fry TJ, Moniuszko M, Creekmore S, Donohue SJ, Douek DC, Giardina S, Hecht TT, Hill BJ, Komschlies K, Tomaszewski J, et al. IL-7 therapy dramatically alters peripheral T-cell homeostasis in normal and SIV-infected nonhuman primates. Blood. 2003;101(6):2294–99. doi:10.1182/blood-2002-07-2297.
   PubMed Web of Science ®Google Scholar
• Park J-H, Yu Q, Erman B, Appelbaum JS, Montoya-Durango D, Grimes HL, Singer A. Suppression of IL7Ralpha transcription by IL-7 and other prosurvival cytokines: a novel mechanism for maximizing IL-7-dependent T cell survival. Immunity. 2004;21(2):289–302. doi:10.1016/j.immuni.2004.07.016.
   PubMed Web of Science ®Google Scholar
• Huang J, Long Z, Jia R, Wang M, Zhu D, Liu M, Chen S, Zhao X, Yang Q, Wu Y, et al. The broad immunomodulatory effects of IL-7 and its application in vaccines. Front Immunol. 2021;12:680442. doi:10.3389/fimmu.2021.680442.
   PubMed Web of Science ®Google Scholar
• Sportès 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(2):727–35. doi:10.1158/1078-0432.CCR-09-1303.
   PubMed Web of Science ®Google Scholar
• Sportès C, Hakim FT, Memon SA, Zhang H, Chua KS, Brown MR, Fleisher TA, Krumlauf MC, Babb RR, Chow CK, et al. Administration of rhIL-7 in humans increases in vivo TCR repertoire diversity by preferential expansion of naive T cell subsets. J Exp Med. 2008;205(7):1701–14. doi:10.1084/jem.20071681.
   PubMed Web of Science ®Google Scholar
• Trédan O, Ménétrier-Caux C, Ray-Coquard I, Garin G, Cropet C, Verronèse 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(7):1353–62. doi:10.1093/annonc/mdv173.
   PubMed Web of Science ®Google Scholar
• Sereti I, Dunham RM, Spritzler J, Aga E, Proschan MA, Medvik K, Battaglia CA, Landay AL, Pahwa S, Fischl MA, et al. IL-7 administration drives T cell–cycle entry and expansion in HIV-1 infection. Blood. 2009;113(25):6304–14. doi:10.1182/blood-2008-10-186601.
   PubMed Web of Science ®Google Scholar
• Lévy Y, Lacabaratz C, Weiss L, Viard J-P, Goujard C, Lelièvre J-D, Boué F, Molina J-M, Rouzioux C, Avettand-Fénoêl V, et al. Enhanced T cell recovery in HIV-1–infected adults through IL-7 treatment. J Clin Invest. 2009;119(4):997–1007. doi:10.1172/JCI38052.
   PubMed Web of Science ®Google Scholar
• Francois B, Jeannet R, Daix T, Walton AH, Shotwell MS, Unsinger J, Monneret G, Rimmelé T, Blood T, Morre M, et al. Interleukin-7 restores lymphocytes in septic shock: the IRIS-7 randomized clinical trial. JCI Insight. 2018;3(5):e98960. doi:10.1172/jci.insight.98960.
   PubMed Web of Science ®Google Scholar
• Turnbull IR, Mazer MB, Hoofnagle MH, Kirby JP, Leonard JM, Mejia-Chew C, Spec A, Blood J, Miles SM, Ransom EM, et al. IL-7 immunotherapy in a nonimmunocompromised patient with intractable fungal wound sepsis. Open Forum Infect Dis. 2021;8(6):ofab256. doi:10.1093/ofid/ofab256.
   PubMed Web of Science ®Google Scholar
• Monneret G, de Marignan D, Coudereau R, Bernet C, Ader F, Frobert E, Gossez M, Viel S, Venet F, Wallet F. Immune monitoring of interleukin-7 compassionate use in a critically ill COVID-19 patient. Cell Mol Immunol. 2020;17(9):1001–03. doi:10.1038/s41423-020-0516-6.
   PubMed Web of Science ®Google Scholar
• Mazer MB, Turnbull IR, Miles S, Blood TM, Sadler B, Hess A, Botney MD, Martin RS, Bosanquet JP, Striker DA, et al. Interleukin-7 reverses lymphopenia and improves T-cell function in coronavirus disease 2019 patient with inborn error of toll-like receptor 3: a case report. Crit Care Explor. 2021;3(7):e0500. doi:10.1097/CCE.0000000000000500.
   PubMedGoogle Scholar
• Laterre PF, François B, Collienne C, Hantson P, Jeannet R, Remy KE, Hotchkiss RS. Association of interleukin 7 immunotherapy with lymphocyte counts among patients with severe coronavirus disease 2019 (COVID-19). JAMA Network Open. 2020;3(7):e2016485. doi:10.1001/jamanetworkopen.2020.16485.
   PubMed Web of Science ®Google Scholar
• Nugeyre M-T, Monceaux V, Beq S, Cumont M-C, Ho Tsong Fang R, Chêne L, Morre M, Barré-Sinoussi F, Hurtrel B, Israël N. IL-7 stimulates T cell renewal without increasing viral replication in simian immunodeficiency virus-infected macaques. J Immunol. 2003;171(8):4447–53. doi:10.4049/jimmunol.171.8.4447.
   PubMed Web of Science ®Google Scholar
• Beq S, Nugeyre M-T, Ho Tsong Fang R, Gautier D, Legrand R, Schmitt N, Estaquier J, Barré-Sinoussi F, Hurtrel B, Cheynier R, et al. IL-7 induces immunological improvement in SIV-infected rhesus macaques under antiviral therapy. J Immunol. 2006;176(2):914–22. doi:10.4049/jimmunol.176.2.914.
   PubMed Web of Science ®Google Scholar
• Beq S, Rozlan S, Gautier D, Parker R, Mersseman V, Schilte C, Assouline B, Rancé I, Lavedan P, Morre M, et al. Injection of glycosylated recombinant simian IL-7 provokes rapid and massive T-cell homing in rhesus macaques. Blood. 2009;114(4):816–25. doi:10.1182/blood-2008-11-191288.
   PubMed Web of Science ®Google Scholar
• Leone A, Rohankhedkar M, Okoye A, Legasse A, Axthelm MK, Villinger F, Piatak M, Lifson JD, Assouline B, Morre M, et al. Increased CD4+ T cell levels during IL-7 administration of antiretroviral therapy-treated simian immunodeficiency virus-positive macaques are not dependent on strong proliferative responses. J Immunol. 2010;185(3):1650–59. doi:10.4049/jimmunol.0902626.
   PubMed Web of Science ®Google Scholar
• Parker R, Dutrieux J, Beq S, Lemercier B, Rozlan S, Fabre-Mersseman V, Rancez M, Gommet C, Assouline B, Rancé I, et al. Interleukin-7 treatment counteracts IFN-α therapy-induced lymphopenia and stimulates SIV-specific cytotoxic T lymphocyte responses in SIV-infected rhesus macaques. Blood. 2010;116(25):5589–99. doi:10.1182/blood-2010-03-276261.
   PubMed Web of Science ®Google Scholar
• Storek J, Gillespy T, Lu H, Joseph A, Dawson MA, Gough M, Morris J, Hackman RC, Horn PA, Sale GE, et al. Interleukin-7 improves CD4 T-cell reconstitution after autologous CD34 cell transplantation in monkeys. Blood. 2003;101(10):4209–18. doi:10.1182/blood-2002-08-2671.
   PubMed Web of Science ®Google Scholar
• Vassena L, Miao H, Cimbro R, Malnati MS, Cassina G, Proschan MA, Hirsch VM, Lafont BA, Morre M, Fauci AS, et al. Treatment with IL-7 prevents the decline of circulating CD4+ T cells during the acute phase of SIV infection in rhesus macaques. PLoS Pathog. 2012;8(4):e1002636. doi:10.1371/journal.ppat.1002636.
   PubMed Web of Science ®Google Scholar
• Okoye AA, Rohankhedkar M, Konfe AL, Abana CO, Reyes MD, Clock JA, Duell DM, Sylwester AW, Sammader P, Legasse AW, et al. Effect of IL-7 therapy on naive and memory T cell homeostasis in aged rhesus macaques. J Immunol. 2015;195(9):4292–305. doi:10.4049/jimmunol.1500609.
   PubMed Web of Science ®Google Scholar
• Ura T, Okuda K, Shimada M. Developments in viral vector-based vaccines. Vaccines (Basel). 2014;2(3):624–41. doi:10.3390/vaccines2030624.
   PubMedGoogle Scholar
• Zhao L, Mei Y, Sun Q, Guo L, Wu Y, Yu X, Hu B, Liu X, Liu H. Autologous tumor vaccine modified with recombinant new castle disease virus expressing IL-7 promotes antitumor immune response. J Immunol. 2014;193(2):735–45. doi:10.4049/jimmunol.1400004.
   PubMed Web of Science ®Google Scholar
• Ohs I, Windmann S, Wildner O, Dittmer U, Bayer W. Interleukin-encoding adenoviral vectors as genetic adjuvant for vaccination against retroviral infection. PLoS ONE. 2013;8(12):e82528. doi:10.1371/journal.pone.0082528.
   PubMed Web of Science ®Google Scholar
• Li Y, Zhou M, Luo Z, Zhang Y, Cui M, Chen H, Fu ZF, Zhao L, Williams BRG. Overexpression of interleukin-7 extends the humoral immune response induced by rabies vaccination. J Virol. 2017;91(7). doi:10.1128/JVI.02324-16.
   Web of Science ®Google Scholar
• Lélu K, Dubois C, Evlachev A, Crausaz M, Baldazza M, Kehrer N, Brandely R, Schlesinger Y, Silvestre N, Marchand J-B, et al. Viral delivery of IL-7 is a potent immunotherapy stimulating innate and adaptive immunity and confers survival in sepsis models. J Immunol. 2022;209(1):99–117. doi:10.4049/jimmunol.2101145.
   PubMed Web of Science ®Google Scholar
• Delaloye J, Roger T, Steiner-Tardivel Q-G, Le Roy D, Knaup Reymond M, Akira S, Petrilli V, Gomez CE, Perdiguero B, Tschopp J, et al. Innate immune sensing of modified vaccinia virus Ankara (MVA) is mediated by TLR2-TLR6, MDA-5 and the NALP3 inflammasome. PLoS Pathog. 2009;5(6):e1000480. doi:10.1371/journal.ppat.1000480.
   PubMed Web of Science ®Google Scholar
• Price PJR, Torres-Domínguez LE, Brandmüller C, Sutter G, Lehmann MH. Modified Vaccinia virus Ankara: innate immune activation and induction of cellular signalling. Vaccine. 2013;31(39):4231–34. doi:10.1016/j.vaccine.2013.03.017.
   PubMed Web of Science ®Google Scholar
• Verheust C, Goossens M, Pauwels K, Breyer D. Biosafety aspects of modified vaccinia virus Ankara (MVA)-based vectors used for gene therapy or vaccination. Vaccine. 2012;30(16):2623–32. doi:10.1016/j.vaccine.2012.02.016.
   PubMed Web of Science ®Google Scholar
• Sockolosky JT, Szoka FC. The neonatal Fc receptor, FcRn, as a target for drug delivery and therapy. Adv Drug Deliv Rev. 2015;91:109–24. doi:10.1016/j.addr.2015.02.005.
   PubMed Web of Science ®Google Scholar
• US Food and Drug Administration - Center for Drug Evaluation and Research. 2005. Guidance for Industry - Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/estimating-maximum-safe-starting-dose-initial-clinical-trials-therapeutics-adult-healthy-volunteers.
   Google Scholar
• Mire-Sluis AR, Healey L, Griffiths S, Hockley D, Thorpe R. Development of a continuous IL-7-dependent murine pre-B cell line PB-1 suitable for the biological characterisation and assay of human IL-7. J Immunol Methods. 2000;236(1–2):71–76. doi:10.1016/s0022-1759(99)00237-9.
   PubMed Web of Science ®Google Scholar
• Richig JW, Sleeper MM. Electrocardiography of nonhuman primates. pp. 57–71. doi:10.1016/B978-0-12-809469-3.00008-6.
   Google Scholar
• Sanchez J, Gonçalves E, Llano A, Gonzáles P, Fernández-Maldonado M, Vogt A, Soria A, Perez S, Cedeño S, Fernández MA, et al. Immune profiles identification by vaccinomics after MVA immunization in randomized clinical study. Front Immunol. 2020;11:586124. doi:10.3389/fimmu.2020.586124.
   PubMed Web of Science ®Google Scholar
• Velazquez-Salinas L, Verdugo-Rodriguez A, Rodriguez LL, Borca MV. The role of interleukin 6 during viral infections. Front Microbiol. 2019;10:1057. doi:10.3389/fmicb.2019.01057.
   PubMed Web of Science ®Google Scholar
• Ghazawi FM, Faller EM, Sugden SM, Kakal JA, MacPherson PA. IL-7 downregulates IL-7Rα expression in human CD8 T cells by two independent mechanisms. Immunol Cell Biol. 2013;91(2):149–58. doi:10.1038/icb.2012.69.
   PubMed Web of Science ®Google Scholar
• Lee SW, Choi D, Heo M, Shin E-C, Park S-H, Kim SJ, Oh Y-K, 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(6):1161–69. doi:10.1111/cts.12800.
   PubMed Web of Science ®Google Scholar
• Hatano S, Tamura T, Umemura M, Matsuzaki G, Ohara N, Yoshikai Y. Recombinant mycobacterium bovis bacillus Calmette-Guerin expressing Ag85B-IL-7 fusion protein enhances IL-17A-producing innate γδ T cells. Vaccine. 2016;34(22):2490–95. doi:10.1016/j.vaccine.2016.03.096.
   PubMed Web of Science ®Google Scholar
• Lévy Y, Sereti I, Tambussi G, Routy JP, Lelièvre JD, Delfraissy JF, Molina JM, Fischl M, Goujard C, Rodriguez B, et al. Effects of recombinant human interleukin 7 on T-cell recovery and thymic output in HIV-infected patients receiving antiretroviral therapy: results of a phase I/IIa randomized, placebo-controlled, multicenter study. Clin Infect Dis. 2012;55(2):291–300. doi:10.1093/cid/cis383.
   PubMed Web of Science ®Google Scholar
• Perales M-A, 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(24):4882–91. doi:10.1182/blood-2012-06-437236.
   PubMed Web of Science ®Google Scholar
• Knauf MJ, Bell DP, Hirtzer P, Luo ZP, Young JD, Katre NV. Relationship of effective molecular size to systemic clearance in rats of recombinant interleukin-2 chemically modified with water-soluble polymers. J Biol Chem. 1988;263(29):15064–70. doi:10.1016/S0021-9258(18)68146-3.
   PubMed Web of Science ®Google Scholar
• Fend L, Gatard-Scheikl T, Kintz J, Gantzer M, Schaedler E, Rittner K, Cochin S, Fournel S, Préville X. Intravenous injection of MVA virus targets CD8+ lymphocytes to tumors to control tumor growth upon combinatorial treatment with a TLR9 agonist. Cancer Immunol Res. 2014;2(12):1163–74. doi:10.1158/2326-6066.CIR-14-0050.
   PubMed Web of Science ®Google Scholar
• Ramirez JC, Finke D, Esteban M, Kraehenbuhl JP, Acha-Orbea H. Tissue distribution of the Ankara strain of vaccinia virus (MVA) after mucosal or systemic administration. Arch Virol. 2003;148(5):827–39. doi:10.1007/s00705-003-0006-z.
   PubMed Web of Science ®Google Scholar
• Moniuszko M, Fry T, Tsai W-P, Morre M, Assouline B, Cortez P, Lewis MG, Cairns S, Mackall C, Franchini G. Recombinant interleukin-7 induces proliferation of naive macaque CD4+ and CD8+ T cells in vivo. J Virol. 2004;78(18):9740–49. doi:10.1128/JVI.78.18.9740-9749.2004.
   PubMed Web of Science ®Google Scholar
• Steele AK, Carrasco-Medina L, Sodora DL, Crawley AM. Increased soluble IL-7 receptor concentrations associate with improved IL-7 therapy outcomes in SIV-infected ART-treated rhesus macaques. PLoS ONE. 2017;12(12):e0188427. doi:10.1371/journal.pone.0188427.
   PubMed Web of Science ®Google Scholar
• Corfe SA, Paige CJ. The many roles of IL-7 in B cell development; mediator of survival, proliferation and differentiation. Semin Immunol. 2012;24(3):198–208. doi:10.1016/j.smim.2012.02.001.
   PubMed Web of Science ®Google Scholar
• Sammicheli S, Ruffin N, Lantto R, Vivar N, Chiodi F, Rethi B. IL-7 modulates B cells survival and activation by inducing BAFF and CD70 expression in T cells. J Autoimmun. 2012;38(4):304–14. doi:10.1016/j.jaut.2012.01.012.
   PubMed Web of Science ®Google Scholar
• DeMaria PJ, Lee-Wisdom K, Donahue RN, Madan RA, Karzai F, Schwab A, Palena C, Jochems C, Floudas C, Strauss J, et al. Phase 1 open-label trial of intravenous administration of MVA-BN-brachyury-TRICOM vaccine in patients with advanced cancer. J Immunother Cancer. 2021;9(9):e003238. doi:10.1136/jitc-2021-003238.
   PubMed Web of Science ®Google Scholar
• Lehmann MH, Kastenmuller W, Kandemir JD, Brandt F, Suezer Y, Sutter G. Modified vaccinia virus ankara triggers chemotaxis of monocytes and early respiratory immigration of leukocytes by induction of CCL2 expression. J Virol. 2009;83(6):2540–52. doi:10.1128/JVI.01884-08.
   PubMed Web of Science ®Google Scholar
• Mangaonkar AA, Tande AJ, Bekele DI. Differential diagnosis and workup of monocytosis: a systematic approach to a common hematologic finding. Curr Hematol Malig Rep. 2021;16(3):267–75. doi:10.1007/s11899-021-00618-4.
   PubMed Web of Science ®Google Scholar
• Milo I, Blecher-Gonen R, Barnett-Itzhaki Z, Bar-Ziv R, Tal O, Gurevich I, Feferman T, Drexler I, Amit I, Bousso P, et al. The bone marrow is patrolled by NK cells that are primed and expand in response to systemic viral activation. Eur J Immunol. 2018;48(7):1137–52. doi:10.1002/eji.201747378.
   PubMed Web of Science ®Google Scholar
• Palgen J-L, Tchitchek N, Huot N, Elhmouzi-Younes J, Lefebvre C, Rosenbaum P, Dereuddre-Bosquet N, Martinon F, Hocini H, Cosma A, et al. NK cell immune responses differ after prime and boost vaccination. J Leukoc Biol. 2019;105(5):1055–73. doi:10.1002/JLB.4A1018-391RR.
   PubMed Web of Science ®Google Scholar
• Michaud A, Dardari R, Charrier E, Cordeiro P, Herblot S, Duval M. IL-7 enhances survival of human CD56bright NK cells. J Immunother (1991). 2010;33(4):382–90. doi:10.1097/CJI.0b013e3181cd872d.
   PubMed Web of Science ®Google Scholar
• Marton C, Minaud A, Coupet C-A, Vallet H, Boddaert J, Kehrer N, Inchauspe G, Barraud L, Sauce D. A novel virotherapy encoding human interleukin-7 enhances ex vivo human immune functions in immunosenescent hip fracture trauma patients. Unpublished results.
   Google Scholar
• Crausaz M, Monneret G, Conti F, Lukaszewicz A-C, Marchand J-B, Martin P, Inchauspé G, Venet F. A novel virotherapy encoding human interleukin-7 improves ex vivo T lymphocyte functions in immunosuppressed patients with septic shock and critically ill COVID-19. Front Immunol. 2022;13. doi:10.3389/fimmu.2022.939899.
   PubMed Web of Science ®Google Scholar