Rapidly generated multivirus-specific cytotoxic T lymphocytes for the prophylaxis and treatment of viral infections
Ulrike Gerdemann, Jacqueline M Keirnan, Usha L Katari, Ryu Yanagisawa, Anne S Christin, Leslie E Huye, Serena K Perna, Sravya Ennamuri, Stephen Gottschalk, Malcolm K Brenner, Helen E Heslop, Cliona M Rooney, Ann M Leen, Ulrike Gerdemann, Jacqueline M Keirnan, Usha L Katari, Ryu Yanagisawa, Anne S Christin, Leslie E Huye, Serena K Perna, Sravya Ennamuri, Stephen Gottschalk, Malcolm K Brenner, Helen E Heslop, Cliona M Rooney, Ann M Leen
Abstract
Severe and fatal viral infections remain common after hematopoietic stem cell transplantation. Adoptive transfer of cytotoxic T lymphocytes (CTLs) specific for Epstein-Barr virus (EBV), cytomegalovirus (CMV), and adenoviral antigens can treat infections that are impervious to conventional therapies, but broader implementation and extension to additional viruses is limited by competition between virus-derived antigens and time-consuming and laborious manufacturing procedures. We now describe a system that rapidly generates a single preparation of polyclonal (CD4(+) and CD8(+)) CTLs that is consistently specific for 15 immunodominant and subdominant antigens derived from 7 viruses (EBV, CMV, Adenovirus (Adv), BK, human herpes virus (HHV)-6, respiratory syncytial virus (RSV), and Influenza) that commonly cause post-transplant morbidity and mortality. CTLs can be rapidly produced (10 days) by a single stimulation of donor peripheral blood mononuclear cells (PBMCs) with a peptide mixture spanning the target antigens in the presence of the potent prosurvival cytokines interleukin-4 (IL4) and IL7. This approach reduces the impact of antigenic competition with a consequent increase in the antigenic repertoire and frequency of virus-specific T cells. Our approach can be readily introduced into clinical practice and should be a cost-effective alternative to common antiviral prophylactic agents for allogeneic hematopoietic stem cell transplant (HSCT) recipients.
Figures
References
- Schönberger S, Meisel R, Adams O, Pufal Y, Laws HJ, Enczmann al. (2010Prospective, comprehensive, and effective viral monitoring in children undergoing allogeneic hematopoietic stem cell transplantation Biol Blood Marrow Transplant 161428–1435.
- Verdeguer A, de Heredia CD, González M, Martínez AM, Fernández-Navarro JM, Pérez-Hurtado JM, GETMON: Spanish Working Party for Blood and Marrow Transplantation in Children et al. Observational prospective study of viral infections in children undergoing allogeneic hematopoietic cell transplantation: a 3-year GETMON experience. Bone Marrow Transplant. 2011;46:119–124.
- Lang P., and, Handgretinger R. Haploidentical SCT in children: an update and future perspectives. Bone Marrow Transplant. 2008;42 Suppl 2:S54–S59.
- Sauter C, Abboud M, Jia X, Heller G, Gonzales AM, Lubin al. (2011Serious infection risk and immune recovery after double-unit cord blood transplantation without antithymocyte globulin Biol Blood Marrow Transplant 171460–1471.
- Hantz S, Garnier-Geoffroy F, Mazeron MC, Garrigue I, Merville P, Mengelle C, French CMV Resistance Survey Study Group et al. Drug-resistant cytomegalovirus in transplant recipients: a French cohort study. J Antimicrob Chemother. 2010;65:2628–2640.
- Ljungman P, Ribaud P, Eyrich M, Matthes-Martin S, Einsele H, Bleakley M, Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation et al. Cidofovir for adenovirus infections after allogeneic hematopoietic stem cell transplantation: a survey by the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant. 2003;31:481–486.
- Heslop HE, Brenner MK., and, Rooney CM. Donor T cells to treat EBV-associated lymphoma. N Engl J Med. 1994;331:679–680.
- Leen AM, Myers GD, Sili U, Huls MH, Weiss H, Leung al. (2006Monoculture-derived T lymphocytes specific for multiple viruses expand and produce clinically relevant effects in immunocompromised individuals Nat Med 121160–1166.
- Leen AM, Christin A, Myers GD, Liu H, Cruz CR, Hanley al. (2009Cytotoxic T lymphocyte therapy with donor T cells prevents and treats adenovirus and Epstein-Barr virus infections after haploidentical and matched unrelated stem cell transplantation Blood 1144283–4292.
- Haque T, Wilkie GM, Jones MM, Higgins CD, Urquhart G, Wingate al. (2007Allogeneic cytotoxic T-cell therapy for EBV-positive posttransplantation lymphoproliferative disease: results of a phase 2 multicenter clinical trial Blood 1101123–1131.
- Kedl RM, Rees WA, Hildeman DA, Schaefer B, Mitchell T, Kappler al. (2000T cells compete for access to antigen-bearing antigen-presenting cells J Exp Med 1921105–1113.
- Kedl RM, Schaefer BC, Kappler JW., and, Marrack P. T cells down-modulate peptide-MHC complexes on APCs in vivo. Nat Immunol. 2002;3:27–32.
- Cobbold M, Khan N, Pourgheysari B, Tauro S, McDonald D, Osman al. (2005Adoptive transfer of cytomegalovirus-specific CTL to stem cell transplant patients after selection by HLA-peptide tetramers J Exp Med 202379–386.
- Feuchtinger T, Matthes-Martin S, Richard C, Lion T, Fuhrer M, Hamprecht al. (2006Safe adoptive transfer of virus-specific T-cell immunity for the treatment of systemic adenovirus infection after allogeneic stem cell transplantation Br J Haematol 13464–76.
- Feuchtinger T, Opherk K, Bethge WA, Topp MS, Schuster FR, Weissinger al. (2010Adoptive transfer of pp65-specific T cells for the treatment of chemorefractory cytomegalovirus disease or reactivation after haploidentical and matched unrelated stem cell transplantation Blood 1164360–4367.
- Khanna N, Stuehler C, Conrad B, Lurati S, Krappmann S, Einsele al. (2011Generation of a multipathogen-specific T-cell product for adoptive immunotherapy based on activation-dependent expression of CD154 Blood 1181121–1131.
- Leen AM, Sili U, Savoldo B, Jewell AM, Piedra PA, Brenner al. (2004Fiber-modified adenoviruses generate subgroup cross-reactive, adenovirus-specific cytotoxic T lymphocytes for therapeutic applications Blood 1031011–1019.
- Leen AM, Christin A, Khalil M, Weiss H, Gee AP, Brenner al. (2008Identification of hexon-specific CD4 and CD8 T-cell epitopes for vaccine and immunotherapy J Virol 82546–554.
- Hislop AD, Taylor GS, Sauce D., and, Rickinson AB. Cellular responses to viral infection in humans: lessons from Epstein-Barr virus. Annu Rev Immunol. 2007;25:587–617.
- Badr G, Bédard N, Abdel-Hakeem MS, Trautmann L, Willems B, Villeneuve al. (2008Early interferon therapy for hepatitis C virus infection rescues polyfunctional, long-lived CD8+ memory T cells J Virol 8210017–10031.
- Kannanganat S, Ibegbu C, Chennareddi L, Robinson HL., and, Amara RR. Multiple-cytokine-producing antiviral CD4 T cells are functionally superior to single-cytokine-producing cells. J Virol. 2007;81:8468–8476.
- Leen A, Meij P, Redchenko I, Middeldorp J, Bloemena E, Rickinson al. (2001Differential immunogenicity of Epstein-Barr virus latent-cycle proteins for human CD4(+) T-helper 1 responses J Virol 758649–8659.
- Heslop HE, Ng CY, Li C, Smith CA, Loftin SK, Krance al. (1996Long-term restoration of immunity against Epstein-Barr virus infection by adoptive transfer of gene-modified virus-specific T lymphocytes Nat Med 2551–555.
- Gotch F, McMichael A, Smith G., and, Moss B. Identification of viral molecules recognized by influenza-specific human cytotoxic T lymphocytes. J Exp Med. 1987;165:408–416.
- McMichael AJ, Gotch F, Cullen P, Askonas B., and, Webster RG. The human cytotoxic T cell response to influenza A vaccination. Clin Exp Immunol. 1981;43:276–284.
- Bunde T, Kirchner A, Hoffmeister B, Habedank D, Hetzer R, Cherepnev al. (2005Protection from cytomegalovirus after transplantation is correlated with immediate early 1-specific CD8 T cells J Exp Med 2011031–1036.
- Bickham K, Münz C, Tsang ML, Larsson M, Fonteneau JF, Bhardwaj al. (2001EBNA1-specific CD4+ T cells in healthy carriers of Epstein-Barr virus are primarily Th1 in function J Clin Invest 107121–130.
- Münz C, Bickham KL, Subklewe M, Tsang ML, Chahroudi A, Kurilla al. (2000Human CD4(+) T lymphocytes consistently respond to the latent Epstein-Barr virus nuclear antigen EBNA1 J Exp Med 1911649–1660.
- Balduzzi A, Lucchini G, Hirsch HH, Basso S, Cioni M, Rovelli al. (2011Polyomavirus JC-targeted T-cell therapy for progressive multiple leukoencephalopathy in a hematopoietic cell transplantation recipient Bone Marrow Transplant 46987–992.
- Rock MT, McKinney BA, Yoder SM, Prudom CE, Wright DW., and, Crowe JE., Jr Identification of potential human respiratory syncytial virus and metapneumovirus T cell epitopes using computational prediction and MHC binding assays. J Immunol Methods. 2011;374:13–17.
- Shao HY, Lin YW, Yu SL, Lin HY, Chitra E, Chang al. (2011Immunoprotectivity of HLA-A2 CTL peptides derived from respiratory syncytial virus fusion protein in HLA-A2 transgenic mouse PLoS ONE 6e25500.
- Feuchtinger T, Richard C, Joachim S, Scheible MH, Schumm M, Hamprecht al. (2008Clinical grade generation of hexon-specific T cells for adoptive T-cell transfer as a treatment of adenovirus infection after allogeneic stem cell transplantation J Immunother 31199–206.
- Gerdemann U, Christin AS, Vera JF, Ramos CA, Fujita Y, Liu al. (2009Nucleofection of DCs to generate Multivirus-specific T cells for prevention or treatment of viral infections in the immunocompromised host Mol Ther 171616–1625.
- Heslop HE, Slobod KS, Pule MA, Hale GA, Rousseau A, Smith al. (2010Long-term outcome of EBV-specific T-cell infusions to prevent or treat EBV-related lymphoproliferative disease in transplant recipients Blood 115925–935.
- Kenter GG, Welters MJ, Valentijn AR, Lowik MJ, Berends-van der Meer DM, Vloon al. (2009Vaccination against HPV-16 oncoproteins for vulvar intraepithelial neoplasia N Engl J Med 3611838–1847.
- Maecker HT, Dunn HS, Suni MA, Khatamzas E, Pitcher CJ, Bunde al. (2001Use of overlapping peptide mixtures as antigens for cytokine flow cytometry J Immunol Methods 25527–40.
- Kozlowski S, Corr M, Shirai M, Boyd LF, Pendleton CD, Berzofsky al. (1993Multiple pathways are involved in the extracellular processing of MHC class I-restricted peptides J Immunol 1514033–4044.
- Toes RE, van der Voort EI, Schoenberger SP, Drijfhout JW, van Bloois L, Storm al. (1998Enhancement of tumor outgrowth through CTL tolerization after peptide vaccination is avoided by peptide presentation on dendritic cells J Immunol 1604449–4456.
- Sherman LA, Burke TA., and, Biggs JA. Extracellular processing of peptide antigens that bind class I major histocompatibility molecules. J Exp Med. 1992;175:1221–1226.
- Larsen SL, Pedersen LO, Buus S., and, Stryhn A. T cell responses affected by aminopeptidase N (CD13)-mediated trimming of major histocompatibility complex class II-bound peptides. J Exp Med. 1996;184:183–189.
- Rosenberg SA, Yannelli JR, Yang JC, Topalian SL, Schwartzentruber DJ, Weber al. (1994Treatment of patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and interleukin 2 J Natl Cancer Inst 861159–1166.
- Becker TC, Wherry EJ, Boone D, Murali-Krishna K, Antia R, Ma al. (2002Interleukin 15 is required for proliferative renewal of virus-specific memory CD8 T cells J Exp Med 1951541–1548.
- Vella AT, Dow S, Potter TA, Kappler J., and, Marrack P. Cytokine-induced survival of activated T cells in vitro and in vivo. Proc Natl Acad Sci USA. 1998;95:3810–3815.
- Tan JT, Ernst B, Kieper WC, LeRoy E, Sprent J., and, Surh CD. Interleukin (IL)-15 and IL-7 jointly regulate homeostatic proliferation of memory phenotype CD8+ cells but are not required for memory phenotype CD4+ cells. J Exp Med. 2002;195:1523–1532.
- Melchionda F, Fry TJ, Milliron MJ, McKirdy MA, Tagaya Y., and, Mackall CL. Adjuvant IL-7 or IL-15 overcomes immunodominance and improves survival of the CD8+ memory cell pool. J Clin Invest. 2005;115:1177–1187.
- Chetoui N, Boisvert M, Gendron S., and, Aoudjit F. Interleukin-7 promotes the survival of human CD4+ effector/memory T cells by up-regulating Bcl-2 proteins and activating the JAK/STAT signalling pathway. Immunology. 2010;130:418–426.
- Sportès C, Babb RR, Krumlauf MC, Hakim FT, Steinberg SM, Chow al. (2010Phase I study of recombinant human interleukin-7 administration in subjects with refractory malignancy Clin Cancer Res 16727–735.
- Majhail NS, Hussein M, Olencki TE, Budd GT, Wood L, Elson al. (2004Phase I trial of continuous infusion recombinant human interleukin-4 in patients with cancer Invest New Drugs 22421–426.
- von Rossum A, Krall R, Escalante NK., and, Choy JC. Inflammatory cytokines determine the susceptibility of human CD8 T cells to Fas-mediated activation-induced cell death through modulation of FasL and c-FLIP(S) expression. J Biol Chem. 2011;286:21137–21144.
- Maus MV, Thomas AK, Leonard DG, Allman D, Addya K, Schlienger al. (2002Ex vivo expansion of polyclonal and antigen-specific cytotoxic T lymphocytes by artificial APCs expressing ligands for the T-cell receptor, CD28 and 4-1BB Nat Biotechnol 20143–148.
Source: PubMed