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Gene Therapy-Mediated Reprogramming Tumor Infiltrating T Cells Using IL-2 and Inhibiting NF-κB Signaling Improves the Efficacy of Immunotherapy in a Brain Cancer Model

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Neurotherapeutics

Abstract

Immune-mediated gene therapy using adenovirus expressing Flt3 ligand and thymidine kinase followed by ganciclovir administration (Flt3/TK) effectively elicits tumor regression in preclinical glioma models. Herein, we assessed new strategies to optimize Flt3L/TK therapeutic efficacy in a refractory RG2 orthotopic glioblastoma model. Specifically, we aimed to optimize the therapeutic efficacy of Flt3L/TK treatment in the RG2 model by overexpressing the following genes within the brain tumor microenvironment: 1) a TK mutant with enhanced cytotoxicity (SR39 mutant TK), 2) Flt3L-IgG fusion protein that has a longer half-life, 3) CD40L to stimulate DC maturation, 4) T helper cell type 1 polarizing dendritic cell cytokines interleukin-12 or C-X-C motif ligand 10 chemokine (CXCL)-10, 5) C-C motif ligand 2 chemokine (CCL2) or C-C motif ligand 3 chemokine (CCL3) to enhance dendritic cell recruitment into the tumor microenvironment, 6) T helper cell type 1 cytokines interferon-γ or interleukin-2 to enhance effector T-cell functions, and 7) IκBα or p65RHD (nuclear factor kappa-B [NF-κB] inhibitors) to suppress the function of Foxp3+ Tregs and enhanced effector T-cell functions. Anti-tumor immunity and tumor specific effector T-cell functions were assessed by cytotoxic T lymphocyte assay and intracellular IFN-γ staining. Our data showed that overexpression of interferon-γ or interleukin-2, or inhibition of the nuclear factor kappa-B within the tumor microenvironment, enhanced cytotoxic T lymphocyte-mediated immune responses and successfully extended the median survival of rats bearing intracranial RG2 when combined with Flt3L/TK. These findings indicate that enhancement of T-cell functions constitutes a critical therapeutic target to overcome immune evasion and enhance therapeutic efficacy for brain cancer. In addition, our study provides novel targets to be used in combination with immune-therapeutic strategies for glioblastoma, which are currently being tested in the clinic.

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References

  1. Meyers CA, Brown PD. Role and relevance of neurocognitive assessment in clinical trials of patients with CNS tumors. J Clin Oncol 2006;24:1305-1309.

    Article  PubMed  Google Scholar 

  2. Weitzner MA, Meyers CA. Cognitive functioning and quality of life in malignant glioma patients: a review of the literature. Psychooncology 1997;6:169-177.

    Article  PubMed  CAS  Google Scholar 

  3. Grossman SA, Ye X, Piantadosi S, et al. Survival of patients with newly diagnosed glioblastoma treated with radiation and temozolomide in research studies in the United States. Clin Cancer Res 2010;16:2443-2449.

    Article  PubMed  CAS  Google Scholar 

  4. Heimberger AB, Sun W, Hussain SF, et al. Immunological responses in a patient with glioblastoma multiforme treated with sequential courses of temozolomide and immunotherapy: case study. Neuro Oncol 2008;10:98-103.

    Article  PubMed  CAS  Google Scholar 

  5. Vauleon E, Avril T, Collet B, Mosser J, and Quillien V. Overview of cellular immunotherapy for patients with glioblastoma. Clin Dev Immunol 2010;1–18.

  6. Schmittling RJ, Archer GE, Mitchell DA, et al. Detection of humoral response in patients with glioblastoma receiving EGFRvIII-KLH vaccines. J Immunol Methods 2008;339:74-81.

    Article  PubMed  CAS  Google Scholar 

  7. Sampson JH, Archer GE, Mitchell DA, Heimberger AB, Bigner DD. Tumor-specific immunotherapy targeting the EGFRvIII mutation in patients with malignant glioma. Semin Immunol 2008;20:267-275.

    Article  PubMed  CAS  Google Scholar 

  8. Sampson JH, Heimberger AB, Archer GE, et al. Immunologic escape after prolonged progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma. J Clin Oncol 2010;28:4722-4729.

    Article  PubMed  Google Scholar 

  9. Wheeler CJ, Das A, Liu G, Yu JS, Black KL. Clinical responsiveness of glioblastoma multiforme to chemotherapy after vaccination. Clin Cancer Res 2004;10:5316-5326.

    Article  PubMed  CAS  Google Scholar 

  10. Yu JS, Liu G, Ying H, et al. Vaccination with tumor lysate-pulsed dendritic cells elicits antigen-specific, cytotoxic T-cells in patients with malignant glioma. Cancer Res 2004;64:4973-4979.

    Article  PubMed  CAS  Google Scholar 

  11. Liau LM, Prins RM, Kiertscher SM, et al. Dendritic cell vaccination in glioblastoma patients induces systemic and intracranial T-cell responses modulated by the local central nervous system tumor microenvironment. Clin Cancer Res 2005;11:5515-5525.

    Article  PubMed  CAS  Google Scholar 

  12. Prins RM, Soto H, Konkankit V, et al. Gene expression profile correlates with T cell infiltration and survival in glioblastoma patients vaccinated with dendritic cell immunotherapy. Clin Cancer Res 2010;17:1603–1615.

    Google Scholar 

  13. Walker DG, Laherty R, Tomlinson FH, Chuah T, Schmidt C. Results of a phase I dendritic cell vaccine trial for malignant astrocytoma: potential interaction with adjuvant chemotherapy. J Clin Neurosci 2008;15:114-121.

    Article  PubMed  CAS  Google Scholar 

  14. Yamanaka R, Homma J, Yajima N, et al. Clinical evaluation of dendritic cell vaccination for patients with recurrent glioma: results of a clinical phase I/II trial. Clin Cancer Res 2005;11:4160-4167.

    Article  PubMed  CAS  Google Scholar 

  15. Okada H, Kalinski P, Ueda R, et al. Induction of CD8+ T-cell responses against novel glioma-associated antigen peptides and clinical activity by vaccinations with {alpha}-type 1 polarized dendritic cells and polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose in patients with recurrent malignant glioma. J Clin Oncol 2011;29:330-336.

    Article  PubMed  CAS  Google Scholar 

  16. Berger C, Turtle CJ, Jensen MC, Riddell SR. Adoptive transfer of virus-specific and tumor-specific T cell immunity. Curr Opin Immunol 2009;21:224-232.

    Article  PubMed  CAS  Google Scholar 

  17. Brenner MK, Heslop HE. Adoptive T cell therapy of cancer. Curr Opin Immunol 2010;22:251-257.

    Article  PubMed  CAS  Google Scholar 

  18. Dietrich PY, Dutoit V, Tran Thang NN, Walker PR. T-cell immunotherapy for malignant glioma: toward a combined approach. Curr Opin Oncol 2010;22:604-610.

    Article  PubMed  Google Scholar 

  19. Heslop HE, Slobod KS, Pule MA, et al. Long-term outcome of EBV-specific T-cell infusions to prevent or treat EBV-related lymphoproliferative disease in transplant recipients. Blood 2010;115: 925-935.

    Article  PubMed  CAS  Google Scholar 

  20. Leen AM, Myers GD, Sili U, et al. Monoculture-derived T lymphocytes specific for multiple viruses expand and produce clinically relevant effects in immunocompromised individuals. Nat Med 2006;12:1160-1166.

    Article  PubMed  CAS  Google Scholar 

  21. Dudley ME, Wunderlich JR, Yang JC, et al. Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol 2005;23:2346-2357.

    Article  PubMed  CAS  Google Scholar 

  22. Ahmed N, Salsman VS, Kew Y, et al. HER2-specific T cells target primary glioblastoma stem cells and induce regression of autologous experimental tumors. Clin Cancer Res 2010;16:474-485.

    Article  PubMed  CAS  Google Scholar 

  23. Ali S, King GD, Curtin JF, et al. Combined immunostimulation and conditional cytotoxic gene therapy provide long-term survival in a large glioma model. Cancer Res J 2005;65:7194-7204.

    Article  CAS  Google Scholar 

  24. Curtin JF, Liu N, Candolfi M, et al. HMGB1 mediates endogenous TLR2 activation and brain tumor regression. PLoS medicine 2009;6:e10.

    Article  PubMed  Google Scholar 

  25. Ghulam Muhammad AKM, Candolfi M, King GD, et al. Antiglioma immunological memory in response to conditional cytotoxic/immune-stimulatory gene therapy: humoral and cellular immunity lead to tumor regression. Clin Cancer Res 2009;15:6113-6127.

    Article  PubMed  CAS  Google Scholar 

  26. Mineharu Y, King GD, Muhammad AK, et al. Engineering the brain tumor microenvironment enhances the efficacy of dendritic cell vaccination: implications for clinical trial design. Clin Cancer Res 2011;17:4705-4718.

    Article  PubMed  CAS  Google Scholar 

  27. Candolfi M, Yagiz K, Foulad D, et al. Release of HMGB1 in response to proapoptotic glioma killing strategies: efficacy and neurotoxicity. Clin Cancer Res 2009;15:4401-4414.

    Article  PubMed  CAS  Google Scholar 

  28. Kalinski P, Hilkens CM, Wierenga EA, Kapsenberg ML. T-cell priming by type-1 and type-2 polarized dendritic cells: the concept of a third signal. Immunol Today 1999;20:561-567.

    Article  PubMed  CAS  Google Scholar 

  29. Inge TH, McCoy KM, Susskind BM, et al. Immunomodulatory effects of transforming growth factor-beta on T lymphocytes. Induction of CD8 expression in the CTLL-2 cell line and in normal thymocytes. J Immunol 1992;148:3847-3856.

    PubMed  CAS  Google Scholar 

  30. Colombo F, Barzon L, Franchin E, et al. Combined HSV-TK/IL-2 gene therapy in patients with recurrent glioblastoma multiforme: biological and clinical results. Cancer Gene Ther 2005;12:835-848.

    Article  PubMed  CAS  Google Scholar 

  31. Bettelli E, Dastrange M, and Oukka M. Foxp3 interacts with nuclear factor of activated T cells and NF- {kappa} B to repress cytokine gene expression and effector functions of T helper cells. Proc Natl Acad Sci U S A 2005;102:5138-5143.

    Article  PubMed  CAS  Google Scholar 

  32. El Andaloussi A and Lesniak MS. CD4+ CD25+ FoxP3+ T-cell infiltration and heme oxygenase-1 expression correlate with tumor grade in human gliomas. J Neurooncol 2007;83:145-152.

    Article  PubMed  Google Scholar 

  33. Eckerstorfer P, Novy M, Burgstaller-Muehlbacher S, et al. Proximal human FOXP3 promoter transactivated by NF-kappaB and negatively controlled by feedback loop and SP3. Mol Immunol 2010;47:2094-2102.

    Article  PubMed  CAS  Google Scholar 

  34. Long M, Park S-G, Strickland I, Hayden MS, Ghosh S. Nuclear factor-kappaB modulates regulatory T cell development by directly regulating expression of Foxp3 transcription factor. Immunity 2009;31:921-931.

    Article  PubMed  CAS  Google Scholar 

  35. Isomura I, Palmer S, Grumont RJ, et al. c-Rel is required for the development of thymic Foxp3+ CD4 regulatory T cells. J Exp Med 2009;206:3001-3014.

    Article  PubMed  CAS  Google Scholar 

  36. Ruan Q, Kameswaran V, Tone Y, et al. Development of Foxp3(+) regulatory t cells is driven by the c-Rel enhanceosome. Immunity 2009;31:932-940.

    Article  PubMed  CAS  Google Scholar 

  37. Weizsacker M, Nagamune A, Winkelstroter R, Vieten H, and Wechsler W. Radiation and drug response of the rat glioma RG2. Eur J Cancer Clin Oncol 1982;18:891-895.

    Article  PubMed  CAS  Google Scholar 

  38. Oshiro S, Liu Y, Fukushima T, Asotra K, Black KL. Modified immunoregulation associated with interferon-γ treatment of rat glioma. Neurological Research 2001;23:359-366.

    Article  PubMed  CAS  Google Scholar 

  39. Ghulam Muhammad AK, Candolfi M, King GD, et al. Antiglioma immunological memory in response to conditional cytotoxic/immune-stimulatory gene therapy: humoral and cellular immunity lead to tumor regression. Clin Cancer Res 2009;15:6113-6127.

    Article  PubMed  CAS  Google Scholar 

  40. Heimberger AB and Sampson JH. Immunotherapy coming of age: what will it take to make it standard of care for glioblastoma? Neuro Oncol 2010;13:3-13.

    Article  PubMed  Google Scholar 

  41. Matsukado K, Inamura T, Nakano S, et al. Enhanced tumor uptake of carboplatin and survival in glioma-bearing rats by intracarotid infusion of bradykinin analog, RMP-7. Neurosurgery 1996;39:125-134.

    Google Scholar 

  42. Yang WQ, Lun X, Palmer CA, et al. Efficacy and safety evaluation of human reovirus type 3 in immunocompetent animals: racine and nonhuman primates. Clin Cancer Res 2004;10:8561-8576.

    Article  PubMed  Google Scholar 

  43. Lun X, Alain T, Zemp FJ, et al. Myxoma virus virotherapy for glioma in immunocompetent animal models: optimizing administration routes and synergy with rapamycin. Cancer Res 2010;70:598-608.

    Article  PubMed  CAS  Google Scholar 

  44. Lun X, Chan J, Zhou H, et al. Efficacy and safety/toxicity study of recombinant vaccinia virus JX-594 in two immunocompetent animal models of glioma. Mol Ther 2010;18:1927-1936.

    Article  PubMed  CAS  Google Scholar 

  45. Ali S, King GD, Curtin JF, et al. Combined immunostimulation and conditional cytotoxic gene therapy provide long-term survival in a large glioma model. Cancer Res 2005;65:7194-7204.

    Article  PubMed  CAS  Google Scholar 

  46. Candolfi M, Yagiz K, Foulad D, et al. Release of HMGB1 in response to proapoptotic glioma killing strategies: efficacy and neurotoxicity. Clin Cancer Res 2009;15:4401-4414.

    Article  PubMed  CAS  Google Scholar 

  47. Black ME, Kokoris MS, Sabo P. Herpes simplex virus-1 thymidine kinase mutants created by semi-random sequence mutagenesis improve prodrug-mediated tumor cell killing. Cancer Res 2001;61:3022-3026.

    PubMed  CAS  Google Scholar 

  48. Robinson SN, Chavez JM, Pisarev VM, et al. Delivery of Flt3 ligand (Flt3L) using a poloxamer-based formulation increases biological activity in mice. Bone Marrow Transplant 2003;31:361-369.

    Article  PubMed  CAS  Google Scholar 

  49. Curran MA, Allison JP. Tumor vaccines expressing flt3 ligand synergize with ctla-4 blockade to reject preimplanted tumors. Cancer Res 2009;69:7747-7755.

    Article  PubMed  CAS  Google Scholar 

  50. He J, Wang T, Yao L, et al. Construction and delivery of gene therapy vector containing soluble TNFalpha receptor-IgGFc fusion gene for the treatment of allergic rhinitis. Cytokine 2006;36:296-304.

    Article  PubMed  CAS  Google Scholar 

  51. Mihara M, Tan I, Chuzhin Y, et al. CTLA4Ig inhibits T cell-dependent B-cell maturation in murine systemic lupus erythematosus. The Journal of clinical investigation 2000;106:91-101.

    Article  PubMed  CAS  Google Scholar 

  52. Kremer JM, Westhovens R, Leon M, et al. Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig. N Engl J Med 2003;349:1907-1915.

    Article  PubMed  CAS  Google Scholar 

  53. Fujita M, Zhu X, Ueda R, et al. Effective immunotherapy against murine gliomas using type 1 polarizing dendritic cells--significant roles of CXCL10. Cancer Res 2009;69:1587-1595.

    Article  PubMed  CAS  Google Scholar 

  54. Dohnal AM, Luger R, Paul P, Fuchs D, Felzmann T. CD40 ligation restores type 1 polarizing capacity in TLR4 activated dendritic cells that have ceased interleukin-12 expression. J Cell Mol Med 2008;13:1741-1750.

    Article  Google Scholar 

  55. Vecchi A, Massimiliano L, Ramponi S, et al. Differential responsiveness to constitutive vs. inducible chemokines of immature and mature mouse dendritic cells. J Leukoc Biol 1999;66:489-494.

    PubMed  CAS  Google Scholar 

  56. Edukulla R, Woller N, Mundt B, et al. Antitumoral immune response by recruitment and expansion of dendritic cells in tumors infected with telomerase-dependent oncolytic viruses. Cancer Res 2009;69:1448-1458.

    Article  PubMed  Google Scholar 

  57. Horckmans M, Marcet B, Marteau F, et al. Extracellular adenine nucleotides inhibit the release of major monocyte recruiters by human monocyte-derived dendritic cells. FEBS Lett 2006;580:747-754.

    Article  PubMed  CAS  Google Scholar 

  58. Klebanoff CA, Gattinoni L, Torabi-Parizi P, et al. Central memory self/tumor-reactive CD8+ T cells confer superior antitumor immunity compared with effector memory T cells. Proc Natl Acad Sci U S A 2005;102:9571-9576.

    Article  PubMed  CAS  Google Scholar 

  59. Berger C, Jensen MC, Lansdorp PM, et al. Adoptive transfer of effector CD8+ T cells derived from central memory cells establishes persistent T cell memory in primates. J Clin Invest 2008;118:294-305.

    Article  PubMed  CAS  Google Scholar 

  60. Barth RF, Kaur B. Rat brain tumor models in experimental neuro-oncology: the C6, 9L, T9, RG2, F98, BT4C, RT-2 and CNS-1 gliomas. Journal of neuro-oncology 2009;94:299-312.

    Article  Google Scholar 

  61. Sibenaller Za, Etame AB, Ali MM, et al. Genetic characterization of commonly used glioma cell lines in the rat animal model system. Neurosurgical focus 2005;19:E1.

    Article  Google Scholar 

  62. Pulkkanen KJ, Yla-Herttuala S. Gene therapy for malignant glioma: current clinical status. Mol Ther 2005;12:585-598.

    Article  PubMed  CAS  Google Scholar 

  63. Sandmair AM, Loimas S, Puranen P, et al. Thymidine kinase gene therapy for human malignant glioma, using replication-deficient retroviruses or adenoviruses. Hum Gene Ther 2000;11:2197-2205.

    Article  PubMed  CAS  Google Scholar 

  64. Puumalainen AM, Vapalahti M, Agrawal RS, et al. Beta-galactosidase gene transfer to human malignant glioma in vivo using replication-deficient retroviruses and adenoviruses. Hum Gene Ther 1998;9:1769-1774.

    Article  PubMed  CAS  Google Scholar 

  65. Germano IM, Fable J, Gultekin SH, Silvers A. Adenovirus/herpes simplex-thymidine kinase/ganciclovir complex: preliminary results of a phase I trial in patients with recurrent malignant gliomas. J Neurooncol 2003;65:279-289.

    Article  PubMed  Google Scholar 

  66. Immonen A, Vapalahti M, Tyynela K, et al. AdvHSV-tk gene therapy with intravenous ganciclovir improves survival in human malignant glioma: a randomised, controlled study. Mol Ther 2004;10:967-972.

    Article  PubMed  CAS  Google Scholar 

  67. Eck SL, Alavi JB, Judy K, et al. Treatment of recurrent or progressive malignant glioma with a recombinant adenovirus expressing human interferon-beta (H5.010CMVhIFN-beta): a phase I trial. Hum Gene Ther 2001;12:97-113.

    Article  PubMed  CAS  Google Scholar 

  68. Chiocca EA, Abbed KM, Tatter S, et al. A phase I open-label, dose-escalation, multi-institutional trial of injection with an E1B-Attenuated adenovirus, ONYX-015, into the peritumoral region of recurrent malignant gliomas, in the adjuvant setting. Mol Ther 2004;10:958-966.

    Article  PubMed  CAS  Google Scholar 

  69. Lang FF, Bruner JM, Fuller GN, et al. Phase I trial of adenovirus-mediated p53 gene therapy for recurrent glioma: biological and clinical results. J Clin Oncol 2003;21:2508-2518.

    Article  PubMed  CAS  Google Scholar 

  70. Candolfi M, Curtin JF, Xiong WD, et al. Effective high-capacity gutless adenoviral vectors mediate transgene expression in human glioma cells. Mol Ther 2006;14:371-381.

    Article  PubMed  CAS  Google Scholar 

  71. Candolfi M, Xiong W, Yagiz K, et al. Gene therapy-mediated delivery of targeted cytotoxins for glioma therapeutics. Proc Natl Acad Sci U S A 2010;107:20021-20026.

    Article  PubMed  CAS  Google Scholar 

  72. Chiocca EA, Aguilar LK, Bell SD, et al. Phase IB study of gene-mediated cytotoxic immunotherapy adjuvant to up-front surgery and intensive timing radiation for malignant glioma. J Clin Oncol 2011;29:3611-3619.

    Article  PubMed  CAS  Google Scholar 

  73. Maatta AM, Samaranayake H, Pikkarainen J, Wirth T, Yla-Herttuala S. Adenovirus mediated herpes simplex virus-thymidine kinase/ganciclovir gene therapy for resectable malignant glioma. Curr Gene Ther 2009;9:356-367.

    Article  PubMed  CAS  Google Scholar 

  74. Kim CY, Park SH, Jeong M, et al. Preclinical studies for pharmacokinetics and biodistribution of Ad-stTRAIL, an adenovirus delivering secretable trimeric TRAIL for gene therapy. Exp Mol Med 2011;43:580-586.

    Article  PubMed  CAS  Google Scholar 

  75. Rainov NG and Heidecke V. Clinical development of experimental virus-mediated gene therapy for malignant glioma. Anticancer Agents Med Chem 2011;11:739-747.

    PubMed  CAS  Google Scholar 

  76. Jiang H, Gomez-Manzano C, Lang FF, Alemany R, Fueyo J. Oncolytic adenovirus: preclinical and clinical studies in patients with human malignant gliomas. Curr Gene Ther 2009;9:422-427.

    Article  PubMed  CAS  Google Scholar 

  77. Hokey DA, Larregina AT, Erdos G, Watkins SC, Falo LD Jr. Tumor cell loaded type-1 polarized dendritic cells induce Th1-mediated tumor immunity. Cancer Res 2005;65:10059-10067.

    Article  PubMed  CAS  Google Scholar 

  78. Borges L, Miller RE, Jones J, et al. Synergistic action of fms-like tyrosine kinase 3 ligand and CD40 ligand in the induction of dendritic cells and generation of antitumor immunity in vivo. J Immunol 1999;163:1289-1297.

    PubMed  CAS  Google Scholar 

  79. Smith CM, Wilson NS, Waithman J, et al. Cognate CD4(+) T cell licensing of dendritic cells in CD8(+) T cell immunity. Nat Immunol 2004;5:1143-1148.

    Article  PubMed  CAS  Google Scholar 

  80. Bevan MJ. Helping the CD8(+) T-cell response. Nat Rev Immunol 2004;4:595-602.

    Article  PubMed  CAS  Google Scholar 

  81. Wilson EB, Livingstone AM. Cutting edge: CD4+ T cell-derived IL-2 is essential for help-dependent primary CD8+ T cell responses. J Immunol 2008;181:7445-7448.

    PubMed  CAS  Google Scholar 

  82. Mitchell DM, Ravkov EV, Williams Ma. Distinct roles for IL-2 and IL-15 in the differentiation and survival of CD8+ effector and memory T cells. J Immunol 2010;184:6719-6730.

    Article  PubMed  CAS  Google Scholar 

  83. Williams Ma, Tyznik AJ, Bevan MJ. Interleukin-2 signals during priming are required for secondary expansion of CD8+ memory T cells. Nature 2006;441:890-893.

    Article  PubMed  CAS  Google Scholar 

  84. Blachère NE, Morris HK, Braun D, et al. IL-2 is required for the activation of memory CD8+ T cells via antigen cross-presentation. J Immunol 2006;176:7288-7300.

    PubMed  Google Scholar 

  85. Mescher MF, Curtsinger JM, Agarwal P, et al. Signals required for programming effector and memory development by CD8+ T cells. Immunol Rev 2006;211:81-92.

    Article  PubMed  CAS  Google Scholar 

  86. Almeida AR, Legrand N, Papiernik M, and Freitas AA. Homeostasis of peripheral CD4+ T cells: IL-2R alpha and IL-2 shape a population of regulatory cells that controls CD4+ T cell numbers. J Immunol 2002;169:4850-4860.

    PubMed  Google Scholar 

  87. Furtado GC, Curotto de Lafaille MA, Kutchukhidze N, Lafaille JJ. Interleukin 2 signaling is required for CD4(+) regulatory T cell function. J Exp Med 2002;196:851-857.

    Article  PubMed  CAS  Google Scholar 

  88. Barron L, Dooms H, Hoyer KK, et al. Cutting edge: mechanisms of IL-2-dependent maintenance of functional regulatory T cells. J Immunol 2010;185:6426-6430.

    Google Scholar 

  89. Tran DQ, Glass DD, Uzel G, et al. Analysis of adhesion molecules, target cells, and role of IL-2 in human FOXP3+ regulatory T cell suppressor function. J Immunol 2009;182:2929-2938.

    Article  PubMed  CAS  Google Scholar 

  90. Ingram W, Kordasti S, Chan L, et al. Human CD80/IL2 lentivirus transduced acute myeloid leukaemia cells enhance cytolytic activity in vitro in spite of an increase in regulatory CD4+ T cells in a subset of cultures. Cancer Immunol Immunother 2009;58:1679-1690.

    Article  PubMed  CAS  Google Scholar 

  91. Jean WC, Spellman SR, Wallenfriedman Ma, et al. Effects of combined granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2, and interleukin-12 based immunotherapy against intracranial glioma in the rat. J Neurooncol 2004;66:39-49.

    Article  PubMed  Google Scholar 

  92. Sanlioglu AD, Koksal IT, Karacay B, et al. Adenovirus-mediated IKKbetaKA expression sensitizes prostate carcinoma cells to TRAIL-induced apoptosis. Cancer Gene Ther 2006;13:21-31.

    Article  PubMed  CAS  Google Scholar 

  93. Sanlioglu S, Luleci G, and Thomas KW. Simultaneous inhibition of Rac1 and IKK pathways sensitizes lung cancer cells to TNFalpha-mediated apoptosis. Cancer Gene Ther 2001;8:897-905.

    Article  PubMed  CAS  Google Scholar 

  94. Tsuboi Y, Kurimoto M, Nagai S, et al. Induction of autophagic cell death and radiosensitization by the pharmacological inhibition of neuclear factor=kjappa B activation in human glioma cell lines. J Neurosurg 2009; 110(3):594–604.

    Google Scholar 

  95. Tas SW, Vervoordeldonk MJ, and Tak PP. Gene therapy targeting nuclear factor-kappaB: towards clinical application in inflammatory diseases and cancer. Curr Gene Ther 2009;9:160-170.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

The authors are grateful to Nicholas Sanderson for his technical advice and support and to Mohammed Saleh for his assistance with editing and preparing the manuscript for publication. This work was supported by grants from the National Institutes of Health/National Institute of Neurological Disorders & Stroke (NIH/NINDS); 1UO1 NS052465; UO1-NS052465-04S1; 1RO1-NS057711 and 1RO1-NS074387 to M.G.C.; NIH/NINDS Grants 1RO1-NS 054193; and 1RO1-NS061107 to P.R.L.; The Bram and Elaine Goldsmith and the Medallions Group Endowed Chairs in Gene Therapeutics to P.R.L. and M.G.C., respectively and the Board of Governors at CSMC. M.C. was supported by an NIH/NINDS 1F32 NS058156 fellowship and by the National Council of Science and Technology (CONICET, Argentina). Y.M. received a fellowship from Uehara Memorial Foundation.

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Authors and Affiliations

  1. Gene Therapeutics Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90095, USA

    Yohei Mineharu, AKM Ghulam Muhammad, Kader Yagiz, Marianela Candolfi, Kurt M. Kroeger, Weidong Xiong, Mariana Puntel, Chunyan Liu, Eva Levy, Claudia Lugo, Adrina Kocharian, Pedro R. Lowenstein & Maria G. Castro

  2. Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA

    Yohei Mineharu, AKM Ghulam Muhammad, Kader Yagiz, Marianela Candolfi, Kurt M. Kroeger, Weidong Xiong, Mariana Puntel, Chunyan Liu, Eva Levy, Claudia Lugo, Adrina Kocharian, Pedro R. Lowenstein & Maria G. Castro

  3. Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA

    Yohei Mineharu, AKM Ghulam Muhammad, Kader Yagiz, Marianela Candolfi, Kurt M. Kroeger, Weidong Xiong, Mariana Puntel, Chunyan Liu, Eva Levy, Claudia Lugo, Adrina Kocharian, Pedro R. Lowenstein & Maria G. Castro

  4. Howard Hughes Medical Institute, Department of Immunology, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, USA

    James P. Allison & Michael A. Curran

  5. Department of Neurosurgery, University of Michigan School of Medicine, Ann Arbor, MI, 48109-0650, USA

    Pedro R. Lowenstein & Maria G. Castro

  6. Department of Cell and Developmental Biology, University of Michigan School of Medicine, Ann Arbor, MI, 48109-0650, USA

    Pedro R. Lowenstein & Maria G. Castro

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  1. Yohei Mineharu
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Correspondence to Maria G. Castro.

Additional information

Kurt M. Kroeger is deceased

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Mineharu, Y., Muhammad, A.G., Yagiz, K. et al. Gene Therapy-Mediated Reprogramming Tumor Infiltrating T Cells Using IL-2 and Inhibiting NF-κB Signaling Improves the Efficacy of Immunotherapy in a Brain Cancer Model. Neurotherapeutics 9, 827–843 (2012). https://doi.org/10.1007/s13311-012-0144-7

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