Rapamycin-resistant effector T-cell therapy

Immunological Reviews

Volumn 257, Issue 1, 2014, Pages 210-225

  Fowler, Daniel H ^a  

^a NATIONAL CANCER INSTITUTE   (United States)

Author keywords

Apoptosis autophagy; Cytokines; Graft versus host disease; Th1 Th2 Th17; Transplantation

Indexed keywords

CYCLOPHOSPHAMIDE; CYTOKINE RECEPTOR; FLUDARABINE; GAMMA INTERFERON; GROWTH FACTOR RECEPTOR; INSULIN RECEPTOR SUBSTRATE; INTERLEUKIN 10; INTERLEUKIN 12; INTERLEUKIN 2; INTERLEUKIN 4; INTERLEUKIN 7; MAMMALIAN TARGET OF RAPAMYCIN; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 2; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PROTEIN KINASE B; PROTEIN P53; RAPAMYCIN; TRANSCRIPTION FACTOR FOXP3; TRANSCRIPTION FACTOR GATA 3;

ADOPTIVE TRANSFER; ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION; ALLOGENIC BONE MARROW TRANSPLANTATION; ANTIGEN PRESENTING CELL; ARTICLE; AUTOPHAGY; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CELL DIFFERENTIATION; CELL SURFACE; CELL THERAPY; CYTOKINE RELEASE; DRUG DOSE REDUCTION; DRUG MEGADOSE; EFFECTOR CELL; EX VIVO STUDY; GRAFT REJECTION; GRAFT VERSUS HOST REACTION; HUMAN; IN VIVO STUDY; KIDNEY METASTASIS; MAJOR HISTOCOMPATIBILITY COMPLEX; MEMORY T LYMPHOCYTE; MITOCHONDRIAL MEMBRANE POTENTIAL; OXIDATIVE PHOSPHORYLATION; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHENOTYPE; POSITIVE FEEDBACK; PRIORITY JOURNAL; PROTEIN EXPRESSION; RAPAMYCIN RESISTANT EFFECTOR T CELL; REDUCED INTENSITY CONDITIONING; REGULATORY T LYMPHOCYTE; SHORT COURSE THERAPY; SIGNAL TRANSDUCTION; STABLE EXPRESSION; T CELL DEPLETION; T LYMPHOCYTE; TH1 CELL; TH17 CELL; TH2 CELL; TUMOR SUPPRESSOR GENE; UPREGULATION;

APOPTOSIS/AUTOPHAGY; CYTOKINES; GRAFT VERSUS HOST DISEASE; TH1/TH2/TH17; TRANSPLANTATION;

ANIMALS; CELL- AND TISSUE-BASED THERAPY; CLINICAL TRIALS AS TOPIC; DRUG RESISTANCE; GRAFT VS HOST DISEASE; HEMATOPOIETIC STEM CELL TRANSPLANTATION; HUMANS; NEOPLASMS; SIROLIMUS; T-LYMPHOCYTE SUBSETS; TH1 CELLS; TH2 CELLS; TOR SERINE-THREONINE KINASES; TRANSPLANTATION, HOMOLOGOUS;

EID: 84890238278     PISSN: 01052896     EISSN: 1600065X     Source Type: Journal    
DOI: 10.1111/imr.12127     Document Type: Article

References (147)

1. Vezina C, Kudelski A, Sehgal SN. Rapamycin (AY-22, 989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J Antibiotics 1975;28:721-726.
2. Hudes G, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007;356:2271-2281.
3. Motzer RJ, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 2008;372:449-456.
4. Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell 2012;149:274-293.
5. Brown EJ, et al. A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature 1994;369:756-758.
6. Kim DH, et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 2002;110:163-175.
7. Yip CK, Murata K, Walz T, Sabatini DM, Kang SA. Structure of the human mTOR complex I and its implications for rapamycin inhibition. Mol Cell 2010;38:768-774.
8. Inoki K, Li Y, Zhu T, Wu J, Guan KL. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 2002;4:648-657.
9. Ma L, Chen Z, Erdjument-Bromage H, Tempst P, Pandolfi PP. Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell 2005;121:179-193.
10. Roux PP, Ballif BA, Anjum R, Gygi SP, Blenis J. Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase. Proc Natl Acad Sci USA 2004;101:13489-13494.
11. Lee DF, et al. IKK beta suppression of TSC1 links inflammation and tumor angiogenesis via the mTOR pathway. Cell 2007;130:440-455.
12. Inoki K, et al. TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth. Cell 2006;126:955-968.
13. Inoki K, Zhu T, Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell 2003;115:577-590.
14. Brugarolas J, et al. Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev 2004;18:2893-2904.
15. Feng Z, Zhang H, Levine AJ, Jin S. The coordinate regulation of the p53 and mTOR pathways in cells. Proc Natl Acad Sci USA 2005;102:8204-8209.
16. Kim E, Goraksha-Hicks P, Li L, Neufeld TP, Guan KL. Regulation of TORC1 by Rag GTPases in nutrient response. Nat Cell Biol 2008;10:935-945.
17. Sancak Y, et al. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 2008;320:1496-1501.
18. Fang Y, Vilella-Bach M, Bachmann R, Flanigan A, Chen J. Phosphatidic acid-mediated mitogenic activation of mTOR signaling. Science 2001;294:1942-1945.
19. Toschi A, Lee E, Xu L, Garcia A, Gadir N, Foster DA. Regulation of mTORC1 and mTORC2 complex assembly by phosphatidic acid: competition with rapamycin. Mol Cell Biol 2009;29:1411-1420.
20. Ma XM, Blenis J. Molecular mechanisms of mTOR-mediated translational control. Nat Rev Mol Cell Biol 2009;10:307-318.
21. Laplante M, Sabatini DM. An emerging role of mTOR in lipid biosynthesis. Curr Biol 2009;19:R1046-R1052.
22. Waickman AT, Powell JD. mTOR, metabolism, and the regulation of T-cell differentiation and function. Immunol Rev 2012;249:43-58.
23. Ganley IG, du Lam H, Wang J, Ding X, Chen S, Jiang X. ULK1.ATG13.FIP200 complex mediates mTOR signaling and is essential for autophagy. J Biol Chem 2009;284:12297-12305.
24. Jung CH, Ro SH, Cao J, Otto NM, Kim DH. mTOR regulation of autophagy. FEBS Lett 2010;584:1287-1295.
25. Oh WJ, Jacinto E. mTOR complex 2 signaling and functions. Cell Cycle 2011;10:2305-2316.
26. Dibble CC, Asara JM, Manning BD. Characterization of Rictor phosphorylation sites reveals direct regulation of mTOR complex 2 by S6K1. Mol Cell Biol 2009;29:5657-5670.
27. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 2005;307:1098-1101.
28. Zinzalla V, Stracka D, Oppliger W, Hall MN. Activation of mTORC2 by association with the ribosome. Cell 2011;144:757-768.
29. Sarbassov DD, et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 2004;14:1296-1302.
30. Sarbassov DD, et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 2006;22:159-168.
31. Phung TL, et al. Pathological angiogenesis is induced by sustained Akt signaling and inhibited by rapamycin. Cancer Cell 2006;10:159-170.
32. Zeng Z, et al. Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation in AML. Blood 2007;109:3509-3512.
33. Ye L, Varamini B, Lamming DW, Sabatini DM, Baur JA. Rapamycin has a biphasic effect on insulin sensitivity in C2C12 myotubes due to sequential disruption of mTORC1 and mTORC2. Front Genet 2012;3:177.
34. Lamming DW, et al. Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science 2012;335:1638-1643.
35. Dilling MB, Dias P, Shapiro DN, Germain GS, Johnson RK, Houghton PJ. Rapamycin selectively inhibits the growth of childhood rhabdomyosarcoma cells through inhibition of signaling via the type I insulin-like growth factor receptor. Cancer Res 1994;54:903-907.
36. Fruman DA, Wood MA, Gjertson CK, Katz HR, Burakoff SJ, Bierer BE. FK506 binding protein 12 mediates sensitivity to both FK506 and rapamycin in murine mast cells. Eur J Immunol 1995;25:563-571.
37. Lorenz MC, Heitman J. TOR mutations confer rapamycin resistance by preventing interaction with FKBP12-rapamycin. J Biol Chem 1995;270:27531-27537.
38. Huang S, Houghton PJ. Mechanisms of resistance to rapamycins. Drug Resist Updat 2001;4:378-391.
39. Carew JS, Kelly KR, Nawrocki ST. Mechanisms of mTOR inhibitor resistance in cancer therapy. Target Oncol 2011;6:17-27.
40. Gomez-Pinillos A, Ferrari AC. TOR signaling pathway and mTOR inhibitors in cancer therapy. Hematol Oncol Clinics N Am 2012;26:483-505, vii.
41. Feldman ME, et al. Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol 2009;7:e38.
42. Chresta CM, et al. AZD8055 is a potent, selective, and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity. Cancer Res 2010;70:288-298.
43. Thoreen CC, Chantranupong L, Keys HR, Wang T, Gray NS, Sabatini DM. A unifying model for mTORC1-mediated regulation of mRNA translation. Nature 2012;485:109-113.
44. Janes MR, et al. Effective and selective targeting of leukemia cells using a TORC1/2 kinase inhibitor. Nat Med 2010;16:205-213.
45. Falcon BL, et al. Reduced VEGF production, angiogenesis, and vascular regrowth contribute to the antitumor properties of dual mTORC1/mTORC2 inhibitors. Cancer Res 2011;71:1573-1583.
46. Thoreen CC, et al. An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J Biol Chem 2009;284:8023-8032.
47. Rosborough BR, et al. Murine dendritic cell rapamycin-resistant and rictor-independent mTOR controls IL-10, B7-H1, and regulatory T-cell induction. Blood 2013;121:3619-3630.
48. Wang BT, Ducker GS, Barczak AJ, Barbeau R, Erle DJ, Shokat KM. The mammalian target of rapamycin regulates cholesterol biosynthetic gene expression and exhibits a rapamycin-resistant transcriptional profile. Proc Natl Acad Sci USA 2011;108:15201-15206.
49. Gupta M, Ansell SM, Novak AJ, Kumar S, Kaufmann SH, Witzig TE. Inhibition of histone deacetylase overcomes rapamycin-mediated resistance in diffuse large B-cell lymphoma by inhibiting Akt signaling through mTORC2. Blood 2009;114:2926-2935.
50. Narlik-Grassow M, Blanco-Aparicio C, Carnero A. The PIM family of serine/threonine kinases in cancer. Medicinal Res Rev 2013; doi:10.1002/med.21284.
51. Fox CJ, Hammerman PS, Cinalli RM, Master SR, Chodosh LA, Thompson CB. The serine/threonine kinase Pim-2 is a transcriptionally regulated apoptotic inhibitor. Genes Dev 2003;17:1841-1854.
52. Nawijn MC, Alendar A, Berns A. For better or for worse: the role of Pim oncogenes in tumorigenesis. Nat Rev Cancer 2011;11:23-34.
53. O'Shea JJ, Kontzias A, Yamaoka K, Tanaka Y, Laurence A. Janus kinase inhibitors in autoimmune diseases. Ann Rheum Dis 2013;72(Suppl):ii111-ii115.
54. Wang Z, Bhattacharya N, Mixter PF, Wei W, Sedivy J, Magnuson NS. Phosphorylation of the cell cycle inhibitor p21Cip1/WAF1 by Pim-1 kinase. Biochim Biophys Acta 2002;1593:45-55.
55. Morishita D, Katayama R, Sekimizu K, Tsuruo T, Fujita N. Pim kinases promote cell cycle progression by phosphorylating and down-regulating p27Kip1 at the transcriptional and posttranscriptional levels. Cancer Res 2008;68:5076-5085.
56. Ellwood-Yen K, et al. Myc-driven murine prostate cancer shares molecular features with human prostate tumors. Cancer Cell 2003;4:223-238.
57. Shirogane T, Fukada T, Muller JM, Shima DT, Hibi M, Hirano T. Synergistic roles for Pim-1 and c-Myc in STAT3-mediated cell cycle progression and antiapoptosis. Immunity 1999;11:709-719.
58. Amaravadi RK, et al. Principles and current strategies for targeting autophagy for cancer treatment. Clin Cancer Res 2011;17:654-666.
59. Mathew R, White E. Autophagy, stress, and cancer metabolism: what doesn't kill you makes you stronger. Cold Spring Harbor Symp Quant Biol 2011;76:389-396.
60. Townsend KN, Hughson LR, Schlie K, Poon VI, Westerback A, Lum JJ. Autophagy inhibition in cancer therapy: metabolic considerations for antitumor immunity. Immunol Rev 2012;249:176-194.
61. Nakamura O, Hitora T, Akisue T, Kawamoto T, Yamagami Y, Yamamoto T. Inhibition of induced autophagy increases apoptosis of Nara-H cells. Int J Oncol 2011;39:1545-1552.
62. Carayol N, et al. Critical roles for mTORC2- and rapamycin-insensitive mTORC1-complexes in growth and survival of BCR-ABL-expressing leukemic cells. Proc Natl Acad Sci USA 2010;107:12469-12474.
63. Sini P, James D, Chresta C, Guichard S. Simultaneous inhibition of mTORC1 and mTORC2 by mTOR kinase inhibitor AZD8055 induces autophagy and cell death in cancer cells. Autophagy 2010;6:553-554.
64. Rosner M, Hanneder M, Siegel N, Valli A, Fuchs C, Hengstschlager M. The mTOR pathway and its role in human genetic diseases. Mutation Res 2008;659:284-292.
65. Huang S, Liu LN, Hosoi H, Dilling MB, Shikata T, Houghton PJ. p53/p21(CIP1) cooperate in enforcing rapamycin-induced G(1) arrest and determine the cellular response to rapamycin. Cancer Res 2001;61:3373-3381.
66. Di Nicolantonio F, et al. Deregulation of the PI3K and KRAS signaling pathways in human cancer cells determines their response to everolimus. J Clin Invest 2010;120:2858-2866.
67. Masri J, et al. mTORC2 activity is elevated in gliomas and promotes growth and cell motility via overexpression of rictor. Cancer Res 2007;67:11712-11720.
68. Um SH, et al. Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature 2004;431:200-205.
69. Peterson TR, et al. DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell 2009;137:873-886.
70. Britschgi A, et al. JAK2/STAT5 inhibition circumvents resistance to PI3K/mTOR blockade: a rationale for cotargeting these pathways in metastatic breast cancer. Cancer Cell 2012;22:796-811.
71. Powell JD, Lerner CG, Schwartz RH. Inhibition of cell cycle progression by rapamycin induces T cell clonal anergy even in the presence of costimulation. J Immunol 1999;162:2775-2784.
72. Xie DL, Wu J, Lou YL, Zhong XP. Tumor suppressor TSC1 is critical for T-cell anergy. Proc Natl Acad Sci USA 2012;109:14152-14157.
73. Powell JD, Pollizzi KN, Heikamp EB, Horton MR. Regulation of immune responses by mTOR. Annu Rev Immunol 2012;30:39-68.
74. Chi H. Regulation and function of mTOR signalling in T cell fate decisions. Nat Rev Immunol 2012;12:325-338.
75. Delgoffe GM, et al. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity 2009;30:832-844.
76. Delgoffe GM, et al. The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nat Immunol 2011;12:295-303.
77. Lee K, et al. Mammalian target of rapamycin protein complex 2 regulates differentiation of Th1 and Th2 cell subsets via distinct signaling pathways. Immunity 2010;32:743-753.
78. Nyfeler B, et al. Relieving autophagy and 4EBP1 from rapamycin resistance. Mol Cell Biol 2011;31:2867-2876.
79. Kay JE, Wellhausen A, Frost V, Morgan GY, Smith MC, Morley SJ. Rapamycin-resistant human lymphoid cell lines. Biochem Soc Trans 1996;24:89S.
80. Valentine JE, Sewell WA. Induction of IL-5 expression by IL-2 is resistant to the immunosuppressive agents cyclosporin A and rapamycin. Int Immunol 1997;9:975-982.
81. Luo Y, Marx SO, Kiyokawa H, Koff A, Massague J, Marks AR. Rapamycin resistance tied to defective regulation of p27Kip1. Mol Cell Biol 1996;16:6744-6751.
82. Slavik JM, Lim DG, Burakoff SJ, Hafler DA. Rapamycin-resistant proliferation of CD8+ T cells correlates with p27kip1 down-regulation and bcl-xL induction, and is prevented by an inhibitor of phosphoinositide 3-kinase activity. J Biol Chem 2004;279:910-919.
83. Slavik JM, Lim DG, Burakoff SJ, Hafler DA. Uncoupling p70(s6) kinase activation and proliferation: rapamycin-resistant proliferation of human CD8(+) T lymphocytes. J Immunol 2001;166:3201-3209.
84. Huye LE, et al. Combining mTor inhibitors with rapamycin-resistant T cells: a two-pronged approach to tumor elimination. Mol Ther 2011;19:2239-2248.
85. Battaglia M, Stabilini A, Roncarolo MG. Rapamycin selectively expands CD4+CD25+FoxP3+ regulatory T cells. Blood 2005;105:4743-4748.
86. Basu S, Golovina T, Mikheeva T, June CH, Riley JL. Cutting edge: Foxp3-mediated induction of pim 2 allows human T regulatory cells to preferentially expand in rapamycin. J Immunol 2008;180:5794-5798.
87. Wang Y, Souabni A, Flavell RA, Wan YY. An intrinsic mechanism predisposes Foxp3-expressing regulatory T cells to Th2 conversion in vivo. J Immunol 2010;185:5983-5992.
88. O'Malley JT, et al. Signal transducer and activator of transcription 4 limits the development of adaptive regulatory T cells. Immunology 2009;127:587-595.
89. Zhao J, Zhao J, Perlman S. Differential effects of IL-12 on Tregs and non-Treg T cells: roles of IFN-gamma, IL-2 and IL-2R. PLoS ONE 2012;7:e46241.
90. Xu X, Ye L, Araki K, Ahmed R. mTOR, linking metabolism and immunity. Semin Immunol 2012;24:429-435.
91. Araki K, et al. mTOR regulates memory CD8 T-cell differentiation. Nature 2009;460:108-112.
92. Rao RR, Li Q, Odunsi K, Shrikant PA. The mTOR kinase determines effector versus memory CD8+ T cell fate by regulating the expression of transcription factors T-bet and Eomesodermin. Immunity 2010;32:67-78.
93. Li Q, et al. A central role for mTOR kinase in homeostatic proliferation induced CD8+ T cell memory and tumor immunity. Immunity 2011;34:541-553.
94. Rao RR, Li Q. Gubbels Bupp MR, Shrikant PA. Transcription factor Foxo1 represses T-bet-mediated effector functions and promotes memory CD8(+) T cell differentiation. Immunity 2012;36:374-387.
95. Sinclair LV, et al. Phosphatidylinositol-3-OH kinase and nutrient-sensing mTOR pathways control T lymphocyte trafficking. Nat Imunol 2008;9:513-521.
96. He S, et al. Characterization of the metabolic phenotype of rapamycin-treated CD8+ T cells with augmented ability to generate long-lasting memory cells. PLoS ONE 2011;6:e20107.
97. Gatza E, et al. Manipulating the bioenergetics of alloreactive T cells causes their selective apoptosis and arrests graft-versus-host disease. Sci Transl Med 2011;3:67ra68.
98. Shlomchik WD, et al. Prevention of graft versus host disease by inactivation of host antigen-presenting cells. Science 1999;285:412-415.
99. Zimmerman ZF, Levy RB. MiHA reactive CD4 and CD8 T-cells effect resistance to hematopoietic engraftment following reduced intensity conditioning. Am J Transplant 2006;6:2089-2098.
100. Korngold R. Lethal graft-versus-host disease in mice directed to multiple minor histocompatibility antigens: features of CD8+ and CD4+ T cell responses. Bone Marrow Transplant 1992;9:355-364.
101. Blazar BR, Taylor PA, Sehgal SN, Vallera DA. Rapamycin, a potent inhibitor of T-cell function, prevents graft rejection in murine recipients of allogeneic T-cell-depleted donor marrow. Blood 1994;83:600-609.
102. Blazar BR, Taylor PA, Panoskaltsis-Mortari A, Vallera DA. Rapamycin inhibits the generation of graft-versus-host disease- and graft-versus-leukemia-causing T cells by interfering with the production of Th1 or Th1 cytotoxic cytokines. J Immunol 1998;160:5355-5365.
103. Fowler DH. Shared biology of GVHD and GVT effects: potential methods of separation. Crit Rev Oncol Hematol 2006;57:225-244.
104. Shin HJ, Baker J, Leveson-Gower DB, Smith AT, Sega EI, Negrin RS. Rapamycin and IL-2 reduce lethal acute graft-versus-host disease associated with increased expansion of donor type CD4+CD25+Foxp3+ regulatory T cells. Blood 2011;118:2342-2350.
105. Zeiser R, et al. Differential impact of mammalian target of rapamycin inhibition on CD4+CD25+Foxp3+ regulatory T cells compared with conventional CD4+ T cells. Blood 2008;111:453-462.
106. Robb RJ, et al. Identification and expansion of highly suppressive CD8(+)FoxP3(+) regulatory T cells after experimental allogeneic bone marrow transplantation. Blood 2012;119:5898-5908.
107. Wang Y, et al. Regulatory T cells require mammalian target of rapamycin signaling to maintain both homeostasis and alloantigen-driven proliferation in lymphocyte-replete mice. J Immunol 2011;186:2809-2818.
108. Reichardt W, et al. Impact of mammalian target of rapamycin inhibition on lymphoid homing and tolerogenic function of nanoparticle-labeled dendritic cells following allogeneic hematopoietic cell transplantation. J Immunol 2008;181:4770-4779.
109. Jung U, et al. Ex vivo rapamycin generates Th1/Tc1 or Th2/Tc2 Effector T cells with enhanced in vivo function and differential sensitivity to post-transplant rapamycin therapy. Biol Blood Marrow Transplant 2006;12:905-918.
110. Gattinoni L, et al. Acquisition of full effector function in vitro paradoxically impairs the in vivo antitumor efficacy of adoptively transferred CD8+ T cells. J Clin Invest 2005;115:1616-1626.
111. Gattinoni L, et al. Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells. Nat Med 2009;15:808-813.
112. Huang J, et al. Pivotal role for glycogen synthase kinase-3 in hematopoietic stem cell homeostasis in mice. J Clin Invest 2009;119:3519-3529.
113. Gattinoni L, Klebanoff CA, Restifo NP. Pharmacologic induction of CD8+ T cell memory: better living through chemistry. Sci Transl Med 2009;1:11ps12.
114. Berger C, Jensen MC, Lansdorp PM, Gough M, Elliott C, Riddell SR. 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.
115. Chen BJ, Cui X, Sempowski GD, Liu C, Chao NJ. Transfer of allogeneic CD62L- memory T cells without graft-versus-host disease. Blood 2004;103:1534-1541.
116. Zheng H, et al. Effector memory CD4+ T cells mediate graft-versus-leukemia without inducing graft-versus-host disease. Blood 2008;111:2476-2484.
117. Zheng H, Matte-Martone C, Jain D, McNiff J, Shlomchik WD. Central memory CD8+ T cells induce graft-versus-host disease and mediate graft-versus-leukemia. J Immunol 2009;182:5938-5948.
118. Taylor PA, et al. L-Selectin(hi) but not the L-selectin(lo) CD4+25+ T-regulatory cells are potent inhibitors of GVHD and BM graft rejection. Blood 2004;104:3804-3812.
119. Carlson MJ, et al. L-selectin is dispensable for T regulatory cell function postallogeneic bone marrow transplantation. Am J Transplant 2010;10:2596-2603.
120. Foley JE, et al. Ex vivo rapamycin generates donor Th2 cells that potently inhibit graft-versus-host disease and graft-versus-tumor effects via an IL-4-dependent mechanism. J Immunol 2005;175:5732-5743.
121. Foley JE, Mariotti J, Ryan K, Eckhaus M, Fowler DH. Th2 cell therapy of established acute graft-versus-host disease requires IL-4 and IL-10 and is abrogated by IL-2 or host-type antigen-presenting cells. Biol Blood Marrow Transplant 2008;14:959-972.
122. Martin PJ, Akatsuka Y, Hahne M, Sale G. Involvement of donor T-cell cytotoxic effector mechanisms in preventing allogeneic marrow graft rejection. Blood 1998;92:2177-2181.
123. Mariotti J, et al. Graft rejection as a Th1-type process amenable to regulation by donor Th2-type cells through an interleukin-4/STAT6 pathway. Blood 2008;112:4765-4775.
124. Amarnath S, et al. Host-based Th2 cell therapy for prolongation of cardiac allograft viability. PLoS ONE 2011;6:e18885.
125. Mariotti J, et al. Ex vivo rapamycin generates apoptosis-resistant donor Th2 cells that persist in vivo and prevent hemopoietic stem cell graft rejection. J Immunol 2008;180:89-105.
126. Amarnath S, et al. Rapamycin generates anti-apoptotic human Th1/Tc1 cells via autophagy for induction of xenogeneic GVHD. Autophagy 2010;6:523-541.
127. Amarnath S, Fowler DH. Harnessing autophagy for adoptive T-cell therapy. Immunotherapy 2012;4:1-4.
128. Tahvanainen J, et al. Proviral integration site for Moloney murine leukemia virus (PIM) kinases promote human T helper 1 cell differentiation. J Biol Chem 2013;288:3048-3058.
129. Fowler DH, et al. Phase I clinical trial of costimulated, IL-4 polarized donor CD4+ T cells as augmentation of allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 2006;12:1150-1160.
130. Floisand Y, et al. Ultra-short course sirolimus contributes to effective GVHD prophylaxis after reduced-intensity allogeneic hematopoietic cell transplantation. Bone Marrow Transplant 2012;47:1552-1557.
131. Cutler C, et al. Sirolimus and tacrolimus without methotrexate as graft-versus-host disease prophylaxis after matched related donor peripheral blood stem cell transplantation. Biol Blood Marrow Transplant 2004;10:328-336.
132. Armand P, et al. Improved survival in lymphoma patients receiving sirolimus for graft-versus-host disease prophylaxis after allogeneic hematopoietic stem-cell transplantation with reduced-intensity conditioning. J Clin Oncol 2008;26:5767-5774.
133. Fowler DH, et al. Phase 2 clinical trial of rapamycin-resistant donor CD4+ Th2/Th1 (T-Rapa) cells after low-intensity allogeneic hematopoietic cell transplantation. Blood 2013;121:2864-2874.
134. Dudley ME, et al. CD8+ enriched "young" tumor infiltrating lymphocytes can mediate regression of metastatic melanoma. Clin Cancer Res 2010;16:6122-6131.
135. Castiello L, et al. Differential gene expression profile of first-generation and second-generation rapamycin-resistant allogeneic T cells. Cytotherapy 2013;15:598-609.
136. Matsui W, Borrello I, Mitsiades C. Autologous stem cell transplantation and multiple myeloma cancer stem cells. Biol Blood Marrow Transplant 2012;18:S27-S32.
137. Rapoport AP, et al. Restoration of immunity in lymphopenic individuals with cancer by vaccination and adoptive T-cell transfer. Nat Med 2005;11:1230-1237.
138. Rapoport AP, et al. Rapid immune recovery and graft-versus-host disease-like engraftment syndrome following adoptive transfer of Costimulated autologous T cells. Clin Cancer Res 2009;15:4499-4507.
139. Mariotti J, et al. The pentostatin plus cyclophosphamide nonmyeloablative regimen induces durable host T cell functional deficits and prevents murine marrow allograft rejection. Biol Blood Marrow Transplant 2011;17:620-631.
140. Mossoba ME, et al. Pentostatin plus cyclophosphamide safely and effectively prevents immunotoxin immunogenicity in murine hosts. Clin Cancer Res 2011;17:3697-3705.
141. Hsieh MM, et al. Allogeneic hematopoietic stem-cell transplantation for sickle cell disease. N Engl J Med 2009;361:2309-2317.
142. Felizardo TC, et al. Harnessing autophagy for cell fate control gene therapy. Autophagy 2013;9:1069-1079.
143. Sato T, Neschadim A, Konrad M, Fowler DH, Lavie A, Medin JA. Engineered human tmpk/AZT as a novel enzyme/prodrug axis for suicide gene therapy. Mol Ther 2007;15:962-970.
144. Ciceri F, et al. Infusion of suicide-gene-engineered donor lymphocytes after family haploidentical haemopoietic stem-cell transplantation for leukaemia (the TK007 trial): a non-randomised phase I-II study. Lancet Oncol 2009;10:489-500.
145. Di Stasi A, et al. Inducible apoptosis as a safety switch for adoptive cell therapy. N Engl J Med 2011;365:1673-1683.
146. Luznik L, et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant 2008;14:641-650.
147. Amarnath S, et al. The PDL1-PD1 axis converts human TH1 cells into regulatory T cells. Sci Transl Med 2011;3:111ra120.