Chimeric antigen receptor engineering: A right step in the evolution of adoptive cellular immunotherapy

International Reviews of Immunology

Volumn 34, Issue 2, 2015, Pages 154-187

  Figueroa, Jose A ^a,b   Reidy, Adair ^a,b   Mirandola, Leonardo ^a,b,c   Trotter, Kayley ^a,b   Suvorava, Natallia ^a   Figueroa, Alejandro ^a,b   Konala, Venu ^a   Aulakh, Amardeep ^a   Littlefield, Lauren ^a,b   Grizzi, Fabio ^f   Rahman, Rakhshanda Layeequr ^d   R Jenkins, Marjorie ^c   Musgrove, Breeanna ^a,b   Radhi, Saba ^a   D'Cunha, Nicholas ^a   D'Cunha, Luke N ^a   Hermonat, Paul L ^e   Cobos, Everardo ^a,b   Chiriva Internati, Maurizio ^a,b,c,d  

^a TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER SCHOOL OF MEDICINE   (United States)

^b Kiromic Inc   (United States)

^c TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER   (United States)

^d TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER   (United States)

^e UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES   (United States)

^f HUMANITAS CLINICAL AND RESEARCH CENTER   (Italy)

Author keywords

AAV: adeno associated virus; ACI: adoptive cellular immunotherapy; Ad: adenovirus; AKAP4: A kinase anchoring protein 4; ALL: acute lymphoblastic leukemia; AlloSCT: allogeneic stem cell transplant; AML: acute myeloid leukemia; ASP: AKAP associated sperm protein; CAIX: carbonic anhydrase IX; CAR: chimeric antigen receptor; CAReTC: chimeric antigen receptor engineered T cell; CEA: carcinoembryonic antigen; CLL: chronic lymphocytic leukemia; CTA: cancer testis antigen; CTL: cytotoxic T lymphocyte; DC: dendritic cell; EBV: Epstein Bar virus; ERK: extracellular signal regulated kinase; FAP: fibroblast activation protein; FITC: fluorescein isothiocyanate; GVHD: graft vs. host disease; HAMA: human anti mouse antibodies; HLA: human leukocyte antigen; HSCT: hematopoietic stem cell transplant; HSV: herpes simplex virus; HvG: host versus graft; IL 1, IL 2: interleukin 1, interleukin 2; ITR: inverted terminal repeat; JNK: c Jun N terminal kinase; LAK: lymphokine activated killer cell; Ly CM: lymphocyte conditioned medium; MHC: major histocompatibility complex; NF B: nuclear factor kappa light chain enhancer of activated B cells; NFAT: nuclear factor of activated T cell; NHL: Non Hodgkin's lymphoma; NK: natural killer; NKG2D: natural killer receptor G2D; PD 1: programmed death 1; PKA: protein A kinase; RAAV: recombinant AAV; ScFv: single chain variable fragment; SIRS: systemic inflammatory response syndrome; SP17: sperm protein 17; TAA: tumor associating antigen; TCM: central memory T cell; TCR: T cell receptors; TE: effector T cell; TEM: effector memory T cell; TH: helper T cell; TIL: tumor infiltrating lymphocyte; TNF: tumor necrosis factor; TRAF: TNF receptor associated factor; Treg: regulatory T cell; TRUCK: T cells redirected for universal cytokine killing; TSCM: stem cell memory T cell

Indexed keywords

CHIMERIC ANTIGEN RECEPTOR; LENTIVIRUS VECTOR; MESSENGER RNA; PARVOVIRUS VECTOR; PLASMID DNA; RETROVIRUS VECTOR; HYBRID PROTEIN; LYMPHOCYTE ANTIGEN RECEPTOR;

ADOPTIVE CELLULAR IMMUNOTHERAPY; ADOPTIVE IMMUNOTHERAPY; GENE TRANSFER; GENETIC TRANSDUCTION; HEMATOLOGIC MALIGNANCY; HUMAN; IN VITRO STUDY; NONHUMAN; PRIORITY JOURNAL; PROTEIN ENGINEERING; PROTEIN STRUCTURE; REVIEW; SOLID TUMOR; T LYMPHOCYTE; T LYMPHOCYTE SUBPOPULATION; TRANSPOSON; ANIMAL; GENETIC ENGINEERING; GENETICS; IMMUNOLOGY; METABOLISM; NEOPLASMS; PHYSIOLOGY; TRANSPLANTATION;

ANIMALS; GENETIC ENGINEERING; HUMANS; IMMUNOTHERAPY, ADOPTIVE; NEOPLASMS; RECEPTORS, ANTIGEN, T-CELL; RECOMBINANT FUSION PROTEINS; T-LYMPHOCYTES;

EID: 84928565398     PISSN: 08830185     EISSN: 15635244     Source Type: Journal    
DOI: 10.3109/08830185.2015.1018419     Document Type: Review

References (201)

1. Mitchison NA. Studies on the immunological response to foreign tumor transplants in the mouse. I. The role of lymph node cells in conferring immunity by adoptive transfer. J Exp Med 1955;102:157-177.
2. Mathe G, Amiel JL, Schwarzenberg L, et al. Adoptive immunotherapy of acute leukemia: experimental and clinical results. Cancer Res 1965;25:1525-1531.
3. Weiden PL, Flournoy N, ThomasED, et al.Antileukemic effect of graft-versus-host disease inhuman recipients of allogeneic-marrow grafts. N Engl JMed 1979;300:1068-1073.
4. Morgan DA, Ruscetti FW, Gallo R. Selective in vitro growth of T lymphocytes from normal human bonemarrows. Science 1976;193(4257):1007-1008.
5. Smith KA, Gilbride KJ, FavataMF. Lymphocyte activating factor promotes T-cell growth factor production by clonedmurine lymphoma cells. Nature 1980;287:853-855.
6. Smith KA, Lachman LB, Oppenheim JJ, Favata MF.The functional relationship of the interleukins. ExpMed 1980;151(6):1551-1556.
7. Rosenberg SA, Grimm EA, McGrogan M, et al. Biological activity of recombinant human interleukin-2 produced in Escherichia coli. Science 1984;223(4643):1412-1414.
8. LotzeMT, Matory YL, Ettinghausen SE, et al. In vivo administration of purified human interleukin 2. II.Half life, immunologic effects, and expansion of peripheral lymphoid cells in vivowith recombinant IL 2. J Immunol 1985;135(4):2865-2875.
9. Rosenberg SA, Lotze MT, Muul LM, et al. Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl JMed 1985;313(23):1485-1492.
10. Silberner J.Therapeutic monoclonal antibody okayed. Science News 1986:407-407.
11. Rosenberg SA, Spiess P, Lafreniere R. A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes. Science 1986;233(4770):1318-1321.
12. Dudley ME, Wunderlich JR, Yang JC, et al. Adoptive cell transfer therapy following nonmyeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol 2005;23(10):2346-2357.
13. Rosenberg SA. Cell transfer immunotherapy for metastatic solid cancer-what clinicians need to know. Nat Rev Clin Oncol 2011;8:577-585.
14. Yee C. Adoptive T cell therapy: addressing challenges in cancer immunotherapy. J Translational Med 2005;3(1):17.
15. Gajewski TF, Meng Y, Harlin H. Immune suppression in the tumor microenvironment. J Immunother 2006;29(3):233-240.
16. Clay TM, Custer MC, Sachs J, et al. Efficient transfer of a tumor antigen-reactive TCR to human peripheral blood lymphocytes confers anti-tumor reactivity. J Immunol 1999;163(1):507-513.
17. Cohen CJ, Zhao Y, Zheng Z, et al. Enhanced antitumor activity of murine-human hybrid T-cell receptor (TCR) in human lymphocytes is associated with improved pairing and TCR/CD3 stability. Cancer Res 2006;66(17):8878-8886.
18. Zhao Y, Zheng Z, Robbins PF, et al. Primary human lymphocytes transduced with NY-ESO-1 antigen-specific TCR genes recognize and kill diverse human tumor cell lines. J Immunol 2005;174:4415-4423.
19. Cohen CJ, Zheng Z, Bray R, et al. Recognition of fresh human tumor by human peripheral blood lymphocytes transduced with a bicistronic retroviral vector encoding amurine anti-p53 TCR. J Immunol 2005;175:5799-5808.
20. Morgan RA, DudleyME, Wunderlich JR, et al. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 2006;314(5796):126-129.
21. Johnson LA, Morgan RA, Dudley ME, et al. Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen. Blood 2009;114(3):535-546.
22. Matsui K, Boniface JJ, Steffner P, et al. Kinetics of T-cell receptor binding to peptide/I-Ek complexes: correlation of the dissociation rate with T-cell responsiveness. Proc Natl Acad Sci 1994;91(26):12862-12866.
23. Mckeithan TW. Kinetic proofreading in T-cell receptor signal transduction. Proc Natl Acad Sci 1995;92(11):5042-5046.
24. Gross G, Waks, T, Eshhar Z. Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc Natl Acad Sci 1989;86(24):10024-10028.
25. Shirasu N, Kuroki M. Functional design of chimeric T-cell antigen receptors for adoptive immunotherapy of cancer: architecture and outcomes. Anticancer Res 2012;32:2377-2384.
26. Cheadle EJ, GornallH, Baldan V, et al.CAR T cells: driving the road fromthe laboratory to the clinic. Immunol Rev 2014;257:91-106.
27. Sadelian M, Brentjens R, Riviere I. The basic principle of chimeric antigen receptor design. Cancer Discov 2013;3:388-398.
28. Kahlon KS, Brown C, Cooper LJ, et al. Specific recognition and killing of glioblastoma multiforme by interleukin 13-zetakine redirected cytolytic T cells. Cancer Res 2004;64(24):9160-9166.
29. Guest RD, Hawkins RE, Kirillova N, et al.The role of extracellular spacer regions in the optimal design of chimeric immune receptors: evaluation of four different scFvs and antigens. J Immunother 2005;28(3):203-211.
30. Bridgeman JS, Hawkins RE, Bagley S, et al.The optimal antigen response of chimeric antigen receptors harboring the CD3 transmembrane domain is dependent upon incorporation of the receptor into the endogenous TCR/CD3 complex. J Immunol 2010;184(12):6938-6949.
31. Wang J, JensenM, LinY, et al. Optimizing adoptive polyclonalTcellimmunotherapy oflymphomas, using a chimeric T cell receptor possessing CD28 and CD137 costimulatory domains.Human Gene Ther 2007;18(8):712-725.
32. Jensen M, Riddell S. Design and implementation of adoptive therapy with chimeric antigen receptor-modified T cells. Immunol Rev 2014;257:127-144.
33. Eshhar Z, Waks T, GrossG, SchindlerDG. Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the gamma or zeta subunits of the immunoglobulin and T-cell receptors. Proc Natl Acad Sci 1993;90:720-724.
34. Brocker T, and Karjalainen K. Signals through T cell receptor-zeta chain alone are insufficient to prime resting T lymphocytes. J Exp Med 1995;181(5):1653-1659.
35. Mueller DL.Mechanismsmaintaining peripheral tolerance. Nature Immunol 2010;11(1):21-27.
36. Heuser C, Hombach A, Lsch C, Manista K, & Abken H. T-cell activation by recombinant immunoreceptors: impact of the intracellular signallingdomain on the stability of receptor expression and antigen-specific activation of grafted T cells. GeneTher 2003;10(17):1408-1419.
37. Brentjens RJ, Latouche JB, Santos E, et al. Eradication of systemic B-cell tumors by genetically targeted human T lymphocytes co-stimulated by CD80 and interleukin-15. Nature Med 2003;9(3):279-286.
38. Kowolik CM, Topp MS, Gonzalez S, et al. CD28 costimulation provided through a CD19-specific chimeric antigen receptor enhances in vivo persistence and antitumor efficacy of adoptively transferred T cells. Cancer Res 2006;66(22):10995-11004.
39. Croft M.The role of TNF superfamily members in T-cell function and diseases. Nat Rev Immunol 2009;9(4):271-285.
40. Gramaglia I, Jember A, Pippig SD, et al.The OX40 costimulatory receptor determines the development of CD4memory by regulating primary clonal expansion. J Immunol 2000;165(6):3043-3050.
41. Milone MC, Fish JD, Carpenito C, et al. Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased anti-leukemic efficacy in vivo. Mol Ther 2009;17(8):1453-1464.
42. Finney HM, Akbar AN, Lawson ADG. Activation of resting human primary T cells with chimeric receptors: costimulation fromCD28, inducible costimulator, CD134, and CD137 in serieswith signals from the TCR zeta chain. J Immunol 2004;172:104-113.
43. Zhao Y, Wang QJ, Yang S, et al. A herceptin-based chimeric antigen receptor with modified signaling domains leads to enhanced survival of transduced T lymphocytes and antitumor activity. J Immunol 2009;183(9):5563-5574.
44. Zhong XS, Matsushita M, Plotkin J, et al. Chimeric antigen receptors combining 4-1BB and CD28 signaling domains augment PI3kinase/AKT/Bcl-XL activation and CD8+ T cell-mediated tumor eradication.MolTher 2010;18(2):413-420.
45. Pulè MA, Straathof KC, Dotti G, et al. A chimeric T cell antigen receptor that augments cytokine release and supports clonal expansion of primary human T cells. Mol Ther 2005;12(5):933-941.
46. Hombach AA, Heiders J, Foppe M, et al. OX40 costimulation by a chimeric antigen receptor abrogates CD28 and IL-2 induced IL-10 secretion by redirected CD4 (+) T cells. Oncoimmunology 2012;1(4):458-466.
47. Kawabata Y, Hirokawa M, Kitabayashi A, et al. Defective apoptotic signal transduction pathway downstream of caspase-3 in human B-lymphoma cells: a novel mechanism of nuclear apoptosis resistance. Blood 1999;94(10):3523-3530.
48. Croci DO, Fluck MFZ, Rico MJ, et al. Dynamic cross-talk between tumor and immune cells in orchestrating the immunosuppressive network at the tumor microenvironment. Cancer Immunol Immunoth 2007;56(11):1687-1700.
49. Wagner HJ, Bollard CM, Vigouroux S, et al. A strategy for treatment of Epstein-Barr virus-positive Hodgkin's disease by targeting interleukin 12 to the tumor environment using tumor antigenspecific T cells. Cancer Gene therapy 2004;11(2):81-91.
50. Zhang L, Kerkar SP, Yu Z, et al. Improving adoptive T cell therapy by targeting and controlling IL-12 expression to the tumor environment.Mol Ther 2011;19(4):751-759.
51. Fan H, Walters CS, Dunston GM, Tackey R. IL-12 plays a significant role in the apoptosis of human T cells in the absence of antigenic stimulation. Cytokine 2002;19(3):126-137.
52. Chmielewski M, Kopecky C, Hombach AA, Abken H. IL-12 release by engineered T cells expressing chimeric antigen receptors can effectively muster an antigen-independent macrophage response on tumor cells that have shut down tumor antigen expression.CancerRes 2011;71(17):5697-5706.
53. Kerkar SP, Goldszmid RS, Muranski P, et al. IL-12 triggers a programmatic change in dysfunctional myeloid-derived cells withinmouse tumors. J Clin Invest 2011;121(12):4746.
54. Hunter CA. New IL-12-family members: IL-23 and IL-27, cytokines with divergent functions. Nat Rev Immunol 2005;5(7):521-531.
55. Ju DW, Tao Q, Lou G, et al. Interleukin 18 transfection enhances antitumor immunity induced by dendritic cell-tumor cell conjugates. Cancer Res 2001;61(9):3735-3740.
56. Wagner HJ, Sili U, Gahn B, et al. Expansion of EBV latentmembrane protein 2a specific cytotoxic T cells for the adoptive immunotherapy ofEBVlatency type 2malignancies: influence of recombinant IL12 and IL15. Cytotherapy 2003;5(3):231-240.
57. Cheadle EJ, Sheard V, Hombach AA, et al. Chimeric antigen receptors for T-cell based therapy. In Antibody Engineering (pp. 645-666). Humana Press. 2012.
58. Robbins PF, Lu YC, El-Gamil M, et al.Mining exomic sequencing data to identifymutated antigens recognized by adoptively transferred tumor-reactive T cells. NatMed 2013;19(6):747-752.
59. Rosenberg SA. Finding suitable targets is the major obstacle to cancer gene therapy. Cancer Gene Ther 2014;21:45-47.
60. Cooper LJ, Al-Kadhimi Z, DiGiusto D, et al. Development and application of CD19-specific T cells for adoptive immunotherapy of B cellmalignancies. Blood CellsMol Dis 2004;33:83-89.
61. Gross G, Waks T, Eshhar Z. Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc Natl Acad Sci 1989;86(24):10024-10028.
62. Fitzer-Attas CJ, Eshhar Z. Tyrosine kinase chimeras for antigen-selective T-body therapy. Adv Drug Del Rev 1998;31(1):171-182.
63. Kay MA, Glorioso JC, Naldini L. Viral vectors for gene therapy: the art of turning infectious agents into vehicles of therapeutics. NatMed 2001;7(1):33-40.
64. Miller AD, Miller DG, Garcia JV, Lynch CM. Use of retroviral vectors for gene transfer and expression. Methods Enzymol 1992;217:581-599.
65. Suerth JD, Schambach A, Baum C. Genetic modification of lymphocytes by retrovirus-based vectors. Curr Opin Immunol 2012;24(5):598-608.
66. Engels B, Cam H, Schler T, et al. Retroviral vectors for high-level transgene expression in T lymphocytes. Hum Gene Ther 2003;14(12):1155-1168.
67. Zufferey R, Donello JE, Trono D, Hope TJ. Woodchuck hepatitis virus posttranscriptional regulatory element enhances expression of transgenes delivered by retroviral vectors. J Virol 1999;73(4):2886-2892.
68. Lamers CH, Willemsen R, van Elzakker P, et al. Immune responses to transgene and retroviral vector in patients treated with ex vivo-engineered T cells. Blood 2011;117(1):72-82.
69. Howe SJ, Mansour MR, Schwarzwaelder K, et al. Insertionalmutagenesis combined with acquired somaticmutations causes leukemogenesis following gene therapy of SCID-X1 patients. JClin Invest 2008;118(9):3143.
70. Lewinski MK, Bushman FD. Retroviral DNA integration-mechanism and consequences. Adv Genet 2005;55:147-181.
71. Kaufmann KB, Bning H, Galy A, et al. Gene therapy on the move. EMBO Mol Med 2013;5(11):1642-1661.
72. Mtrai J, Chuah MK, VandenDriessche T. Recent advances in lentiviral vector development and applications.Mol Ther 2010;18(3):477-490.
73. Zennou V, Petit C, Guetard D, et al. HIV-1 genome nuclear import is mediated by a central DNA flap. Cell 2000;101(2):173-185.
74. Cronin J, Zhang XY, Reiser J. Altering the tropism of lentiviral vectors through pseudotyping. Curr Gene Ther 2005;5(4):387.
75. Lewinski MK, Yamashita M, EmermanM, et al. RetroviralDNA integration: viral and cellular determinants of target-site selection. PLoS Pathogens 2006;2(6):e60.
76. Ciuffi A. Mechanisms governing lentivirus integration site selection. Curr Gene Ther 2008;8(6):419-429.
77. Pistello M, Vannucci L, Ravani A, et al. Streamlined design of a self-inactivating feline immunodeficiency virus vector for transducing ex vivo dendritic cells and T lymphocytes. Genet VaccinesTher 2007;5(1):8.
78. Vannucci L, Lai M, Chiuppesi F, et al. Viral vectors: a look back and ahead on gene transfer technology. NewMicrobiol 2013;36(1):1-22.
79. ChoiVW, McCartyDM, SamulskiRJ.AAVhybrid serotypes: improved vectors for gene delivery.Curr Gene Ther 2005;5(3):299.
80. Rivera VM, Gao GP, Grant RL, et al. Long-termpharmacologically regulated expression of erythropoietin in primates following AAV-mediated gene transfer. Blood 2005;105:1424-1430.
81. Buie LK, RasmussenCA, Porterfield EC, et al. Self-complementaryAAVvirus (scAAV) safe and longterm gene transfer in the trabecular meshwork of living rats and monkeys. Invest Ophthalmol Vis Sci 2010;51(1):236-248.
82. Hicks MJ, Rosenberg JB, De BP, et al. AAV-directed persistent expression of a gene encoding anti-nicotine antibody for smoking cessation. Sci Transl Med 2012;4:140ra87. doi: 10.1126/scitranslmed. 3003611.
83. Huang J, Li X, Coelho-dos-Reis JG, et al. An AAV vector-mediated gene delivery approach facilitates reconstitution of functional human CD8+ T cells in mice. PloS One 2014;9(2):e88205.
84. Zhu H, Cao M, Mirandola L, et al. Comparison of efficacy of the disease-specific LOX1-and constitutive cytomegalovirus-promoters in expressing interleukin 10 through adeno-associated virus 2/8 delivery in atherosclerotic mice. PLoS ONE 2014;9(4):e94665. doi:10.1371/journal.pone. 0094665.
85. DeKelver RC, Choi VM, Moehle EA, et al. Functional genomics, proteomics, and regulatory DNA analysis in isogenic settings using zinc finger nuclease-driven transgenesis into a safe harbor locus in the human genome. Genome Res 2010;20(8):1133-1142.
86. Meyer M, Wagner E. Recent developments in the application of plasmid DNA-based vectors and small interfering RNA therapeutics for cancer. Hum Gene Ther 2006;17(11):1062-1076.
87. Fratantoni JC, Dzekunov S, Singh JC, Liu LN. A non-viral gene delivery system designed for clinical use. Cytotherapy 2003;5:208-210. [PubMed: 12850788]
88. Park JR, Digiusto DL, Slovak M, et al. Adoptive transfer of chimeric antigen receptor re-directed cytolytic T lymphocyte clones in patients with neuroblastoma. Mol Ther 2007;15:825-833.
89. Ivics Z, Izsvak Z. Transposons for gene therapy. Curr GeneTher 2006;6(5):593-607.
90. Nakazawa Y, Huye LE, Salsman VS, et al. PiggyBac-mediated cancer immunotherapy using EBV-specific cytotoxic T cells expressing HER2-specific chimeric antigen receptor. Mol Ther 2011;19(12):2133-2143.
91. Wilson MH, Coates CJ, George AL. PiggyBac transposon-mediated gene transfer in human cells. MolTher 2007;15(1):139-145.
92. Singh H, Manuri PR, Olivares S, et al. Redirecting specificity of T-cell populations for CD19 using the Sleeping Beauty system. Cancer research 2008;68(8):2961-2971.
93. Manuri PVR, Wilson MH, Maiti SN, et al. piggyBac transposon/transposase system to generate CD19-specific T cells for the treatment of B-lineage malignancies. Hum Gene Ther 2010;21(4):427-437.
94. Nakazawa Y, Huye LE, Salsman VS, et al. PiggyBac-mediated cancer immunotherapy using EBV-specific cytotoxic T cells expressing HER2-specific chimeric antigen receptor. Mol Ther 2011;19(12):2133-2143.
95. Tavernier G, Andries O, Demeester J, et al. mRNA as gene therapeutic: how to control protein expression. J Control Release 2011;150(3):238-247.
96. Zhao Y, Zheng Z, Cohen CJ, et al.High-efficiency transfection of primary human and mouse T lymphocytes using RNA electroporation.MolTher 2006;13(1):151-159.
97. Zhao Y, Moon E, Carpenito C, et al. Multiple injections of electroporated autologous T cells expressing a chimeric antigen receptor mediate regression of human disseminated tumor. Cancer Res 2010;70(22):9053-9061.
98. Yoon SH, Lee JM, Cho HI, et al. Adoptive immunotherapy using human peripheral blood lymphocytes transferredwithRNAencodingHer-2/neu-specific chimeric immune receptor inovarian cancer xenograft model. Cancer Gene Ther 2009;16(6):489-497.
99. Barrett DM, Zhao Y, Liu X, et al. Treatment of advanced leukemia in mice with mRNA engineered T cells. Hum Gene Ther 2011;22(12):1575-1586.
100. Klebanoff CA, Gattinoni L, Restifo NP. Sorting through subsets: which T cell populations mediate highly effective adoptive immunotherapy J Immunother 2012;35(9):651-660.
101. 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(10):294-305.
102. Gattinoni L, Lugli E, ji Y, et al. A human memory T cell subset with stem cell-like properties. Nat Med 2011;17(10):1290-1297.
103. Muranski P, Boni A, Antony PA, et al. Tumor-specific Th17-polarized cells eradicate large established melanoma. Blood 2008;112(2):362-373.
104. Kondo M, Sakuta K, Noguchi A, et al. Zoledronate facilitates large-scale ex vivo expansion of functional T cells from cancer patients for use in adoptive immunotherapy. Cytotherapy 2008;10(8):842-856.
105. BrandesM, Willimann K, Moser B. Professional antigen-presentation function by human T cells. Science 2005;309(5732):264-268.
106. Todaro M, D'AsaroM, Caccamo N, et al. Efficient killing of human colon cancer stem cells by T lymphocytes. J Immunol 2009;182(11):7287-7296.
107. Kabelitz D, Wesch D, Pitters E, ZllerM. Characterization of tumor reactivity of human V 9V2 T cells in vitro and in SCID mice in vivo. J Immunol 2004;173(11):6767-6776.
108. Kobayashi H, Tanaka Y, Yagi J, et al. Safety profile and anti-tumor effects of adoptive immunotherapy using gamma-delta T cells against advanced renal cell carcinoma: a pilot study. Cancer Immunology Immunotherapy 2007;56(4):469-476.
109. Rischer M, Pscherer S, Duwe S, et al. Human T cells as mediators of chimaeric-receptor redirected anti-tumour immunity. Br J Haematol 2004;126(4):583-592.
110. Rogers PR, Matsumoto A, Naidenko O, et al. Expansion of human V24+ NKT cells by repeated stimulation with KRN7000. J ImmunolMethods 2004;285(2):197-214.
111. Ishikawa A, Motohashi S, Ishikawa E, et al. A phase I study of-galactosylceramide (KRN7000)-pulsed dendritic cells in patients with advanced and recurrent non-small cell lung cancer. Clin Cancer Res 2005;11(5):1910-1917.
112. Kunii N, Horiguchi S, Motohashi S, et al. Combination therapy of in vitro-expanded natural killer T cells and-galactosylceramide-pulsed antigen-presenting cells in patients with recurrent head and neck carcinoma. Cancer Sci 2009;100(6):1092-1098.
113. MullerT, UherekC, MakiG, et al.Expression of aCD20-specific chimeric antigen receptor enhances cytotoxic activity ofNKcells and overcomesNK-resistance of lymphoma and leukemia cells.Cancer Immunol Immunother 2008;57(3):411-423.
114. Riley JL, June CH, Blazar BR.Human T regulatory cell therapy: take a billion or so and callme in the morning. Immunity 2009;30(5):656-665.
115. Mekala DJ, Geiger TL. Immunotherapy of autoimmune encephalomyelitis with redirected CD4+ CD25+ T lymphocytes. Blood 2005;105(5):2090-2092.
116. Elinav E, Adam N, Waks T, Eshhar Z. Amelioration of colitis by genetically engineered murine regulatory T cells redirected by antigen-specific chimeric receptor. Gastroenterology 2009;136(5):1721-1731.
117. Stemberger C, Dreher S, Tschulik C, et al.Novel serial positive enrichment technology enables clinicalmultiparameter cell sorting. PloS One. 2012;7(4):e35798.
118. Mitsuyasu RT, Anton PA, Deeks SG, et al. Prolonged survival and tissue trafficking following adoptive transfer of CD4 gene-modified autologous CD4+ and CD8+ T cells in human immunodeficiency virus-infected subjects. Blood 2000;96(3):785-793.
119. Jensen MC, Cooper LJN, Wu AM, et al. Engineered CD20-specific primary human cytotoxic T lymphocytes for targeting B-cellmalignancy. Cytotherapy 2003;5(2):131-138.
120. Cooper LJ, Topp MS, Serrano LM, et al. T-cell clones can be rendered specific for CD19: toward the selective augmentation of the graft-versus-B-lineage leukemia effect. Blood 2003;101(4):1637-1644.
121. Till BG, Jensen MC, Wang J, et al. Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T cells. Blood 2008;112(6):2261-2271.
122. Carter RH, Fearon DT. CD19: lowering the threshold for antigen receptor stimulation of B lymphocytes. Science 1992;256(5053):105-107.
123. Scheuermann RH, Racila E. CD19 antigen in leukemia and lymphoma diagnosis and immunotherapy. Leuk Lymphoma 1995;18(5-6):385-397.
124. Jensen MC, Popplewell L, Cooper LJ, et al. Anti-transgene rejection responses contribute to attenuated persistence of adoptively transferred CD20/CD19-specific chimeric antigen receptor redirected T cells in humans. Biol BloodMarrow Transplant 2010;16(9):1245-1256.
125. Savoldo B, Ramos CA, Liu E, et al. CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. J Clin Invest 2011;121(5): 1822.
126. Kochenderfer JN, Dudley ME, Feldman SA, et al. B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigenreceptor-transduced T cells. Blood 2012;119(12):2709-2720.
127. Brentjens RJ, Rivière I, Park JH, et al. Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patientswith relapsed or chemotherapy refractory B-cell leukemias. Blood 2011;118(18):4817-4828.
128. Porter DL, Levine BL, Kalos M, et al. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl JMed 2011;365(8):725-733.
129. Kalos M, Levine BL, Porter DL, et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci TranslationalMed 2011;3(95):95ra73-95ra73.
130. Brentjens RJ, Davila ML, Riviere I, et al. CD19-targeted T cells rapidly induce molecular remissions in adultswith chemotherapy-refractory acute lymphoblastic leukemia. Sci TranslationalMed 2013;5(177):177ra38-177ra38.
131. Davila ML, Riviere I, Wang X, et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Translational Med 2014;6( 224):224ra25-224ra25.
132. Grupp SA, KalosM, Barrett D, et al. Chimeric antigen receptor-Modified T cells for acute lymphoid leukemia. N Engl JMed 2013;368(16):1509-1518.
133. RitchieDS, NeesonPJ, KhotA, et al.Persistence and efficacy of second generationCARTcell against the LeY antigen in acutemyeloid leukemia.Mol Ther 2013;21(11):2122-2129.
134. Cooper LJ, Al-Kadhimi Z, Serrano LM, et al. Enhanced antilymphoma efficacy of CD19-redirected influenza MP1-specific CTLs by cotransfer of T cells modified to present influenza MP1. Blood 2005;105(4):1622-1631.
135. Savoldo B, Rooney CM, Di Stasi A, et al. Epstein Barr virus-specific cytotoxic T lymphocytes expressing the anti-CD30 artificial chimeric T-cell receptor for immunotherapy of Hodgkin disease. Blood 2007;110(7):2620-2630.
136. Cruz CRY, Micklethwaite KP, Savoldo B, et al. Infusion of donor-derived CD19-redirected virusspecific T cells for B-cell malignancies relapsed after allogeneic stem cell transplant: a phase 1 study. Blood 2013;122(17):2965-2973.
137. Kochenderfer JN, Dudley ME, Carpenter RO, et al. Donor-derived CD19-targeted T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation. Blood 2013;122(25):4129-4139.
138. Lamers CH, Sleijfer S, Vulto AG, et al. Treatment of metastatic renal cell carcinomawith autologous T-lymphocytes genetically retargeted against carbonic anhydrase IX: first clinical experience. J Clin Oncol 2006;24(13):e20-e22.
139. Kershaw MH, Westwood JA, Parker LL, et al. A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer. Clin Cancer Res 2006;12(20):6106-6115.
140. Park JR, DiGiusto DL, Slovak M, et al. Adoptive transfer of chimeric antigen receptor re-directed cytolytic T lymphocyte clones in patients with neuroblastoma.MolTher 2007;15(4):825-833.
141. Pule MA, Savoldo B, Myers GD, et al. Virus-specific T cells engineered to coexpress tumorspecific receptors: persistence and antitumor activity in individuals with neuroblastoma. NatMed 2008;14(11):1264-1270.
142. Louis CU, Savoldo B, Dotti G, et al. Antitumor activity and long-term fate of chimeric antigen receptor-positive T cells in patients with neuroblastoma. Blood 2011;118(23):6050-6056.
143. Morgan RA, Yang JC, Kitano M, et al. Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. MolTher 2010;18(4):843-851.
144. AhmedN, Brawley V, DioufO, et al.Tcells redirected againstHER2for the adoptive immunotherapy for HER2-positive osteosarcoma. Cancer Res 2012;72(8 Suppl): 3500.
145. Maus MV, Haas AR, Beatty GL, et al. T cells expressing chimeric antigen receptors can cause anaphylaxis in humans. Cancer Immunol Res 2013;1(1):26-31.
146. Hacein-Bey-Abina S, von Kalle C, Schmidt M, et al. A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. N Engl J Med 2003;348(3): 255-256.
147. Hacein-Bey-Abina S, Garrigue A, Wang GP, et al. Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. J Clin Invest 2008;118(9):3132-3142.
148. Wang GP, Levine BL, Binder GK, et al. Analysis of lentiviral vector integration in HIV+ study subjects receiving autologous infusions of gene modified CD4+ T cells.Mol Ther 2009;17(5):844-850.
149. Scholler J, Brady TL, Binder-Scholl G, et al. Decade-long safety and function of retroviral-modified chimeric antigen receptor T cells. Sci TranslationalMed 2012;4(132):132ra53-132ra53.
150. Maude SL, Barrett D, Teachey DT, Grupp SA.Managing cytokine release syndrome associated with novel T cell-engaging therapies. Cancer J 2014;20(2):119-122.
151. BarrettDM, TeacheyDT, Grupp SA. Toxicitymanagement for patients receiving novel T-cell engaging therapies. Curr Opin Pediatr 2014;26(1):43-49.
152. Whitehurst AW. Cause and consequence of cancer/testis antigen activation in cancer. Annu Rev Pharmacol Toxicol 2014;54:251-272.
153. Robbins PF, Morgan RA, Feldman SA, et al. Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J Clin Oncol 2011;29(7):917-924.
154. Morgan RA, Chinnasamy N, Abate-Daga D, et al. Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy. J Immunother 2013;36(2):133-151.
155. Chiriva-Internati M, Cobos E, Da Silva DM, Kast WM. Sperm fibrous sheath proteins: a potential new class of target antigens for use in human therapeutic cancer vaccines. CancerImmun 2008;8:8.
156. Lim SH, Wang Z, Chiriva-Internati M, Xue Y. Sperm protein 17 is a novel cancer-testis antigen in multiplemyeloma. Blood 2001;97(5):1508-1510.
157. Mirandola L, Cannon MJ, Cobos E, et al. Cancer testis antigens: novel biomarkers and targetable proteins for ovarian cancer. Int Rev Immunol 2011;30(2-3):127-137.
158. Chiriva-Internati M, Mirandola L, Yu Y, et al. Cancer testis antigen, ropporin, is a potential target formultiplemyeloma immunotherapy. J Immunother 2011;34(6):490-499.
159. Chiriva-InternatiM, Yu Y, Mirandola L, et al. Identification ofAKAP-4 as anewcancer/testis antigen for detection and immunotherapy of prostate cancer. Prostate 2012;72(1):2-23.
160. Chiriva-Internati M, Ferrari R, Yu Y, et al. AKAP-4: a novel cancer testis antigen for multiple myeloma. Br J Haematol 2008;140(4):465-468.
161. Ferrari R, Grizzi F, Fiore B, et al. Akap-associated spermprotein overexpression in ovarian cancer: 116. J InvestigMed 2007;55(1):S265-S266.
162. Wen Y, Richardson R, Widgren E, Orand M. Characterization of Sp17: a ubiquitous three domain protein that binds heparin. Biochem J 357(2001):25-31.
163. Saba R, Saadeh C, Wade R, et al. Selective expression of the Sp17/AKAP4/PTTG1 in NSCLC for detection and therapy. J Clin Oncol 2013;31:(suppl) e18527.
164. Chiriva-internati M, Wang Z, Salati E, et al. Successful generation of sperm protein 17 (Sp17)-specific cytotoxic T lymphocytes fromnormal donors: implication for tumour-specific adoptive immunotherapy following allogeneic stem cell transplantation for Sp17-positive multiple myeloma. Scand J Immunol 2002;56(4):429-433.
165. Grizzi F, Chiriva-InternatiM, Franceschini B, et al. Spermprotein 17 is expressed in human somatic ciliated epithelia. J Histochem Cytochem 2004;52(4):549-554.
166. RaymondW, Radhi S, Chiriva-InternatiM, et al. The impact of sex on ropporin expression inmultiplemyeloma patients. J Clin Oncol 2013;31:(suppl; e22052).
167. McConnachie G, Langeberg LK, Scott JD. AKAP signaling complexes: getting to the heart of the matter. TrendsMolMed 2006;12(7):317-323.
168. Tfelt-Hansen J, Kanuparthi D, ChattopadhyayN.The emerging role of pituitary tumor transforming gene in tumorigenesis. ClinMed Res 2006;4(2): 130-137.
169. Zhang X, Horwitz GA, Prezant TR, et al. Structure, expression, and function of human pituitary tumor-transforming gene (PTTG).Mol Endocrinol 1999;13(1): 156-166.
170. Yu R, Melmed S. Oncogene activation in pituitary tumors. Brain Pathol 2001;11(3): 328-341.
171. Alalawi R, Kim M, Mirandola L, et al. New antigens in non-small cell lung cancer detected both in serology and tissue. Chest JMeeting Abstracts 2011;140(4):938A-938A.
172. Chiriva-Internati M, Ferrari R, Prabhakar M, et al.Thepituitary tumor transforming gene 1 (PTTG-1): an immunological target formultiplemyeloma. J TranslMed 2008;6:15.
173. Hudecek M, Lupo-Stanghellini MT, Kosasih PL, et al. Receptor affinity and extracellular domain modifications affect tumor recognition by ROR1-specific chimeric antigen receptor T cells. Clin Cancer Res 2013;19(12):3153-3164.
174. Chmielewski M, Hombach A, Heuser C, et al. T cell activation by antibody-like immunoreceptors: increase in affinity of the single-chain fragment domain above threshold does not increase T cell activation against antigen-positive target cells but decreases selectivity. J Immunol 2004;173(12):7647-7653.
175. Giao PQ, Rosenberg SA. Adoptive cell transfer for patientswithmetastaticmelanoma: the potential and promise of cancer immunotherapy. Cancer Control 2013;20(4):289-297.
176. National Center for Biotechnology Information. U.S. National Library ofMedicine, Oct. 2013.Web. 18 Feb. 2014.
177. Gill S, KalosM. T cell-based gene therapy of cancer. Transl Res 2013;161(4):365-379.
178. Kong S, Sengupta S, Tyler B, et al. Suppression of human glioma xenograftswith second-generation IL13R-specific chimeric antigen receptor-modified T cells. Clin Cancer Res 2012;18(21):5949-5960.
179. Barber A, Zhang T, Sentman CL. Immunotherapy with chimeric NKG2D receptors leads to longtermtumor-free survival and development of host antitumor immunity inmurine ovarian cancer. J Immunol 2008;180(1):72-78.
180. Shaffer DR, Savoldo B, Yi Z, et al. T cells redirected against CD70 for the immunotherapy of CD70-positivemalignancies. Blood 2011;117(16):4304-4314.
181. Davies DM, Pereira AC, van der Stegen SJ. et al. Flexible targeting of diverse ErbB dimers that drive tumorigenesis using genetically targeted T cells. Hum Gene Ther 2011;22(10):A118-A118.
182. Huguenot Street, 3rd Fl, New Rochelle NY 10801 USA:Mary Ann Liebert Inc.
183. Kloss CC, Condomines M, Cartellieri M, et al. Combinatorial antigen recognition with balanced signaling promotes selective tumor eradication by engineered T cells. Nat Biotechnol 2013;31(1):71-75.
184. Urbanska K, Lanitis E, PoussinM, et al. A universal strategy for adoptive immunotherapy of cancer through use of a novel T-cell antigen receptor. Cancer Res 2012;72(7):1844-1852.
185. Tamada K, Geng D, Sakoda Y, et al. Redirecting gene-modified T cells toward various cancer types using tagged antibodies. Clin Cancer Res 2012;18(23):6436-6445.
186. Zhang Q, Li H, Yang J, et al. Strategies to improve the clinical performance of chimeric antigen receptor-modified T cells for cancer. Curr Gene Ther 2013;13(1):65-70.
187. Lombardo A, Genovese P, Beausejour CM, et al.Gene editing in human stem cells using zinc finger nucleases and integrase-defective lentiviral vector delivery.Nat Biotechnol 2007;25(11):1298-1306.
188. Trobridge GD, Miller DG, Jacobs MA, et al. Foamy virus vector integration sites in normal human cells. Proc Natl Acad Sci USA 2006;103(5):1498-1503.
189. Mori Y. Recent topics related to human herpesvirus 6 cell tropism. Cell Microbiol 2009;11(7):1001-1006.
190. Zhou J, Shen X, Huang J, et al. Telomere length of transferred lymphocytes correlates with in vivo persistence and tumor regression in melanoma patients receiving cell transfer therapy. J Immunol 2005;175(10):7046-7052.
191. Nelson BH. IL-2, regulatory T cells, and tolerance. J Immunol 2004;172(7):3983-3988.
192. Ma A, Koka R, Burkett P. Diverse functions of IL-2, IL-15, and IL-7 in lymphoid homeostasis. Annu Rev Immunol 2006;24:657-679.
193. AlmasbakH, Rian E, HoelHJ, et al. Transiently redirected T cells for adoptive transfer. Cytotherapy 2011;13(5):629-640.
194. Wrzesinski C, Paulos CM, Kaiser A, et al. Increased intensity lymphodepletion enhances tumor treatment efficacy of adoptively transferred tumor-specific T cells. J Immunother 2010;33(1):1-7.
195. Corti A, Ponzoni M. Tumor vascular targeting with tumor necrosis factor alpha and chemotherapeutic drugs. Ann N Y Acad Sci 2004;1028:104.
196. Gaj T, Gersbach CA, Barbas III, CF. ZFN, TALEN, and CRISPR/Cas-based methods for genome engineering. Trends Biotechnol 2013;31(7):397-405.
197. Budde LE, Berger C, Lin Y, et al. Combining a CD20 chimeric antigen receptor and an inducible caspase 9 suicide switch to improve the efficacy and safety of T cell adoptive immunotherapy for lymphoma. PloS One 2013;8(12):e82742.
198. Leen AM, Heslop HE, BrennerMK. Antiviral T-cell therapy. Immunol Rev 2014;258(1):12-29.
199. Gill S, Porter DL. CAR-modified anti-CD19 T cells for the treatment of B-cellmalignancies: rules of the road. Exp Opin Biol Therapy 2014;14(1):37-49.
200. Jensen MC, Riddell SR. Design and implementation of adoptive therapy with chimeric antigen receptor-modified T cells. Immunol Rev 2014;257(1):127-144
201. Fedorov VD, Themeli M, Sadelain M. PD-1-and CTLA-4-based inhibitory chimeric antigen receptors (iCARs) divert off-target immunotherapy responses. Sci Translational Med 2013;5(215):215ra172-215ra172.