Engineering Therapeutic T Cells: From Synthetic Biology to Clinical Trials

Annual Review of Pathology: Mechanisms of Disease

Volumn 12, Issue , 2017, Pages 305-330

  Esensten, Jonathan H ^a   Bluestone, Jeffrey A ^a   Lim, Wendell A ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

Cellular engineering; Cellular therapy; Immunotherapy; Synthetic biology; T cells

Indexed keywords

NUCLEASE; RNA;

ALLOTRANSPLANTATION; CELL ENGINEERING; CELL THERAPY; CELLULAR IMMUNITY; CLINICAL TRIAL (TOPIC); DRUG APPROVAL; FOOD AND DRUG ADMINISTRATION; GENE EXPRESSION; GENETIC ENGINEERING; GOOD MANUFACTURING PRACTICE; GOVERNMENT REGULATION; GRAFT VERSUS HOST REACTION; HUMAN; LYMPHOCYTE TRANSFER; NONHUMAN; PRIORITY JOURNAL; REVIEW; SYNTHETIC BIOLOGY; T LYMPHOCYTE; TRANSGENICS; TRANSPOSON; ANIMAL; AUTOIMMUNE DISEASES; BIOLOGICAL THERAPY; IMMUNOLOGY; NEOPLASMS;

ANIMALS; AUTOIMMUNE DISEASES; CELL- AND TISSUE-BASED THERAPY; CLINICAL TRIALS AS TOPIC; HUMANS; NEOPLASMS; SYNTHETIC BIOLOGY; T-LYMPHOCYTES;

EID: 85011278012     PISSN: 15534006     EISSN: 15534014     Source Type: Book Series    
DOI: 10.1146/annurev-pathol-052016-100304     Document Type: Review

References (148)

1. Barrett DM, Grupp SA, June CH. 2015. Chimeric antigen receptor-and TCR-modified T cells enter Main Street andWall Street. J. Immunol. 195:755-61
2. Depil S, Deconinck E, Milpied N, Sutton L, Witz F, et al. 2004. Donor lymphocyte infusion to treat relapse after allogeneic bonemarrow transplantation formyelodysplastic syndrome. Bone Marrow Transplant. 33:531-34
3. Kolb HJ, Schmid C, Barrett AJ, Schendel DJ. 2004. Graft-versus-leukemia reactions in allogeneic chimeras. Blood 103:767-76
4. Rosenberg SA, Packard BS, Aebersold PM, Solomon D, Topalian SL, et al. 1988. Use of tumorinfiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report. N. Engl. J. Med. 319:1676-80
5. Feldman SA, Assadipour Y, Kriley I, Goff SL, Rosenberg SA. 2015. Adoptive cell therapy-tumorinfiltrating lymphocytes, T-cell receptors, and chimeric antigen receptors. Semin. Oncol. 42:626-39
6. Yannelli JR, Hyatt C, McConnell S, Hines K, Jacknin L, et al. 1996. Growth of tumor-infiltrating lymphocytes from human solid cancers: summary of a 5-year experience. Int. J. Cancer 65:413-21
7. Morgan RA, Dudley ME, Wunderlich JR, Hughes MS, Yang JC, et al. 2006. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314:126-29
8. Johnson LA, Morgan RA, Dudley ME, Cassard L, Yang JC, et al. 2009. Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen. Blood 114:535-46
9. Robbins PF, Kassim SH, Tran TL, Crystal JS, Morgan RA, et al. 2015. A pilot trial using lymphocytes genetically engineered with an NY-ESO-1-reactive T-cell receptor: long-term follow-up and correlates with response. Clin. Cancer Res. 21:1019-27
10. Rapoport AP, Stadtmauer EA, Binder-Scholl GK, Goloubeva O, Vogl DT, et al. 2015. NY-ESO-1-specific TCR-engineered T cells mediate sustained antigen-specific antitumor effects in myeloma. Nat. Med. 21:914-21
11. Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, et al. 2013. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N. Engl. J. Med. 368:1509-18
12. Porter DL, Hwang WT, Frey NV, Lacey SF, Shaw PA, et al. 2015. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci. Transl. Med. 7:303ra139
13. Maude SL, Teachey DT, Porter DL, Grupp SA. 2015. CD19-targeted chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Blood 125:4017-23
14. Garfall AL, Maus MV, Hwang WT, Lacey SF, Mahnke YD, et al. 2015. Chimeric antigen receptor T cells against CD19 for multiple myeloma. N. Engl. J. Med. 373:1040-47
15. Lee DW, Kochenderfer JN, Stetler-Stevenson M, Cui YK, Delbrook C, et al. 2015. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet 385:517-28
16. Brentjens RJ, Davila ML, Riviere I, Park J, Wang X, et al. 2013. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci. Transl. Med. 5:177ra38
17. Srivastava S, Riddell SR. 2015. Engineering CAR-T cells: design concepts. Trends Immunol. 36:494-502
18. Maus MV, Fraietta JA, Levine BL, Kalos M, Zhao Y, June CH. 2014. Adoptive immunotherapy for cancer or viruses. Annu. Rev. Immunol. 32:189-225
19. Barrett DM, Singh N, Porter DL, Grupp SA, June CH. 2014. Chimeric antigen receptor therapy for cancer. Annu. Rev. Med. 65:333-47
20. Liu X, Jiang S, Fang C, Yang S, Olalere D, et al. 2015. Affinity-tuned ErbB2 or EGFR chimeric antigen receptor T cells exhibit an increased therapeutic index against tumors in mice. Cancer Res. 75:3596-607
21. Johnson LA, Scholler J, Ohkuri T, Kosaka A, Patel PR, et al. 2015. Rational development and characterization of humanized anti-EGFR variant III chimeric antigen receptor T cells for glioblastoma. Sci. Transl. Med. 7:275ra22
22. Hudecek M, Sommermeyer D, Kosasih PL, Silva-Benedict A, Liu L, et al. 2015. The nonsignaling extracellular spacer domain of chimeric antigen receptors is decisive for in vivo antitumor activity. Cancer Immunol. Res. 3:125-35
23. Kawalekar OU, O'Connor RS, Fraietta JA, Guo L, McGettigan SE, et al. 2016. Distinct signaling of coreceptors regulates specific metabolism pathways and impacts memory development in CAR T cells. Immunity 44:380-90
24. Scholler J, Brady TL, Binder-Scholl G, Hwang WT, Plesa G, et al. 2012. Decade-long safety and function of retroviral-modified chimeric antigen receptor T cells. Sci. Transl. Med. 4:132ra53
25. Brusko TM, Putnam AL, Bluestone JA. 2008. Human regulatory T cells: role in autoimmune disease and therapeutic opportunities. Immunol. Rev. 223:371-90
26. Bluestone JA, Buckner JH, FitchM, Gitelman SE, Gupta S, et al. 2015. Type 1 diabetes immunotherapy using polyclonal regulatory T cells. Sci. Transl. Med. 7:315ra189
27. Putnam AL, Safinia N,Medvec A, Laszkowska M, Wray M, et al. 2013. Clinical grade manufacturing of human alloantigen-reactive regulatory T cells for use in transplantation. Am. J. Transplant. 13:3010-20
28. Tang Q, Bluestone JA. 2013. Regulatory T-cell therapy in transplantation: moving to the clinic. Cold Spring Harb. Perspect. Med. 3:a015552
29. Bailey AM, Arcidiacono J, Benton KA, Taraporewala Z, Winitsky S. 2015. United States Food andDrug Administration regulation of gene and cell therapies. Adv. Exp. Med. Biol. 871:1-29
30. DowningNS, Aminawung JA, ShahND, KrumholzHM,Ross JS. 2014. Clinical trial evidence supporting FDA approval of novel therapeutic agents, 2005-2012. JAMA 311:368-77
31. Harvath L. 2009. A brief history of US FDA regulation of human cells and tissues. In Cellular Therapy: Principles, Methods, and Regulations, ed. EM Areman, K Loper, pp. 2-12. Bethesda, MD: AABB
32. Kennett S, Porter C, Bloom E, Wonnacott K. 2009. The FDA perspective on the manufacturing, production, and processing of regulated cellular therapies. In Cellular Therapy: Principles, Methods, and Regulations, ed. EM Areman, K Loper, pp. 18-25. Bethesda, MD: AABB
33. US Dep. Health Hum. Serv., Food Drug Adm. 2008. Guidance for Industry: CGMP for Phase 1 Investigational Drugs. Rockville, MD: FDA. http://www.fda.gov/downloads/drugs/ guidancecomplianceregulatoryinformation/guidances/ucm070273.pdf
34. Au P, Hursh DA, Lim A, Moos MCJr., Oh SS, et al. 2012. FDA oversight of cell therapy clinical trials. Sci. Transl. Med. 4:149fs31
35. Chambers RW, Foley HT, Schmidt PJ. 1969. Transmission of syphilis by fresh blood components. Transfusion 9:32-34
36. Orton S. 2001. Syphilis and blood donors: what we know, what we do not know, and what we need to know. Transfus. Med. Rev. 15:282-91
37. Gee AP. 1999. Product release assays. Cytotherapy 1:485-91
38. US Dep. Health Hum. Serv., Food Drug Adm. 2011. Guidance for Industry: Potency Tests for Cellular and Gene Therapy Products.Rockville,MD:FDA.http://www.fda.gov/downloads/BiologicsBloodVaccines/ GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/UCM243392. pdf
39. US Dep. Health Hum. Serv., Cent. Medicare and Medicaid Serv. 2011. Clinical Laboratory Improvement Amendments of 1988 (CLIA)-CLIA Applicability for Laboratory Testing Associated with Blood, Cells/Tissue, and Organs. Baltimore, MD: CMS. https://www.cms.gov/Medicare/Provider-Enrollment-and-Certification/SurveyCertificationGenInfo/Downloads/SCLetter11-08.pdf
40. Osborn MJ, Webber BR, Knipping F, Lonetree CL, Tennis N, et al. 2016. Evaluation of TCR gene editing achieved by TALENs, CRISPR/Cas9, and megaTAL nucleases. Mol. Ther. 24:570-81
41. GajT,Gersbach CA, Barbas CF. 2013. ZFN, TALEN, and CRISPR/Cas-based methods for genome engineering. Trends Biotechnol. 31:397-405
42. Kim H, Kim JS. 2014. A guide to genome engineering with programmable nucleases. Nat. Rev. Genet. 15:321-34
43. Osborn MJ, Tolar J. 2016. Cellular engineering and disease modeling with gene-editing nucleases. In Genome Editing: The Next Step in Gene Therapy, ed. T Cathomen, M Hirsch, M Porteus, pp. 223-58. New York: Springer
44. Yuan J, Wang J, Crain K, Fearns C, Kim KA, et al. 2012. Zinc-finger nuclease editing of human cxcr4 promotes HIV-1 CD4+ T cell resistance and enrichment. Mol. Ther. 20:849-59
45. Santiago Y, Chan E, Liu PQ, Orlando S, Zhang L, et al. 2008. Targeted gene knockout in mammalian cells by using engineered zinc-finger nucleases. PNAS 105:5809-14
46. Davis L, Maizels N. 2011. DNA nicks promote efficient and safe targeted gene correction. PLOS ONE 6:e23981
47. Schumann K, Lin S, Boyer E, Simeonov DR, Subramaniam M, et al. 2015. Generation of knock-in primary human T cells using Cas9 ribonucleoproteins. PNAS 112:10437-42
48. Provasi E, Genovese P, Lombardo A,Magnani Z, Liu PQ, et al. 2012. Editing T cell specificity towards leukemia by zinc finger nucleases and lentiviral gene transfer. Nat. Med. 18:807-15
49. Wang J, DeClercq JJ, Hayward SB, Li PW, Shivak DA, et al. 2016. Highly efficient homology-driven genome editing in human T cells by combining zinc-finger nuclease mRNA and AAV6 donor delivery. Nucleic Acids Res. 44:e30
50. Szczepek M, Brondani V, Buchel J, Serrano L, Segal DJ, Cathomen T. 2007. Structure-based redesign of the dimerization interface reduces the toxicity of zinc-finger nucleases. Nat. Biotechnol. 25:786-93
51. Cornu TI, Thibodeau-Beganny S, Guhl E, Alwin S, Eichtinger M, et al. 2008. DNA-binding specificity is a major determinant of the activity and toxicity of zinc-finger nucleases. Mol. Ther. 16:352-58
52. Ousterout DG, Gersbach CA. 2016. The development of TALE nucleases for biotechnology. Methods Mol. Biol. 1338:27-42
53. Moscou MJ, Bogdanove AJ. 2009. A simple cipher governs DNA recognition by TAL effectors. Science 326:1501
54. Boch J, Scholze H, Schornack S, Landgraf A, Hahn S, et al. 2009. Breaking the code of DNA binding specificity of TAL-type III effectors. Science 326:1509-12
55. Holkers M, Maggio I, Liu J, Janssen JM, Miselli F, et al. 2013. Differential integrity of TALE nuclease genes following adenoviral and lentiviral vector gene transfer into human cells. Nucleic Acids Res. 41:e63
56. Valton J, Guyot V, Marechal A, Filhol JM, Juillerat A, et al. 2015. A multidrug-resistant engineered CAR T cell for allogeneic combination immunotherapy. Mol. Ther. 23:1507-18
57. Berdien B, Mock U, Atanackovic D, Fehse B. 2014. TALEN-mediated editing of endogenous T-cell receptors facilitates efficient reprogramming of T lymphocytes by lentiviral gene transfer. Gene Ther. 21:539-48
58. Menger L, Gouble A, Marzolini MA, Pachnio A, Bergerhoff K, et al. 2015. TALEN-mediated genetic inactivation of the glucocorticoid receptor in cytomegalovirus-specific T cells. Blood 126:2781-89
59. Boissel S, Jarjour J, Astrakhan A, Adey A, Gouble A, et al. 2014. MegaTALs: a rare-cleaving nuclease architecture for therapeutic genome engineering. Nucleic Acids Res. 42:2591-601
60. Smith J, Grizot S, Arnould S, Duclert A, Epinat JC, et al. 2006. A combinatorial approach to create artificial homing endonucleases cleaving chosen sequences. Nucleic Acids Res. 34:e149
61. Fu Y, Foden JA, Khayter C, Maeder ML, Reyon D, et al. 2013. High-frequency off-target mutagenesis induced by CRISPR-Cas nucleases in human cells. Nat. Biotechnol. 31:822-26
62. Slaymaker IM, Gao L, Zetsche B, Scott DA, Yan WX, Zhang F. 2016. Rationally engineered Cas9 nucleases with improved specificity. Science 351:84-88
63. Hou P,Chen S,Wang S, Yu X,Chen Y, et al. 2015. Genome editing ofCXCR4 by CRISPR/cas9 confers cells resistant to HIV-1 infection. Sci. Rep. 5:15577
64. Kaminski R, Chen Y, Fischer T, Tedaldi E, Napoli A, et al. 2016. Elimination of HIV-1 genomes from human T-lymphoid cells by CRISPR/Cas9 gene editing. Sci. Rep. 6:22555
65. Suerth JD, Schambach A, Baum C. 2012. Genetic modification of lymphocytes by retrovirus-based vectors. Curr. Opin. Immunol. 24:598-608
66. Hacein-Abina S, Garrigue A,Wang GP, Soulier J, Lim A, et al. 2008. Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. J. Clin. Investig. 118:3132-42
67. Geng X, Doitsh G, Yang Z, Galloway NL, Greene WC. 2014. Efficient delivery of lentiviral vectors into resting human CD4 T cells. Gene Ther. 21:444-49
68. Frecha C, Levy C, Costa C, Negre D, Amirache F, et al. 2011. Measles virus glycoprotein-pseudotyped lentiviral vector-mediated gene transfer into quiescent lymphocytes requires binding to both SLAM and CD46 entry receptors. J. Virol. 85:5975-85
69. Modlich U, Navarro S, Zychlinski D, Maetzig T, Knoess S, et al. 2009. Insertional transformation of hematopoietic cells by self-inactivating lentiviral and gammaretroviral vectors. Mol. Ther. 17:1919-28
70. Singh H, Huls H, Kebriaei P, Cooper LJ. 2014. A new approach to gene therapy using Sleeping Beauty to genetically modify clinical-grade T cells to target CD19. Immunol. Rev. 257:181-90
71. SinghH, Figliola MJ,DawsonMJ, Olivares S, Zhang L, et al. 2013. Manufacture of clinical-gradeCD19-specific T cells stably expressing chimeric antigen receptor using Sleeping Beauty system and artificial antigen presenting cells. PLOS ONE 8:e64138
72. Field AC, Vink C, Gabriel R, Al-Subki R, Schmidt M, et al. 2013. Comparison of lentiviral and Sleeping Beauty mediated αβT cell receptor gene transfer. PLOS ONE 8:e68201
73. Turchiano G, Latella MC, Gogol-Doring A, Cattoglio C, Mavilio F, et al. 2014. Genomic analysis of Sleeping Beauty transposon integration in human somatic cells. PLOS ONE 9:e112712
74. Manuri PV,Wilson MH,Maiti SN, Mi T, Singh H, et al. 2010. piggyBac transposon/transposase system to generate CD19-specific T cells for the treatment of B-lineage malignancies. Hum. Gene Ther. 21:427-37
75. Galvan DL, Nakazawa Y, Kaja A, Kettlun C, Cooper LJ, et al. 2009. Genome-wide mapping of PiggyBac transposon integrations in primary human T cells. J. Immunother. 32:837-44
76. Beatty GL, Haas AR, Maus MV, Torigian DA, Soulen MC, et al. 2014. Mesothelin-specific chimeric antigen receptor mRNA-engineered T cells induce anti-tumor activity in solid malignancies. Cancer Immunol. Res. 2:112-20
77. Holling TM, van der Stoep N, Quinten E, van den Elsen PJ. 2002. Activated human T cells accomplish MHC class II expression through T cell-specific occupation of class II transactivator promoter III. J. Immunol. 168:763-70
78. Gragert L, Eapen M, Williams E, Freeman J, Spellman S, et al. 2014. HLA match likelihoods for hematopoietic stem-cell grafts in the U.S. registry. N. Engl. J. Med. 371:339-48
79. HeddleNM, Soutar RL,O'Hoski PL, Singer J,McBride JA, et al. 1995. A prospective study to determine the frequency and clinical significance of alloimmunization post-transfusion. Br. J. Haematol. 91:1000-5
80. Davis JL, Theoret MR, Zheng Z, Lamers CH, Rosenberg SA, Morgan RA. 2010. Development of human anti-murine T-cell receptor antibodies in both responding and nonresponding patients enrolled in TCR gene therapy trials. Clin. Cancer Res. 16:5852-61
81. Jensen MC, Popplewell L, Cooper LJ, DiGiusto D, Kalos M, et al. 2010. Antitransgene rejection responses contribute to attenuated persistence of adoptively transferred CD20/CD19-specific chimeric antigen receptor redirected T cells in humans. Biol. Blood Marrow Transplant. 16:1245-56
82. Heeger PS. 2003. T-cell allorecognition and transplant rejection: a summary and update. Am. J. Transplant. 3:525-33
83. Wagner FF, Flegel WA. 1995. Transfusion-associated graft-versus-host disease: risk due to homozygous HLA haplotypes. Transfusion 35:284-91
84. Takahashi K, Juji T, Miyamoto M, Uchida S, Akaza T, et al. 1994. Analysis of risk factors for posttransfusion graft-versus-host disease in Japan. Japanese Red Cross PT-GVHD Study Group. Lancet 343:700-2
85. Lee TH, Paglieroni T, Ohto H, Holland PV, Busch MP. 1999. Survival of donor leukocyte subpopulations in immunocompetent transfusion recipients: frequent long-term microchimerism in severe trauma patients. Blood 93:3127-39
86. Reed W, Lee TH, Norris PJ, Utter GH, Busch MP. 2007. Transfusion-associated microchimerism: a new complication of blood transfusions in severely injured patients. Semin. Hematol. 44:24-31
87. Utter GH, Owings JT, Lee TH, Paglieroni TG, Reed WF, et al. 2004. Blood transfusion is associated with donor leukocyte microchimerism in trauma patients. J. Trauma 57:702-7; discussion 7-8
88. Lee TH, Paglieroni T, Utter GH, Chafets D, Gosselin RC, et al. 2005. High-level long-term white blood cell microchimerism after transfusion of leukoreduced blood components to patients resuscitated after severe traumatic injury. Transfusion 45:1280-90
89. Poirot L, Philip B, Schiffer-Mannioui C, Le Clerre D, Chion-Sotinel I, et al. 2015. Multiplex genomeedited T-cell manufacturing platform for "off-The-shelf" adoptive T-cell immunotherapies. Cancer Res. 75:3853-64
90. Scarisbrick JJ, Dignan FL, Tulpule S, Gupta ED, Kolade S, et al. 2015. A multicentre UK study of GVHD following DLI: Rates of GVHD are high but mortality from GVHD is infrequent. Bone Marrow Transplant. 50:62-67
91. Cruz CR,MicklethwaiteKP, Savoldo B,Ramos CA,Lam S, et al. 2013. Infusion of donor-derived CD19-redirected virus-specific T cells for B-cell malignancies relapsed after allogeneic stem cell transplant: a phase 1 study. Blood 122:2965-73
92. Gerdemann U, Katari UL, Papadopoulou A, Keirnan JM, Craddock JA, et al. 2013. Safety and clinical efficacy of rapidly-generated trivirus-directed T cells as treatment for adenovirus, EBV, and CMV infections after allogeneic hematopoietic stem cell transplant. Mol. Ther. 21:2113-21
93. Papadopoulou A, Gerdemann U, Katari UL, Tzannou I, Liu H, et al. 2014. Activity of broad-spectrum T cells as treatment for AdV, EBV, CMV, BKV, and HHV6 infections after HSCT. Sci. Transl. Med. 6:242ra83
94. Papadopoulos EB, Ladanyi M, Emanuel D, Mackinnon S, Boulad F, et al. 1994. Infusions of donor leukocytes to treat Epstein-Barr virus-associated lymphoproliferative disorders after allogeneic bone marrow transplantation. N. Engl. J. Med. 330:1185-91
95. Haque T, Wilkie GM, Jones MM, Higgins CD, Urquhart G, et al. 2007. Allogeneic cytotoxic T-cell therapy for EBV-positive posttransplantation lymphoproliferative disease: results of a phase 2multicenter clinical trial. Blood 110:1123-31
96. Leen AM, Bollard CM, Mendizabal AM, Shpall EJ, Szabolcs P, et al. 2013. Multicenter study of banked third-party virus-specific T cells to treat severe viral infections after hematopoietic stem cell transplantation. Blood 121:5113-23
97. Themeli M, Kloss CC, Ciriello G, Fedorov VD, Perna F, et al. 2013. Generation of tumor-targeted humanTlymphocytes from induced pluripotent stem cells for cancer therapy. Nat. Biotechnol. 31:928-33
98. Vizcardo R, Masuda K, Yamada D, Ikawa T, Shimizu K, et al. 2013. Regeneration of human tumor antigen-specific T cells from iPSCs derived from mature CD8+ T cells. Cell Stem Cell 12:31-36
99. NishimuraT, Kaneko S, Kawana-TachikawaA,TajimaY,GotoH, et al. 2013. Generation of rejuvenated antigen-specificTcells by reprogramming to pluripotency and redifferentiation. Cell Stem Cell 12:114-26
100. Torikai H, Reik A, Soldner F, Warren EH, Yuen C, et al. 2013. Toward eliminating HLA class I expression to generate universal cells from allogeneic donors. Blood 122:1341-49
101. Torikai H, Reik A, Liu PQ, Zhou Y, Zhang L, et al. 2012. A foundation for universal T-cell based immunotherapy: T cells engineered to express a CD19-specific chimeric-antigen-receptor and eliminate expression of endogenous TCR. Blood 119:5697-705
102. Riteau B, Menier C, Khalil-Daher I, Martinozzi S, Pla M, et al. 2001. HLA-G1 co-expression boosts the HLA class I-mediated NK lysis inhibition. Int. Immunol. 13:193-201
103. Rouas-Freiss N, Marchal RE, Kirszenbaum M, Dausset J, Carosella ED. 1997. The α1 domain of HLAG1 and HLA-G2 inhibits cytotoxicity induced by natural killer cells: Is HLA-G the public ligand for natural killer cell inhibitory receptors? PNAS 94:5249-54
104. QasimW, Amrolia PJ, Samarasinghe S, ZhanH, Stafford S, et al. 2015. First clinical application ofTalen engineered universal CAR19 T cells in B-ALL. Blood 126:2046
105. WayJC, Collins JJ, Keasling JD, Silver PA. 2014. Integrating biological redesign:where synthetic biology came from and where it needs to go. Cell 157:151-61
106. Kwok R. 2010. Five hard truths for synthetic biology. Nature 463:288-90
107. Silver PA,Way JC, Arnold FH, Meyerowitz JT. 2014. Synthetic biology: engineering explored. Nature 509:166-67
108. Dotti G, Gottschalk S, Savoldo B, Brenner MK. 2014. Design and development of therapies using chimeric antigen receptor-expressing T cells. Immunol. Rev. 257:107-26
109. Kloss CC, Condomines M, Cartellieri M, Bachmann M, Sadelain M. 2013. Combinatorial antigen recognition with balanced signaling promotes selective tumor eradication by engineered T cells. Nat. Biotechnol. 31:71-75
110. Wilkie S, van Schalkwyk MC, Hobbs S, Davies DM, van der Stegen SJ, et al. 2012. Dual targeting of ErbB2 and MUC1 in breast cancer using chimeric antigen receptors engineered to provide complementary signaling. J. Clin. Immunol. 32:1059-70
111. Fedorov VD, Themeli M, Sadelain M. 2013. PD-1-and CTLA-4-based inhibitory chimeric antigen receptors (iCARs) divert off-target immunotherapy responses. Sci. Transl. Med. 5:215ra172
112. Morsut L, Roybal KT, Xiong X, Gordley RM, Coyle SM, et al. 2016. Engineering customized cell sensing and response behaviors using synthetic notch receptors. Cell 164:780-91
113. Roybal KT, Rupp LJ, Morsut L, Walker WJ, McNally KA, et al. 2016. Precision tumor recognition by T cells with combinatorial antigen-sensing circuits. Cell 164:770-79
114. Conklin BR, Hsiao EC, Claeysen S, Dumuis A, Srinivasan S, et al. 2008. Engineering GPCR signaling pathways with RASSLs. Nat. Methods 5:673-78
115. Park JS, Rhau B, Hermann A, McNally KA, Zhou C, et al. 2014. Synthetic control of mammalian-cell motility by engineering chemotaxis to an orthogonal bioinert chemical signal. PNAS 111:5896-901
116. Townshend B, Kennedy AB, Xiang JS, Smolke CD. 2015. High-throughput cellular RNA device engineering. Nat. Methods 12:989-94
117. Chen YY, Jensen MC, Smolke CD. 2010. Genetic control of mammalian T-cell proliferation with synthetic RNA regulatory systems. PNAS 107:8531-36
118. Wu CY, Roybal KT, Puchner EM, Onuffer J, Lim WA. 2015. Remote control of therapeutic T cells through a small molecule-gated chimeric receptor. Science 350:aab4077
119. MaJS, Kim JY, Kazane SA, Choi SH, Yun HY, et al. 2016. Versatile strategy for controlling the specificity and activity of engineered T cells. PNAS 113:450-58
120. RodgersDT, MazagovaM,Hampton EN, Cao Y, RamadossNS, et al. 2016. Switch-mediated activation and retargeting of CAR-T cells for B-cell malignancies. PNAS 113:459-68
121. Tamada K, Geng D, Sakoda Y, Bansal N, Srivastava R, et al. 2012. Redirecting gene-modified T cells toward various cancer types using tagged antibodies. Clin. Cancer Res. 18:6436-45
122. Urbanska K, Lanitis E, Poussin M, Lynn RC, Gavin BP, et al. 2012. A universal strategy for adoptive immunotherapy of cancer through use of a novel T-cell antigen receptor. Cancer Res. 72:1844-52
123. Weissinger EM, Borchers S, Silvani A, Provasi E, Radrizzani M, et al. 2015. Long term follow up of patients after allogeneic stem cell transplantation and transfusion of HSV-TK transduced T-cells. Front. Pharmacol. 6:76
124. Morgan RA, Yang JC, Kitano M, Dudley ME, Laurencot CM, Rosenberg SA. 2010. Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol. Ther. 18:843-51
125. Morgan RA, Chinnasamy N, Abate-Daga D, Gros A, Robbins PF, et al. 2013. Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy. J. Immunother. 36:133-51
126. Linette GP, Stadtmauer EA, Maus MV, Rapoport AP, Levine BL, et al. 2013. Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma. Blood 122:863-71
127. Lamers CH, Sleijfer S, van Steenbergen S, van Elzakker P, van Krimpen B, et al. 2013. Treatment of metastatic renal cell carcinoma with CAIX CAR-engineered T cells: clinical evaluation and management of on-target toxicity. Mol. Ther. 21:904-12
128. ParkhurstMR, Yang JC, Langan RC, Dudley ME, Nathan DA, et al. 2011. T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis. Mol. Ther. 19:620-26
129. Davila ML, Riviere I, Wang X, Bartido S, Park J, et al. 2014. Efficacy and toxicitymanagement of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci. Transl. Med. 6:224ra25
130. Kochenderfer JN, Dudley ME, Feldman SA, Wilson WH, Spaner DE, et al. 2012. B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells. Blood 119:2709-20
131. Gross G, Eshhar Z. 2016. Therapeutic potential of T cell chimeric antigen receptors (CARs) in cancer treatment: counteracting off-tumor toxicities for safe CAR T cell therapy. Annu. Rev. Pharmacol. Toxicol. 56:59-83
132. Tey SK, Dotti G, Rooney CM, Heslop HE, Brenner MK. 2007. Inducible caspase 9 suicide gene to improve the safety of allodepletedTcells after haploidentical stem cell transplantation. Biol. Blood Marrow Transplant. 13:913-24
133. Di Stasi A, Tey SK, Dotti G, Fujita Y, Kennedy-Nasser A, et al. 2011. Inducible apoptosis as a safety switch for adoptive cell therapy. N. Engl. J. Med. 365:1673-83
134. Budde LE, Berger C, LinY,Wang J,Lin X, et al. 2013. Combining aCD20chimeric antigen receptor and an inducible caspase 9 suicide switch to improve the efficacy and safety ofTcell adoptive immunotherapy for lymphoma. PLOS ONE 8:e82742
135. Zhou X, Di Stasi A, Tey SK,KranceRA, Martinez C, et al. 2014. Long-term outcome after haploidentical stem cell transplant and infusion of T cells expressing the inducible caspase 9 safety transgene. Blood 123:3895-905
136. Spencer DM, Belshaw PJ, Chen L, Ho SN, Randazzo F, et al. 1996. Functional analysis of Fas signaling in vivo using synthetic inducers of dimerization. Curr. Biol. 6:839-47
137. Belshaw PJ, Spencer DM, Crabtree GR, Schreiber SL. 1996. Controlling programmed cell death with a cyclophilin-cyclosporin-based chemical inducer of dimerization. Chem. Biol. 3:731-38
138. Thomis DC, Marktel S, Bonini C, Traversari C, Gilman M, et al. 2001. A Fas-based suicide switch in human T cells for the treatment of graft-versus-host disease. Blood 97:1249-57
139. Bonini C, Ferrari G, Verzeletti S, Servida P, Zappone E, et al. 1997. HSV-TK gene transfer into donor lymphocytes for control of allogeneic graft-versus-leukemia. Science 276:1719-24
140. Berger C, FlowersME, Warren EH, Riddell SR. 2006. Analysis of transgene-specific immune responses that limit the in vivo persistence of adoptively transferred HSV-TK-modified donor T cells after allogeneic hematopoietic cell transplantation. Blood 107:2294-302
141. Mercier-LetondalP,DeschampsM,SauceD,Certoux JM,MilpiedN, et al. 2008. Early immuneresponse against retrovirally transduced herpes simplex virus thymidine kinase-expressing gene-modified T cells coinfused with a T cell-depleted marrow graft: an altered immune response? Hum. Gene Ther. 19:937-50
142. Philip B, Kokalaki E, Mekkaoui L, Thomas S, Straathof K, et al. 2014. A highly compact epitope-based marker/suicide gene for easier and safer T-cell therapy. Blood 124:1277-87
143. Griffioen M, van Egmond EH, KesterMG, Willemze R, Falkenburg JH, HeemskerkMH. 2009. Retroviral transfer of human CD20 as a suicide gene for adoptive T-cell therapy. Haematologica 94:1316-20
144. Kieback E, Charo J, Sommermeyer D, Blankenstein T, Uckert W. 2008. A safeguard eliminates T cell receptor gene-modified autoreactive T cells after adoptive transfer. PNAS 105:623-28
145. Wang X, ChangWC, Wong CW, Colcher D, Sherman M, et al. 2011. A transgene-encoded cell surface polypeptide for selection, in vivo tracking, and ablation of engineered cells. Blood 118:1255-63
146. Zhao Y, Zheng Z, Cohen CJ, Gattinoni L, Palmer DC, et al. 2006. High-efficiency transfection of primary human and mouse T lymphocytes using RNA electroporation. Mol. Ther. 13:151-59
147. Wu C-Y, Roybal KT, Puchner EM, Onuffer J, Lim WA. 2015. Remote control of therapeutic T cells through a small molecule-gated chimeric receptor. Science 350:aab4077
148. Fischbach MA, Bluestone JA, Lim WA. 2013. Cell-based therapeutics: the next pillar of medicine. Sci. Transl. Med. 5:179ps7