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Strategies to genetically engineer T cells for cancer immunotherapy

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Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Immunotherapy is one of the most promising and innovative approaches to treat cancer, viral infections, and other immune-modulated diseases. Adoptive immunotherapy using gene-modified T cells is an exciting and rapidly evolving field. Exploiting knowledge of basic T cell biology and immune cell receptor function has fostered innovative approaches to modify immune cell function. Highly translatable clinical technologies have been developed to redirect T cell specificity by introducing designed receptors. The ability to engineer T cells to manifest desired phenotypes and functions is now a thrilling reality. In this review, we focus on outlining different varieties of genetically engineered T cells, their respective advantages and disadvantages as tools for immunotherapy, and their promise and drawbacks in the clinic.

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Abbreviations

ACT:

Adoptive cell transfer

AICD:

Activation-induced cell death

B-ALL:

Acute B lymphoblastic leukemia

CAIX:

Carbonic anhydrase IX

CEA:

Carcinoembryonic antigen

CLL:

Chronic lymphocytic leukemia

CTA:

Cancer–testis antigen

FBP:

Folate-binding protein

HSV-tk:

Herpes simplex virus thymidine kinase

iC9:

Inducible caspase 9

iCAR:

Inhibitory chimeric antigen receptor

NHL:

Non-Hodgkin lymphoma

pMHC:

Peptide–major histocompatibility complex

RCC:

Renal cell carcinoma

siRNA:

Small interfering ribonucleic acid

References

  1. Mule JJ, Shu S, Schwarz SL, Rosenberg SA (1984) Adoptive immunotherapy of established pulmonary metastases with LAK cells and recombinant interleukin-2. Science 225(4669):1487–1489

    Article  CAS  PubMed  Google Scholar 

  2. Dudley ME, Wunderlich JR, Robbins PF, Yang JC, Hwu P, Schwartzentruber DJ, Topalian SL, Sherry R, Restifo NP, Hubicki AM, Robinson MR, Raffeld M, Duray P, Seipp CA, Rogers-Freezer L, Morton KE, Mavroukakis SA, White DE, Rosenberg SA (2002) Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 298(5594):850–854. doi:10.1126/science.1076514

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Rosenberg SA, Yannelli JR, Yang JC, Topalian SL, Schwartzentruber DJ, Weber JS, Parkinson DR, Seipp CA, Einhorn JH, White DE (1994) Treatment of patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and interleukin 2. J Natl Cancer Inst 86(15):1159–1166

    Article  CAS  PubMed  Google Scholar 

  4. Dudley ME, Wunderlich J, Nishimura MI, Yu D, Yang JC, Topalian SL, Schwartzentruber DJ, Hwu P, Marincola FM, Sherry R, Leitman SF, Rosenberg SA (2001) Adoptive transfer of cloned melanoma-reactive T lymphocytes for the treatment of patients with metastatic melanoma. J Immunother 24(4):363–373

    Article  CAS  PubMed  Google Scholar 

  5. Mackensen A, Meidenbauer N, Vogl S, Laumer M, Berger J, Andreesen R (2006) Phase I study of adoptive T-cell therapy using antigen-specific CD8+ T cells for the treatment of patients with metastatic melanoma. J Clin Oncol 24(31):5060–5069. doi:10.1200/jco.2006.07.1100

    Article  CAS  PubMed  Google Scholar 

  6. Vignard V, Lemercier B, Lim A, Pandolfino MC, Guilloux Y, Khammari A, Rabu C, Echasserieau K, Lang F, Gougeon ML, Dreno B, Jotereau F, Labarriere N (2005) Adoptive transfer of tumor-reactive Melan-A-specific CTL clones in melanoma patients is followed by increased frequencies of additional Melan-A-specific T cells. J Immunol 175(7):4797–4805

    Article  CAS  PubMed  Google Scholar 

  7. Yee C, Thompson JA, Byrd D, Riddell SR, Roche P, Celis E, Greenberg PD (2002) Adoptive T cell therapy using antigen-specific CD8+ T cell clones for the treatment of patients with metastatic melanoma: in vivo persistence, migration, and antitumor effect of transferred T cells. Proc Natl Acad Sci USA 99(25):16168–16173. doi:10.1073/pnas.242600099

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Muul LM, Spiess PJ, Director EP, Rosenberg SA (1987) Identification of specific cytolytic immune responses against autologous tumor in humans bearing malignant melanoma. J Immunol 138(3):989–995

    CAS  PubMed  Google Scholar 

  9. Rosenberg SA, Spiess P, Lafreniere R (1986) A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes. Science 233(4770):1318–1321

    Article  CAS  PubMed  Google Scholar 

  10. Rosenberg SA, Packard BS, Aebersold PM, Solomon D, Topalian SL, Toy ST, Simon P, Lotze MT, Yang JC, Seipp CA et al (1988) Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report. N Engl J Med 319(25):1676–1680. doi:10.1056/nejm198812223192527

    Article  CAS  PubMed  Google Scholar 

  11. Gross G, Waks T, Eshhar Z (1989) Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc Natl Acad Sci USA 86(24):10024–10028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Letourneur F, Klausner RD (1991) T-cell and basophil activation through the cytoplasmic tail of T-cell-receptor zeta family proteins. Proc Natl Acad Sci USA 88(20):8905–8909

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hombach A, Heuser C, Sircar R, Tillmann T, Diehl V, Kruis W, Pohl C, Abken H (1997) T cell targeting of TAG72+ tumor cells by a chimeric receptor with antibody-like specificity for a carbohydrate epitope. Gastroenterology 113(4):1163–1170

    Article  CAS  PubMed  Google Scholar 

  14. Rossig C, Bollard CM, Nuchtern JG, Merchant DA, Brenner MK (2001) Targeting of G(D2)-positive tumor cells by human T lymphocytes engineered to express chimeric T-cell receptor genes. Int J Cancer 94(2):228–236

    Article  CAS  PubMed  Google Scholar 

  15. Inaguma Y, Akahori Y, Murayama Y, Shiraishi K, Tsuzuki-Iba S, Endoh A, Tsujikawa J, Demachi-Okamura A, Hiramatsu K, Saji H, Yamamoto Y, Yamamoto N, Nishimura Y, Takahashi T, Kuzushima K, Emi N, Akatsuka Y (2014) Construction and molecular characterization of a T-cell receptor-like antibody and CAR-T cells specific for minor histocompatibility antigen HA-1H. Gene Ther 21(6):575–584. doi:10.1038/gt.2014.30

    Article  CAS  PubMed  Google Scholar 

  16. Reiter Y, Di Carlo A, Fugger L, Engberg J, Pastan I (1997) Peptide-specific killing of antigen-presenting cells by a recombinant antibody-toxin fusion protein targeted to major histocompatibility complex/peptide class I complexes with T cell receptor-like specificity. Proc Natl Acad Sci USA 94(9):4631–4636

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Sergeeva A, Alatrash G, He H, Ruisaard K, Lu S, Wygant J, McIntyre BW, Ma Q, Li D, St John L, Clise-Dwyer K, Molldrem JJ (2011) An anti-PR1/HLA-A2 T-cell receptor-like antibody mediates complement-dependent cytotoxicity against acute myeloid leukemia progenitor cells. Blood 117(16):4262–4272. doi:10.1182/blood-2010-07-299248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Willemsen RA, Ronteltap C, Chames P, Debets R, Bolhuis RL (2005) T cell retargeting with MHC class I-restricted antibodies: the CD28 costimulatory domain enhances antigen-specific cytotoxicity and cytokine production. J Immunol 174(12):7853–7858

    Article  CAS  PubMed  Google Scholar 

  19. Sadelain M, Brentjens R, Riviere I (2009) The promise and potential pitfalls of chimeric antigen receptors. Curr Opin Immunol 21(2):215–223. doi:10.1016/j.coi.2009.02.009

    Article  CAS  PubMed  Google Scholar 

  20. Gardner R, Wu D, Cherian S, Fang M, Hanafi LA, Finney O, Smithers H, Jensen MC, Riddell SR, Maloney DG, Turtle CJ (2016) Acquisition of a CD19 negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T cell therapy. Blood. doi:10.1182/blood-2015-08-665547

    PubMed  Google Scholar 

  21. Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, Teachey DT, Chew A, Hauck B, Wright JF, Milone MC, Levine BL, June CH (2013) Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med 368(16):1509–1518. doi:10.1056/NEJMoa1215134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Burga RA, Thorn M, Point GR, Guha P, Nguyen CT, Licata LA, DeMatteo RP, Ayala A, Joseph Espat N, Junghans RP, Katz SC (2015) Liver myeloid-derived suppressor cells expand in response to liver metastases in mice and inhibit the anti-tumor efficacy of anti-CEA CAR-T. Cancer Immunol Immunother 64(7):817–829. doi:10.1007/s00262-015-1692-6

    Article  CAS  PubMed  Google Scholar 

  23. Davis MM (2004) The evolutionary and structural ‘logic’ of antigen receptor diversity. Semin Immunol 16(4):239–243. doi:10.1016/j.smim.2004.08.003

    Article  CAS  PubMed  Google Scholar 

  24. Krug C, Birkholz K, Paulus A, Schwenkert M, Schmidt P, Hoffmann N, Hombach A, Fey G, Abken H, Schuler G, Schuler-Thurner B, Dorrie J, Schaft N (2015) Stability and activity of MCSP-specific chimeric antigen receptors (CARs) depend on the scFv antigen-binding domain and the protein backbone. Cancer Immunol Immunother 64(12):1623–1635. doi:10.1007/s00262-015-1767-4

    Article  CAS  PubMed  Google Scholar 

  25. Lamers CH, Willemsen R, van Elzakker P, van Steenbergen-Langeveld S, Broertjes M, Oosterwijk-Wakka J, Oosterwijk E, Sleijfer S, Debets R, Gratama JW (2011) Immune responses to transgene and retroviral vector in patients treated with ex vivo-engineered T cells. Blood 117(1):72–82. doi:10.1182/blood-2010-07-294520

    Article  CAS  PubMed  Google Scholar 

  26. Casucci M, Hawkins RE, Dotti G, Bondanza A (2015) Overcoming the toxicity hurdles of genetically targeted T cells. Cancer Immunol Immunother 64(1):123–130. doi:10.1007/s00262-014-1641-9

    Article  CAS  PubMed  Google Scholar 

  27. Dao T, Yan S, Veomett N, Pankov D, Zhou L, Korontsvit T, Scott A, Whitten J, Maslak P, Casey E, Tan T, Liu H, Zakhaleva V, Curcio M, Doubrovina E, O’Reilly RJ, Liu C, Scheinberg DA (2013) Targeting the intracellular WT1 oncogene product with a therapeutic human antibody. Sci Transl Med 5(176):176ra133. doi:10.1126/scitranslmed.3005661

  28. June CH, Maus MV, Plesa G, Johnson LA, Zhao Y, Levine BL, Grupp SA, Porter DL (2014) Engineered T cells for cancer therapy. Cancer Immunol Immunother 63(9):969–975. doi:10.1007/s00262-014-1568-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Muniappan A, Banapour B, Lebkowski J, Talib S (2000) Ligand-mediated cytolysis of tumor cells: use of heregulin-zeta chimeras to redirect cytotoxic T lymphocytes. Cancer Gene Ther 7(1):128–134. doi:10.1038/sj.cgt.7700100

    Article  CAS  PubMed  Google Scholar 

  30. Niederman TM, Ghogawala Z, Carter BS, Tompkins HS, Russell MM, Mulligan RC (2002) Antitumor activity of cytotoxic T lymphocytes engineered to target vascular endothelial growth factor receptors. Proc Natl Acad Sci USA 99(10):7009–7014. doi:10.1073/pnas.092562399

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Zhang T, Wu MR, Sentman CL (2012) An NKp30-based chimeric antigen receptor promotes T cell effector functions and antitumor efficacy in vivo. J Immunol 189(5):2290–2299. doi:10.4049/jimmunol.1103495

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Lehner M, Gotz G, Proff J, Schaft N, Dorrie J, Full F, Ensser A, Muller YA, Cerwenka A, Abken H, Parolini O, Ambros PF, Kovar H, Holter W (2012) Redirecting T cells to Ewing’s sarcoma family of tumors by a chimeric NKG2D receptor expressed by lentiviral transduction or mRNA transfection. PLoS ONE 7(2):e31210. doi:10.1371/journal.pone.0031210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Song DG, Ye Q, Santoro S, Fang C, Best A, Powell DJ Jr (2013) Chimeric NKG2D CAR-expressing T cell-mediated attack of human ovarian cancer is enhanced by histone deacetylase inhibition. Hum Gene Ther 24(3):295–305. doi:10.1089/hum.2012.143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Zhang T, Barber A, Sentman CL (2006) Generation of antitumor responses by genetic modification of primary human T cells with a chimeric NKG2D receptor. Cancer Res 66(11):5927–5933. doi:10.1158/0008-5472.can-06-0130

    Article  CAS  PubMed  Google Scholar 

  35. Ramos CA, Dotti G (2011) Chimeric antigen receptor (CAR)-engineered lymphocytes for cancer therapy. Expert Opin Biol Ther 11(7):855–873. doi:10.1517/14712598.2011.573476

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Carpenito C, Milone MC, Hassan R, Simonet JC, Lakhal M, Suhoski MM, Varela-Rohena A, Haines KM, Heitjan DF, Albelda SM, Carroll RG, Riley JL, Pastan I, June CH (2009) Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains. Proc Natl Acad Sci USA 106(9):3360–3365. doi:10.1073/pnas.0813101106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Haynes NM, Trapani JA, Teng MW, Jackson JT, Cerruti L, Jane SM, Kershaw MH, Smyth MJ, Darcy PK (2002) Single-chain antigen recognition receptors that costimulate potent rejection of established experimental tumors. Blood 100(9):3155–3163. doi:10.1182/blood-2002-04-1041

    Article  CAS  PubMed  Google Scholar 

  38. Hombach A, Wieczarkowiecz A, Marquardt T, Heuser C, Usai L, Pohl C, Seliger B, Abken H (2001) Tumor-specific T cell activation by recombinant immunoreceptors: CD3 zeta signaling and CD28 costimulation are simultaneously required for efficient IL-2 secretion and can be integrated into one combined CD28/CD3 zeta signaling receptor molecule. J Immunol 167(11):6123–6131

    Article  CAS  PubMed  Google Scholar 

  39. Maher J, Brentjens RJ, Gunset G, Riviere I, Sadelain M (2002) Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRzeta/CD28 receptor. Nat Biotechnol 20(1):70–75. doi:10.1038/nbt0102-70

    Article  CAS  PubMed  Google Scholar 

  40. Milone MC, Fish JD, Carpenito C, Carroll RG, Binder GK, Teachey D, Samanta M, Lakhal M, Gloss B, Danet-Desnoyers G, Campana D, Riley JL, Grupp SA, June CH (2009) Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo. Mol Ther 17(8):1453–1464. doi:10.1038/mt.2009.83

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Moeller M, Haynes NM, Trapani JA, Teng MW, Jackson JT, Tanner JE, Cerutti L, Jane SM, Kershaw MH, Smyth MJ, Darcy PK (2004) A functional role for CD28 costimulation in tumor recognition by single-chain receptor-modified T cells. Cancer Gene Ther 11(5):371–379. doi:10.1038/sj.cgt.7700710

    Article  CAS  PubMed  Google Scholar 

  42. Yvon E, Del Vecchio M, Savoldo B, Hoyos V, Dutour A, Anichini A, Dotti G, Brenner MK (2009) Immunotherapy of metastatic melanoma using genetically engineered GD2-specific T cells. Clin Cancer Res 15(18):5852–5860. doi:10.1158/1078-0432.ccr-08-3163

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Wang J, Jensen M, Lin Y, Sui X, Chen E, Lindgren CG, Till B, Raubitschek A, Forman SJ, Qian X, James S, Greenberg P, Riddell S, Press OW (2007) Optimizing adoptive polyclonal T cell immunotherapy of lymphomas, using a chimeric T cell receptor possessing CD28 and CD137 costimulatory domains. Hum Gene Ther 18(8):712–725. doi:10.1089/hum.2007.028

    Article  CAS  PubMed  Google Scholar 

  44. Liu L, Sun M, Wang Z (2012) Adoptive T-cell therapy of B-cell malignancies: conventional and physiological chimeric antigen receptors. Cancer Lett 316(1):1–5. doi:10.1016/j.canlet.2011.10.027

    Article  CAS  PubMed  Google Scholar 

  45. Wang J, Press OW, Lindgren CG, Greenberg P, Riddell S, Qian X, Laugen C, Raubitschek A, Forman SJ, Jensen MC (2004) Cellular immunotherapy for follicular lymphoma using genetically modified CD20-specific CD8+ cytotoxic T lymphocytes. Mol Ther 9(4):577–586. doi:10.1016/j.ymthe.2003.12.011

    Article  CAS  PubMed  Google Scholar 

  46. Wilkie S, Picco G, Foster J, Davies DM, Julien S, Cooper L, Arif S, Mather SJ, Taylor-Papadimitriou J, Burchell JM, Maher J (2008) Retargeting of human T cells to tumor-associated MUC1: the evolution of a chimeric antigen receptor. J Immunol 180(7):4901–4909

    Article  CAS  PubMed  Google Scholar 

  47. Zhao Y, Wang QJ, Yang S, Kochenderfer JN, Zheng Z, Zhong X, Sadelain M, Eshhar Z, Rosenberg SA, Morgan RA (2009) A herceptin-based chimeric antigen receptor with modified signaling domains leads to enhanced survival of transduced T lymphocytes and antitumor activity. J Immunol 183(9):5563–5574. doi:10.4049/jimmunol.0900447

    Article  CAS  PubMed  Google Scholar 

  48. Zhong XS, Matsushita M, Plotkin J, Riviere I, Sadelain M (2010) Chimeric antigen receptors combining 4-1BB and CD28 signaling domains augment PI3kinase/AKT/Bcl-XL activation and CD8+ T cell-mediated tumor eradication. Mol Ther 18(2):413–420. doi:10.1038/mt.2009.210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. 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(4):843–851. doi:10.1038/mt.2010.24

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Kershaw MH, Westwood JA, Parker LL, Wang G, Eshhar Z, Mavroukakis SA, White DE, Wunderlich JR, Canevari S, Rogers-Freezer L, Chen CC, Yang JC, Rosenberg SA, Hwu P (2006) A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer. Clin Cancer Res 12(20 Pt 1):6106–6115. doi:10.1158/1078-0432.ccr-06-1183

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Lamers CH, Sleijfer S, Vulto AG, Kruit WH, Kliffen M, Debets R, Gratama JW, Stoter G, Oosterwijk E (2006) Treatment of metastatic renal cell carcinoma with autologous T-lymphocytes genetically retargeted against carbonic anhydrase IX: first clinical experience. J Clin Oncol 24(13):e20–e22. doi:10.1200/jco.2006.05.9964

    Article  PubMed  Google Scholar 

  52. Brentjens RJ, Riviere I, Park JH, Davila ML, Wang X, Stefanski J, Taylor C, Yeh R, Bartido S, Borquez-Ojeda O, Olszewska M, Bernal Y, Pegram H, Przybylowski M, Hollyman D, Usachenko Y, Pirraglia D, Hosey J, Santos E, Halton E, Maslak P, Scheinberg D, Jurcic J, Heaney M, Heller G, Frattini M, Sadelain M (2011) Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood 118(18):4817–4828. doi:10.1182/blood-2011-04-348540

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Jensen MC, Popplewell L, Cooper LJ, DiGiusto D, Kalos M, Ostberg JR, Forman SJ (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(9):1245–1256. doi:10.1016/j.bbmt.2010.03.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Kalos M, Levine BL, Porter DL, Katz S, Grupp SA, Bagg A, June CH (2011) T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med 3(95):95ra73. doi:10.1126/scitranslmed.3002842

  55. Kochenderfer JN, Dudley ME, Feldman SA, Wilson WH, Spaner DE, Maric I, Stetler-Stevenson M, Phan GQ, Hughes MS, Sherry RM, Yang JC, Kammula US, Devillier L, Carpenter R, Nathan DA, Morgan RA, Laurencot C, Rosenberg SA (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(12):2709–2720. doi:10.1182/blood-2011-10-384388

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Kochenderfer JN, Wilson WH, Janik JE, Dudley ME, Stetler-Stevenson M, Feldman SA, Maric I, Raffeld M, Nathan DA, Lanier BJ, Morgan RA, Rosenberg SA (2010) Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. Blood 116(20):4099–4102. doi:10.1182/blood-2010-04-281931

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Porter DL, Levine BL, Kalos M, Bagg A, June CH (2011) Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med 365(8):725–733. doi:10.1056/NEJMoa1103849

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Savoldo B, Ramos CA, Liu E, Mims MP, Keating MJ, Carrum G, Kamble RT, Bollard CM, Gee AP, Mei Z, Liu H, Grilley B, Rooney CM, Heslop HE, Brenner MK, Dotti G (2011) CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. J Clin Invest 121(5):1822–1826. doi:10.1172/jci46110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Brentjens RJ, Davila ML, Riviere I, Park J, Wang X, Cowell LG, Bartido S, Stefanski J, Taylor C, Olszewska M, Borquez-Ojeda O, Qu J, Wasielewska T, He Q, Bernal Y, Rijo IV, Hedvat C, Kobos R, Curran K, Steinherz P, Jurcic J, Rosenblat T, Maslak P, Frattini M, Sadelain M (2013) CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med 5(177):177ra138. doi:10.1126/scitranslmed.3005930

  60. Lee DW, Kochenderfer JN, Stetler-Stevenson M, Cui YK, Delbrook C, Feldman SA, Fry TJ, Orentas R, Sabatino M, Shah NN, Steinberg SM, Stroncek D, Tschernia N, Yuan C, Zhang H, Zhang L, Rosenberg SA, Wayne AS, Mackall CL (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(9967):517–528. doi:10.1016/s0140-6736(14)61403-3

    Article  CAS  PubMed  Google Scholar 

  61. Ahmed N, Brawley VS, Hegde M, Robertson C, Ghazi A, Gerken C, Liu E, Dakhova O, Ashoori A, Corder A, Gray T, Wu MF, Liu H, Hicks J, Rainusso N, Dotti G, Mei Z, Grilley B, Gee A, Rooney CM, Brenner MK, Heslop HE, Wels WS, Wang LL, Anderson P, Gottschalk S (2015) Human Epidermal Growth Factor Receptor 2 (HER2)-Specific Chimeric Antigen Receptor-Modified T Cells for the Immunotherapy of HER2-Positive Sarcoma. J Clin Oncol 33(15):1688–1696. doi:10.1200/jco.2014.58.0225

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Miao H, Choi BD, Suryadevara CM, Sanchez-Perez L, Yang S, De Leon G, Sayour EJ, McLendon R, Herndon JE II, Healy P, Archer GE, Bigner DD, Johnson LA, Sampson JH (2014) EGFRvIII-specific chimeric antigen receptor T cells migrate to and kill tumor deposits infiltrating the brain parenchyma in an invasive xenograft model of glioblastoma. PLoS ONE 9(4):e94281. doi:10.1371/journal.pone.0094281

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Brentjens RJ, Latouche JB, Santos E, Marti F, Gong MC, Lyddane C, King PD, Larson S, Weiss M, Riviere I, Sadelain M (2003) Eradication of systemic B-cell tumors by genetically targeted human T lymphocytes co-stimulated by CD80 and interleukin-15. Nat Med 9(3):279–286. doi:10.1038/nm827

    Article  CAS  PubMed  Google Scholar 

  64. Rossig C, Bollard CM, Nuchtern JG, Rooney CM, Brenner MK (2002) Epstein-Barr virus-specific human T lymphocytes expressing antitumor chimeric T-cell receptors: potential for improved immunotherapy. Blood 99(6):2009–2016

    Article  CAS  PubMed  Google Scholar 

  65. Lo AS, Ma Q, Liu DL, Junghans RP (2010) Anti-GD3 chimeric sFv-CD28/T-cell receptor zeta designer T cells for treatment of metastatic melanoma and other neuroectodermal tumors. Clin Cancer Res 16(10):2769–2780. doi:10.1158/1078-0432.ccr-10-0043

    Article  CAS  PubMed  Google Scholar 

  66. Yun CO, Nolan KF, Beecham EJ, Reisfeld RA, Junghans RP (2000) Targeting of T lymphocytes to melanoma cells through chimeric anti-GD3 immunoglobulin T-cell receptors. Neoplasia (New York, NY) 2(5):449–459

    Article  CAS  Google Scholar 

  67. Burns WR, Zhao Y, Frankel TL, Hinrichs CS, Zheng Z, Xu H, Feldman SA, Ferrone S, Rosenberg SA, Morgan RA (2010) A high molecular weight melanoma-associated antigen-specific chimeric antigen receptor redirects lymphocytes to target human melanomas. Cancer Res 70(8):3027–3033. doi:10.1158/0008-5472.can-09-2824

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. James SE, Greenberg PD, Jensen MC, Lin Y, Wang J, Till BG, Raubitschek AA, Forman SJ, Press OW (2008) Antigen sensitivity of CD22-specific chimeric TCR is modulated by target epitope distance from the cell membrane. J Immunol 180(10):7028–7038

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Jensen MC, Cooper LJ, Wu AM, Forman SJ, Raubitschek A (2003) Engineered CD20-specific primary human cytotoxic T lymphocytes for targeting B-cell malignancy. Cytotherapy 5(2):131–138. doi:10.1080/14653240310001028

    Article  CAS  PubMed  Google Scholar 

  70. Till BG, Jensen MC, Wang J, Qian X, Gopal AK, Maloney DG, Lindgren CG, Lin Y, Pagel JM, Budde LE, Raubitschek A, Forman SJ, Greenberg PD, Riddell SR, Press OW (2012) CD20-specific adoptive immunotherapy for lymphoma using a chimeric antigen receptor with both CD28 and 4-1BB domains: pilot clinical trial results. Blood 119(17):3940–3950. doi:10.1182/blood-2011-10-387969

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Yu K, Hu Y, Tan Y, Shen Z, Jiang S, Qian H, Liang B, Shan D (2008) Immunotherapy of lymphomas with T cells modified by anti-CD20 scFv/CD28/CD3zeta recombinant gene. Leuk Lymphoma 49(7):1368–1373. doi:10.1080/10428190802064958

    Article  CAS  PubMed  Google Scholar 

  72. Giordano Attianese GM, Marin V, Hoyos V, Savoldo B, Pizzitola I, Tettamanti S, Agostoni V, Parma M, Ponzoni M, Bertilaccio MT, Ghia P, Biondi A, Dotti G, Biagi E (2011) In vitro and in vivo model of a novel immunotherapy approach for chronic lymphocytic leukemia by anti-CD23 chimeric antigen receptor. Blood 117(18):4736–4745. doi:10.1182/blood-2010-10-311845

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Di Stasi A, De Angelis B, Rooney CM, Zhang L, Mahendravada A, Foster AE, Heslop HE, Brenner MK, Dotti G, Savoldo B (2009) T lymphocytes coexpressing CCR4 and a chimeric antigen receptor targeting CD30 have improved homing and antitumor activity in a Hodgkin tumor model. Blood 113(25):6392–6402. doi:10.1182/blood-2009-03-209650

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Hombach A, Muche JM, Gerken M, Gellrich S, Heuser C, Pohl C, Sterry W, Abken H (2001) T cells engrafted with a recombinant anti-CD30 receptor target autologous CD30(+) cutaneous lymphoma cells. Gene Ther 8(11):891–895. doi:10.1038/sj.gt.3301467

    Article  CAS  PubMed  Google Scholar 

  75. Savoldo B, Rooney CM, Di Stasi A, Abken H, Hombach A, Foster AE, Zhang L, Heslop HE, Brenner MK, Dotti G (2007) Epstein Barr virus specific cytotoxic T lymphocytes expressing the anti-CD30zeta artificial chimeric T-cell receptor for immunotherapy of Hodgkin disease. Blood 110(7):2620–2630. doi:10.1182/blood-2006-11-059139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Ma Q, Safar M, Holmes E, Wang Y, Boynton AL, Junghans RP (2004) Anti-prostate specific membrane antigen designer T cells for prostate cancer therapy. Prostate 61(1):12–25. doi:10.1002/pros.20073

    Article  CAS  PubMed  Google Scholar 

  77. Moritz D, Wels W, Mattern J, Groner B (1994) Cytotoxic T lymphocytes with a grafted recognition specificity for ERBB2-expressing tumor cells. Proc Natl Acad Sci USA 91(10):4318–4322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Stancovski I, Schindler DG, Waks T, Yarden Y, Sela M, Eshhar Z (1993) Targeting of T lymphocytes to Neu/HER2-expressing cells using chimeric single chain Fv receptors. J Immunol 151(11):6577–6582

    CAS  PubMed  Google Scholar 

  79. Darcy PK, Kershaw MH, Trapani JA, Smyth MJ (1998) Expression in cytotoxic T lymphocytes of a single-chain anti-carcinoembryonic antigen antibody. Redirected Fas ligand-mediated lysis of colon carcinoma. Eur J Immunol 28(5):1663–1672. doi:10.1002/(sici)1521-4141(199805)28:05<1663:aid-immu1663>3.0.co;2-l

    Article  CAS  PubMed  Google Scholar 

  80. Hombach A, Koch D, Sircar R, Heuser C, Diehl V, Kruis W, Pohl C, Abken H (1999) A chimeric receptor that selectively targets membrane-bound carcinoembryonic antigen (mCEA) in the presence of soluble CEA. Gene Ther 6(2):300–304. doi:10.1038/sj.gt.3300813

    Article  CAS  PubMed  Google Scholar 

  81. Nolan KF, Yun CO, Akamatsu Y, Murphy JC, Leung SO, Beecham EJ, Junghans RP (1999) Bypassing immunization: optimized design of “designer T cells” against carcinoembryonic antigen (CEA)-expressing tumors, and lack of suppression by soluble CEA. Clin Cancer Res 5(12):3928–3941

    CAS  PubMed  Google Scholar 

  82. Daly T, Royal RE, Kershaw MH, Treisman J, Wang G, Li W, Herlyn D, Eshhar Z, Hwu P (2000) Recognition of human colon cancer by T cells transduced with a chimeric receptor gene. Cancer Gene Ther 7(2):284–291. doi:10.1038/sj.cgt.7700121

    Article  CAS  PubMed  Google Scholar 

  83. Chinnasamy D, Yu Z, Theoret MR, Zhao Y, Shrimali RK, Morgan RA, Feldman SA, Restifo NP, Rosenberg SA (2010) Gene therapy using genetically modified lymphocytes targeting VEGFR-2 inhibits the growth of vascularized syngenic tumors in mice. J Clin Invest 120(11):3953–3968. doi:10.1172/jci43490

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Wang S, Yin ZF, Cui ZF, Wu ZD, Qian HH, Kang XY, Wu MC (2004) The specific cytotoxic effect of tumor infiltrating lymphocytes transfected with chimeric T cell receptor on cells which express KDR. Zhonghua Zhong Liu Za Zhi 26(2):82–84

    PubMed  Google Scholar 

  85. Chekmasova AA, Rao TD, Nikhamin Y, Park KJ, Levine DA, Spriggs DR, Brentjens RJ (2010) Successful eradication of established peritoneal ovarian tumors in SCID-Beige mice following adoptive transfer of T cells genetically targeted to the MUC16 antigen. Clin Cancer Res 16(14):3594–3606. doi:10.1158/1078-0432.ccr-10-0192

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Brentjens R, Yeh R, Bernal Y, Riviere I, Sadelain M (2010) Treatment of chronic lymphocytic leukemia with genetically targeted autologous T cells: case report of an unforeseen adverse event in a phase I clinical trial. Mol Ther 18(4):666–668. doi:10.1038/mt.2010.31

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Xu XJ, Tang YM (2014) Cytokine release syndrome in cancer immunotherapy with chimeric antigen receptor engineered T cells. Cancer Lett 343(2):172–178. doi:10.1016/j.canlet.2013.10.004

    Article  CAS  PubMed  Google Scholar 

  88. Clay TM, Custer MC, Sachs J, Hwu P, Rosenberg SA, Nishimura MI (1999) Efficient transfer of a tumor antigen-reactive TCR to human peripheral blood lymphocytes confers anti-tumor reactivity. J Immunol 163(1):507–513

    CAS  PubMed  Google Scholar 

  89. Cole DJ, Weil DP, Shilyansky J, Custer M, Kawakami Y, Rosenberg SA, Nishimura MI (1995) Characterization of the functional specificity of a cloned T-cell receptor heterodimer recognizing the MART-1 melanoma antigen. Cancer Res 55(4):748–752

    CAS  PubMed  Google Scholar 

  90. Roszkowski JJ, Lyons GE, Kast WM, Yee C, Van Besien K, Nishimura MI (2005) Simultaneous generation of CD8+ and CD4+ melanoma-reactive T cells by retroviral-mediated transfer of a single T-cell receptor. Cancer Res 65(4):1570–1576. doi:10.1158/0008-5472.can-04-2076

    Article  CAS  PubMed  Google Scholar 

  91. Callender GG, Rosen HR, Roszkowski JJ, Lyons GE, Li M, Moore T, Brasic N, McKee MD, Nishimura MI (2006) Identification of a hepatitis C virus-reactive T cell receptor that does not require CD8 for target cell recognition. Hepatology 43(5):973–981. doi:10.1002/hep.21157

    Article  CAS  PubMed  Google Scholar 

  92. Spear TT, Callender GG, Roszkowski JJ, Moxley KM, Simms PE, Foley KC, Murray DC, Scurti GM, Li M, Thomas JT, Langerman A, Garrett-Mayer E, Zhang Y, Nishimura MI (2016) TCR gene-modified T cells can efficiently treat established hepatitis C-associated hepatocellular carcinoma tumors. Cancer Immunol Immunother 65(3):293–304. doi:10.1007/s00262-016-1800-2

    Article  CAS  PubMed  Google Scholar 

  93. Zhang Y, Liu Y, Moxley KM, Golden-Mason L, Hughes MG, Liu T, Heemskerk MH, Rosen HR, Nishimura MI (2010) Transduction of human T cells with a novel T-cell receptor confers anti-HCV reactivity. PLoS Pathog 6(7):e1001018. doi:10.1371/journal.ppat.1001018

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Combadiere B, Reis e Sousa C, Trageser C, Zheng LX, Kim CR, Lenardo MJ (1998) Differential TCR signaling regulates apoptosis and immunopathology during antigen responses in vivo. Immunity 9(3):305–313

    Article  CAS  PubMed  Google Scholar 

  95. Lenardo MJ, Boehme S, Chen L, Combadiere B, Fisher G, Freedman M, McFarland H, Pelfrey C, Zheng L (1995) Autocrine feedback death and the regulation of mature T lymphocyte antigen responses. Int Rev Immunol 13(2):115–134

    Article  CAS  PubMed  Google Scholar 

  96. Johnson LA, Morgan RA, Dudley ME, Cassard L, Yang JC, Hughes MS, Kammula US, Royal RE, Sherry RM, Wunderlich JR, Lee CC, Restifo NP, Schwarz SL, Cogdill AP, Bishop RJ, Kim H, Brewer CC, Rudy SF, VanWaes C, Davis JL, Mathur A, Ripley RT, Nathan DA, Laurencot CM, Rosenberg SA (2009) Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen. Blood 114(3):535–546. doi:10.1182/blood-2009-03-211714

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Mehrotra S, Al-Khami AA, Klarquist J, Husain S, Naga O, Eby JM, Murali AK, Lyons GE, Li M, Spivey ND, Norell H, Martins da Palma T, Onicescu G, Diaz-Montero CM, Garrett-Mayer E, Cole DJ, Le Poole IC, Nishimura MI (2012) A coreceptor-independent transgenic human TCR mediates anti-tumor and anti-self immunity in mice. J Immunol 189(4):1627–1638. doi:10.4049/jimmunol.1103271

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Parkhurst MR, Yang JC, Langan RC, Dudley ME, Nathan DA, Feldman SA, Davis JL, Morgan RA, Merino MJ, Sherry RM, Hughes MS, Kammula US, Phan GQ, Lim RM, Wank SA, Restifo NP, Robbins PF, Laurencot CM, Rosenberg SA (2011) T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis. Mol Ther 19(3):620–626. doi:10.1038/mt.2010.272

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Bicknell DC, Rowan A, Bodmer WF (1994) Beta 2-microglobulin gene mutations: a study of established colorectal cell lines and fresh tumors. Proc Natl Acad Sci USA 91(11):4751–4755

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Hicklin DJ, Marincola FM, Ferrone S (1999) HLA class I antigen downregulation in human cancers: T-cell immunotherapy revives an old story. Mol Med Today 5(4):178–186

    Article  CAS  PubMed  Google Scholar 

  101. Leisegang M, Engels B, Meyerhuber P, Kieback E, Sommermeyer D, Xue SA, Reuss S, Stauss H, Uckert W (2008) Enhanced functionality of T cell receptor-redirected T cells is defined by the transgene cassette. J Mol Med (Berl) 86(5):573–583. doi:10.1007/s00109-008-0317-3

    Article  CAS  Google Scholar 

  102. Scholten KB, Kramer D, Kueter EW, Graf M, Schoedl T, Meijer CJ, Schreurs MW, Hooijberg E (2006) Codon modification of T cell receptors allows enhanced functional expression in transgenic human T cells. Clin Immunol 119(2):135–145. doi:10.1016/j.clim.2005.12.009

    Article  CAS  PubMed  Google Scholar 

  103. Yang S, Cohen CJ, Peng PD, Zhao Y, Cassard L, Yu Z, Zheng Z, Jones S, Restifo NP, Rosenberg SA, Morgan RA (2008) Development of optimal bicistronic lentiviral vectors facilitates high-level TCR gene expression and robust tumor cell recognition. Gene Ther 15(21):1411–1423. doi:10.1038/gt.2008.90

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Leisegang M, Turqueti-Neves A, Engels B, Blankenstein T, Schendel DJ, Uckert W, Noessner E (2010) T-cell receptor gene-modified T cells with shared renal cell carcinoma specificity for adoptive T-cell therapy. Clin Cancer Res 16(8):2333–2343. doi:10.1158/1078-0432.ccr-09-2897

    Article  CAS  PubMed  Google Scholar 

  105. Meyerhuber P, Conrad H, Starck L, Leisegang M, Busch DH, Uckert W, Bernhard H (2010) Targeting the epidermal growth factor receptor (HER) family by T cell receptor gene-modified T lymphocytes. J Mol Med (Berl) 88(11):1113–1121. doi:10.1007/s00109-010-0660-z

    Article  CAS  Google Scholar 

  106. Hart DP, Xue SA, Thomas S, Cesco-Gaspere M, Tranter A, Willcox B, Lee SP, Steven N, Morris EC, Stauss HJ (2008) Retroviral transfer of a dominant TCR prevents surface expression of a large proportion of the endogenous TCR repertoire in human T cells. Gene Ther 15(8):625–631. doi:10.1038/sj.gt.3303078

    Article  CAS  PubMed  Google Scholar 

  107. Bendle GM, Linnemann C, Hooijkaas AI, Bies L, de Witte MA, Jorritsma A, Kaiser AD, Pouw N, Debets R, Kieback E, Uckert W, Song JY, Haanen JB, Schumacher TN (2010) Lethal graft-versus-host disease in mouse models of T cell receptor gene therapy. Nat Med 16(5):565–570. doi:10.1038/nm.2128

    Article  CAS  PubMed  Google Scholar 

  108. van Loenen MM, de Boer R, Amir AL, Hagedoorn RS, Volbeda GL, Willemze R, van Rood JJ, Falkenburg JH, Heemskerk MH (2010) Mixed T cell receptor dimers harbor potentially harmful neoreactivity. Proc Natl Acad Sci USA 107(24):10972–10977. doi:10.1073/pnas.1005802107

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Rosenberg SA (2010) Of mice, not men: no evidence for graft-versus-host disease in humans receiving T-cell receptor-transduced autologous T cells. Mol Ther 18(10):1744–1745. doi:10.1038/mt.2010.195

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Kuball J, Dossett ML, Wolfl M, Ho WY, Voss RH, Fowler C, Greenberg PD (2007) Facilitating matched pairing and expression of TCR chains introduced into human T cells. Blood 109(6):2331–2338. doi:10.1182/blood-2006-05-023069

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Chang HC, Bao Z, Yao Y, Tse AG, Goyarts EC, Madsen M, Kawasaki E, Brauer PP, Sacchettini JC, Nathenson SG et al (1994) A general method for facilitating heterodimeric pairing between two proteins: application to expression of alpha and beta T-cell receptor extracellular segments. Proc Natl Acad Sci USA 91(24):11408–11412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Kuball J, Hauptrock B, Malina V, Antunes E, Voss RH, Wolfl M, Strong R, Theobald M, Greenberg PD (2009) Increasing functional avidity of TCR-redirected T cells by removing defined N-glycosylation sites in the TCR constant domain. J Exp Med 206(2):463–475. doi:10.1084/jem.20082487

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Cohen CJ, Zhao Y, Zheng Z, Rosenberg SA, Morgan RA (2006) 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 66(17):8878–8886. doi:10.1158/0008-5472.can-06-1450

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Sommermeyer D, Uckert W (2010) Minimal amino acid exchange in human TCR constant regions fosters improved function of TCR gene-modified T cells. J Immunol 184(11):6223–6231. doi:10.4049/jimmunol.0902055

    Article  CAS  PubMed  Google Scholar 

  115. Voss RH, Thomas S, Pfirschke C, Hauptrock B, Klobuch S, Kuball J, Grabowski M, Engel R, Guillaume P, Romero P, Huber C, Beckhove P, Theobald M (2010) Coexpression of the T-cell receptor constant alpha domain triggers tumor reactivity of single-chain TCR-transduced human T cells. Blood 115(25):5154–5163. doi:10.1182/blood-2009-11-254078

    Article  CAS  PubMed  Google Scholar 

  116. Blank U, Boitel B, Mege D, Ermonval M, Acuto O (1993) Analysis of tetanus toxin peptide/DR recognition by human T cell receptors reconstituted into a murine T cell hybridoma. Eur J Immunol 23(12):3057–3065. doi:10.1002/eji.1830231203

    Article  CAS  PubMed  Google Scholar 

  117. Hastings AE, Hurley CK, Robinson ED, Salerno K, Hernandez E, Richert JR (1996) Molecular interactions between transfected human TCR, immunodominant myelin basic protein peptide 152-165, and HLA-DR13. J Immunol 157(8):3460–3471

    CAS  PubMed  Google Scholar 

  118. Roszkowski JJ, Yu DC, Rubinstein MP, McKee MD, Cole DJ, Nishimura MI (2003) CD8-independent tumor cell recognition is a property of the T cell receptor and not the T cell. J Immunol 170(5):2582–2589

    Article  CAS  PubMed  Google Scholar 

  119. Aggen DH, Chervin AS, Schmitt TM, Engels B, Stone JD, Richman SA, Piepenbrink KH, Baker BM, Greenberg PD, Schreiber H, Kranz DM (2012) Single-chain ValphaVbeta T-cell receptors function without mispairing with endogenous TCR chains. Gene Ther 19(4):365–374. doi:10.1038/gt.2011.104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Stone JD, Harris DT, Soto CM, Chervin AS, Aggen DH, Roy EJ, Kranz DM (2014) A novel T cell receptor single-chain signaling complex mediates antigen-specific T cell activity and tumor control. Cancer Immunol Immunother 63(11):1163–1176. doi:10.1007/s00262-014-1586-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Okamoto S, Mineno J, Ikeda H, Fujiwara H, Yasukawa M, Shiku H, Kato I (2009) Improved expression and reactivity of transduced tumor-specific TCRs in human lymphocytes by specific silencing of endogenous TCR. Cancer Res 69(23):9003–9011. doi:10.1158/0008-5472.can-09-1450

    Article  CAS  PubMed  Google Scholar 

  122. Provasi E, Genovese P, Lombardo A, Magnani Z, Liu PQ, Reik A, Chu V, Paschon DE, Zhang L, Kuball J, Camisa B, Bondanza A, Casorati G, Ponzoni M, Ciceri F, Bordignon C, Greenberg PD, Holmes MC, Gregory PD, Naldini L, Bonini C (2012) Editing T cell specificity towards leukemia by zinc finger nucleases and lentiviral gene transfer. Nat Med 18(5):807–815. doi:10.1038/nm.2700

    Article  CAS  PubMed  Google Scholar 

  123. Dembic Z, Haas W, Weiss S, McCubrey J, Kiefer H, von Boehmer H, Steinmetz M (1986) Transfer of specificity by murine alpha and beta T-cell receptor genes. Nature 320(6059):232–238. doi:10.1038/320232a0

    Article  CAS  PubMed  Google Scholar 

  124. Duval L, Schmidt H, Kaltoft K, Fode K, Jensen JJ, Sorensen SM, Nishimura MI, von der Maase H (2006) Adoptive transfer of allogeneic cytotoxic T lymphocytes equipped with a HLA-A2 restricted MART-1 T-cell receptor: a phase I trial in metastatic melanoma. Clin Cancer Res 12(4):1229–1236. doi:10.1158/1078-0432.ccr-05-1485

    Article  CAS  PubMed  Google Scholar 

  125. Morgan RA, Dudley ME, Wunderlich JR, Hughes MS, Yang JC, Sherry RM, Royal RE, Topalian SL, Kammula US, Restifo NP, Zheng Z, Nahvi A, de Vries CR, Rogers-Freezer LJ, Mavroukakis SA, Rosenberg SA (2006) Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314(5796):126–129. doi:10.1126/science.1129003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Robbins PF, Morgan RA, Feldman SA, Yang JC, Sherry RM, Dudley ME, Wunderlich JR, Nahvi AV, Helman LJ, Mackall CL, Kammula US, Hughes MS, Restifo NP, Raffeld M, Lee CC, Levy CL, Li YF, El-Gamil M, Schwarz SL, Laurencot C, Rosenberg SA (2011) Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J Clin Oncol 29(7):917–924. doi:10.1200/jco.2010.32.2537

    Article  PubMed  PubMed Central  Google Scholar 

  127. Morgan RA, Chinnasamy N, Abate-Daga D, Gros A, Robbins PF, Zheng Z, Dudley ME, Feldman SA, Yang JC, Sherry RM, Phan GQ, Hughes MS, Kammula US, Miller AD, Hessman CJ, Stewart AA, Restifo NP, Quezado MM, Alimchandani M, Rosenberg AZ, Nath A, Wang T, Bielekova B, Wuest SC, Akula N, McMahon FJ, Wilde S, Mosetter B, Schendel DJ, Laurencot CM, Rosenberg SA (2013) Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy. J Immunother 36(2):133–151. doi:10.1097/CJI.0b013e3182829903

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Cameron BJ, Gerry AB, Dukes J, Harper JV, Kannan V, Bianchi FC, Grand F, Brewer JE, Gupta M, Plesa G, Bossi G, Vuidepot A, Powlesland AS, Legg A, Adams KJ, Bennett AD, Pumphrey NJ, Williams DD, Binder-Scholl G, Kulikovskaya I, Levine BL, Riley JL, Varela-Rohena A, Stadtmauer EA, Rapoport AP, Linette GP, June CH, Hassan NJ, Kalos M, Jakobsen BK (2013) Identification of a Titin-derived HLA-A1-presented peptide as a cross-reactive target for engineered MAGE A3-directed T cells. Sci Transl Med 5(197):197ra103. doi:10.1126/scitranslmed.3006034

  129. Linette GP, Stadtmauer EA, Maus MV, Rapoport AP, Levine BL, Emery L, Litzky L, Bagg A, Carreno BM, Cimino PJ, Binder-Scholl GK, Smethurst DP, Gerry AB, Pumphrey NJ, Bennett AD, Brewer JE, Dukes J, Harper J, Tayton-Martin HK, Jakobsen BK, Hassan NJ, Kalos M, June CH (2013) Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma. Blood 122(6):863–871. doi:10.1182/blood-2013-03-490565

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Schub A, Schuster IG, Hammerschmidt W, Moosmann A (2009) CMV-specific TCR-transgenic T cells for immunotherapy. J Immunol 183(10):6819–6830. doi:10.4049/jimmunol.0902233

    Article  CAS  PubMed  Google Scholar 

  131. van Lent AU, Nagasawa M, van Loenen MM, Schotte R, Schumacher TN, Heemskerk MH, Spits H, Legrand N (2007) Functional human antigen-specific T cells produced in vitro using retroviral T cell receptor transfer into hematopoietic progenitors. J Immunol 179(8):4959–4968

    Article  PubMed  Google Scholar 

  132. Orentas RJ, Roskopf SJ, Nolan GP, Nishimura MI (2001) Retroviral transduction of a T cell receptor specific for an Epstein-Barr virus-encoded peptide. Clin Immunol 98(2):220–228. doi:10.1006/clim.2000.4977

    Article  CAS  PubMed  Google Scholar 

  133. Yang D, Shao Q, Sun H, Mu X, Gao Y, Jiang R, Hou J, Yao K, Chen Y, Sun B (2011) Evaluation of Epstein-Barr virus latent membrane protein 2 specific T-cell receptors driven by T-cell specific promoters using lentiviral vector. Clin Dev Immunol 2011:716926. doi:10.1155/2011/716926

    PubMed  PubMed Central  Google Scholar 

  134. Zheng Y, Parsonage G, Zhuang X, Machado LR, James CH, Salman A, Searle PF, Hui EP, Chan AT, Lee SP (2015) Human leukocyte antigen (HLA) A*1101-restricted Epstein-Barr virus-specific T-cell receptor gene transfer to target nasopharyngeal carcinoma. Cancer Immunol Res 3(10):1138–1147. doi:10.1158/2326-6066.cir-14-0203-T

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Hofmann C, Hofflin S, Huckelhoven A, Bergmann S, Harrer E, Schuler G, Dorrie J, Schaft N, Harrer T (2011) Human T cells expressing two additional receptors (TETARs) specific for HIV-1 recognize both epitopes. Blood 118(19):5174–5177. doi:10.1182/blood-2011-04-347005

    Article  CAS  PubMed  Google Scholar 

  136. Ueno T, Fujiwara M, Tomiyama H, Onodera M, Takiguchi M (2004) Reconstitution of anti-HIV effector functions of primary human CD8 T lymphocytes by transfer of HIV-specific alphabeta TCR genes. Eur J Immunol 34(12):3379–3388. doi:10.1002/eji.200425568

    Article  CAS  PubMed  Google Scholar 

  137. Varela-Rohena A, Molloy PE, Dunn SM, Li Y, Suhoski MM, Carroll RG, Milicic A, Mahon T, Sutton DH, Laugel B, Moysey R, Cameron BJ, Vuidepot A, Purbhoo MA, Cole DK, Phillips RE, June CH, Jakobsen BK, Sewell AK, Riley JL (2008) Control of HIV-1 immune escape by CD8 T cells expressing enhanced T-cell receptor. Nat Med 14(12):1390–1395. doi:10.1038/nm.1779

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Pasetto A, Frelin L, Aleman S, Holmstrom F, Brass A, Ahlen G, Brenndorfer ED, Lohmann V, Bartenschlager R, Sallberg M, Bertoletti A, Chen M (2012) TCR-redirected human T cells inhibit hepatitis C virus replication: hepatotoxic potential is linked to antigen specificity and functional avidity. J Immunol 189(9):4510–4519. doi:10.4049/jimmunol.1201613

    Article  CAS  PubMed  Google Scholar 

  139. Spear TT, Riley TP, Lyons GE, Callender GG, Roszkowski JJ, Wang Y, Simms PE, Scurti GM, Foley KC, Murray DC, Hellman LM, McMahan RH, Iwashima M, Garrett-Mayer E, Rosen HR, Baker BM, Nishimura MI (2016) Hepatitis C virus-cross-reactive TCR gene-modified T cells: a model for immunotherapy against diseases with genomic instability. J Leukoc Biol. doi:10.1189/jlb.2A1215-561R

    PubMed  Google Scholar 

  140. Scholten KB, Turksma AW, Ruizendaal JJ, van den Hende M, van der Burg SH, Heemskerk MH, Meijer CJ, Hooijberg E (2011) Generating HPV specific T helper cells for the treatment of HPV induced malignancies using TCR gene transfer. J Transl Med 9:147. doi:10.1186/1479-5876-9-147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Lyons GE, Roszkowski JJ, Man S, Yee C, Kast WM, Nishimura MI (2006) T-cell receptor tetramer binding or the lack there of does not necessitate antigen reactivity in T-cell receptor transduced T cells. Cancer Immunol Immunother 55(9):1142–1150. doi:10.1007/s00262-005-0103-9

    Article  CAS  PubMed  Google Scholar 

  142. Wilkie S, van Schalkwyk MC, Hobbs S, Davies DM, van der Stegen SJ, Pereira AC, Burbridge SE, Box C, Eccles SA, Maher J (2012) Dual targeting of ErbB2 and MUC1 in breast cancer using chimeric antigen receptors engineered to provide complementary signaling. J Clin Immunol 32(5):1059–1070. doi:10.1007/s10875-012-9689-9

    Article  CAS  PubMed  Google Scholar 

  143. 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(215):215ra172. doi:10.1126/scitranslmed.3006597

  144. Liu K, Rosenberg SA (2001) Transduction of an IL-2 gene into human melanoma-reactive lymphocytes results in their continued growth in the absence of exogenous IL-2 and maintenance of specific antitumor activity. J Immunol 167(11):6356–6365

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Kerkar SP, Muranski P, Kaiser A, Boni A, Sanchez-Perez L, Yu Z, Palmer DC, Reger RN, Borman ZA, Zhang L, Morgan RA, Gattinoni L, Rosenberg SA, Trinchieri G, Restifo NP (2010) Tumor-specific CD8+ T cells expressing interleukin-12 eradicate established cancers in lymphodepleted hosts. Cancer Res 70(17):6725–6734. doi:10.1158/0008-5472.can-10-0735

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Spear P, Barber A, Rynda-Apple A, Sentman CL (2012) Chimeric antigen receptor T cells shape myeloid cell function within the tumor microenvironment through IFN-gamma and GM-CSF. J Immunol 188(12):6389–6398. doi:10.4049/jimmunol.1103019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Kerkar SP, Goldszmid RS, Muranski P, Chinnasamy D, Yu Z, Reger RN, Leonardi AJ, Morgan RA, Wang E, Marincola FM, Trinchieri G, Rosenberg SA, Restifo NP (2011) IL-12 triggers a programmatic change in dysfunctional myeloid-derived cells within mouse tumors. J Clin Invest 121(12):4746–4757. doi:10.1172/jci58814

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Koneru M, O’Cearbhaill R, Pendharkar S, Spriggs DR, Brentjens RJ (2015) A phase I clinical trial of adoptive T cell therapy using IL-12 secreting MUC-16(ecto) directed chimeric antigen receptors for recurrent ovarian cancer. J Transl Med 13:102. doi:10.1186/s12967-015-0460-x

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  149. Craddock JA, Lu A, Bear A, Pule M, Brenner MK, Rooney CM, Foster AE (2010) Enhanced tumor trafficking of GD2 chimeric antigen receptor T cells by expression of the chemokine receptor CCR2b. J Immunother 33(8):780–788. doi:10.1097/CJI.0b013e3181ee6675

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Kershaw MH, Wang G, Westwood JA, Pachynski RK, Tiffany HL, Marincola FM, Wang E, Young HA, Murphy PM, Hwu P (2002) Redirecting migration of T cells to chemokine secreted from tumors by genetic modification with CXCR2. Hum Gene Ther 13(16):1971–1980. doi:10.1089/10430340260355374

    Article  CAS  PubMed  Google Scholar 

  151. Chinnasamy D, Yu Z, Kerkar SP, Zhang L, Morgan RA, Restifo NP, Rosenberg SA (2012) Local delivery of interleukin-12 using T cells targeting VEGF receptor-2 eradicates multiple vascularized tumors in mice. Clin Cancer Res 18(6):1672–1683. doi:10.1158/1078-0432.ccr-11-3050

    Article  CAS  PubMed  Google Scholar 

  152. Legler DF, Johnson-Leger C, Wiedle G, Bron C, Imhof BA (2004) The alpha v beta 3 integrin as a tumor homing ligand for lymphocytes. Eur J Immunol 34(6):1608–1616. doi:10.1002/eji.200424938

    Article  CAS  PubMed  Google Scholar 

  153. Buckanovich RJ, Facciabene A, Kim S, Benencia F, Sasaroli D, Balint K, Katsaros D, O’Brien-Jenkins A, Gimotty PA, Coukos G (2008) Endothelin B receptor mediates the endothelial barrier to T cell homing to tumors and disables immune therapy. Nat Med 14(1):28–36. doi:10.1038/nm1699

    Article  CAS  PubMed  Google Scholar 

  154. Dudley ME, Yang JC, Sherry R, Hughes MS, Royal R, Kammula U, Robbins PF, Huang J, Citrin DE, Leitman SF, Wunderlich J, Restifo NP, Thomasian A, Downey SG, Smith FO, Klapper J, Morton K, Laurencot C, White DE, Rosenberg SA (2008) Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J Clin Oncol 26(32):5233–5239. doi:10.1200/jco.2008.16.5449

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Wallen H, Thompson JA, Reilly JZ, Rodmyre RM, Cao J, Yee C (2009) Fludarabine modulates immune response and extends in vivo survival of adoptively transferred CD8 T cells in patients with metastatic melanoma. PLoS ONE 4(3):e4749. doi:10.1371/journal.pone.0004749

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  156. Khammari A, Labarriere N, Vignard V, Nguyen JM, Pandolfino MC, Knol AC, Quereux G, Saiagh S, Brocard A, Jotereau F, Dreno B (2009) Treatment of metastatic melanoma with autologous Melan-A/MART-1-specific cytotoxic T lymphocyte clones. J Invest Dermatol 129(12):2835–2842. doi:10.1038/jid.2009.144

    Article  CAS  PubMed  Google Scholar 

  157. Gattinoni L, Finkelstein SE, Klebanoff CA, Antony PA, Palmer DC, Spiess PJ, Hwang LN, Yu Z, Wrzesinski C, Heimann DM, Surh CD, Rosenberg SA, Restifo NP (2005) Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells. J Exp Med 202(7):907–912. doi:10.1084/jem.20050732

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Cho BK, Rao VP, Ge Q, Eisen HN, Chen J (2000) Homeostasis-stimulated proliferation drives naive T cells to differentiate directly into memory T cells. J Exp Med 192(4):549–556

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Kedl RM, Rees WA, Hildeman DA, Schaefer B, Mitchell T, Kappler J, Marrack P (2000) T cells compete for access to antigen-bearing antigen-presenting cells. J Exp Med 192(8):1105–1113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Antony PA, Piccirillo CA, Akpinarli A, Finkelstein SE, Speiss PJ, Surman DR, Palmer DC, Chan CC, Klebanoff CA, Overwijk WW, Rosenberg SA, Restifo NP (2005) CD8+ T cell immunity against a tumor/self-antigen is augmented by CD4+ T helper cells and hindered by naturally occurring T regulatory cells. J Immunol 174(5):2591–2601

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Besser MJ, Shapira-Frommer R, Itzhaki O, Treves AJ, Zippel DB, Levy D, Kubi A, Shoshani N, Zikich D, Ohayon Y, Ohayon D, Shalmon B, Markel G, Yerushalmi R, Apter S, Ben-Nun A, Ben-Ami E, Shimoni A, Nagler A, Schachter J (2013) Adoptive transfer of tumor-infiltrating lymphocytes in patients with metastatic melanoma: intent-to-treat analysis and efficacy after failure to prior immunotherapies. Clin Cancer Res 19(17):4792–4800. doi:10.1158/1078-0432.ccr-13-0380

    Article  CAS  PubMed  Google Scholar 

  162. Ellebaek E, Iversen TZ, Junker N, Donia M, Engell-Noerregaard L, Met O, Holmich LR, Andersen RS, Hadrup SR, Andersen MH, thor Straten P, Svane IM (2012) Adoptive cell therapy with autologous tumor infiltrating lymphocytes and low-dose Interleukin-2 in metastatic melanoma patients. J Transl Med 10:169. doi:10.1186/1479-5876-10-169

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Butler MO, Friedlander P, Milstein MI, Mooney MM, Metzler G, Murray AP, Tanaka M, Berezovskaya A, Imataki O, Drury L, Brennan L, Flavin M, Neuberg D, Stevenson K, Lawrence D, Hodi FS, Velazquez EF, Jaklitsch MT, Russell SE, Mihm M, Nadler LM, Hirano N (2011) Establishment of antitumor memory in humans using in vitro-educated CD8+ T cells. Sci Transl Med 3(80):80ra34. doi:10.1126/scitranslmed.3002207

  164. Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, Jungbluth A, Gnjatic S, Thompson JA, Yee C (2008) Treatment of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N Engl J Med 358(25):2698–2703. doi:10.1056/NEJMoa0800251

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Ciceri F, Bonini C, Stanghellini MT, Bondanza A, Traversari C, Salomoni M, Turchetto L, Colombi S, Bernardi M, Peccatori J, Pescarollo A, Servida P, Magnani Z, Perna SK, Valtolina V, Crippa F, Callegaro L, Spoldi E, Crocchiolo R, Fleischhauer K, Ponzoni M, Vago L, Rossini S, Santoro A, Todisco E, Apperley J, Olavarria E, Slavin S, Weissinger EM, Ganser A, Stadler M, Yannaki E, Fassas A, Anagnostopoulos A, Bregni M, Stampino CG, Bruzzi P, Bordignon C (2009) 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 10(5):489–500. doi:10.1016/s1470-2045(09)70074-9

    Article  PubMed  Google Scholar 

  166. Recchia A, Bonini C, Magnani Z, Urbinati F, Sartori D, Muraro S, Tagliafico E, Bondanza A, Stanghellini MT, Bernardi M, Pescarollo A, Ciceri F, Bordignon C, Mavilio F (2006) Retroviral vector integration deregulates gene expression but has no consequence on the biology and function of transplanted T cells. Proc Natl Acad Sci USA 103(5):1457–1462. doi:10.1073/pnas.0507496103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Berger C, Flowers ME, 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(6):2294–2302. doi:10.1182/blood-2005-08-3503

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Riddell SR, Elliott M, Lewinsohn DA, Gilbert MJ, Wilson L, Manley SA, Lupton SD, Overell RW, Reynolds TC, Corey L, Greenberg PD (1996) T-cell mediated rejection of gene-modified HIV-specific cytotoxic T lymphocytes in HIV-infected patients. Nat Med 2(2):216–223

    Article  CAS  PubMed  Google Scholar 

  169. Budde LE, Berger C, Lin Y, Wang J, Lin X, Frayo SE, Brouns SA, Spencer DM, Till BG, Jensen MC, Riddell SR, Press OW (2013) 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 8(12):e82742. doi:10.1371/journal.pone.0082742

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  170. Di Stasi A, Tey SK, Dotti G, Fujita Y, Kennedy-Nasser A, Martinez C, Straathof K, Liu E, Durett AG, Grilley B, Liu H, Cruz CR, Savoldo B, Gee AP, Schindler J, Krance RA, Heslop HE, Spencer DM, Rooney CM, Brenner MK (2011) Inducible apoptosis as a safety switch for adoptive cell therapy. N Engl J Med 365(18):1673–1683. doi:10.1056/NEJMoa1106152

    Article  PubMed  PubMed Central  Google Scholar 

  171. Hoyos V, Savoldo B, Quintarelli C, Mahendravada A, Zhang M, Vera J, Heslop HE, Rooney CM, Brenner MK, Dotti G (2010) Engineering CD19-specific T lymphocytes with interleukin-15 and a suicide gene to enhance their anti-lymphoma/leukemia effects and safety. Leukemia 24(6):1160–1170. doi:10.1038/leu.2010.75

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Straathof KC, Pule MA, Yotnda P, Dotti G, Vanin EF, Brenner MK, Heslop HE, Spencer DM, Rooney CM (2005) An inducible caspase 9 safety switch for T-cell therapy. Blood 105(11):4247–4254. doi:10.1182/blood-2004-11-4564

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Griffioen M, van Egmond EH, Kester MG, Willemze R, Falkenburg JH, Heemskerk MH (2009) Retroviral transfer of human CD20 as a suicide gene for adoptive T-cell therapy. Haematologica 94(9):1316–1320. doi:10.3324/haematol.2008.001677

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Wang X, Chang WC, Wong CW, Colcher D, Sherman M, Ostberg JR, Forman SJ, Riddell SR, Jensen MC (2011) A transgene-encoded cell surface polypeptide for selection, in vivo tracking, and ablation of engineered cells. Blood 118(5):1255–1263. doi:10.1182/blood-2011-02-337360

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Nagaraj S, Gupta K, Pisarev V, Kinarsky L, Sherman S, Kang L, Herber DL, Schneck J, Gabrilovich DI (2007) Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer. Nat Med 13(7):828–835. doi:10.1038/nm1609

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Chhabra A, Yang L, Wang P, Comin-Anduix B, Das R, Chakraborty NG, Ray S, Mehrotra S, Yang H, Hardee CL, Hollis R, Dorsky DI, Koya R, Kohn DB, Ribas A, Economou JS, Baltimore D, Mukherji B (2008) CD4+ CD25− T cells transduced to express MHC class I-restricted epitope-specific TCR synthesize Th1 cytokines and exhibit MHC class I-restricted cytolytic effector function in a human melanoma model. J Immunol 181(2):1063–1070

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Ray S, Chhabra A, Chakraborty NG, Hegde U, Dorsky DI, Chodon T, von Euw E, Comin-Anduix B, Koya RC, Ribas A, Economou JS, Rosenberg SA, Mukherji B (2010) MHC-I-restricted melanoma antigen specific TCR-engineered human CD4+ T cells exhibit multifunctional effector and helper responses, in vitro. Clin Immunol 136(3):338–347. doi:10.1016/j.clim.2010.04.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Eisen HN, Sykulev Y, Tsomides TJ (1996) Antigen-specific T-cell receptors and their reactions with complexes formed by peptides with major histocompatibility complex proteins. Adv Protein Chem 49:1–56

    Article  CAS  PubMed  Google Scholar 

  179. Vitiello A, Marchesini D, Furze J, Sherman LA, Chesnut RW (1991) Analysis of the HLA-restricted influenza-specific cytotoxic T lymphocyte response in transgenic mice carrying a chimeric human-mouse class I major histocompatibility complex. J Exp Med 173(4):1007–1015

    Article  CAS  PubMed  Google Scholar 

  180. Parkhurst MR, Joo J, Riley JP, Yu Z, Li Y, Robbins PF, Rosenberg SA (2009) Characterization of genetically modified T-cell receptors that recognize the CEA:691-699 peptide in the context of HLA-A2.1 on human colorectal cancer cells. Clin Cancer Res 15(1):169–180. doi:10.1158/1078-0432.ccr-08-1638

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Kuball J, Schmitz FW, Voss RH, Ferreira EA, Engel R, Guillaume P, Strand S, Romero P, Huber C, Sherman LA, Theobald M (2005) Cooperation of human tumor-reactive CD4+ and CD8+ T cells after redirection of their specificity by a high-affinity p53A2.1-specific TCR. Immunity 22(1):117–129. doi:10.1016/j.immuni.2004.12.005

    Article  CAS  PubMed  Google Scholar 

  182. Holler PD, Holman PO, Shusta EV, O’Herrin S, Wittrup KD, Kranz DM (2000) In vitro evolution of a T cell receptor with high affinity for peptide/MHC. Proc Natl Acad Sci USA 97(10):5387–5392. doi:10.1073/pnas.080078297

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Li Y, Moysey R, Molloy PE, Vuidepot AL, Mahon T, Baston E, Dunn S, Liddy N, Jacob J, Jakobsen BK, Boulter JM (2005) Directed evolution of human T-cell receptors with picomolar affinities by phage display. Nat Biotechnol 23(3):349–354. doi:10.1038/nbt1070

    Article  CAS  PubMed  Google Scholar 

  184. Zhao Y, Bennett AD, Zheng Z, Wang QJ, Robbins PF, Yu LY, Li Y, Molloy PE, Dunn SM, Jakobsen BK, Rosenberg SA, Morgan RA (2007) High-affinity TCRs generated by phage display provide CD4+ T cells with the ability to recognize and kill tumor cell lines. J Immunol 179(9):5845–5854

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Chlewicki LK, Holler PD, Monti BC, Clutter MR, Kranz DM (2005) High-affinity, peptide-specific T cell receptors can be generated by mutations in CDR1, CDR2 or CDR3. J Mol Biol 346(1):223–239. doi:10.1016/j.jmb.2004.11.057

    Article  CAS  PubMed  Google Scholar 

  186. de Witte MA, Kierkels GJ, Straetemans T, Britten CM, Kuball J (2015) Orchestrating an immune response against cancer with engineered immune cells expressing alphabetaTCRs, CARs, and innate immune receptors: an immunological and regulatory challenge. Cancer Immunol Immunother 64(7):893–902. doi:10.1007/s00262-015-1710-8

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  187. Guest RD, Kirillova N, Mowbray S, Gornall H, Rothwell DG, Cheadle EJ, Austin E, Smith K, Watt SM, Kuhlcke K, Westwood N, Thistlethwaite F, Hawkins RE, Gilham DE (2014) Definition and application of good manufacturing process-compliant production of CEA-specific chimeric antigen receptor expressing T-cells for phase I/II clinical trial. Cancer Immunol Immunother 63(2):133–145. doi:10.1007/s00262-013-1492-9

    Article  CAS  PubMed  Google Scholar 

  188. Krug C, Wiesinger M, Abken H, Schuler-Thurner B, Schuler G, Dorrie J, Schaft N (2014) A GMP-compliant protocol to expand and transfect cancer patient T cells with mRNA encoding a tumor-specific chimeric antigen receptor. Cancer Immunol Immunother 63(10):999–1008. doi:10.1007/s00262-014-1572-5

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors would like to acknowledge funding kindly provided by the National Cancer Institute of the National Institutes of Health. These include Grants P01 CA154778 (Nishimura) and F30 CA180731 (Spear).

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  1. Department of Surgery, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Loyola University Chicago, 2160 S. 1st Ave, Bldg 112, Room 308, Maywood, IL, 60153, USA

    Timothy T. Spear, Kaoru Nagato & Michael I. Nishimura

  2. Department of General Thoracic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan

    Kaoru Nagato

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Spear, T.T., Nagato, K. & Nishimura, M.I. Strategies to genetically engineer T cells for cancer immunotherapy. Cancer Immunol Immunother 65, 631–649 (2016). https://doi.org/10.1007/s00262-016-1842-5

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