Skip to main content
SpringerLink
Log in

Influence of Antigen Receptor Avidity, Affinity, and Specificity on Genetically Engineered T Cells

  • Chapter
Developments in T Cell Based Cancer Immunotherapies

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

  • 1781 Accesses

Abstract

Affinity of a T cell receptor (TCR) refers to the strength of binding between a single TCR and a peptide/MHC (pMHC) complex while avidity of a TCR refers to the overall strength of binding between multiple cell-bound receptors and their ligands. Affinity of a TCR plays a role in thymic T cell selection and the generation of the TCR repertoire. In the absence of sensitivity to strong or weak antigen receptor signals, the homeostasis of the immune system is compromised and the risk of autoimmunity and/or infection ensues. Over the past few decades, T cells which have been genetically modified to target tumor antigens have been used to treat cancer patients. Antibody-based chimeric antigen receptors (CAR) were the first molecules used to redirect the specificity of normal T cells. CAR gene modified T cells can direct tumor rejection in mice and humans. Another class of receptors used to redirect the specificity of T cells is the T cell receptor (TCR). TCR gene modified T cells can also direct tumor rejection in mice and humans. CAR and TCR engineered T cells reactive against tumors have emerged as a promising advance in tumor immunotherapy. The rationale of this chapter is to study how CAR and TCR gene modified T cells modulate tumor immunity.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Rosenberg SA, Restifo NP, Yang JC, Morgan RA, Dudley ME (2008) Adoptive cell transfer: a clinical path to effective cancer immunotherapy. Nat Rev Cancer 8(4):299–308

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. June CH, Blazar BR, Riley JL (2009) Engineering lymphocyte subsets: tools, trials and tribulations. Nat Rev Immunol 9(10):704–716

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Weber J, Atkins M, Hwu P, Radvanyi L, Sznol M, Yee C (2011) White paper on adoptive cell therapy for cancer with tumor-infiltrating lymphocytes: a report of the CTEP subcommittee on adoptive cell therapy. Clin Cancer Res 17(7):1664–1673

    Article  CAS  PubMed  Google Scholar 

  4. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, Royal RE, Kammula U, White DE, Mavroukakis SA, Rogers LJ, Gracia GJ, Jones SA, Mangiameli DP, Pelletier MM, Gea-Banacloche J, Robinson MR, Berman DM, Filie AC, Abati A, Rosenberg SA (2005) Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol 23(10):2346–2357

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Stevanovic S, Draper LM, Langhan MM, Campbell TE, Kwong ML, Wunderlich JR, Dudley ME, Yang JC, Sherry RM, Kammula US, Restifo NP, Rosenberg SA, Hinrichs CS (2015) Complete regression of metastatic cervical cancer after treatment with human papillomavirus-targeted tumor-infiltrating T cells. J Clin Oncol 33(14):1543–1550

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 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 U S A 86(24):10024–10028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. 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 

  10. Zhang T, Lemoi BA, Sentman CL (2005) Chimeric NK-receptor-bearing T cells mediate antitumor immunotherapy. Blood 106(5):1544–1551

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Curran KJ, Pegram HJ, Brentjens RJ (2012) Chimeric antigen receptors for T cell immunotherapy: current understanding and future directions. J Gene Med 14(6):405–415

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Jensen MC, Riddell SR (2015) Designing chimeric antigen receptors to effectively and safely target tumors. Curr Opin Immunol 33:9–15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Cambier JC (1995) Antigen and Fc receptor signaling. The awesome power of the immunoreceptor tyrosine-based activation motif (ITAM). J Immunol 155(7):3281–3285

    CAS  PubMed  Google Scholar 

  14. Romeo C, Seed B (1991) Cellular immunity to HIV activated by CD4 fused to T cell or Fc receptor polypeptides. Cell 64(5):1037–1046

    Article  CAS  PubMed  Google Scholar 

  15. Romeo C, Kolanus W, Amiot M, Seed B (1992) Activation of immune system effector function by T-cell or Fc receptor intracellular domains. Cold Spring Harb Symp Quant Biol 57:117–125

    Article  CAS  PubMed  Google Scholar 

  16. 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 

  17. Eshhar Z (2010) Adoptive cancer immunotherapy using genetically engineered designer T-cells: first steps into the clinic. Curr Opin Mol Ther 12(1):55–63

    CAS  PubMed  Google Scholar 

  18. Pegram HJ, Park JH, Brentjens RJ (2014) CD28z CARs and armored CARs. Cancer J 20(2):127–133

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. 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

    Article  CAS  PubMed  Google Scholar 

  20. 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

    Article  CAS  PubMed  Google Scholar 

  21. Moeller M, Haynes NM, Kershaw MH, Jackson JT, Teng MW, Street SE, Cerutti L, Jane SM, Trapani JA, Smyth MJ, Darcy PK (2005) Adoptive transfer of gene-engineered CD4+ helper T cells induces potent primary and secondary tumor rejection. Blood 106(9):2995–3003

    Article  CAS  PubMed  Google Scholar 

  22. Dotti G, Gottschalk S, Savoldo B, Brenner MK (2014) Design and development of therapies using chimeric antigen receptor-expressing T cells. Immunol Rev 257(1):107–126

    Article  CAS  PubMed  Google Scholar 

  23. Jena B, Moyes JS, Huls H, Cooper LJ (2014) Driving CAR-based T-cell therapy to success. Curr Hematol Malig Rep 9(1):50–56

    Article  PubMed  PubMed Central  Google Scholar 

  24. Jensen MC, Riddell SR (2014) Design and implementation of adoptive therapy with chimeric antigen receptor-modified T cells. Immunol Rev 257(1):127–144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Zhao A, Tohidkia MR, Siegel DL, Coukos G, Omidi Y (2014) Phage antibody display libraries: a powerful antibody discovery platform for immunotherapy. Crit Rev Biotechnol 1–14

    Google Scholar 

  26. Iannello A, Raulet DH (2013) Immune surveillance of unhealthy cells by natural killer cells. Cold Spring Harb Symp Quant Biol 78:249–257

    Article  PubMed  PubMed Central  Google Scholar 

  27. Paschen A, Baingo J, Schadendorf D (2014) Expression of stress ligands of the immunoreceptor NKG2D in melanoma: regulation and clinical significance. Eur J Cell Biol 93(1–2):49–54

    Article  CAS  PubMed  Google Scholar 

  28. Sentman CL, Meehan KR (2014) NKG2D CARs as cell therapy for cancer. Cancer J 20(2):156–159

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Zhang T, Barber A, Sentman CL (2007) Chimeric NKG2D modified T cells inhibit systemic T-cell lymphoma growth in a manner involving multiple cytokines and cytotoxic pathways. Cancer Res 67(22):11029–11036

    Article  CAS  PubMed  Google Scholar 

  30. Barber A, Meehan KR, Sentman CL (2011) Treatment of multiple myeloma with adoptively transferred chimeric NKG2D receptor-expressing T cells. Gene Ther 18(5):509–516

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Barber A, Zhang T, Sentman CL (2008) Immunotherapy with chimeric NKG2D receptors leads to long-term tumor-free survival and development of host antitumor immunity in murine ovarian cancer. J Immunol 180(1):72–78

    Article  CAS  PubMed  Google Scholar 

  32. Barber A, Rynda A, Sentman CL (2009) Chimeric NKG2D expressing T cells eliminate immunosuppression and activate immunity within the ovarian tumor microenvironment. J Immunol 183(11):6939–6947

    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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Chang YH, Connolly J, Shimasaki N, Mimura K, Kono K, Campana D (2013) A chimeric receptor with NKG2D specificity enhances natural killer cell activation and killing of tumor cells. Cancer Res 73(6):1777–1786

    Article  CAS  PubMed  Google Scholar 

  35. McIntyre BW, Allison JP (1983) The mouse T cell receptor: structural heterogeneity of molecules of normal T cells defined by xenoantiserum. Cell 34(3):739–746

    Article  CAS  PubMed  Google Scholar 

  36. Sangster RN, Minowada J, Suciu-Foca N, Minden M, Mak TW (1986) Rearrangement and expression of the alpha, beta, and gamma chain T cell receptor genes in human thymic leukemia cells and functional T cells. J Exp Med 163(6):1491–1508

    Article  CAS  PubMed  Google Scholar 

  37. Toyonaga B, Mak TW (1987) Genes of the T-cell antigen receptor in normal and malignant T cells. Annu Rev Immunol 5:585–620

    Article  CAS  PubMed  Google Scholar 

  38. Bjorkman PJ, Saper MA, Samraoui B, Bennett WS, Strominger JL, Wiley DC (1987) The foreign antigen binding site and T cell recognition regions of class I histocompatibility antigens. Nature 329(6139):512–518

    Article  CAS  PubMed  Google Scholar 

  39. Davis MM, Bjorkman PJ (1989) A model for T cell receptor and MHC/peptide interaction. Adv Exp Med Biol 254:13–16

    CAS  PubMed  Google Scholar 

  40. Davis MM, Chien YH, Bjorkman PJ, Elliott JF, Iwashima M, Rock EP, Patten PA (1989) A possible basis for major histocompatibility complex-restricted T-cell recognition. Philos Trans R Soc Lond B Biol Sci 323(1217):521–524

    Article  CAS  PubMed  Google Scholar 

  41. Brown JH, Jardetzky TS, Gorga JC, Stern LJ, Urban RG, Strominger JL, Wiley DC (1993) Three-dimensional structure of the human class II histocompatibility antigen HLA-DR1. Nature 364(6432):33–39

    Article  CAS  PubMed  Google Scholar 

  42. Stern LJ, Brown JH, Jardetzky TS, Gorga JC, Urban RG, Strominger JL, Wiley DC (1994) Crystal structure of the human class II MHC protein HLA-DR1 complexed with an influenza virus peptide. Nature 368(6468):215–221

    Article  CAS  PubMed  Google Scholar 

  43. Davis MM, Boniface JJ, Reich Z, Lyons D, Hampl J, Arden B, Chien Y (1998) Ligand recognition by alpha beta T cell receptors. Annu Rev Immunol 16:523–544

    Article  CAS  PubMed  Google Scholar 

  44. Shilyansky J, Nishimura MI, Yannelli JR, Kawakami Y, Jacknin LS, Charmley P, Rosenberg SA (1994) T-cell receptor usage by melanoma-specific clonal and highly oligoclonal tumor-infiltrating lymphocyte lines. Proc Natl Acad Sci U S A 91(7):2829–2833

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. 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 

  46. 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

    Article  CAS  PubMed  Google Scholar 

  47. Stanislawski T, Voss RH, Lotz C, Sadovnikova E, Willemsen RA, Kuball J, Ruppert T, Bolhuis RL, Melief CJ, Huber C, Stauss HJ, Theobald M (2001) Circumventing tolerance to a human MDM2-derived tumor antigen by TCR gene transfer. Nat Immunol 2(10):962–970

    Article  CAS  PubMed  Google Scholar 

  48. Heemskerk MH, Hoogeboom M, de Paus RA, Kester MG, van der Hoorn MA, Goulmy E, Willemze R, Falkenburg JH (2003) Redirection of antileukemic reactivity of peripheral T lymphocytes using gene transfer of minor histocompatibility antigen HA-2-specific T-cell receptor complexes expressing a conserved alpha joining region. Blood 102(10):3530–3540

    Article  CAS  PubMed  Google Scholar 

  49. Morgan RA, Dudley ME, Yu YY, Zheng Z, Robbins PF, Theoret MR, Wunderlich JR, Hughes MS, Restifo NP, Rosenberg SA (2003) High efficiency TCR gene transfer into primary human lymphocytes affords avid recognition of melanoma tumor antigen glycoprotein 100 and does not alter the recognition of autologous melanoma antigens. J Immunol 171(6):3287–3295

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. 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 

  51. Heemskerk MH, Hoogeboom M, Hagedoorn R, Kester MG, Willemze R, Falkenburg JH (2004) Reprogramming of virus-specific T cells into leukemia-reactive T cells using T cell receptor gene transfer. J Exp Med 199(7):885–894

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Hughes MS, Yu YY, Dudley ME, Zheng Z, Robbins PF, Li Y, Wunderlich J, Hawley RG, Moayeri M, Rosenberg SA, Morgan RA (2005) Transfer of a TCR gene derived from a patient with a marked antitumor response conveys highly active T-cell effector functions. Hum Gene Ther 16(4):457–472

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. 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

    Article  CAS  PubMed  Google Scholar 

  54. Mommaas B, van Halteren AG, Pool J, van der Veken L, Wieles B, Heemskerk MH, Goulmy E (2005) Adult and cord blood T cells can acquire HA-1 specificity through HA-1 T-cell receptor gene transfer. Haematologica 90(10):1415–1421

    CAS  PubMed  Google Scholar 

  55. 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

    Article  CAS  PubMed  Google Scholar 

  56. Zhao Y, Zheng Z, Robbins PF, Khong HT, Rosenberg SA, Morgan RA (2005) Primary human lymphocytes transduced with NY-ESO-1 antigen-specific TCR genes recognize and kill diverse human tumor cell lines. J Immunol 174(7):4415–4423

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. 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

    Article  CAS  PubMed  Google Scholar 

  58. 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

    Article  CAS  PubMed  Google Scholar 

  59. Zhao Y, Zheng Z, Khong HT, Rosenberg SA, Morgan RA (2006) Transduction of an HLA-DP4-restricted NY-ESO-1-specific TCR into primary human CD4+ lymphocytes. J Immunother 29(4):398–406

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Gostick E, Cole DK, Hutchinson SL, Wooldridge L, Tafuro S, Laugel B, Lissina A, Oxenius A, Boulter JM, Price DA, Sewell AK (2007) Functional and biophysical characterization of an HLA-A*6801-restricted HIV-specific T cell receptor. Eur J Immunol 37(2):479–486

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Purbhoo MA, Li Y, Sutton DH, Brewer JE, Gostick E, Bossi G, Laugel B, Moysey R, Baston E, Liddy N, Cameron B, Bennett AD, Ashfield R, Milicic A, Price DA, Classon BJ, Sewell AK, Jakobsen BK (2007) The HLA A*0201-restricted hTERT(540–548) peptide is not detected on tumor cells by a CTL clone or a high-affinity T-cell receptor. Mol Cancer Ther 6(7):2081–2091

    Article  CAS  PubMed  Google Scholar 

  62. 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 

  63. Hiasa A, Hirayama M, Nishikawa H, Kitano S, Nukaya I, Yu SS, Mineno J, Kato I, Shiku H (2008) Long-term phenotypic, functional and genetic stability of cancer-specific T-cell receptor (TCR) alphabeta genes transduced to CD8+ T cells. Gene Ther 15(9):695–699

    Article  CAS  PubMed  Google Scholar 

  64. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Voelkl S, Moore TV, Rehli M, Nishimura MI, Mackensen A, Fischer K (2009) Characterization of MHC class-I restricted TCRalphabeta + CD4–CD8- double negative T cells recognizing the gp100 antigen from a melanoma patient after gp100 vaccination. Cancer Immunol Immunother 58(5):709–718

    Article  CAS  PubMed  Google Scholar 

  66. 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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Chinnasamy N, Wargo JA, Yu Z, Rao M, Frankel TL, Riley JP, Hong JJ, Parkhurst MR, Feldman SA, Schrump DS, Restifo NP, Robbins PF, Rosenberg SA, Morgan RA (2011) A TCR targeting the HLA-A*0201-restricted epitope of MAGE-A3 recognizes multiple epitopes of the MAGE-A antigen superfamily in several types of cancer. J Immunol 186(2):685–696

    Article  CAS  PubMed  Google Scholar 

  68. Ochi T, Fujiwara H, Okamoto S, An J, Nagai K, Shirakata T, Mineno J, Kuzushima K, Shiku H, Yasukawa M (2011) Novel adoptive T-cell immunotherapy using a WT1-specific TCR vector encoding silencers for endogenous TCRs shows marked antileukemia reactivity and safety. Blood 118(6):1495–1503

    Article  CAS  PubMed  Google Scholar 

  69. 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

    Article  CAS  PubMed  Google Scholar 

  70. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Spranger S, Jeremias I, Wilde S, Leisegang M, Starck L, Mosetter B, Uckert W, Heemskerk MH, Schendel DJ, Frankenberger B (2012) TCR-transgenic lymphocytes specific for HMMR/Rhamm limit tumor outgrowth in vivo. Blood 119(15):3440–3449

    Article  CAS  PubMed  Google Scholar 

  72. Linnemann C, Heemskerk B, Kvistborg P, Kluin RJ, Bolotin DA, Chen X, Bresser K, Nieuwland M, Schotte R, Michels S, Gomez-Eerland R, Jahn L, Hombrink P, Legrand N, Shu CJ, Mamedov IZ, Velds A, Blank CU, Haanen JB, Turchaninova MA, Kerkhoven RM, Spits H, Hadrup SR, Heemskerk MH, Blankenstein T, Chudakov DM, Bendle GM, Schumacher TN (2013) High-throughput identification of antigen-specific TCRs by TCR gene capture. Nat Med 19(11):1534–1541

    Article  CAS  PubMed  Google Scholar 

  73. Miyazaki Y, Fujiwara H, Asai H, Ochi F, Ochi T, Azuma T, Ishida T, Okamoto S, Mineno J, Kuzushima K, Shiku H, Yasukawa M (2013) Development of a novel redirected T-cell-based adoptive immunotherapy targeting human telomerase reverse transcriptase for adult T-cell leukemia. Blood 121(24):4894–4901

    Article  CAS  PubMed  Google Scholar 

  74. Schmitt TM, Aggen DH, Stromnes IM, Dossett ML, Richman SA, Kranz DM, Greenberg PD (2013) Enhanced-affinity murine T-cell receptors for tumor/self-antigens can be safe in gene therapy despite surpassing the threshold for thymic selection. Blood 122(3):348–356

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Abate-Daga D, Speiser DE, Chinnasamy N, Zheng Z, Xu H, Feldman SA, Rosenberg SA, Morgan RA (2014) Development of a T cell receptor targeting an HLA-A*0201 restricted epitope from the cancer-testis antigen SSX2 for adoptive immunotherapy of cancer. PLoS One 9(3), e93321

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Rosati SF, Parkhurst MR, Hong Y, Zheng Z, Feldman SA, Rao M, Abate-Daga D, Beard RE, Xu H, Black MA, Robbins PF, Schrump DA, Rosenberg SA, Morgan RA (2014) A novel murine T-cell receptor targeting NY-ESO-1. J Immunother 37(3):135–146

    Article  CAS  PubMed  Google Scholar 

  77. 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

    Article  CAS  PubMed  Google Scholar 

  78. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Koya RC, Mok S, Comin-Anduix B, Chodon T, Radu CG, Nishimura MI, Witte ON, Ribas A (2010) Kinetic phases of distribution and tumor targeting by T cell receptor engineered lymphocytes inducing robust antitumor responses. Proc Natl Acad Sci U S A 107(32):14286–14291

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. 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

    Article  PubMed  PubMed Central  Google Scholar 

  81. 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

    Article  CAS  PubMed  Google Scholar 

  82. Shirakura Y, Mizuno Y, Wang L, Imai N, Amaike C, Sato E, Ito M, Nukaya I, Mineno J, Takesako K, Ikeda H, Shiku H (2012) T-cell receptor gene therapy targeting melanoma-associated antigen-A4 inhibits human tumor growth in non-obese diabetic/SCID/gammacnull mice. Cancer Sci 103(1):17–25

    Article  CAS  PubMed  Google Scholar 

  83. Chinnasamy D, Tran E, Yu Z, Morgan RA, Restifo NP, Rosenberg SA (2013) Simultaneous targeting of tumor antigens and the tumor vasculature using T lymphocyte transfer synergize to induce regression of established tumors in mice. Cancer Res 73(11):3371–3380

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Chodon T, Comin-Anduix B, Chmielowski B, Koya RC, Wu Z, Auerbach M, Ng C, Avramis E, Seja E, Villanueva A, McCannel TA, Ishiyama A, Czernin J, Radu CG, Wang X, Gjertson DW, Cochran AJ, Cornetta K, Wong DJ, Kaplan-Lefko P, Hamid O, Samlowski W, Cohen PA, Daniels GA, Mukherji B, Yang L, Zack JA, Kohn DB, Heath JR, Glaspy JA, Witte ON, Baltimore D, Economou JS, Ribas A (2014) Adoptive transfer of MART-1 T-cell receptor transgenic lymphocytes and dendritic cell vaccination in patients with metastatic melanoma. Clin Cancer Res 20(9):2457–2465

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Kageyama S, Ikeda H, Miyahara Y, Imai N, Ishihara M, Saito K, Sugino S, Ueda S, Ishikawa T, Kokura S, Naota H, Ohishi K, Shiraishi T, Inoue N, Tanabe M, Kidokoro T, Yoshioka H, Tomura D, Nukaya I, Mineno J, Takesako K, Katayama N, Shiku H (2015) Adoptive transfer of MAGE-A4 T-cell receptor gene-transduced lymphocytes in patients with recurrent esophageal cancer. Clin Cancer Res 21(10):2268–2277

    Article  CAS  PubMed  Google Scholar 

  87. Borst J, Alexander S, Elder J, Terhorst C (1983) The T3 complex on human T lymphocytes involves four structurally distinct glycoproteins. J Biol Chem 258(8):5135–5141

    CAS  PubMed  Google Scholar 

  88. Oettgen HC, Kappler J, Tax WJ, Terhorst C (1984) Characterization of the two heavy chains of the T3 complex on the surface of human T lymphocytes. J Biol Chem 259(19):12039–12048

    CAS  PubMed  Google Scholar 

  89. Samelson LE, Harford JB, Klausner RD (1985) Identification of the components of the murine T cell antigen receptor complex. Cell 43(1):223–231

    Article  CAS  PubMed  Google Scholar 

  90. Leontsini E, Brown T, Biddison WE (1986) Physical and functional association of the T cell receptor and the T3 molecular complex on cytotoxic T cell clones that are differentially inhibitable by anti-T3 antibodies. Cell Immunol 102(1):21–32

    Article  CAS  PubMed  Google Scholar 

  91. Oettgen HC, Pettey CL, Maloy WL, Terhorst C (1986) A T3-like protein complex associated with the antigen receptor on murine T cells. Nature 320(6059):272–275

    Article  CAS  PubMed  Google Scholar 

  92. Lanier LL, Federspiel NA, Ruitenberg JJ, Phillips JH, Allison JP, Littman D, Weiss A (1987) The T cell antigen receptor complex expressed on normal peripheral blood CD4-, CD8- T lymphocytes. A CD3-associated disulfide-linked gamma chain heterodimer. J Exp Med 165(4):1076–1094

    Article  CAS  PubMed  Google Scholar 

  93. Weiss A, Littman DR (1994) Signal transduction by lymphocyte antigen receptors. Cell 76(2):263–274

    Article  CAS  PubMed  Google Scholar 

  94. Dialynas DP, Wilde DB, Marrack P, Pierres A, Wall KA, Havran W, Otten G, Loken MR, Pierres M, Kappler J et al (1983) Characterization of the murine antigenic determinant, designated L3T4a, recognized by monoclonal antibody GK1.5: expression of L3T4a by functional T cell clones appears to correlate primarily with class II MHC antigen-reactivity. Immunol Rev 74:29–56

    Article  CAS  PubMed  Google Scholar 

  95. Swain SL (1983) T cell subsets and the recognition of MHC class. Immunol Rev 74:129–142

    Article  CAS  PubMed  Google Scholar 

  96. Emmrich F, Strittmatter U, Eichmann K (1986) Synergism in the activation of human CD8 T cells by cross-linking the T-cell receptor complex with the CD8 differentiation antigen. Proc Natl Acad Sci U S A 83(21):8298–8302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. de Vries JE, Yssel H, Spits H (1989) Interplay between the TCR/CD3 complex and CD4 or CD8 in the activation of cytotoxic T lymphocytes. Immunol Rev 109:119–141

    Article  PubMed  Google Scholar 

  98. Veillette A, Bookman MA, Horak EM, Bolen JB (1988) The CD4 and CD8 T cell surface antigens are associated with the internal membrane tyrosine-protein kinase p56lck. Cell 55(2):301–308

    Article  CAS  PubMed  Google Scholar 

  99. Barber EK, Dasgupta JD, Schlossman SF, Trevillyan JM, Rudd CE (1989) The CD4 and CD8 antigens are coupled to a protein-tyrosine kinase (p56lck) that phosphorylates the CD3 complex. Proc Natl Acad Sci U S A 86(9):3277–3281

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Taniguchi RT, Anderson MS (2011) The role of Aire in clonal selection. Immunol Cell Biol 89(1):40–44

    Article  CAS  PubMed  Google Scholar 

  101. Davis MM, Bjorkman PJ (1988) T-cell antigen receptor genes and T-cell recognition. Nature 334(6181):395–402

    Article  CAS  PubMed  Google Scholar 

  102. Toyonaga B, Yoshikai Y, Vadasz V, Chin B, Mak TW (1985) Organization and sequences of the diversity, joining, and constant region genes of the human T-cell receptor beta chain. Proc Natl Acad Sci U S A 82(24):8624–8628

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Koop BF, Rowen L, Wang K, Kuo CL, Seto D, Lenstra JA, Howard S, Shan W, Deshpande P, Hood L (1994) The human T-cell receptor TCRAC/TCRDC (C alpha/C delta) region: organization, sequence, and evolution of 97.6 kb of DNA. Genomics 19(3):478–493

    Article  CAS  PubMed  Google Scholar 

  104. 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 

  105. Rosenberg SA (2000) Identification of cancer antigens: impact on development of cancer immunotherapies. Cancer J 6(Suppl 3):S200–S207

    PubMed  Google Scholar 

  106. Van Der Bruggen P, Zhang Y, Chaux P, Stroobant V, Panichelli C, Schultz ES, Chapiro J, Van Den Eynde BJ, Brasseur F, Boon T (2002) Tumor-specific shared antigenic peptides recognized by human T cells. Immunol Rev 188:51–64

    Article  Google Scholar 

  107. Coulie PG, Van den Eynde BJ, van der Bruggen P, Boon T (2014) Tumour antigens recognized by T lymphocytes: at the core of cancer immunotherapy. Nat Rev Cancer 14(2):135–146

    Article  CAS  PubMed  Google Scholar 

  108. Kawakami Y, Nishimura MI, Restifo NP, Topalian SL, O'Neil BH, Shilyansky J, Yannelli JR, Rosenberg SA (1993) T-cell recognition of human melanoma antigens. J Immunother Emphasis Tumor Immunol 14(2):88–93

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Cole DJ, Weil DP, Shamamian P, Rivoltini L, Kawakami Y, Topalian S, Jennings C, Eliyahu S, Rosenberg SA, Nishimura MI (1994) Identification of MART-1-specific T-cell receptors: T cells utilizing distinct T-cell receptor variable and joining regions recognize the same tumor epitope. Cancer Res 54(20):5265–5268

    CAS  PubMed  Google Scholar 

  110. Nishimura MI, Kawakami Y, Charmley P, O'Neil B, Shilyansky J, Yannelli JR, Rosenberg SA, Hood L (1994) T-cell receptor repertoire in tumor-infiltrating lymphocytes. Analysis of melanoma-specific long-term lines. J Immunother Emphasis Tumor Immunol 16(2):85–94

    Article  CAS  PubMed  Google Scholar 

  111. Cole DJ, Wilson MC, Rivoltini L, Custer M, Nishimura MI (1997) T-cell receptor repertoire in matched MART-1 peptide-stimulated peripheral blood lymphocytes and tumor-infiltrating lymphocytes. Cancer Res 57(23):5320–5327

    CAS  PubMed  Google Scholar 

  112. Nishimura MI, Custer MC, Schwarz SL, Parker LL, Mixon A, Clay TM, Yannelli JR, Rosenberg SA (1998) T cell-receptor V gene use by CD4+ melanoma-reactive clonal and oligoclonal T-cell lines. J Immunother 21(5):352–362

    Article  CAS  PubMed  Google Scholar 

  113. Sensi M, Castelli C, Anichini A, Grossberger D, Mazzocchi A, Mortarini R, Parmiani G (1991) Two autologous melanoma-specific and MHC-restricted human T cell clones with identical intra-tumour reactivity do not share the same TCR V alpha and V beta gene families. Melanoma Res 1(4):261–271

    Article  CAS  PubMed  Google Scholar 

  114. Loftus DJ, Castelli C, Clay TM, Squarcina P, Marincola FM, Nishimura MI, Parmiani G, Appella E, Rivoltini L (1996) Identification of epitope mimics recognized by CTL reactive to the melanoma/melanocyte-derived peptide MART-1(27–35). J Exp Med 184(2):647–657

    Article  CAS  PubMed  Google Scholar 

  115. McKee MD, Clay TM, Diamond RA, Rosenberg SA, Nishimura MI (2000) Quantitation of T-cell receptor frequencies by competitive polymerase chain reaction: dynamics of T-cell clonotype frequencies in an expanding tumor-infiltrating lymphocyte culture. J Immunother 23(4):419–429

    Article  CAS  PubMed  Google Scholar 

  116. Gros A, Robbins PF, Yao X, Li YF, Turcotte S, Tran E, Wunderlich JR, Mixon A, Farid S, Dudley ME, Hanada K, Almeida JR, Darko S, Douek DC, Yang JC, Rosenberg SA (2014) PD-1 identifies the patient-specific CD8(+) tumor-reactive repertoire infiltrating human tumors. J Clin Invest 124(5):2246–2259

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Linnemann C, Mezzadra R, Schumacher TN (2014) TCR repertoires of intratumoral T-cell subsets. Immunol Rev 257(1):72–82

    Article  CAS  PubMed  Google Scholar 

  118. Linnemann C, van Buuren MM, Bies L, Verdegaal EM, Schotte R, Calis JJ, Behjati S, Velds A, Hilkmann H, Atmioui DE, Visser M, Stratton MR, Haanen JB, Spits H, van der Burg SH, Schumacher TN (2015) High-throughput epitope discovery reveals frequent recognition of neo-antigens by CD4+ T cells in human melanoma. Nat Med 21(1):81–85

    Article  CAS  PubMed  Google Scholar 

  119. Nishimura MI, Avichezer D, Custer MC, Lee CS, Chen C, Parkhurst MR, Diamond RA, Robbins PF, Schwartzentruber DJ, Rosenberg SA (1999) MHC class I-restricted recognition of a melanoma antigen by a human CD4+ tumor infiltrating lymphocyte. Cancer Res 59(24):6230–6238

    CAS  PubMed  Google Scholar 

  120. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. 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 

  122. Sherman LA, Hesse SV, Irwin MJ, La Face D, Peterson P (1992) Selecting T cell receptors with high affinity for self-MHC by decreasing the contribution of CD8. Science 258(5083):815–818

    Article  CAS  PubMed  Google Scholar 

  123. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Moore TV, Lyons GE, Brasic N, Roszkowski JJ, Voelkl S, Mackensen A, Kast WM, Le Poole IC, Nishimura MI (2009) Relationship between CD8-dependent antigen recognition, T cell functional avidity, and tumor cell recognition. Cancer Immunol Immunother 58(5):719–728

    Article  CAS  PubMed  Google Scholar 

  125. 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

    Article  CAS  PubMed  Google Scholar 

  126. Jones LL, Brophy SE, Bankovich AJ, Colf LA, Hanick NA, Garcia KC, Kranz DM (2006) Engineering and characterization of a stabilized alpha1/alpha2 module of the class I major histocompatibility complex product Ld. J Biol Chem 281(35):25734–25744

    Article  CAS  PubMed  Google Scholar 

  127. Malecek K, Zhong S, McGary K, Yu C, Huang K, Johnson LA, Rosenberg SA, Krogsgaard M (2013) Engineering improved T cell receptors using an alanine-scan guided T cell display selection system. J Immunol Methods 392(1–2):1–11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Malecek K, Grigoryan A, Zhong S, Gu WJ, Johnson LA, Rosenberg SA, Cardozo T, Krogsgaard M (2014) Specific increase in potency via structure-based design of a TCR. J Immunol 193(5):2587–2599

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Dunn SM, Rizkallah PJ, Baston E, Mahon T, Cameron B, Moysey R, Gao F, Sami M, Boulter J, Li Y, Jakobsen BK (2006) Directed evolution of human T cell receptor CDR2 residues by phage display dramatically enhances affinity for cognate peptide-MHC without increasing apparent cross-reactivity. Protein Sci 15(4):710–721

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Langerman A, Callender GG, Nishimura MI (2004) Retroviral transduction of peptide stimulated t cells can generate dual t cell receptor-expressing (bifunctional) t cells reactive with two defined antigens. J Transl Med 2(1):42

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. Heemskerk MH, Hagedoorn RS, van der Hoorn MA, van der Veken LT, Hoogeboom M, Kester MG, Willemze R, Falkenburg JH (2007) Efficiency of T-cell receptor expression in dual-specific T cells is controlled by the intrinsic qualities of the TCR chains within the TCR-CD3 complex. Blood 109(1):235–243

    Article  CAS  PubMed  Google Scholar 

  132. 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

    Article  CAS  PubMed  Google Scholar 

  133. 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, 561 p following 570

    Google Scholar 

  134. 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 U S A 107(24):10972–10977

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  135. 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

    Article  CAS  PubMed  Google Scholar 

  136. 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

    Article  CAS  Google Scholar 

  137. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. 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 U S A 91(24):11408–11412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Rutledge T, Cosson P, Manolios N, Bonifacino JS, Klausner RD (1992) Transmembrane helical interactions: zeta chain dimerization and functional association with the T cell antigen receptor. EMBO J 11(9):3245–3254

    CAS  PubMed  PubMed Central  Google Scholar 

  141. 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

    Article  CAS  PubMed  Google Scholar 

  142. 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 

  143. 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

    Article  CAS  PubMed  Google Scholar 

  144. 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

    Article  CAS  PubMed  Google Scholar 

  145. Foote J, Eisen HN (2000) Breaking the affinity ceiling for antibodies and T cell receptors. Proc Natl Acad Sci U S A 97(20):10679–10681

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. 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 

  147. 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

    Google Scholar 

  148. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Kroger CJ, Alexander-Miller MA (2007) Cutting edge: CD8+ T cell clones possess the potential to differentiate into both high- and low-avidity effector cells. J Immunol 179(2):748–751

    Article  CAS  PubMed  Google Scholar 

  150. Marigo I, Dolcetti L, Serafini P, Zanovello P, Bronte V (2008) Tumor-induced tolerance and immune suppression by myeloid derived suppressor cells. Immunol Rev 222:162–179

    Article  CAS  PubMed  Google Scholar 

  151. Riley JL, June CH, Blazar BR (2009) Human T regulatory cell therapy: take a billion or so and call me in the morning. Immunity 30(5):656–665

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Ostrand-Rosenberg S (2010) Myeloid-derived suppressor cells: more mechanisms for inhibiting antitumor immunity. Cancer Immunol Immunother 59(10):1593–1600

    Article  PubMed  PubMed Central  Google Scholar 

  153. Leguern C (2011) Regulatory T cells for tolerance therapy: revisiting the concept. Crit Rev Immunol 31(3):189–207

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Josefowicz SZ, Lu LF, Rudensky AY (2012) Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol 30:531–564

    Article  CAS  PubMed  Google Scholar 

  155. Raber P, Ochoa AC, Rodriguez PC (2012) Metabolism of L-arginine by myeloid-derived suppressor cells in cancer: mechanisms of T cell suppression and therapeutic perspectives. Immunol Invest 41(6–7):614–634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Kumar V, Gabrilovich DI (2014) Hypoxia-inducible factors in regulation of immune responses in tumour microenvironment. Immunology 143(4):512–519

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Kono K, Salazar-Onfray F, Petersson M, Hansson J, Masucci G, Wasserman K, Nakazawa T, Anderson P, Kiessling R (1996) Hydrogen peroxide secreted by tumor-derived macrophages down-modulates signal-transducing zeta molecules and inhibits tumor-specific T cell-and natural killer cell-mediated cytotoxicity. Eur J Immunol 26(6):1308–1313

    Article  CAS  PubMed  Google Scholar 

  158. Kusmartsev S, Nefedova Y, Yoder D, Gabrilovich DI (2004) Antigen-specific inhibition of CD8+ T cell response by immature myeloid cells in cancer is mediated by reactive oxygen species. J Immunol 172(2):989–999

    Article  CAS  PubMed  Google Scholar 

  159. Lu T, Gabrilovich DI (2012) Molecular pathways: tumor-infiltrating myeloid cells and reactive oxygen species in regulation of tumor microenvironment. Clin Cancer Res 18(18):4877–4882

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. De Sanctis F, Sandri S, Ferrarini G, Pagliarello I, Sartoris S, Ugel S, Marigo I, Molon B, Bronte V (2014) The emerging immunological role of post-translational modifications by reactive nitrogen species in cancer microenvironment. Front Immunol 5:69

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  161. Mao Y, Poschke I, Kiessling R (2014) Tumour-induced immune suppression: role of inflammatory mediators released by myelomonocytic cells. J Intern Med 276(2):154–170

    Article  CAS  PubMed  Google Scholar 

  162. Pecht I, Gakamsky DM (2005) Spatial coordination of CD8 and TCR molecules controls antigen recognition by CD8+ T-cells. FEBS Lett 579(15):3336–3341

    Article  CAS  PubMed  Google Scholar 

  163. Cawthon AG, Alexander-Miller MA (2002) Optimal colocalization of TCR and CD8 as a novel mechanism for the control of functional avidity. J Immunol 169(7):3492–3498

    Article  CAS  PubMed  Google Scholar 

  164. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. 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 

  166. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Brusko TM, Koya RC, Zhu S, Lee MR, Putnam AL, McClymont SA, Nishimura MI, Han S, Chang LJ, Atkinson MA, Ribas A, Bluestone JA (2010) Human antigen-specific regulatory T cells generated by T cell receptor gene transfer. PLoS One 5(7), e11726

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  168. Kessels HW, Wolkers MC, van den Boom MD, van der Valk MA, Schumacher TN (2001) Immunotherapy through TCR gene transfer. Nat Immunol 2(10):957–961

    Article  CAS  PubMed  Google Scholar 

  169. Abad JD, Wrzensinski C, Overwijk W, De Witte MA, Jorritsma A, Hsu C, Gattinoni L, Cohen CJ, Paulos CM, Palmer DC, Haanen JB, Schumacher TN, Rosenberg SA, Restifo NP, Morgan RA (2008) T-cell receptor gene therapy of established tumors in a murine melanoma model. J Immunother 31(1):1–6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. de Witte MA, Bendle GM, van den Boom MD, Coccoris M, Schell TD, Tevethia SS, van Tinteren H, Mesman EM, Song JY, Schumacher TN (2008) TCR gene therapy of spontaneous prostate carcinoma requires in vivo T cell activation. J Immunol 181(4):2563–2571

    Article  PubMed  PubMed Central  Google Scholar 

  171. Stauss HJ, Thomas S, Cesco-Gaspere M, Hart DP, Xue SA, Holler A, King J, Wright G, Perro M, Pospori C, Morris E (2008) WT1-specific T cell receptor gene therapy: improving TCR function in transduced T cells. Blood Cells Mol Dis 40(1):113–116

    Article  CAS  PubMed  Google Scholar 

  172. Frankel TL, Burns WR, Peng PD, Yu Z, Chinnasamy D, Wargo JA, Zheng Z, Restifo NP, Rosenberg SA, Morgan RA (2010) Both CD4 and CD8 T cells mediate equally effective in vivo tumor treatment when engineered with a highly avid TCR targeting tyrosinase. J Immunol 184(11):5988–5998

    Article  CAS  PubMed  Google Scholar 

  173. Kerkar SP, Sanchez-Perez L, Yang S, Borman ZA, Muranski P, Ji Y, Chinnasamy D, Kaiser AD, Hinrichs CS, Klebanoff CA, Scott CD, Gattinoni L, Morgan RA, Rosenberg SA, Restifo NP (2011) Genetic engineering of murine CD8+ and CD4+ T cells for preclinical adoptive immunotherapy studies. J Immunother 34(4):343–352

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Xue SA, Gao L, Ahmadi M, Ghorashian S, Barros RD, Pospori C, Holler A, Wright G, Thomas S, Topp M, Morris EC, Stauss HJ (2013) Human MHC Class I-restricted high avidity CD4 T cells generated by co-transfer of TCR and CD8 mediate efficient tumor rejection in vivo. Oncoimmunology 2(1), e22590

    Article  PubMed  PubMed Central  Google Scholar 

  175. Calogero A, Hospers GA, Kruse KM, Schrier PI, Mulder NH, Hooijberg E, de Leij LF (2000) Retargeting of a T cell line by anti MAGE-3/HLA-A2 alpha beta TCR gene transfer. Anticancer Res 20(3A):1793–1799

    CAS  PubMed  Google Scholar 

  176. Straetemans T, van Brakel M, van Steenbergen S, Broertjes M, Drexhage J, Hegmans J, Lambrecht BN, Lamers C, van Der Bruggen P, Coulie PG, Debets R (2012) TCR gene transfer: MAGE-C2/HLA-A2 and MAGE-A3/HLA-DP4 epitopes as melanoma-specific immune targets. Clin Dev Immunol 2012:586314

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  177. Sommermeyer D, Conrad H, Kronig H, Gelfort H, Bernhard H, Uckert W (2013) NY-ESO-1 antigen-reactive T cell receptors exhibit diverse therapeutic capability. Int J Cancer 132(6):1360–1367

    Article  CAS  PubMed  Google Scholar 

  178. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. 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

    Article  CAS  PubMed  Google Scholar 

  180. Restifo NP, Dudley ME, Rosenberg SA (2012) Adoptive immunotherapy for cancer: harnessing the T cell response. Nat Rev Immunol 12(4):269–281

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Surgery, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL, 60153, USA

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

Authors
  1. Kaoru Nagato
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Timothy T. Spear
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael I. Nishimura
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael I. Nishimura .

Editor information

Editors and Affiliations

  1. Unit of Melanoma & Cancer Immunotherapy, National Tumor Institute Fondazione G., Naples, Italy

    Paolo A. Ascierto

  2. Department of Transfusion Medicine, National Institutes of Health, Bethesda, Maryland, USA

    David F. Stroncek

  3. Department of Transfusion Medicine, National Institutes of Health, BETHESDA, Maryland, USA

    Ena Wang

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Nagato, K., Spear, T.T., Nishimura, M.I. (2015). Influence of Antigen Receptor Avidity, Affinity, and Specificity on Genetically Engineered T Cells. In: Ascierto, P., Stroncek, D., Wang, E. (eds) Developments in T Cell Based Cancer Immunotherapies. Cancer Drug Discovery and Development. Humana Press, Cham. https://doi.org/10.1007/978-3-319-21167-1_4

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-21167-1_4

  • Publisher Name: Humana Press, Cham

  • Print ISBN: 978-3-319-21166-4

  • Online ISBN: 978-3-319-21167-1

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation