Critical biological parameters modulate affinity as a determinant of function in T-cell receptor gene-modified T-cells

  • Timothy T. Spear
  • Yuan Wang
  • Kendra C. Foley
  • David C. Murray
  • Gina M. Scurti
  • Patricia E. Simms
  • Elizabeth Garrett-Mayer
  • Lance M. Hellman
  • Brian M. Baker
  • Michael I. Nishimura
Original Article

Abstract

T-cell receptor (TCR)-pMHC affinity has been generally accepted to be the most important factor dictating antigen recognition in gene-modified T-cells. As such, there is great interest in optimizing TCR-based immunotherapies by enhancing TCR affinity to augment the therapeutic benefit of TCR gene-modified T-cells in cancer patients. However, recent clinical trials using affinity-enhanced TCRs in adoptive cell transfer (ACT) have observed unintended and serious adverse events, including death, attributed to unpredicted off-tumor or off-target cross-reactivity. It is critical to re-evaluate the importance of other biophysical, structural, or cellular factors that drive the reactivity of TCR gene-modified T-cells. Using a model for altered antigen recognition, we determined how TCR–pMHC affinity influenced the reactivity of hepatitis C virus (HCV) TCR gene-modified T-cells against a panel of naturally occurring HCV peptides and HCV-expressing tumor targets. The impact of other factors, such as TCR–pMHC stabilization and signaling contributions by the CD8 co-receptor, as well as antigen and TCR density were also evaluated. We found that changes in TCR–pMHC affinity did not always predict or dictate IFNγ release or degranulation by TCR gene-modified T-cells, suggesting that less emphasis might need to be placed on TCR–pMHC affinity as a means of predicting or augmenting the therapeutic potential of TCR gene-modified T-cells used in ACT. A more complete understanding of antigen recognition by gene-modified T-cells and a more rational approach to improve the design and implementation of novel TCR-based immunotherapies is necessary to enhance efficacy and maximize safety in patients.

Keywords

T-cell T-cell receptor (TCR) Gene-modified T-cells Adoptive cell therapy Affinity Altered peptide ligands 

Abbreviations

EC50

Half maximal effective concentration

MFI

Median fluorescence intensity

pMHC

Peptide-major histocompatibility complex

SPR

Surface plasmon resonance

WT

Wildtype

Supplementary material

262_2017_2032_MOESM1_ESM.pdf (1012 kb)
Supplementary material 1 (PDF 1012 kb)

References

  1. 1.
    Spear TT, Nagato K, Nishimura MI (2016) Strategies to genetically engineer T cells for cancer immunotherapy. Cancer Immunol Immunother 65(6):631–649. doi:10.1007/s00262-016-1842-5 CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Tian S, Maile R, Collins EJ, Frelinger JA (2007) CD8 + T cell activation is governed by TCR-peptide/MHC affinity, not dissociation rate. J Immunol 179(5):2952–2960CrossRefPubMedGoogle Scholar
  3. 3.
    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):507–513PubMedGoogle Scholar
  4. 4.
    Rees W, Bender J, Teague TK, Kedl RM, Crawford F, Marrack P, Kappler J (1999) An inverse relationship between T cell receptor affinity and antigen dose during CD4(+) T cell responses in vivo and in vitro. Proc Natl Acad Sci USA 96(17):9781–9786CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    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 CrossRefPubMedGoogle Scholar
  6. 6.
    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):1063–1070CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    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 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    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 49:1–56CrossRefPubMedGoogle Scholar
  9. 9.
    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. doi:10.1110/ps.051936406 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    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 CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    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 CrossRefPubMedGoogle Scholar
  12. 12.
    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 CrossRefPubMedGoogle Scholar
  13. 13.
    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. doi:10.4049/jimmunol.1302344 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    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. doi:10.1016/j.jim.2013.02.018 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Cawthon AG, Lu H, Alexander-Miller MA (2001) Peptide requirement for CTL activation reflects the sensitivity to CD3 engagement: correlation with CD8alphabeta versus CD8alphaalpha expression. J Immunol 167(5):2577–2584CrossRefPubMedGoogle Scholar
  16. 16.
    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):748–751CrossRefPubMedGoogle Scholar
  17. 17.
    Nishimura MI, Roszkowski JJ, Moore TV, Brasic N, Mckee MD, Clay TM (2005) Antigen recognition and T-cell biology. In: Khleif SN (ed) Tumor immunology and cancer vaccines. Springer US, Boston, pp 37–59. doi:10.1007/0-387-27545-2_2
  18. 18.
    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 CrossRefGoogle Scholar
  19. 19.
    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 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    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
  21. 21.
    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 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    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 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    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 100(3):545–557. doi:10.1189/jlb.2A1215-561R CrossRefPubMedGoogle Scholar
  24. 24.
    Lyons GE, Moore T, Brasic N, Li M, Roszkowski JJ, Nishimura MI (2006) Influence of human CD8 on antigen recognition by T-cell receptor-transduced cells. Cancer Res 66(23):11455–11461. doi:10.1158/0008-5472.can-06-2379 CrossRefPubMedGoogle Scholar
  25. 25.
    Norell H, Zhang Y, McCracken J, Martins da Palma T, Lesher A, Liu Y, Roszkowski JJ, Temple A, Callender GG, Clay T, Orentas R, Guevara-Patino J, Nishimura MI (2010) CD34-based enrichment of genetically engineered human T cells for clinical use results in dramatically enhanced tumor targeting. Cancer Immunol Immunother 59(6):851–862. doi:10.1007/s00262-009-0810-8 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Garboczi DN, Hung DT, Wiley DC (1992) HLA-A2-peptide complexes: refolding and crystallization of molecules expressed in Escherichia coli and complexed with single antigenic peptides. Proc Natl Acad Sci USA 89(8):3429–3433CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Pierce BG, Hellman LM, Hossain M, Singh NK, Vander Kooi CW, Weng Z, Baker BM (2014) Computational design of the affinity and specificity of a therapeutic T cell receptor. PLoS Comput Biol 10(2):e1003478. doi:10.1371/journal.pcbi.1003478 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Davis-Harrison RL, Armstrong KM, Baker BM (2005) Two different T cell receptors use different thermodynamic strategies to recognize the same peptide/MHC ligand. J Mol Biol 346(2):533–550. doi:10.1016/j.jmb.2004.11.063 CrossRefPubMedGoogle Scholar
  29. 29.
    Piepenbrink KH, Gloor BE, Armstrong KM, Baker BM (2009) Methods for quantifying T cell receptor binding affinities and thermodynamics. Methods Enzymol 466:359–381. doi:10.1016/s0076-6879(09)66015-8 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    McKeithan TW (1995) Kinetic proofreading in T-cell receptor signal transduction. Proc Natl Acad Sci USA 92(11):5042–5046CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Rabinowitz JD, Beeson C, Lyons DS, Davis MM, McConnell HM (1996) Kinetic discrimination in T-cell activation. Proc Natl Acad Sci USA 93(4):1401–1405CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    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 CrossRefPubMedGoogle Scholar
  33. 33.
    Kammertoens T, Blankenstein T (2013) It’s the peptide-MHC affinity, stupid. Cancer Cell 23(4):429–431. doi:10.1016/j.ccr.2013.04.004 CrossRefPubMedGoogle Scholar
  34. 34.
    Wooldridge L, van den Berg HA, Glick M, Gostick E, Laugel B, Hutchinson SL, Milicic A, Brenchley JM, Douek DC, Price DA, Sewell AK (2005) Interaction between the CD8 coreceptor and major histocompatibility complex class I stabilizes T cell receptor-antigen complexes at the cell surface. J Biol Chem 280(30):27491–27501. doi:10.1074/jbc.M500555200 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Turner JM, Brodsky MH, Irving BA, Levin SD, Perlmutter RM, Littman DR (1990) Interaction of the unique N-terminal region of tyrosine kinase p56lck with cytoplasmic domains of CD4 and CD8 is mediated by cysteine motifs. Cell 60(5):755–765CrossRefPubMedGoogle Scholar
  36. 36.
    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 USA 86(9):3277–3281CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Stepanek O, Prabhakar AS, Osswald C, King CG, Bulek A, Naeher D, Beaufils-Hugot M, Abanto ML, Galati V, Hausmann B, Lang R, Cole DK, Huseby ES, Sewell AK, Chakraborty AK, Palmer E (2014) Coreceptor scanning by the T cell receptor provides a mechanism for T cell tolerance. Cell 159(2):333–345. doi:10.1016/j.cell.2014.08.042 CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    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 CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Cebecauer M, Guillaume P, Hozak P, Mark S, Everett H, Schneider P, Luescher IF (2005) Soluble MHC-peptide complexes induce rapid death of CD8 + CTL. J Immunol 174(11):6809–6819CrossRefPubMedGoogle Scholar
  40. 40.
    Wooldridge L, Lissina A, Cole DK, van den Berg HA, Price DA, Sewell AK (2009) Tricks with tetramers: how to get the most from multimeric peptide-MHC. Immunology 126(2):147–164. doi:10.1111/j.1365-2567.2008.02848.x CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Dustin ML, Bromley SK, Davis MM, Zhu C (2001) Identification of self through two-dimensional chemistry and synapses. Annu Rev Cell Dev Biol 17:133–157. doi:10.1146/annurev.cellbio.17.1.133 CrossRefPubMedGoogle Scholar
  42. 42.
    Wu Y, Vendome J, Shapiro L, Ben-Shaul A, Honig B (2011) Transforming binding affinities from three dimensions to two with application to cadherin clustering. Nature 475(7357):510–513. doi:10.1038/nature10183 CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Huang J, Zarnitsyna VI, Liu B, Edwards LJ, Jiang N, Evavold BD, Zhu C (2010) The kinetics of two-dimensional TCR and pMHC interactions determine T-cell responsiveness. Nature 464(7290):932–936. doi:10.1038/nature08944 CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Liu B, Chen W, Evavold BD, Zhu C (2014) Accumulation of dynamic catch bonds between TCR and agonist peptide-MHC triggers T cell signaling. Cell 157(2):357–368. doi:10.1016/j.cell.2014.02.053 CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Adams JJ, Narayanan S, Liu B, Birnbaum ME, Kruse AC, Bowerman NA, Chen W, Levin AM, Connolly JM, Zhu C, Kranz DM, Garcia KC (2011) T cell receptor signaling is limited by docking geometry to peptide-major histocompatibility complex. Immunity 35(5):681–693. doi:10.1016/j.immuni.2011.09.013 CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Jiang N, Huang J, Edwards LJ, Liu B, Zhang Y, Beal CD, Evavold BD, Zhu C (2011) Two-stage cooperative T cell receptor-peptide major histocompatibility complex-CD8 trimolecular interactions amplify antigen discrimination. Immunity 34(1):13–23. doi:10.1016/j.immuni.2010.12.017 CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Kalergis AM, Boucheron N, Doucey MA, Palmieri E, Goyarts EC, Vegh Z, Luescher IF, Nathenson SG (2001) Efficient T cell activation requires an optimal dwell-time of interaction between the TCR and the pMHC complex. Nat Immunol 2(3):229–234. doi:10.1038/85286 CrossRefPubMedGoogle Scholar
  48. 48.
    Valitutti S, Muller S, Cella M, Padovan E, Lanzavecchia A (1995) Serial triggering of many T-cell receptors by a few peptide-MHC complexes. Nature 375(6527):148–151. doi:10.1038/375148a0 CrossRefPubMedGoogle Scholar
  49. 49.
    Schmid DA, Irving MB, Posevitz V, Hebeisen M, Posevitz-Fejfar A, Sarria JC, Gomez-Eerland R, Thome M, Schumacher TN, Romero P, Speiser DE, Zoete V, Michielin O, Rufer N (2010) Evidence for a TCR affinity threshold delimiting maximal CD8 T cell function. J Immunol 184(9):4936–4946. doi:10.4049/jimmunol.1000173 CrossRefPubMedGoogle Scholar
  50. 50.
    Chervin AS, Stone JD, Holler PD, Bai A, Chen J, Eisen HN, Kranz DM (2009) The impact of TCR-binding properties and antigen presentation format on T cell responsiveness. J Immunol 183(2):1166–1178. doi:10.4049/jimmunol.0900054 CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Engels B, Engelhard VH, Sidney J, Sette A, Binder DC, Liu RB, Kranz DM, Meredith SC, Rowley DA, Schreiber H (2013) Relapse or eradication of cancer is predicted by peptide-major histocompatibility complex affinity. Cancer Cell 23(4):516–526. doi:10.1016/j.ccr.2013.03.018 CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    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. doi:10.1007/s00262-008-0594-2 CrossRefPubMedGoogle Scholar
  53. 53.
    van Loenen MM, Hagedoorn RS, de Boer R, Falkenburg JH, Heemskerk MH (2013) Extracellular domains of CD8alpha and CD8ss subunits are sufficient for HLA class I restricted helper functions of TCR-engineered CD4(+) T cells. PLoS ONE 8(5):e65212. doi:10.1371/journal.pone.0065212 CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    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. doi:10.1007/s00262-008-0593-3 CrossRefPubMedGoogle Scholar
  55. 55.
    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):11408–11412CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    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 CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    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 CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    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 CrossRefGoogle Scholar
  59. 59.
    Gras S, Chadderton J, Del Campo CM, Farenc C, Wiede F, Josephs TM, Sng XY, Mirams M, Watson KA, Tiganis T, Quinn KM, Rossjohn J, La Gruta NL (2016) Reversed T cell receptor docking on a major histocompatibility class I complex limits involvement in the immune response. Immunity 45(4):749–760. doi:10.1016/j.immuni.2016.09.007 CrossRefPubMedGoogle Scholar
  60. 60.
    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 CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Johnson LA, Heemskerk B, Powell DJ Jr, Cohen CJ, Morgan RA, Dudley ME, Robbins PF, Rosenberg SA (2006) Gene transfer of tumor-reactive TCR confers both high avidity and tumor reactivity to nonreactive peripheral blood mononuclear cells and tumor-infiltrating lymphocytes. J Immunol 177(9):6548–6559CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Timothy T. Spear
    • 1
  • Yuan Wang
    • 2
  • Kendra C. Foley
    • 1
  • David C. Murray
    • 1
  • Gina M. Scurti
    • 1
  • Patricia E. Simms
    • 3
  • Elizabeth Garrett-Mayer
    • 4
    • 5
  • Lance M. Hellman
    • 2
  • Brian M. Baker
    • 2
  • Michael I. Nishimura
    • 1
  1. 1.Department of Surgery, Cardinal Bernardin Cancer CenterLoyola University ChicagoMaywoodUSA
  2. 2.Department of Chemistry and Biochemistry and the Harper Cancer Research InstituteUniversity of Notre DameNotre DameUSA
  3. 3.Flow Cytometry Core Facility, Office of Research ServicesLoyola University ChicagoMaywoodUSA
  4. 4.Department of Public Health SciencesMedical University of South CarolinaCharlestonUSA
  5. 5.Hollings Cancer CenterMedical University of South CarolinaCharlestonUSA

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