Skip to main content
SpringerLink
Log in

Understanding TCR affinity, antigen specificity, and cross-reactivity to improve TCR gene-modified T cells for cancer immunotherapy

  • Focussed Research Review
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Adoptive cell transfer (ACT) using T cell receptor (TCR) gene-modified T cells is an exciting and rapidly evolving field. Numerous preclinical and clinical studies have demonstrated various levels of feasibility, safety, and efficacy using TCR-engineered T cells to treat cancer and viral infections. Although evidence suggests their use can be effective, to what extent and how to improve these therapeutics are still matters of investigation. As TCR affinity has been generally accepted as the central role in defining T cell specificity and sensitivity, selection for and generation of high affinity TCRs has remained a fundamental approach to design more potent T cells. However, traditional methods for affinity-enhancement by random mutagenesis can induce undesirable cross-reactivity causing on- and off-target adverse events, generate exhausted effectors by overstimulation, and ignore other kinetic and cellular parameters that have been shown to impact antigen specificity. In this Focussed Research Review, we comment on the preclinical and clinical potential of TCR gene-modified T cells, summarize our contributions challenging the role TCR affinity plays in antigen recognition, and explore how structure-guided design can be used to manipulate antigen specificity and TCR cross-reactivity to improve the safety and efficacy of TCR gene-modified T cells used in ACT.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

ACT:

Adoptive cell transfer

APL:

Altered peptide ligand

HCC:

Hepatocellular carcinoma

HCV:

Hepatitis C virus

PBL:

Peripheral blood lymphocyte

pMHC:

Peptide-major histocompatibility complex

TCR:

T cell receptor

References

  1. Spear TT (2016) The Impact of altered T cell receptor—peptide-major histocompatibility complex interactions on antigen recognition and T cell function. Doctoral Disseration, Loyola University Chicago

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. 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 63:969–975. https://doi.org/10.1007/s00262-014-1568-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  5. Morgan RA, Dudley ME, Wunderlich JR et al (2006) Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314:126–129. https://doi.org/10.1126/science.1129003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Johnson LA, Morgan RA, Dudley ME et al (2009) Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen. Blood 114:535–546. https://doi.org/10.1182/blood-2009-03-211714

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Moore T, Wagner CR, Scurti GM et al (2018) Clinical and immunologic evaluation of three metastatic melanoma patients treated with autologous melanoma-reactive TCR-transduced T cells. Cancer Immunol Immunother 67:311–325. https://doi.org/10.1007/s00262-017-2073-0

    Article  CAS  PubMed  Google Scholar 

  8. Parkhurst MR, Yang JC, Langan RC et al (2011) T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis. Mol Ther 19:620–626. https://doi.org/10.1038/mt.2010.272

    Article  CAS  PubMed  Google Scholar 

  9. Cameron BJ, Gerry AB, Dukes J et al (2013) Identification of a Titin-derived HLA-A1-presented peptide as a cross-reactive target for engineered MAGE A3-directed T cells. Science Transl Med 5:197ra03. https://doi.org/10.1126/scitranslmed.3006034

    Article  CAS  Google Scholar 

  10. Linette GP, Stadtmauer EA, Maus MV et al (2013) Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma. Blood 122:863–871. https://doi.org/10.1182/blood-2013-03-490565

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Morgan RA, Chinnasamy N, Abate-Daga D et al (2013) Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy. J Immunother 36:133–151. https://doi.org/10.1097/cji.0b013e3182829903

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Spear TT, Riley TP, Lyons GE et al (2016) Hepatitis C virus-cross-reactive TCR gene-modified T cells: a model for immunotherapy against diseases with genomic instability. J Leukoc Biol 100:545–557. https://doi.org/10.1189/jlb.2A1215-561R

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 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 179:2952–2960

    Article  CAS  PubMed  Google Scholar 

  14. 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 163:507–513

    CAS  PubMed  Google Scholar 

  15. 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. Can Res 55:748–752

    CAS  Google Scholar 

  16. 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. Can Res 65:1570–1576. https://doi.org/10.1158/0008-5472.can-04-2076

    Article  CAS  Google Scholar 

  17. Stone JD, Chervin AS, Kranz DM (2009) T-cell receptor binding affinities and kinetics: impact on T-cell activity and specificity. Immunology 126:165–176. https://doi.org/10.1111/j.1365-2567.2008.03015.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. 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 96:9781–9786

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. 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 43:973–981. https://doi.org/10.1002/hep.21157

    Article  CAS  PubMed  Google Scholar 

  20. 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 177:6548–6559

    Article  CAS  PubMed  Google Scholar 

  21. 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 170:2582–2589

    Article  CAS  PubMed  Google Scholar 

  22. Tsuji T, Yasukawa M, Matsuzaki J et al (2005) Generation of tumor-specific, HLA class I-restricted human Th1 and Tc1 cells by cell engineering with tumor peptide-specific T-cell receptor genes. Blood 106:470–476. https://doi.org/10.1182/blood-2004-09-3663

    Article  CAS  PubMed  Google Scholar 

  23. 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 

  24. 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. https://doi.org/10.1146/annurev.immunol.16.1.523

    Article  CAS  PubMed  Google Scholar 

  25. Kuball J, Schmitz FW, Voss RH et al (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 22:117–129. https://doi.org/10.1016/j.immuni.2004.12.005

    Article  CAS  PubMed  Google Scholar 

  26. 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 15:169–180. https://doi.org/10.1158/1078-0432.ccr-08-1638

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 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 173:1007–1015

    Article  CAS  PubMed  Google Scholar 

  28. 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 97:5387–5392. https://doi.org/10.1073/pnas.080078297

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Li Y, Moysey R, Molloy PE et al (2005) Directed evolution of human T-cell receptors with picomolar affinities by phage display. Nat Biotechnol 23:349–354. https://doi.org/10.1038/nbt1070

    Article  CAS  PubMed  Google Scholar 

  30. Zhao Y, Bennett AD, Zheng Z et al (2007) High-affinity TCRs generated by phage display provide CD4 + T cells with the ability to recognize and kill tumor cell lines. J Immunol 179:5845–5854

    Article  CAS  PubMed  Google Scholar 

  31. Lamers CH, Willemsen R, van Elzakker P et al (2011) Immune responses to transgene and retroviral vector in patients treated with ex vivo-engineered T cells. Blood 117:72–82. https://doi.org/10.1182/blood-2010-07-294520

    Article  CAS  PubMed  Google Scholar 

  32. 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 9:305–313

    Article  CAS  PubMed  Google Scholar 

  33. 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 13:115–134

    Article  CAS  PubMed  Google Scholar 

  34. Riley TP, Baker BM (2018) The intersection of affinity and specificity in the development and optimization of T cell receptor based therapeutics. Semin Cell Dev Biol 84:30–41. https://doi.org/10.1016/j.semcdb.2017.10.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Rosen HR, Hinrichs DJ, Leistikow RL, Callender G, Wertheimer AM, Nishimura MI, Lewinsohn DM (2004) Cutting edge: identification of hepatitis C virus-specific CD8 + T cells restricted by donor HLA alleles following liver transplantation. J Immunol 173:5355–5359

    Article  CAS  PubMed  Google Scholar 

  36. Spear TT, Callender GG, Roszkowski JJ et al (2016) TCR gene-modified T cells can efficiently treat established hepatitis C-associated hepatocellular carcinoma tumors. Cancer Immunol Immunother 65:293–304. https://doi.org/10.1007/s00262-016-1800-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Spear TT, Wang Y, Foley KC et al (2017) Critical biological parameters modulate affinity as a determinant of function in T-cell receptor gene-modified T-cells. Cancer Immunol Immunother 66:1411–1424. https://doi.org/10.1007/s00262-017-2032-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Spear TT, Wang Y, Smith TW Jr, Simms PE, Garrett-Mayer E, Hellman LM, Baker BM, Nishimura MI (2018) Altered peptide ligands impact the diversity of polyfunctional phenotypes in T cell receptor gene-modified T cells. Mol Ther 26:996–1007. https://doi.org/10.1016/j.ymthe.2018.01.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 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. Can Res 66:11455–11461. https://doi.org/10.1158/0008-5472.can-06-2379

    Article  CAS  Google Scholar 

  40. 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 58:719–728. https://doi.org/10.1007/s00262-008-0594-2

    Article  CAS  PubMed  Google Scholar 

  41. Spear TT, Foley KC, Garrett-Mayer E, Nishimura MI (2018) TCR modifications that enhance chain pairing in gene-modified T cells can augment cross-reactivity and alleviate CD8 dependence. J Leukoc Biol 103:973–983. https://doi.org/10.1002/jlb.5a0817-314r

    Article  CAS  PubMed  Google Scholar 

  42. Foley KC, Spear TT, Murray DC, Nagato K, Garrett-Mayer E, Nishimura MI (2017) HCV T cell receptor chain modifications to enhance expression, pairing, and antigen recognition in T cells for adoptive transfer. Mol Ther Oncolytics 17:105–115. https://doi.org/10.1016/j.omto.2017.05.004

    Article  CAS  Google Scholar 

  43. Degano M, Garcia KC, Apostolopoulos V, Rudolph MG, Teyton L, Wilson IA (2000) A functional hot spot for antigen recognition in a superagonist TCR/MHC complex. Immunity 12:251–261

    Article  CAS  PubMed  Google Scholar 

  44. Kalergis AM, Nathenson SG (2000) Altered peptide ligand-mediated TCR antagonism can be modulated by a change in a single amino acid residue within the CDR3 beta of an MHC class I-restricted TCR. J Immunol 165:280–285

    Article  CAS  PubMed  Google Scholar 

  45. Thomson CT, Kalergis AM, Sacchettini JC, Nathenson SG (2001) A structural difference limited to one residue of the antigenic peptide can profoundly alter the biological outcome of the TCR-peptide/MHC class I interaction. J Immunol 166:3994–3997

    Article  CAS  PubMed  Google Scholar 

  46. Wang Y, Singh NK, Spear TT et al (2017) How an alloreactive T-cell receptor achieves peptide and MHC specificity. Proc Natl Acad Sci USA. https://doi.org/10.1073/pnas.1700459114

    Article  PubMed  PubMed Central  Google Scholar 

  47. 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:e1001018. https://doi.org/10.1371/journal.ppat.1001018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Riley TP, Hellman LM, Gee MH et al (2018) T cell receptor cross-reactivity expanded by dramatic peptide-MHC adaptability. Nat Chem Biol 14:934–942. https://doi.org/10.1038/s41589-018-0130-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Hellman LM, Foley KC, Singh NK et al (2018) Improving T cell receptor on-target specificity via structure-guided design. Mol Ther. https://doi.org/10.1016/j.ymthe.2018.12.010

    Article  PubMed  PubMed Central  Google Scholar 

  50. Tsuchiya Y, Namiuchi Y, Wako H, Tsurui H (2018) A study of CDR3 loop dynamics reveals distinct mechanisms of peptide recognition by T-cell receptors exhibiting different levels of cross-reactivity. Immunology 153:466–478. https://doi.org/10.1111/imm.12849

    Article  CAS  PubMed  Google Scholar 

  51. 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. https://doi.org/10.1146/annurev.cellbio.17.1.133

    Article  CAS  PubMed  Google Scholar 

  52. 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 475:510–513. https://doi.org/10.1038/nature10183

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. 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 464:932–936. https://doi.org/10.1038/nature08944

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Liu B, Zhong S, Malecek K, Johnson LA, Rosenberg SA, Zhu C, Krogsgaard M (2014) 2D TCR-pMHC-CD8 kinetics determines T-cell responses in a self-antigen-specific TCR system. Eur J Immunol 44:239–250. https://doi.org/10.1002/eji.201343774

    Article  CAS  PubMed  Google Scholar 

  55. 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 157:357–368. https://doi.org/10.1016/j.cell.2014.02.053

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Pryshchep S, Zarnitsyna VI, Hong J, Evavold BD, Zhu C (2014) Accumulation of serial forces on TCR and CD8 frequently applied by agonist antigenic peptides embedded in MHC molecules triggers calcium in T cells. J Immunol 193:68–76. https://doi.org/10.4049/jimmunol.1303436

    Article  CAS  PubMed  Google Scholar 

  57. 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 375:148–151. https://doi.org/10.1038/375148a0

    Article  CAS  PubMed  Google Scholar 

  58. Haidar JN, Pierce B, Yu Y, Tong W, Li M, Weng Z (2009) Structure-based design of a T-cell receptor leads to nearly 100-fold improvement in binding affinity for pepMHC. Proteins 74:948–960. https://doi.org/10.1002/prot.22203

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. 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 193:2587–2599. https://doi.org/10.4049/jimmunol.1302344

    Article  CAS  PubMed  Google Scholar 

  60. 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:e1003478. https://doi.org/10.1371/journal.pcbi.1003478

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Zoete V, Irving M, Ferber M, Cuendet MA, Michielin O (2013) Structure-based, rational design of T cell receptors. Front Immunol 4:268. https://doi.org/10.3389/fimmu.2013.00268

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Chodon T, Comin-Anduix B, Chmielowski B et al (2014) Adoptive transfer of MART-1 T-cell receptor transgenic lymphocytes and dendritic cell vaccination in patients with metastatic melanoma. Clin Cancer Res 20:2457–2465. https://doi.org/10.1158/1078-0432.ccr-13-3017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Gee MH, Han A, Lofgren SM et al (2018) Antigen identification for orphan T cell receptors expressed on tumor-infiltrating lymphocytes. Cell 172:549–63.e16. https://doi.org/10.1016/j.cell.2017.11.043

    Article  CAS  PubMed  Google Scholar 

  64. Riley TP, Ayres CM, Hellman LM et al (2016) A generalized framework for computational design and mutational scanning of T-cell receptor binding interfaces. Protein Eng Des Sel 29:595–606. https://doi.org/10.1093/protein/gzw050

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Harris DT, Wang N, Riley TP, Anderson SD, Singh NK, Procko E, Baker BM, Kranz DM (2016) Deep mutational scans as a guide to engineering high affinity T cell receptor interactions with peptide-bound major histocompatibility complex. J Biol Chem 291:24566–24578. https://doi.org/10.1074/jbc.M116.748681

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Border EC, Sanderson JP, Weissensteiner T, Gerry AB, Pumphrey NJ (2019) Affinity-enhanced T-cell receptors for adoptive T-cell therapy targeting MAGE-A10: strategy for selection of an optimal candidate. Oncoimmunology 8:e1532759. https://doi.org/10.1080/2162402x.2018.1532759

    Article  CAS  PubMed  Google Scholar 

  67. Gee MH, Sibener LV, Birnbaum ME, Jude KM, Yang X, Fernandes RA, Mendoza JL, Glassman CR, Garcia KC (2018) Stress-testing the relationship between T cell receptor/peptide-MHC affinity and cross-reactivity using peptide velcro. Proc Natl Acad Sci USA 115:E7369–E7378. https://doi.org/10.1073/pnas.1802746115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Audehm S, Glaser M, Pecoraro M et al (2019) Key features relevant to select antigens and TCR from the MHC-mismatched repertoire to treat cancer. Front Immunol 10:1485. https://doi.org/10.3389/fimmu.2019.01485

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Funding

The authors’ original work described and summarized in this Focussed Research Review was funded by the National Cancer Institute (Grants F30 CA180731 to Spear; P01 CA154779 to Nishimura) and the National Institute of Allergy and Infectious Disease (Grants R01 AI129543 to Baker & Nishimura; R01 AI096879 to Evavold).

Author information

Authors and Affiliations

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

    Timothy T. Spear & Michael I. Nishimura

  2. Department of Pathology, Microbiology and Immunology, University of Utah, Salt Lake City, UT, 84112, USA

    Brian D. Evavold

  3. Department of Chemistry and Biochemistry, Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN, 46530, USA

    Brian M. Baker

Authors
  1. Timothy T. Spear
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Brian D. Evavold
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Brian M. Baker
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michael I. Nishimura
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

TT Spear, BD Evavold, BMB, and MIN designed the research, performed experiments, and analyzed the data summarized in the Focussed Research Review as well as wrote and critically revised the manuscript.

Corresponding author

Correspondence to Timothy T. Spear.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Note on previous publication: Portions of the text within this paper were discussed and published within a doctoral dissertation: (Spear [1]).

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Spear, T.T., Evavold, B.D., Baker, B.M. et al. Understanding TCR affinity, antigen specificity, and cross-reactivity to improve TCR gene-modified T cells for cancer immunotherapy. Cancer Immunol Immunother 68, 1881–1889 (2019). https://doi.org/10.1007/s00262-019-02401-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-019-02401-0

Keywords

Search

Navigation