Skip to main content

Advertisement

SpringerLink
Log in

Rebalancing Immune Specificity and Function in Cancer by T-Cell Receptor Gene Therapy

  • REVIEW
  • Published:
Archivum Immunologiae et Therapiae Experimentalis Aims and scope

Abstract

Adoptive immunotherapy with tumor-specific T lymphocytes has demonstrated clinical benefit in some cancers, particularly melanoma. Yet isolating and expanding tumor-specific cells from patients is challenging and there is limited ability to control T-cell affinity and response characteristics. T-cell receptor (TCR) gene therapy, in which T lymphocytes for immunotherapy are redirected using an introduced rearranged TCR, has emerged as an important alternative. Successful TCR gene therapy requires consideration of a number of issues, including TCR specificity and affinity, optimal gene therapy constructs, types of T cells administered, and the survival and activity of the modified cells. In this review we highlight the rationale for and experience with TCR gene therapy as well as new approaches to enhancing it.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Alli R, Nguyen P, Geiger TL (2008) Retrogenic modeling of experimental allergic encephalomyelitis associates T cell frequency but not TCR functional affinity with pathogenicity. J Immunol 181:136–145

    CAS  PubMed  Google Scholar 

  • Amrani A, Verdaguer J, Serra P et al (2000) Progression of autoimmune diabetes driven by avidity maturation of a T-cell population. Nature 406:739–742

    Article  CAS  PubMed  Google Scholar 

  • Arstila TP, Casrouge A, Baron V et al (1999) A direct estimate of the human alphabeta T cell receptor diversity. Science 286:958–961

    Article  CAS  PubMed  Google Scholar 

  • Atanackovic D, Cao Y, Kim JW et al (2008) The local cytokine and chemokine milieu within malignant effusions. Tumour Biol 29:93–104

    Article  CAS  PubMed  Google Scholar 

  • Avril MF, Charpentier P, Margulis A et al (1992) Regression of primary melanoma with metastases. Cancer 69:1377–1381

    Article  CAS  PubMed  Google Scholar 

  • Badoual C, Hans S, Rodriguez J et al (2006) Prognostic value of tumor-infiltrating CD4+ T-cell subpopulations in head and neck cancers. Clin Cancer Res 12:465–472

    Article  CAS  PubMed  Google Scholar 

  • Berger C, Jensen MC, Lansdorp PM et al (2008) Adoptive transfer of effector CD8+ T cells derived from central memory cells establishes persistent T cell memory in primates. J Clin Invest 118:294–305

    Article  CAS  PubMed  Google Scholar 

  • Bernhard H, Neudorfer J, Gebhard K et al (2008) Adoptive transfer of autologous, HER2-specific, cytotoxic T lymphocytes for the treatment of HER2-overexpressing breast cancer. Cancer Immunol Immunother 57:271–280

    Article  PubMed  Google Scholar 

  • Bierie B, Moses HL (2010) Transforming growth factor beta (TGF-beta) and inflammation in cancer. Cytokine Growth Factor Rev 21:49–59

    Article  CAS  PubMed  Google Scholar 

  • Bilgi O, Karagoz B, Turken O et al (2008) Peripheral blood gamma-delta T cells in advanced-stage cancer patients. Adv Ther 25:218–224

    Article  PubMed  Google Scholar 

  • Blades RA, Keating PJ, McWilliam LJ et al (1995) Loss of HLA class I expression in prostate cancer: Implications for immunotherapy. Urology 46:681–687

    Article  CAS  PubMed  Google Scholar 

  • Blair DA, Lefrancois L (2007) Increased competition for antigen during priming negatively impacts the generation of memory CD4 T cells. Proc Natl Acad Sci USA 104:15045–15050

    Article  CAS  PubMed  Google Scholar 

  • Bollard CM, Aguilar L, Straathof KC et al (2004) Cytotoxic T lymphocyte therapy for Epstein-Barr virus + Hodgkin’s disease. J Exp Med 200:1623–1633

    Article  CAS  PubMed  Google Scholar 

  • Boni A, Muranski P, Cassard L et al (2008) Adoptive transfer of allogeneic tumor-specific T cells mediates effective regression of large tumors across major histocompatibility barriers. Blood 112:4746–4754

    Article  CAS  PubMed  Google Scholar 

  • Boulter JM, Jakobsen BK (2005) Stable, soluble, high-affinity, engineered T cell receptors: novel antibody-like proteins for specific targeting of peptide antigens. Clin Exp Immunol 142:454–460

    CAS  PubMed  Google Scholar 

  • Brown IE, Mashayekhi M, Markiewicz M et al (2005) Peripheral survival of naïve CD8+ T cells. Apoptosis 10:5–11

    Article  CAS  PubMed  Google Scholar 

  • Bui JD, Schreiber RD (2007) Cancer immunosurveillance, immunoediting and inflammation: independent or interdependent processes? Curr Opin Immunol 19:203–208

    Article  CAS  PubMed  Google Scholar 

  • Caballero OL, Chen YT (2009) Cancer/testis (CT) antigens: potential targets for immunotherapy. Cancer Sci 100:2014–2021

    Article  CAS  PubMed  Google Scholar 

  • Chang AE, Shu S (1996) Current status of adoptive immunotherapy of cancer. Crit Rev Oncol Hematol 22:213–228

    Article  CAS  PubMed  Google Scholar 

  • Chervin AS, Aggen DH, Raseman JM et al (2008) Engineering higher affinity T cell receptors using a T cell display system. J Immunol Methods 339:175–184

    Article  CAS  PubMed  Google Scholar 

  • Chlewicki LK, Holler PD, Monti BC et al (2005) High-affinity, peptide-specific T cell receptors can be generated by mutations in CDR1, CDR2 or CDR3. J Mol Biol 346:223–239

    Article  CAS  PubMed  Google Scholar 

  • Circosta P, Granziero L, Follenzi A et al (2009) TCR gene transfer with lentiviral vectors allows efficient redirection of tumor specificity in naive and memory T-cells without prior stimulation of endogenous TCR. Hum Gene Ther 29:1576–1588

    Article  CAS  Google Scholar 

  • Cohen CJ, Zhao Y, Zheng Z et al (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 66:8878–8886

    Article  CAS  PubMed  Google Scholar 

  • Connor ME, Stern PL (1990) Loss of MHC class-I expression in cervical carcinomas. Int J Cancer 46:1029–1034

    Article  CAS  PubMed  Google Scholar 

  • Conrad H, Gebhard K, Kronig H et al (2008) CTLs directed against HER2 specifically cross-react with HER3 and HER4. J Immunol 180:8135–8145

    CAS  PubMed  Google Scholar 

  • Cooper LJ, Ausubel L, Gutierrez M et al (2006) Manufacturing of gene-modified cytotoxic T lymphocytes for autologous cellular therapy for lymphoma. Cytotherapy 8:105–117

    Article  CAS  PubMed  Google Scholar 

  • Cui G, Goll R, Olsen T et al (2007) Reduced expression of microenvironmental Th1 cytokines accompanies adenomas-carcinomas sequence of colorectum. Cancer Immunol Immunother 56:985–995

    Article  CAS  PubMed  Google Scholar 

  • Curiel TJ, Coukos G, Zou L et al (2004) Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10:942–949

    Article  CAS  PubMed  Google Scholar 

  • de Herve MG, Cariou A, Simonetta F et al (2008) Heterospecific CD4 help to rescue CD8 T cell killers. J Immunol 181:5974–5980

    Google Scholar 

  • De Vita F, Orditura M, Galizia G et al (1999) Serum interleukin-10 levels in patients with advanced gastrointestinal malignancies. Cancer 86:1936–1943

    Article  PubMed  Google Scholar 

  • De Vita F, Orditura M, Galizia G et al (2000) Serum interleukin-10 levels as a prognostic factor in advanced non-small cell lung cancer patients. Chest 117:365–373

    Article  PubMed  Google Scholar 

  • de Witte MA, Coccoris M, Wolkers MC et al (2006) Targeting self-antigens through allogeneic TCR gene transfer. Blood 108:870–877

    Article  PubMed  CAS  Google Scholar 

  • de Witte MA, Bendle GM, van den Boom MD et al (2008) TCR gene therapy of spontaneous prostate carcinoma requires in vivo T cell activation. J Immunol 181:2563–2571

    PubMed  Google Scholar 

  • Disis ML (2009) Enhancing cancer vaccine efficacy via modulation of the tumor microenvironment. Clin Cancer Res 15:6476–6478

    Article  CAS  PubMed  Google Scholar 

  • Donermeyer DL, Weber KS, Kranz DM et al (2006) The study of high-affinity TCRs reveals duality in T cell recognition of antigen: specificity and degeneracy. J Immunol 177:6911–6919

    CAS  PubMed  Google Scholar 

  • Donnelly ML, Hughes LE, Luke G et al (2001a) The ‘cleavage’ activities of foot-and-mouth disease virus 2A site-directed mutants and naturally occurring ‘2A-like’ sequences. J Gen Virol 82:1027–1041

    CAS  PubMed  Google Scholar 

  • Donnelly ML, Luke G, Mehrotra A et al (2001b) Analysis of the aphthovirus 2A/2B polyprotein ‘cleavage’ mechanism indicates not a proteolytic reaction, but a novel translational effect: a putative ribosomal ‘skip’. J Gen Virol 82:1013–1025

    CAS  PubMed  Google Scholar 

  • Dossett ML, Teague RM, Schmitt TM et al (2009) Adoptive immunotherapy of disseminated leukemia with TCR-transduced, CD8+ T cells expressing a known endogenous TCR. Mol Ther 17:742–749

    Article  CAS  PubMed  Google Scholar 

  • Dudley ME, Rosenberg SA (2007) Adoptive cell transfer therapy. Semin Oncol 34:524–531

    Article  PubMed  Google Scholar 

  • Eberlein TJ, Rosenstein M, Spiess P et al (1982) Adoptive chemoimmunotherapy of a syngeneic murine lymphoma with long-term lymphoid cell lines expanded in T cell growth factor. Cancer Immunol Immunother 13:5–13

    Article  CAS  PubMed  Google Scholar 

  • Ebert LM, Liu YC, Clements CS et al (2009) A long, naturally presented immunodominant epitope from NY-ESO-1 tumor antigen: implications for cancer vaccine design. Cancer Res 69:1046–1054

    Article  CAS  PubMed  Google Scholar 

  • Engels B, Uckert W (2007) Redirecting T lymphocyte specificity by T cell receptor gene transfer—a new era for immunotherapy. Mol Aspects Med 28:115–142

    Article  CAS  PubMed  Google Scholar 

  • Fasso M, Anandasabapathy N, Crawford F et al (2000) T cell receptor (TCR)-mediated repertoire selection and loss of TCR vbeta diversity during the initiation of a CD4(+) T cell response in vivo. J Exp Med 192:1719–1730

    Article  CAS  PubMed  Google Scholar 

  • Feito MJ, Jimenez-Perianez A, Ojeda G et al (2002) The TCR/CD3 complex: molecular interactions in a changing structure. Arch Immunol Ther Exp 50:263–272

    CAS  Google Scholar 

  • Figlin RA, Thompson JA, Bukowski RM et al (1999) Multicenter, randomized, phase III trial of CD8+ tumor-infiltrating lymphocytes in combination with recombinant interleukin-2 in metastatic renal cell carcinoma. J Clin Oncol 17:2521–2529

    CAS  PubMed  Google Scholar 

  • Freudenberg JA, Wang Q, Katsumata M et al (2009) The role of HER2 in early breast cancer metastasis and the origins of resistance to HER2-targeted therapies. Exp Mol Pathol 87:1–11

    Article  CAS  PubMed  Google Scholar 

  • Galizia G, Orditura M, Romano C et al (2002) Prognostic significance of circulating IL-10 and IL-6 serum levels in colon cancer patients undergoing surgery. Clin Immunol 102:169–178

    Article  CAS  PubMed  Google Scholar 

  • Garcia-Lora A, Algarra I, Garrido F (2003) MHC class I antigens, immune surveillance, and tumor immune escape. J Cell Physiol 195:346–355

    Article  CAS  PubMed  Google Scholar 

  • Gattinoni L, Powell DJ Jr, Rosenberg SA et al (2006) Adoptive immunotherapy for cancer: building on success. Nat Rev Immunol 6:383–393

    Article  CAS  PubMed  Google Scholar 

  • Giacomelli L, Gianni W, Belfiore C et al (2003) Persistence of epidermal growth factor receptor and interleukin 10 in blood of colorectal cancer patients after surgery identifies patients with high risk to relapse. Clin Cancer Res 9:2678–2682

    CAS  PubMed  Google Scholar 

  • Gorelik L, Flavell RA (2001) Immune-mediated eradication of tumors through the blockade of transforming growth factor-beta signaling in T cells. Nat Med 7:1118–1122

    Article  CAS  PubMed  Google Scholar 

  • Halliday GM, Patel A, Hunt MJ et al (1995) Spontaneous regression of human melanoma/nonmelanoma skin cancer: association with infiltrating CD4+ T cells. World J Surg 19:352–358

    Article  CAS  PubMed  Google Scholar 

  • Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70

    Article  CAS  PubMed  Google Scholar 

  • Hare BJ, Wyss DF, Osburne MS et al (1999) Structure, specificity and CDR mobility of a class II restricted single-chain T-cell receptor. Nat Struct Biol 6:574–581

    Article  CAS  PubMed  Google Scholar 

  • Heemskerk MH (2006) Optimizing TCR gene transfer. Clin Immunol 119:121–122

    Article  CAS  PubMed  Google Scholar 

  • Heemskerk MH, Hagedoorn RS, van der Hoorn MA et al (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 109:235–243

    Article  CAS  PubMed  Google Scholar 

  • Heslop HE, Slobod KS, Pule MA et al (2010) Long-term outcome of EBV-specific T-cell infusions to prevent or treat EBV-related lymphoproliferative disease in transplant recipients. Blood 115:925–935

    Article  CAS  PubMed  Google Scholar 

  • Hinrichs CS, Borman ZA, Cassard L et al (2009) Adoptively transferred effector cells derived from naive rather than central memory CD8+ T cells mediate superior antitumor immunity. Proc Natl Acad Sci USA 106:17469–17474

    Article  CAS  PubMed  Google Scholar 

  • Hofstetter HH, Targoni OS, Karulin AY et al (2005) Does the frequency and avidity spectrum of the neuroantigen-specific T cells in the blood mirror the autoimmune process in the central nervous system of mice undergoing experimental allergic encephalomyelitis? J Immunol 174:4598–4605

    CAS  PubMed  Google Scholar 

  • Holler PD, Kranz DM (2003) Quantitative analysis of the contribution of TCR/pepMHC affinity and CD8 to T cell activation. Immunity 18:255–264

    Article  CAS  PubMed  Google Scholar 

  • Holler PD, Chlewicki LK, Kranz DM (2003) TCRs with high affinity for foreign pMHC show self-reactivity. Nat Immunol 4:55–62

    Article  CAS  PubMed  Google Scholar 

  • Hong S, Qian J, Yang J et al (2008) Roles of idiotype-specific t cells in myeloma cell growth and survival: Th1 and CTL cells are tumoricidal while Th2 cells promote tumor growth. Cancer Res 68:8456–8464

    Article  CAS  PubMed  Google Scholar 

  • Hori S, Haury M, Coutinho A et al (2002) Specificity requirements for selection and effector functions of CD25+4+ regulatory T cells in anti-myelin basic protein T cell receptor transgenic mice. Proc Natl Acad Sci USA 99:8213–8218

    Article  CAS  PubMed  Google Scholar 

  • Hsieh CS, Zheng Y, Liang Y et al (2006) An intersection between the self-reactive regulatory and nonregulatory T cell receptor repertoires. Nat Immunol 7:401–410

    Article  CAS  PubMed  Google Scholar 

  • Hughes MS, Yu YY, Dudley ME et al (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 16:457–472

    Article  CAS  PubMed  Google Scholar 

  • Hunder NN, Wallen H, Cao J et al (2008) Treatment of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N Engl J Med 358:2698–2703

    Article  CAS  PubMed  Google Scholar 

  • Huter EN, Stummvoll GH, DiPaolo RJ et al (2008) Cutting edge: antigen-specific TGF beta-induced regulatory T cells suppress Th17-mediated autoimmune disease. J Immunol 181:8209–8213

    CAS  PubMed  Google Scholar 

  • Jäger E, Ringhoffer M, Altmannsberger M et al (1997) Immunoselection in vivo: Independent loss of MHC class I and melanocyte differentiation antigen expression in metastatic melanoma. Int J Cancer 71:142–147

    Article  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Jones LL, Colf LA, Bankovich AJ et al (2008) Different thermodynamic binding mechanisms and peptide fine specificities associated with a panel of structurally similar high-affinity T cell receptors. Biochemistry 47:12398–12408

    Article  CAS  PubMed  Google Scholar 

  • Kabelitz D, Wesch D, Pitters E et al (2004) Potential of human gammadelta T lymphocytes for immunotherapy of cancer. Int J Cancer 112:727–732

    Article  CAS  PubMed  Google Scholar 

  • Kammertoens T, Blankenstein T (2009) Making and circumventing tolerance to cancer. Eur J Immunol 39:2345–2353

    Article  CAS  PubMed  Google Scholar 

  • Kedl RM, Kappler JW, Marrack P (2003) Epitope dominance, competition and T cell affinity maturation. Curr Opin Immunol 15:120–127

    Article  CAS  PubMed  Google Scholar 

  • Klein B, Lu ZY, Gu ZJ et al (1999) Interleukin-10 and Gp130 cytokines in human multiple myeloma. Leuk Lymphoma 34:63–70

    CAS  PubMed  Google Scholar 

  • Klein L, Hinterberger M, Wirnsberger G et al (2009) Antigen presentation in the thymus for positive selection and central tolerance induction. Nat Rev Immunol 9:833–844

    Article  CAS  PubMed  Google Scholar 

  • Kline J, Brown IE, Zha YY et al (2008) Homeostatic proliferation plus regulatory T-cell depletion promotes potent rejection of B16 melanoma. Clin Cancer Res 14:3156–3167

    Article  CAS  PubMed  Google Scholar 

  • Kuball J, Dossett ML, Wolfl M et al (2007) Facilitating matched pairing and expression of TCR chains introduced into human T cells. Blood 109:2331–2338

    Article  CAS  PubMed  Google Scholar 

  • Lake DF, Salgaller ML, van der Bruggen P et al (1999) Construction and binding analysis of recombinant single-chain TCR derived from tumor-infiltrating lymphocytes and a cytotoxic T lymphocyte clone directed against MAGE-1. Int Immunol 11:745–751

    Article  CAS  PubMed  Google Scholar 

  • Li B, Lalani AS, Harding TC et al (2006) Vascular endothelial growth factor blockade reduces intratumoral regulatory T cells and enhances the efficacy of a GM-CSF-secreting cancer immunotherapy. Clin Cancer Res 12:6808–6816

    Article  CAS  PubMed  Google Scholar 

  • Li L, Chao QG, Ping LZ et al (2009) The prevalence of FOXP3+ regulatory T-cells in peripheral blood of patients with NSCLC. Cancer Biother Radiopharm 24:357–367

    Article  CAS  PubMed  Google Scholar 

  • Liu G, Yao K, Wang B et al (2009a) Immunotherapy of Epstein-Barr virus associated malignancies using mycobacterial HSP70 and LMP2A356–364 epitope fusion protein. Cell Mol Immunol 6:423–431

    Article  CAS  PubMed  Google Scholar 

  • Liu X, Nguyen P, Liu W et al (2009b) T cell receptor CDR3 sequence but not recognition characteristics distinguish autoreactive effector and Foxp3+ regulatory T cells. Immunity 31:909–920

    Article  CAS  PubMed  Google Scholar 

  • Liyanage UK, Moore TT, Joo H-G et al (2002) Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol 169:2756–2761

    CAS  PubMed  Google Scholar 

  • Lob S, Konigsrainer A, Rammensee HG et al (2009) Inhibitors of indoleamine-2,3-dioxygenase for cancer therapy: can we see the wood for the trees? Nat Rev Cancer 9:445–452

    Article  PubMed  CAS  Google Scholar 

  • Lotze M, Chang A, Seipp C (1986) High-dose recombinant interleukin-2 in the treatment of patients with disseminated cancer. JAMA 256:3117–3124

    Article  CAS  PubMed  Google Scholar 

  • Malherbe L, Hausl C, Teyton L et al (2004) Clonal selection of helper T cells is determined by an affinity threshold with no further skewing of TCR binding properties. Immunity 21:669–679

    Article  CAS  PubMed  Google Scholar 

  • Marrack P, Scott-Browne JP, Dai S et al (2008) Evolutionarily conserved amino acids that control TCR–MHC interaction. Annu Rev Immunol 26:171–203

    Article  CAS  PubMed  Google Scholar 

  • Martin-Orozco N, Muranski P, Chung Y et al (2009) T helper 17 cells promote cytotoxic T cell activation in tumor immunity. Immunity 31:787–798

    Article  CAS  PubMed  Google Scholar 

  • Moo-Young TA, Larson JW, Belt BA et al (2009) Tumor-derived TGF-beta mediates conversion of CD4+ Foxp3+ regulatory T cells in a murine model of pancreas cancer. J Immunother 32:12–21

    Article  CAS  PubMed  Google Scholar 

  • Morgan RA, Dudley ME, Yu Y et al (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 171:3287–3295

    CAS  PubMed  Google Scholar 

  • Morgan RA, Dudley ME, Wunderlich JR et al (2006) Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314:126–129

    Article  CAS  PubMed  Google Scholar 

  • Mule J, Shu S, Schwarz S et al (1984) Adoptive immunotherapy of established pulmonary metastases with LAK cells and recombinant interleukin-2. Science 225:1487–1489

    Article  CAS  PubMed  Google Scholar 

  • Muranski P, Restifo NP (2009) Adoptive immunotherapy of cancer using CD4(+) T cells. Curr Opin Immunol 21:200–208

    Article  CAS  PubMed  Google Scholar 

  • Nakanishi Y, Lu B, Gerard C et al (2009) CD8(+) T lymphocyte mobilization to virus-infected tissue requires CD4(+) T-cell help. Nature 462:510–513

    Article  CAS  PubMed  Google Scholar 

  • Nakui M, Ohta A, Sekimoto M et al (2000) Potentiation of antitumor effect of NKT cell ligand, alpha-galactosylceramide by combination with IL-12 on lung metastasis of malignant melanoma cells. Clin Exp Metastasis 18:147–153

    Article  CAS  PubMed  Google Scholar 

  • Nesbeth Y, Scarlett U, Cubillos-Ruiz J et al (2009) CCL5-mediated endogenous antitumor immunity elicited by adoptively transferred lymphocytes and dendritic cell depletion. Cancer Res 69:6331–6338

    Article  CAS  PubMed  Google Scholar 

  • Nicholaou T, Ebert L, Davis ID et al (2006) Directions in the immune targeting of cancer: Lessons learned from the cancer-testis Ag NY-ESO-1. Immunol Cell Biol 84:303–317

    Article  CAS  PubMed  Google Scholar 

  • Nishimura T, Kitamura H, Iwakabe K et al (2000) The interface between innate and acquired immunity: glycolipid antigen presentation by CD1d-expressing dendritic cells to NKT cells induces the differentiation of antigen-specific cytotoxic T lymphocytes. Int Immunol 12:987–994

    Article  CAS  PubMed  Google Scholar 

  • Norris P, Rosenberg E (2002) CD4+ T helper cells and the role they play in viral control. J Mol Med 80:397–405

    Article  PubMed  Google Scholar 

  • Okamoto S, Mineno J, Ikeda H et al (2009) Improved expression and reactivity of transduced tumor-specific TCRs in human lymphocytes by specific silencing of endogenous TCR. Cancer Res 69:9003–9011

    Article  CAS  PubMed  Google Scholar 

  • Overwijk WW, Lee DS, Surman DR et al (1999) Vaccination with a recombinant vaccinia virus encoding a “self” antigen induces autoimmune vitiligo and tumor cell destruction in mice: requirement for CD4(+) T lymphocytes. Proc Natl Acad Sci USA 96:2982–2987

    Article  CAS  PubMed  Google Scholar 

  • Palmer DC, Chan C-C, Gattinoni L et al (2008) Effective tumor treatment targeting a melanoma/melanocyte-associated antigen triggers severe ocular autoimmunity. Proc Natl Acad Sci USA 105:8061–8066

    Article  CAS  PubMed  Google Scholar 

  • Pardoll DM, Topalian SL (1998) The role of CD4+ T cell responses in antitumor immunity. Curr Opin Immunol 10:588–594

    Article  CAS  PubMed  Google Scholar 

  • Peggs KS, Quezada SA, Chambers CA et al (2009) Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies. J Exp Med 206:1717–1725

    Article  CAS  PubMed  Google Scholar 

  • Peng PD, Cohen CJ, Yang S et al (2009) Efficient nonviral Sleeping Beauty transposon-based TCR gene transfer to peripheral blood lymphocytes confers antigen-specific antitumor reactivity. Gene Ther 16:1042–1049

    Article  CAS  PubMed  Google Scholar 

  • Petrausch U, Jensen SM, Twitty C et al (2009) Disruption of TGF-beta signaling prevents the generation of tumor-sensitized regulatory T cells and facilitates therapeutic antitumor immunity. J Immunol 183:3682–3689

    Article  CAS  PubMed  Google Scholar 

  • Phan GQ, Touloukian CE, Yang JC et al (2003a) Immunization of patients with metastatic melanoma using both class I- and class II-restricted peptides from melanoma-associated antigens. J Immunother 26:349–356

    Article  CAS  PubMed  Google Scholar 

  • Phan GQ, Yang JC, Sherry RM et al (2003b) Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci USA 100:8372–8377

    Article  CAS  PubMed  Google Scholar 

  • Pike-Overzet K, van der Burg M, Wagemaker G et al (2007) New insights and unresolved issues regarding insertional mutagenesis in X-linked SCID gene therapy. Mol Ther 15:1910–1916

    Article  CAS  PubMed  Google Scholar 

  • Poehlein CH, Haley DP, Walker EB et al (2009) Depletion of tumor-induced Treg prior to reconstitution rescues enhanced priming of tumor-specific, therapeutic effector T cells in lymphopenic hosts. Eur J Immunol 39:3121–3133

    Article  CAS  PubMed  Google Scholar 

  • Powell DJ, Dudley M, Robbins P et al (2005) Transition of late-stage effector T cells to CD27+ CD28+ tumor-reactive effector memory T cells in humans after adoptive cell transfer therapy. Blood 105:241–250

    Article  CAS  PubMed  Google Scholar 

  • Preuss KD, Zwick C, Bormann C et al (2002) Analysis of the B-cell repertoire against antigens expressed by human neoplasms. Immunol Rev 188:43–50

    Article  CAS  PubMed  Google Scholar 

  • Price DA, Brenchley JM, Ruff LE et al (2005) Avidity for antigen shapes clonal dominance in CD8+ T cell populations specific for persistent DNA viruses. J Exp Med 202:1349–1361

    Article  CAS  PubMed  Google Scholar 

  • Pule MA, Savoldo B, Myers GD et al (2008) Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma. Nat Med 14:1264–1270

    Article  CAS  PubMed  Google Scholar 

  • Radtke I, Mullighan CG, Ishii M et al (2009) Genomic analysis reveals few genetic alterations in pediatric acute myeloid leukemia. Proc Natl Acad Sci USA 106:12944–12949

    Article  CAS  PubMed  Google Scholar 

  • Rees W, Bender J, Teague TK et al (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  Google Scholar 

  • Richman SA, Kranz DM (2007) Display, engineering, and applications of antigen-specific T cell receptors. Biomol Eng 24:361–373

    Article  CAS  PubMed  Google Scholar 

  • Rimsza LM, Roberts RA, Miller TP et al (2004) Loss of MHC class II gene and protein expression in diffuse large B-cell lymphoma is related to decreased tumor immunosurveillance and poor patient survival regardless of other prognostic factors: a follow-up study from the Leukemia and Lymphoma Molecular Profiling Project. Blood 103:4251–4425

    Article  CAS  PubMed  Google Scholar 

  • Robbins PF, Li YF, El-Gamil M et al (2008) Single and dual amino acid substitutions in TCR CDRs can enhance antigen-specific T cell functions. J Immunol 180:6116–6131

    CAS  PubMed  Google Scholar 

  • Rosenberg SA (1999) A new era for cancer immunotherapy based on the genes that encode cancer antigens. Immunity 10:281–287

    Article  CAS  PubMed  Google Scholar 

  • Rosenberg SA, Yang JC, Sherry RM et al (2003) Inability to immunize patients with metastatic melanoma using plasmid DNA encoding the gp100 melanoma-melanocyte antigen. Hum Gene Ther 14:709–714

    Article  CAS  PubMed  Google Scholar 

  • Rosenberg SA, Yang JC, Restifo NP (2004) Cancer immunotherapy: moving beyond current vaccines. Nat Med 10:909–915

    Article  CAS  PubMed  Google Scholar 

  • Rosenberg SA, Restifo NP, Yang JC et al (2008) Adoptive cell transfer: a clinical path to effective cancer immunotherapy. Nat Rev Cancer 8:299–308

    Article  CAS  PubMed  Google Scholar 

  • Rubnitz JE, Inaba H, Ribeiro RC et al (2010) NKAML: a pilot study to determine the safety and feasibility of haploidentical natural killer cell transplantation in childhood acute myeloid leukemia. J Clin Oncol 28:955–959

    Article  CAS  PubMed  Google Scholar 

  • Schmitt TM, Ragnarsson GB, Greenberg PD (2009) TCR gene therapy for cancer. Hum Gene Ther 20:1240–1248

    Article  CAS  PubMed  Google Scholar 

  • Sebestyen Z, Schooten E, Sals T et al (2008) Human TCR that incorporate CD3zeta induce highly preferred pairing between TCRalpha and beta chains following gene transfer. J Immunol 180:7736–7746

    CAS  PubMed  Google Scholar 

  • Selvaraj RK, Geiger TL (2007) A kinetic and dynamic analysis of Foxp3 induced in T cells by TGF-beta. J Immunol 179:11 p following 1390

    Google Scholar 

  • Selvaraj RK, Geiger TL (2008) Mitigation of experimental allergic encephalomyelitis by TGF-beta induced Foxp3+ regulatory T lymphocytes through the induction of anergy and infectious tolerance. J Immunol 180:2830–2838

    CAS  PubMed  Google Scholar 

  • Shafer-Weaver KA, Anderson MJ, Stagliano K et al (2009a) Cutting Edge: Tumor-specific CD8+ T cells infiltrating prostatic tumors are induced to become suppressor cells. J Immunol 183:4848–4852

    Article  CAS  PubMed  Google Scholar 

  • Shafer-Weaver KA, Watkins SK, Anderson MJ et al (2009b) Immunity to murine prostatic tumors: continuous provision of T-cell help prevents CD8 T-cell tolerance and activates tumor-infiltrating dendritic cells. Cancer Res 69:6256–6264

    Article  CAS  PubMed  Google Scholar 

  • Shankaran V, Ikeda H, Bruce AT et al (2001) IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 410:1107–1111

    Article  CAS  PubMed  Google Scholar 

  • Smyth MJ, Dunn GP, Schreiber RD (2006) Cancer immunosurveillance and immunoediting: the roles of immunity in suppressing tumor development and shaping tumor immunogenicity. Adv Immunol 90:1–50

    Article  CAS  PubMed  Google Scholar 

  • Stockinger B, Veldhoen M (2007) Differentiation and function of Th17 T cells. Curr Opin Immunol 19:281–286

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Suzuki H, Onishi H, Wada J et al (2010) VEGFR2 is selectively expressed by FOXP3(high)CD4(+) regulatory T cells. Eur J Immunol 40:197–203

    Article  CAS  PubMed  Google Scholar 

  • Szymczak AL, Workman CJ, Wang Y et al (2004) Correction of multi-gene deficiency in vivo using a single ‘self-cleaving’ 2A peptide-based retroviral vector. Nat Biotechnol 22:589–594

    Article  CAS  PubMed  Google Scholar 

  • Tang Q, Henriksen KJ, Bi M, Finger EB et al (2004) In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes. J Exp Med 199:1455–1465

    Article  CAS  PubMed  Google Scholar 

  • Terabe M, Matsui S, Noben-Trauth N et al (2000) NKT cell-mediated repression of tumor immunosurveillance by IL-13 and the IL-4R-STAT6 pathway. Nat Immunol 1:515–520

    Article  CAS  PubMed  Google Scholar 

  • Theobald M, Biggs J, Hernández J et al (1997) Tolerance to p53 by A2.1-restricted cytotoxic T lymphocytes. J Exp Med 185:833–841

    Article  CAS  PubMed  Google Scholar 

  • Udyavar A, Alli R, Nguyen P et al (2009) Subtle affinity-enhancing mutations in a myelin oligodendrocyte glycoprotein-specific TCR alter specificity and generate new self-reactivity. J Immunol 182:4439–4447

    Article  CAS  PubMed  Google Scholar 

  • Varani L, Bankovich AJ, Liu CW et al (2007) Solution mapping of T cell receptor docking footprints on peptide-MHC. Proc Natl Acad Sci USA 104:13080–13085

    Article  CAS  PubMed  Google Scholar 

  • Varela-Rohena A, Jakobsen BK, Sewell AK et al (2009) Are affinity-enhanced T cells the future of HIV therapy? HIV Ther 3:105–108

    Article  CAS  Google Scholar 

  • Verbsky JW (2007) Therapeutic use of T regulatory cells. Curr Opin Rheumatol 19:252–258

    Article  PubMed  Google Scholar 

  • Voss R-H, Kuball J, Engel R et al (2006) Redirection of T cells by delivering a transgenic mouse-derived MDM2 tumor antigen-specific TCR and its humanized derivative is governed by the CD8 coreceptor and affects natural human TCR expression. Immunol Res 34:67–87

    Article  CAS  PubMed  Google Scholar 

  • Voss RH, Willemsen RA, Kuball J et al (2008) Molecular design of the Calphabeta interface favors specific pairing of introduced TCRalphabeta in human T cells. J Immunol 180:391–401

    CAS  PubMed  Google Scholar 

  • Wang R-F (2001) The role of MHC class II-restricted tumor antigens and CD4+ T cells in antitumor immunity. Trends Immunol 22:269–276

    Article  PubMed  Google Scholar 

  • Warabi M, Kitagawa M, Hirokawa K (2000) Loss of MHC class II expression is associated with a decrease of tumor-infiltrating T cells and an increase of metastatic potential of colorectal cancer: immunohistological and histopathological analyses as compared with normal colonic mucosa and adenomas. Pathol Res Pract 196:807–815

    CAS  PubMed  Google Scholar 

  • Wargo JA, Robbins PF, Li Y et al (2009) Recognition of NY-ESO-1+ tumor cells by engineered lymphocytes is enhanced by improved vector design and epigenetic modulation of tumor antigen expression. Cancer Immunol Immunother 58:383–394

    Article  CAS  PubMed  Google Scholar 

  • Weber J (2007) Anti-CTLA-4 antibody ipilimumab: case studies of clinical response and immune-related adverse events. Oncologist 12:864–872

    Article  CAS  PubMed  Google Scholar 

  • Weber KS, Donermeyer DL, Allen PM et al (2005) Class II-restricted T cell receptor engineered in vitro for higher affinity retains peptide specificity and function. Proc Natl Acad Sci USA 102:19033–19038

    Article  CAS  PubMed  Google Scholar 

  • Wilson DB, Wilson DH, Schroder K et al (2004) Specificity and degeneracy of T cells. Mol Immunol 40:1047–1055

    Article  CAS  PubMed  Google Scholar 

  • Wong SB, Bos R, Sherman LA (2008) Tumor-specific CD4+ T cells render the tumor environment permissive for infiltration by low-avidity CD8+ T cells. J Immunol 180:3122–3131

    CAS  PubMed  Google Scholar 

  • Workman CJ, Szymczak-Workman AL, Collison LW et al (2009) The development and function of regulatory T cells. Cell Mol Life Sci 66:2603–2622

    Article  CAS  PubMed  Google Scholar 

  • Wright GP, Notley CA, Xue SA et al (2009) Adoptive therapy with redirected primary regulatory T cells results in antigen-specific suppression of arthritis. Proc Natl Acad Sci USA 106:19078–19083

    Article  CAS  PubMed  Google Scholar 

  • Wrzesinski SH, Wan YY, Flavell RA (2007) Transforming growth factor-beta and the immune response: implications for anticancer therapy. Clin Cancer Res 13:5262–5270

    Article  CAS  PubMed  Google Scholar 

  • Xu JJ, Yao K, Yu CJ et al (2006) Anti-tumor immunity against nasopharyngeal carcinoma by means of LMP2A-specific cytotoxic T lymphocytes induced by dendritic cells. Auris Nasus Larynx 33:441–446

    Article  CAS  PubMed  Google Scholar 

  • Yee C, Thompson JA, Roche P et al (2000) Melanocyte destruction after antigen-specific immunotherapy of melanoma: direct evidence of T cell-mediated vitiligo. J Exp Med 192:1637–1643

    Article  CAS  PubMed  Google Scholar 

  • Yeh S, Karne NK, Kerkar SP et al. (2009) Ocular and systemic autoimmunity after successful tumor-infiltrating lymphocyte immunotherapy for recurrent, metastatic melanoma. Ophthalmology 116:981–989.e1

    Google Scholar 

  • Yu P, Fu Y-X (2006) Tumor-infiltrating T lymphocytes: friends or foes? Lab Invest 86:231–245

    Article  CAS  PubMed  Google Scholar 

  • Yue FY, Dummer R, Geertsen R et al (1997) Interleukin-10 is a growth factor for human melanoma cells and down-regulates HLA class-I, HLA class-II and ICAM-1 molecules. Int J Cancer 71:630–637

    Article  CAS  PubMed  Google Scholar 

  • Zhang T, He X, Tsang TC et al (2004) Transgenic TCR expression: comparison of single chain with full-length receptor constructs for T-cell function. Cancer Gene Ther 11:487–496

    Article  CAS  PubMed  Google Scholar 

  • Zhang Y, Wakita D, Chamoto K et al (2007) Th1 cell adjuvant therapy combined with tumor vaccination: a novel strategy for promoting CTL responses while avoiding the accumulation of Tregs. Int Immunol 19:151–161

    Article  CAS  PubMed  Google Scholar 

  • Zhang S, Zhang H, Zhao J (2009) The role of CD4 T cell help for CD8 CTL activation. Biochem Biophys Res Commun 384:405–408

    Article  CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • Zhou X, Cui Y, Huang X et al (2003) Lentivirus-mediated gene transfer and expression in established human tumor antigen-specific cytotoxic T cells and primary unstimulated T cells. Hum Gene Ther 14:089–1105

    Article  CAS  Google Scholar 

  • Zou W (2005) Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat Rev Cancer 5:63–274

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Institutes of Health grant R01 AI056153 (to TLG) and by the American Lebanese Syrian Associated Charities (ALSAC)/St. Jude Children’s Research Hospital.

Author information

Authors and Affiliations

  1. Department of Pathology, St. Jude Children’s Research Hospital, 262 St. Jude Place, D-4047, Memphis, TN, 38105, USA

    Akshata Udyavar & Terrence L. Geiger

Authors
  1. Akshata Udyavar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Terrence L. Geiger
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Terrence L. Geiger.

About this article

Cite this article

Udyavar, A., Geiger, T.L. Rebalancing Immune Specificity and Function in Cancer by T-Cell Receptor Gene Therapy. Arch. Immunol. Ther. Exp. 58, 335–346 (2010). https://doi.org/10.1007/s00005-010-0090-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00005-010-0090-1

Keywords

Search

Navigation