Skip to main content

Advertisement

SpringerLink
Log in

Adoptive T-cell Immunotherapy of Cancer Using Chimeric Antigen Receptor-Grafted T Cells

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

Abstract

Harnessing the power of the immune system to target cancer has long been a goal of tumor immunologists. One avenue under investigation is the modification of T cells to express a chimeric antigen receptor (CAR). Expression of such a receptor enables T-cell specificity to be redirected against a chosen tumor antigen. Substantial research in this field has been carried out, incorporating a wide variety of malignancies and tumor-associated antigens. Ongoing investigations will ensure this area continues to expand at a rapid pace. This review will explain the evolution of CAR technology over the last two decades in addition to detailing the associated benefits and disadvantages. The outcome of recent phase I clinical trials and the impact that these have had upon the direction of future research in this field will also be addressed.

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
Fig. 3

Similar content being viewed by others

Abbreviations

CAR:

Chimeric antigen receptor

HLA:

Human leukocyte antigen

MHC:

Major histocompatibility complex

TCR:

T-cell receptor

chTCR:

Chimeric TCR

scFv:

Single-chain antibody fragment

TNP:

Trinitrophenol

Treg:

Regulatory T-cell

IL:

Interleukin

EBV:

Epstein–Barr virus

HSV-TK:

Herpes simplex virus thymidine kinase

References

  • Ahmed N, Ratnayake M, Savoldo B et al (2007) Regression of experimental medulloblastoma following transfer of HER2-specific T cells. Cancer Res 67:5957–5964

    Article  CAS  PubMed  Google Scholar 

  • Alarcon B, Swamy M, van Santen HM et al (2006) T-cell antigen-receptor stoichiometry: pre-clustering for sensitivity. EMBO Rep 7:490–495

    Article  CAS  PubMed  Google Scholar 

  • Altenschmidt U, Kahl R, Moritz D et al (1996) Cytolysis of tumor cells expressing the Neu/erbB-2, erbB-3, and erbB-4 receptors by genetically targeted naive T lymphocytes. Clin Cancer Res 2:1001–1008

    CAS  PubMed  Google Scholar 

  • Altenschmidt U, Klundt E, Groner B (1997) Adoptive transfer of in vitro-targeted, activated T lymphocytes results in total tumor regression. J Immunol 159:5509–5515

    CAS  PubMed  Google Scholar 

  • Alvarez-Vallina L, Hawkins RE (1996) Antigen-specific targeting of CD28-mediated T cell co-stimulation using chimeric single-chain antibody variable fragment-CD28 receptors. Eur J Immunol 26:2304–2309

    Article  CAS  PubMed  Google Scholar 

  • Becker ML, Near R, Mudgett-Hunter M et al (1989) Expression of a hybrid immunoglobulin-T cell receptor protein in transgenic mice. Cell 58:911–921

    Article  CAS  PubMed  Google Scholar 

  • Bennour E, Ferrand C, Remy-Martin JP et al (2008) Abnormal expression of only the CD34 part of a transgenic CD34/herpes simplex virus-thymidine kinase fusion protein is associated with ganciclovir resistance. Hum Gene Ther 19:699–709

    Article  CAS  PubMed  Google Scholar 

  • Berger C, Flowers ME, Warren EH et al (2006) Analysis of transgene-specific immune responses that limit the in vivo persistence of adoptively transferred HSV-TK-modified donor T cells after allogeneic hematopoietic cell transplantation. Blood 107:2294–2302

    Article  CAS  PubMed  Google Scholar 

  • Bonini C, Ferrari G, Verzeletti S et al (1997) HSV-TK gene transfer into donor lymphocytes for control of allogeneic graft-versus-leukemia. Science 276:1719–1724

    Article  CAS  PubMed  Google Scholar 

  • Brentjens RJ, Latouche JB, Santos E et al (2003) Eradication of systemic B-cell tumors by genetically targeted human T lymphocytes co-stimulated by CD80 and interleukin-15. Nat Med 9:279–286

    Article  CAS  PubMed  Google Scholar 

  • Brentjens RJ, Santos E, Nikhamin Y et al (2007) Genetically targeted T cells eradicate systemic acute lymphoblastic leukemia xenografts. Clin Cancer Res 13:5426–5435

    Article  CAS  PubMed  Google Scholar 

  • Brocker T, Karjalainen K (1995) Signals through T cell receptor-zeta chain alone are insufficient to prime resting T lymphocytes. J Exp Med 181:1653–1659

    Article  CAS  PubMed  Google Scholar 

  • Burt RK, Drobyski WR, Seregina T et al (2003) Herpes simplex thymidine kinase gene-transduced donor lymphocyte infusions. Exp Hematol 31:903–910

    Article  CAS  PubMed  Google Scholar 

  • Carter P, Presta L, Gorman CM et al (1992) Humanization of an anti-p185HER2 antibody for human cancer therapy. Proc Natl Acad Sci USA 89:4285–4289

    Article  CAS  PubMed  Google Scholar 

  • Chalmers D, Ferrand C, Apperley JF et al (2001) Elimination of the truncated message from the herpes simplex virus thymidine kinase suicide gene. Mol Ther 4:146–148

    Article  CAS  PubMed  Google Scholar 

  • Charo J, Finkelstein SE, Grewal N et al (2005) Bcl-2 overexpression enhances tumor-specific T-cell survival. Cancer Res 65:2001–2008

    Article  CAS  PubMed  Google Scholar 

  • Cheadle EJ, Gilham DE, Hawkins RE (2008) The combination of cyclophosphamide and human T cells genetically engineered to target CD19 can eradicate established B-cell lymphoma. Br J Haematol 142:65–68

    Article  CAS  PubMed  Google Scholar 

  • Choudhuri K, Wiseman D, Brown MH et al (2005) T-cell receptor triggering is critically dependent on the dimensions of its peptide-MHC ligand. Nature 436:578–582

    Article  CAS  PubMed  Google Scholar 

  • Chung S, Wucherpfennig KW, Friedman SM et al (1994) Functional three-domain single-chain T-cell receptors. Proc Natl Acad Sci USA 91:12654–12658

    Article  CAS  PubMed  Google Scholar 

  • Cooper LJ, Topp MS, Serrano LM et al (2003) T-cell clones can be rendered specific for CD19: toward the selective augmentation of the graft-versus-B-lineage leukemia effect. Blood 101:1637–1644

    Article  CAS  PubMed  Google Scholar 

  • Cooper LJ, Al-Kadhimi Z, Serrano LM et al (2005) Enhanced antilymphoma efficacy of CD19-redirected influenza MP1-specific CTLs by cotransfer of T cells modified to present influenza MP1. Blood 105:1622–1631

    Article  CAS  PubMed  Google Scholar 

  • Crumpacker CS (1996) Ganciclovir. N Engl J Med 335:721–729

    Article  CAS  PubMed  Google Scholar 

  • Darcy PK, Kershaw MH, Trapani JA et al (1998) Expression in cytotoxic T lymphocytes of a single-chain anti-carcinoembryonic antigen antibody. Redirected Fas ligand-mediated lysis of colon carcinoma. Eur J Immunol 28:1663–1672

    Article  CAS  PubMed  Google Scholar 

  • Daudt L, Maccario R, Locatelli F et al (2008) Interleukin-15 favors the expansion of central memory CD8+ T cells in ex vivo generated, antileukemia human cytotoxic T lymphocyte lines. J Immunother 31:385–393

    Article  CAS  PubMed  Google Scholar 

  • Davis SJ, van der Merwe PA (2006) The kinetic-segregation model: TCR triggering and beyond. Nat Immunol 7:803–809

    Article  CAS  PubMed  Google Scholar 

  • DeBenedette MA, Shahinian A, Mak TW et al (1997) Costimulation of CD28− T lymphocytes by 4-1BB ligand. J Immunol 158:551–559

    CAS  PubMed  Google Scholar 

  • Deeks SG, Wagner B, Anton PA et al (2002) A phase II randomized study of HIV-specific T-cell gene therapy in subjects with undetectable plasma viremia on combination antiretroviral therapy. Mol Ther 5:788–797

    Article  CAS  PubMed  Google Scholar 

  • Dembic Z, Haas W, Weiss S et al (1986) Transfer of specificity by murine alpha and beta T-cell receptor genes. Nature 320:232–238

    Article  CAS  PubMed  Google Scholar 

  • Deschamps M, Mercier-Lethondal P, Certoux JM et al (2007) Deletions within the HSV-tk transgene in long-lasting circulating gene-modified T cells infused with a hematopoietic graft. Blood 110:3842–3852

    Article  CAS  PubMed  Google Scholar 

  • Dotti G, Savoldo B, Pule M et al (2005) Human cytotoxic T lymphocytes with reduced sensitivity to Fas-induced apoptosis. Blood 105:4677–4684

    Article  CAS  PubMed  Google Scholar 

  • Eaton D, Gilham DE, O’Neill A et al (2002) Retroviral transduction of human peripheral blood lymphocytes with Bcl-X(L) promotes in vitro lymphocyte survival in pro-apoptotic conditions. Gene Ther 9:527–535

    Article  CAS  PubMed  Google Scholar 

  • Eshhar Z, Waks T, Gross G et al (1993) Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the gamma or zeta subunits of the immunoglobulin and T-cell receptors. Proc Natl Acad Sci USA 90:720–724

    Article  CAS  PubMed  Google Scholar 

  • Finney HM, Lawson AD, Bebbington CR et al (1998) Chimeric receptors providing both primary and costimulatory signaling in T cells from a single gene product. J Immunol 161:2791–2797

    CAS  PubMed  Google Scholar 

  • Finney HM, Akbar AN, Lawson AD (2004) Activation of resting human primary T cells with chimeric receptors: costimulation from CD28, inducible costimulator, CD134, and CD137 in series with signals from the TCR zeta chain. J Immunol 172:104–113

    CAS  PubMed  Google Scholar 

  • Friedmann-Morvinski D, Bendavid A, Waks T et al (2005) Redirected primary T cells harboring a chimeric receptor require costimulation for their antigen-specific activation. Blood 105:3087–3093

    Article  CAS  PubMed  Google Scholar 

  • Gade TP, Hassen W, Santos E et al (2005) Targeted elimination of prostate cancer by genetically directed human T lymphocytes. Cancer Res 65:9080–9088

    Article  CAS  PubMed  Google Scholar 

  • Garin MI, Garrett E, Tiberghien P et al (2001) Molecular mechanism for ganciclovir resistance in human T lymphocytes transduced with retroviral vectors carrying the herpes simplex virus thymidine kinase gene. Blood 97:122–129

    Article  CAS  PubMed  Google Scholar 

  • Gattenlohner S, Marx A, Markfort B et al (2006) Rhabdomyosarcoma lysis by T cells expressing a human autoantibody-based chimeric receptor targeting the fetal acetylcholine receptor. Cancer Res 66:24–28

    Article  CAS  PubMed  Google Scholar 

  • Gattinoni L, Klebanoff CA, Palmer DC et al (2005) Acquisition of full effector function in vitro paradoxically impairs the in vivo antitumor efficacy of adoptively transferred CD8+ T cells. J Clin Invest 115:1616–1626

    Article  CAS  PubMed  Google Scholar 

  • Gilham DE, O’Neil A, Hughes C et al (2002) Primary polyclonal human T lymphocytes targeted to carcino-embryonic antigens and neural cell adhesion molecule tumor antigens by CD3zeta-based chimeric immune receptors. J Immunother 25:139–151

    Article  CAS  PubMed  Google Scholar 

  • Gong MC, Latouche JB, Krause A et al (1999) Cancer patient T cells genetically targeted to prostate-specific membrane antigen specifically lyse prostate cancer cells and release cytokines in response to prostate-specific membrane antigen. Neoplasia 1:123–127

    Article  CAS  PubMed  Google Scholar 

  • Gonzalez S, Naranjo A, Serrano LM et al (2004) Genetic engineering of cytolytic T lymphocytes for adoptive T-cell therapy of neuroblastoma. J Gene Med 6:704–711

    Article  CAS  PubMed  Google Scholar 

  • Goverman J, Gomez SM, Segesman KD et al (1990) Chimeric immunoglobulin-T cell receptor proteins form functional receptors: implications for T cell receptor complex formation and activation. Cell 60:929–939

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Guest RD, Hawkins RE, Kirillova N et al (2005) The role of extracellular spacer regions in the optimal design of chimeric immune receptors: evaluation of four different scFvs and antigens. J Immunother 28:203–211

    Article  CAS  PubMed  Google Scholar 

  • Habib-Agahi M, Phan TT, Searle PF (2007) Co-stimulation with 4-1BB ligand allows extended T-cell proliferation, synergizes with CD80/CD86 and can reactivate anergic T cells. Int Immunol 19:1383–1394

    Article  CAS  PubMed  Google Scholar 

  • Haynes NM, Snook MB, Trapani JA et al (2001) Redirecting mouse CTL against colon carcinoma: superior signaling efficacy of single-chain variable domain chimeras containing TCR-zeta vs Fc epsilon RI-gamma. J Immunol 166:182–187

    CAS  PubMed  Google Scholar 

  • Haynes NM, Trapani JA, Teng MW et al (2002a) Single-chain antigen recognition receptors that costimulate potent rejection of established experimental tumors. Blood 100:3155–3163

    Article  CAS  PubMed  Google Scholar 

  • Haynes NM, Trapani JA, Teng MW et al (2002b) Rejection of syngeneic colon carcinoma by CTLs expressing single-chain antibody receptors codelivering CD28 costimulation. J Immunol 169:5780–5786

    CAS  PubMed  Google Scholar 

  • Hekele A, Dall P, Moritz D et al (1996) Growth retardation of tumors by adoptive transfer of cytotoxic T lymphocytes reprogrammed by CD44v6-specific scFv:zeta-chimera. Int J Cancer 68:232–238

    Article  CAS  PubMed  Google Scholar 

  • Hinrichs CS, Spolski R, Paulos CM et al (2008) IL-2 and IL-21 confer opposing differentiation programs to CD8+ T cells for adoptive immunotherapy. Blood 111:5326–5333

    Article  CAS  PubMed  Google Scholar 

  • Hollyman D, Stefanski J, Przybylowski M et al (2009) Manufacturing validation of biologically functional T cells targeted to CD19 antigen for autologous adoptive cell therapy. J Immunother 32:169–180

    Article  CAS  PubMed  Google Scholar 

  • Hombach A, Heuser C, Sircar R et al (1997) T cell targeting of TAG72+ tumor cells by a chimeric receptor with antibody-like specificity for a carbohydrate epitope. Gastroenterology 113:1163–1170

    Article  CAS  PubMed  Google Scholar 

  • Hombach A, Heuser C, Sircar R et al (1998) An anti-CD30 chimeric receptor that mediates CD3-zeta-independent T-cell activation against Hodgkin’s lymphoma cells in the presence of soluble CD30. Cancer Res 58:1116–1119

    CAS  PubMed  Google Scholar 

  • Hombach AA, Schildgen V, Heuser C et al (2007) T cell activation by antibody-like immunoreceptors: the position of the binding epitope within the target molecule determines the efficiency of activation of redirected T cells. J Immunol 178:4650–4657

    CAS  PubMed  Google Scholar 

  • Howard FD, Moingeon P, Moebius U et al (1992) The CD3 zeta cytoplasmic domain mediates CD2-induced T cell activation. J Exp Med 176:139–145

    Article  CAS  PubMed  Google Scholar 

  • Hurtado JC, Kim SH, Pollok KE et al (1995) Potential role of 4-1BB in T cell activation. Comparison with the costimulatory molecule CD28. J Immunol 155:3360–3367

    CAS  PubMed  Google Scholar 

  • Huston JS, Levinson D, Mudgett-Hunter M et al (1988) Protein engineering of antibody binding sites: recovery of specific activity in an anti-digoxin single-chain Fv analogue produced in Escherichia coli. Proc Natl Acad Sci USA 85:5879–5883

    Article  CAS  PubMed  Google Scholar 

  • Hwu P, Shafer GE, Treisman J et al (1993) Lysis of ovarian cancer cells by human lymphocytes redirected with a chimeric gene composed of an antibody variable region and the Fc receptor gamma chain. J Exp Med 178:361–366

    Article  CAS  PubMed  Google Scholar 

  • Hwu P, Yang JC, Cowherd R et al (1995) In vivo antitumor activity of T cells redirected with chimeric antibody/T-cell receptor genes. Cancer Res 55:3369–3373

    CAS  PubMed  Google Scholar 

  • Imai C, Mihara K, Andreansky M et al (2004) Chimeric receptors with 4-1BB signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia. Leukemia 18:676–684

    Article  CAS  PubMed  Google Scholar 

  • Introna M, Barbui AM, Bambacioni F et al (2000) Genetic modification of human T cells with CD20: a strategy to purify and lyse transduced cells with anti-CD20 antibodies. Hum Gene Ther 11:611–620

    Article  CAS  PubMed  Google Scholar 

  • Irving BA, Weiss A (1991) The cytoplasmic domain of the T cell receptor zeta chain is sufficient to couple to receptor-associated signal transduction pathways. Cell 64:891–901

    Article  CAS  PubMed  Google Scholar 

  • Jakobsen MK, Restifo NP, Cohen PA et al (1995) Defective major histocompatibility complex class I expression in a sarcomatoid renal cell carcinoma cell line. J Immunother Emphas Tumor Immunol 17:222–228

    CAS  Google Scholar 

  • James SE, Greenberg PD, Jensen MC et al (2008) Antigen sensitivity of CD22-specific chimeric TCR is modulated by target epitope distance from the cell membrane. J Immunol 180:7028–7038

    CAS  PubMed  Google Scholar 

  • Jensen M, Tan G, Forman S et al (1998) CD20 is a molecular target for scFvFc:zeta receptor redirected T cells: implications for cellular immunotherapy of CD20+ malignancy. Biol Blood Marrow Transplant 4:75–83

    Article  CAS  PubMed  Google Scholar 

  • Kahlon KS, Brown C, Cooper LJ et al (2004) Specific recognition and killing of glioblastoma multiforme by interleukin 13-zetakine redirected cytolytic T cells. Cancer Res 64:9160–9166

    Article  CAS  PubMed  Google Scholar 

  • Kershaw MH, Westwood JA, Zhu Z et al (2000) Generation of gene-modified T cells reactive against the angiogenic kinase insert domain-containing receptor (KDR) found on tumor vasculature. Hum Gene Ther 11:2445–2452

    Article  CAS  PubMed  Google Scholar 

  • Kershaw MH, Westwood JA, Hwu P (2002) Dual-specific T cells combine proliferation and antitumor activity. Nat Biotechnol 20:1221–1227

    Article  CAS  PubMed  Google Scholar 

  • Kershaw MH, Jackson JT, Haynes NM et al (2004) Gene-engineered T cells as a superior adjuvant therapy for metastatic cancer. J Immunol 173:2143–2150

    CAS  PubMed  Google Scholar 

  • Kershaw MH, Westwood JA, Parker LL et al (2006) A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer. Clin Cancer Res 12:6106–6115

    Article  CAS  PubMed  Google Scholar 

  • Kieback E, Charo J, Sommermeyer D et al (2008) A safeguard eliminates T cell receptor gene-modified autoreactive T cells after adoptive transfer. Proc Natl Acad Sci USA 105:623–628

    Article  CAS  PubMed  Google Scholar 

  • Klebanoff CA, Finkelstein SE, Surman DR et al (2004) IL-15 enhances the in vivo antitumor activity of tumor-reactive CD8+ T cells. Proc Natl Acad Sci USA 101:1969–1974

    Article  CAS  PubMed  Google Scholar 

  • Kober J, Leitner J, Klauser C et al (2008) The capacity of the TNF family members 4-1BBL, OX40L, CD70, GITRL, CD30L and LIGHT to costimulate human T cells. Eur J Immunol 38:2678–2688

    Article  CAS  PubMed  Google Scholar 

  • Krause A, Guo HF, Latouche JB et al (1998) Antigen-dependent CD28 signaling selectively enhances survival and proliferation in genetically modified activated human primary T lymphocytes. J Exp Med 188:619–626

    Article  CAS  PubMed  Google Scholar 

  • Kuwana Y, Asakura Y, Utsunomiya N et al (1987) Expression of chimeric receptor composed of immunoglobulin-derived V regions and T-cell receptor-derived C regions. Biochem Biophys Res Commun 149:960–968

    Article  CAS  PubMed  Google Scholar 

  • Lamers CH, Sleijfer S, Vulto AG et al (2006) Treatment of metastatic renal cell carcinoma with autologous T-lymphocytes genetically retargeted against carbonic anhydrase IX: first clinical experience. J Clin Oncol 24:e20–e22

    Article  PubMed  Google Scholar 

  • Lei XY, Xu YM, Wang T et al (2009) Knockdown of human bid gene expression enhances survival of CD8(+) T cells. Immunol Lett 122:30–36

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Li Y, Yee C (2008) IL-21 mediated Foxp3 suppression leads to enhanced generation of antigen-specific CD8+ cytotoxic T lymphocytes. Blood 111:229–235

    Article  CAS  PubMed  Google Scholar 

  • Li Q, Carr A, Ito F et al (2003) Polarization effects of 4-1BB during CD28 costimulation in generating tumor-reactive T cells for cancer immunotherapy. Cancer Res 63:2546–2552

    CAS  PubMed  Google Scholar 

  • Li B, Wang H, Zhang D et al (2007a) Construction and characterization of a high-affinity humanized SM5-1 monoclonal antibody. Biochem Biophys Res Commun 357:951–956

    Article  CAS  PubMed  Google Scholar 

  • Li Q, Iuchi T, Jure-Kunkel MN et al (2007b) Adjuvant effect of anti-4-1BB mAb administration in adoptive T cell therapy of cancer. Int J Biol Sci 3:455–462

    CAS  PubMed  Google Scholar 

  • Lin J, Weiss A (2003) The tyrosine phosphatase CD148 is excluded from the immunologic synapse and down-regulates prolonged T cell signaling. J Cell Biol 162:673–682

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Lo AS, Taylor JR, Farzaneh F et al (2008) Harnessing the tumour-derived cytokine, CSF-1, to co-stimulate T-cell growth and activation. Mol Immunol 45:1276–1287

    Article  CAS  PubMed  Google Scholar 

  • Loskog A, Giandomenico V, Rossig C et al (2006) Addition of the CD28 signaling domain to chimeric T-cell receptors enhances chimeric T-cell resistance to T regulatory cells. Leukemia 20:1819–1828

    Article  CAS  PubMed  Google Scholar 

  • Lou Y, Basha G, Seipp RP et al (2008) Combining the antigen processing components TAP and Tapasin elicits enhanced tumor-free survival. Clin Cancer Res 14:1494–1501

    Article  CAS  PubMed  Google Scholar 

  • Ma Q, Safar M, Holmes E et al (2004) Anti-prostate specific membrane antigen designer T cells for prostate cancer therapy. Prostate 61:12–25

    Article  CAS  PubMed  Google Scholar 

  • Maher J, Brentjens RJ, Gunset G et al (2002) Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRzeta/CD28 receptor. Nat Biotechnol 20:70–75

    Article  CAS  PubMed  Google Scholar 

  • Malek TR, Yu A, Vincek V et al (2002) CD4 regulatory T cells prevent lethal autoimmunity in IL-2Rbeta-deficient mice. Implications for the nonredundant function of IL-2. Immunity 17:167–178

    Article  CAS  PubMed  Google Scholar 

  • McGuinness RP, Ge Y, Patel SD et al (1999) Anti-tumor activity of human T cells expressing the CC49-zeta chimeric immune receptor. Hum Gene Ther 10:165–173

    Article  CAS  PubMed  Google Scholar 

  • Mendez MJ, Green LL, Corvalan JR et al (1997) Functional transplant of megabase human immunoglobulin loci recapitulates human antibody response in mice. Nat Genet 15:146–156

    Article  CAS  PubMed  Google Scholar 

  • Mezzanzanica D, Canevari S, Mazzoni A et al (1998) Transfer of chimeric receptor gene made of variable regions of tumor-specific antibody confers anticarbohydrate specificity on T cells. Cancer Gene Ther 5:401–407

    CAS  PubMed  Google Scholar 

  • Milano F, Jorritsma T, Rygiel AM et al (2008) Expression pattern of immune suppressive cytokines and growth factors in oesophageal adenocarcinoma reveal a tumour immune escape-promoting microenvironment. Scand J Immunol 68:616–623

    Article  CAS  PubMed  Google Scholar 

  • Mitsuyasu RT, Anton PA, Deeks SG et al (2000) Prolonged survival and tissue trafficking following adoptive transfer of CD4zeta gene-modified autologous CD4(+) and CD8(+) T cells in human immunodeficiency virus-infected subjects. Blood 96:785–793

    CAS  PubMed  Google Scholar 

  • Moeller M, Haynes NM, Trapani JA et al (2004) A functional role for CD28 costimulation in tumor recognition by single-chain receptor-modified T cells. Cancer Gene Ther 11:371–379

    Article  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 

  • Morgan RA, Yang JC, Kitano M et al (2010) Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol Ther (in press)

  • Morgenroth A, Cartellieri M, Schmitz M et al (2007) Targeting of tumor cells expressing the prostate stem cell antigen (PSCA) using genetically engineered T-cells. Prostate 67:1121–1131

    Article  CAS  PubMed  Google Scholar 

  • Mueller K, Schweier O, Pircher H (2008) Efficacy of IL-2- versus IL-15-stimulated CD8 T cells in adoptive immunotherapy. Eur J Immunol 38:2874–2885

    Article  CAS  PubMed  Google Scholar 

  • Muniappan A, Banapour B, Lebkowski J et al (2000) Ligand-mediated cytolysis of tumor cells: use of heregulin-zeta chimeras to redirect cytotoxic T lymphocytes. Cancer Gene Ther 7:128–134

    Article  CAS  PubMed  Google Scholar 

  • Murata K, Nose M, Ndhlovu LC et al (2002) Constitutive OX40/OX40 ligand interaction induces autoimmune-like diseases. J Immunol 169:4628–4636

    CAS  PubMed  Google Scholar 

  • Murphy A, Westwood JA, Brown LE et al (2007) Antitumor activity of dual-specific T cells and influenza virus. Cancer Gene Ther 14:499–508

    Article  CAS  PubMed  Google Scholar 

  • Niederman TM, Ghogawala Z, Carter BS et al (2002) Antitumor activity of cytotoxic T lymphocytes engineered to target vascular endothelial growth factor receptors. Proc Natl Acad Sci USA 99:7009–7014

    Article  CAS  PubMed  Google Scholar 

  • Nolan KF, Yun CO, Akamatsu Y et al (1999) Bypassing immunization: optimized design of “designer T cells” against carcinoembryonic antigen (CEA)-expressing tumors, and lack of suppression by soluble CEA. Clin Cancer Res 5:3928–3941

    CAS  PubMed  Google Scholar 

  • O’Connell J, O’Sullivan GC, Collins JK et al (1996) The Fas counterattack: Fas-mediated T cell killing by colon cancer cells expressing Fas ligand. J Exp Med 184:1075–1082

    Article  PubMed  Google Scholar 

  • Pameijer CR, Navanjo A, Meechoovet B et al (2007) Conversion of a tumor-binding peptide identified by phage display to a functional chimeric T cell antigen receptor. Cancer Gene Ther 14:91–97

    Article  CAS  PubMed  Google Scholar 

  • Park JR, Digiusto DL, Slovak M et al (2007) Adoptive transfer of chimeric antigen receptor re-directed cytolytic T lymphocyte clones in patients with neuroblastoma. Mol Ther 15:825–833

    CAS  PubMed  Google Scholar 

  • Pegram HJ, Jackson JT, Smyth MJ et al (2008) Adoptive transfer of gene-modified primary NK cells can specifically inhibit tumor progression in vivo. J Immunol 181:3449–3455

    CAS  PubMed  Google Scholar 

  • Pinthus JH, Waks T, Kaufman-Francis K et al (2003) Immuno-gene therapy of established prostate tumors using chimeric receptor-redirected human lymphocytes. Cancer Res 63:2470–2476

    CAS  PubMed  Google Scholar 

  • Pollok KE, Kim YJ, Zhou Z et al (1993) Inducible T cell antigen 4-1BB. Analysis of expression and function. J Immunol 150:771–781

    CAS  PubMed  Google Scholar 

  • Pollok KE, Kim SH, Kwon BS (1995) Regulation of 4-1BB expression by cell-cell interactions and the cytokines, interleukin-2 and interleukin-4. Eur J Immunol 25:488–494

    Article  CAS  PubMed  Google Scholar 

  • Pule MA, Straathof KC, Dotti G et al (2005) A chimeric T cell antigen receptor that augments cytokine release and supports clonal expansion of primary human T cells. Mol Ther 12:933–941

    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 

  • Quintarelli C, Vera JF, Savoldo B et al (2007) Co-expression of cytokine and suicide genes to enhance the activity and safety of tumor-specific cytotoxic T lymphocytes. Blood 110:2793–2802

    Article  CAS  PubMed  Google Scholar 

  • Redmond WL, Gough MJ, Charbonneau B et al (2007) Defects in the acquisition of CD8 T cell effector function after priming with tumor or soluble antigen can be overcome by the addition of an OX40 agonist. J Immunol 179:7244–7253

    CAS  PubMed  Google Scholar 

  • Ren-Heidenreich L, Mordini R, Hayman GT et al (2002) Comparison of the TCR zeta-chain with the FcR gamma-chain in chimeric TCR constructs for T cell activation and apoptosis. Cancer Immunol Immunother 51:417–423

    Article  CAS  PubMed  Google Scholar 

  • Richman SA, Aggen DH, Dossett ML et al (2009) Structural features of T cell receptor variable regions that enhance domain stability and enable expression as single-chain ValphaVbeta fragments. Mol Immunol 46:902–916

    Article  CAS  PubMed  Google Scholar 

  • Robbins PF, Dudley ME, Wunderlich J et al (2004) Cutting edge: persistence of transferred lymphocyte clonotypes correlates with cancer regression in patients receiving cell transfer therapy. J Immunol 173:7125–7130

    CAS  PubMed  Google Scholar 

  • Roberts MR, Qin L, Zhang D et al (1994) Targeting of human immunodeficiency virus-infected cells by CD8+ T lymphocytes armed with universal T-cell receptors. Blood 84:2878–2889

    CAS  PubMed  Google Scholar 

  • Roessig C, Scherer SP, Baer A et al (2002) Targeting CD19 with genetically modified EBV-specific human T lymphocytes. Ann Hematol 81(Suppl 2):S42–S43

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Rosenberg SA, Dudley ME (2009) Adoptive cell therapy for the treatment of patients with metastatic melanoma. Curr Opin Immunol 21:233–240

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Savoldo B, Rooney CM, Di Stasi A et al (2007) Epstein Barr virus specific cytotoxic T lymphocytes expressing the anti-CD30zeta artificial chimeric T-cell receptor for immunotherapy of Hodgkin disease. Blood 110:2620–2630

    Article  CAS  PubMed  Google Scholar 

  • Schluns KS, Williams K, Ma A et al (2002) Cutting edge: requirement for IL-15 in the generation of primary and memory antigen-specific CD8 T cells. J Immunol 168:4827–4831

    CAS  PubMed  Google Scholar 

  • Serafini M, Manganini M, Borleri G et al (2004) Characterization of CD20-transduced T lymphocytes as an alternative suicide gene therapy approach for the treatment of graft-versus-host disease. Hum Gene Ther 15:63–76

    Article  CAS  PubMed  Google Scholar 

  • Sheen AJ, Sherlock DJ, Irlam J et al (2003) T lymphocytes isolated from patients with advanced colorectal cancer are suitable for gene immunotherapy approaches. Br J Cancer 88:1119–1127

    Article  CAS  PubMed  Google Scholar 

  • Shibaguchi H, Luo NX, Kuroki M et al (2006) A fully human chimeric immune receptor for retargeting T-cells to CEA-expressing tumor cells. Anticancer Res 26:4067–4072

    CAS  PubMed  Google Scholar 

  • Shuford WW, Klussman K, Tritchler DD et al (1997) 4-1BB costimulatory signals preferentially induce CD8+ T cell proliferation and lead to the amplification in vivo of cytotoxic T cell responses. J Exp Med 186:47–55

    Article  CAS  PubMed  Google Scholar 

  • Singh R, Paterson Y (2007) Immunoediting sculpts tumor epitopes during immunotherapy. Cancer Res 67:1887–1892

    Article  CAS  PubMed  Google Scholar 

  • Song E, Chen J, Ouyang N et al (2001) Soluble Fas ligand released by colon adenocarcinoma cells induces host lymphocyte apoptosis: an active mode of immune evasion in colon cancer. Br J Cancer 85:1047–1054

    Article  CAS  PubMed  Google Scholar 

  • Stancovski I, Schindler DG, Waks T et al (1993) Targeting of T lymphocytes to Neu/HER2-expressing cells using chimeric single chain Fv receptors. J Immunol 151:6577–6582

    CAS  PubMed  Google Scholar 

  • Stephan MT, Ponomarev V, Brentjens RJ et al (2007) T cell-encoded CD80 and 4-1BBL induce auto- and transcostimulation, resulting in potent tumor rejection. Nat Med 13:1440–1449

    Article  CAS  PubMed  Google Scholar 

  • Straathof KC, Bollard CM, Popat U et al (2005a) Treatment of nasopharyngeal carcinoma with Epstein-Barr virus-specific T lymphocytes. Blood 105:1898–1904

    Article  CAS  PubMed  Google Scholar 

  • Straathof KC, Pule MA, Yotnda P et al (2005b) An inducible caspase 9 safety switch for T-cell therapy. Blood 105:4247–4254

    Article  CAS  PubMed  Google Scholar 

  • Teng MW, Kershaw MH, Moeller M et al (2004) Immunotherapy of cancer using systemically delivered gene-modified human T lymphocytes. Hum Gene Ther 15:699–708

    Article  CAS  PubMed  Google Scholar 

  • Tey SK, Dotti G, Rooney CM et al (2007) Inducible caspase 9 suicide gene to improve the safety of allodepleted T cells after haploidentical stem cell transplantation. Biol Blood Marrow Transplant 13:913–924

    Article  CAS  PubMed  Google Scholar 

  • Thomis DC, Marktel S, Bonini C et al (2001) A Fas-based suicide switch in human T cells for the treatment of graft-versus-host disease. Blood 97:1249–1257

    Article  CAS  PubMed  Google Scholar 

  • Tiberghien P, Ferrand C, Lioure B et al (2001) Administration of herpes simplex-thymidine kinase-expressing donor T cells with a T-cell-depleted allogeneic marrow graft. Blood 97:63–72

    Article  CAS  PubMed  Google Scholar 

  • Till BG, Jensen MC, Wang J et al (2008) Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T cells. Blood 112:2261–2271

    Article  CAS  PubMed  Google Scholar 

  • Traversari C, Marktel S, Magnani Z et al (2007) The potential immunogenicity of the TK suicide gene does not prevent full clinical benefit associated with the use of TK-transduced donor lymphocytes in HSCT for hematologic malignancies. Blood 109:4708–4715

    Article  CAS  PubMed  Google Scholar 

  • Turatti F, Figini M, Alberti P et al (2005) Highly efficient redirected anti-tumor activity of human lymphocytes transduced with a completely human chimeric immune receptor. J Gene Med 7:158–170

    Article  CAS  PubMed  Google Scholar 

  • van Meerten T, Claessen MJ, Hagenbeek A et al (2006) The CD20/alphaCD20 ‘suicide’ system: novel vectors with improved safety and expression profiles and efficient elimination of CD20-transgenic T cells. Gene Ther 13:789–797

    Article  CAS  PubMed  Google Scholar 

  • Vera J, Savoldo B, Vigouroux S et al (2006) T lymphocytes redirected against the kappa light chain of human immunoglobulin efficiently kill mature B lymphocyte-derived malignant cells. Blood 108:3890–3897

    Article  CAS  PubMed  Google Scholar 

  • Vera JF, Hoyos V, Savoldo B et al (2009) Genetic manipulation of tumor-specific cytotoxic T lymphocytes to restore responsiveness to IL-7. Mol Ther 17:880–888

    Article  CAS  PubMed  Google Scholar 

  • Verhoeyen M, Milstein C, Winter G (1988) Reshaping human antibodies: grafting an antilysozyme activity. Science 239:1534–1536

    Article  CAS  PubMed  Google Scholar 

  • Walker RE, Bechtel CM, Natarajan V et al (2000) Long-term in vivo survival of receptor-modified syngeneic T cells in patients with human immunodeficiency virus infection. Blood 96:467–474

    CAS  PubMed  Google Scholar 

  • Wallace A, Kapoor V, Sun J et al (2008) Transforming growth factor-beta receptor blockade augments the effectiveness of adoptive T-cell therapy of established solid cancers. Clin Cancer Res 14:3966–3974

    Article  CAS  PubMed  Google Scholar 

  • Wang J, Press OW, Lindgren CG et al (2004) Cellular immunotherapy for follicular lymphoma using genetically modified CD20-specific CD8+ cytotoxic T lymphocytes. Mol Ther 9:577–586

    Article  CAS  PubMed  Google Scholar 

  • Wang J, Jensen M, Lin Y et al (2007) Optimizing adoptive polyclonal T cell immunotherapy of lymphomas, using a chimeric T cell receptor possessing CD28 and CD137 costimulatory domains. Hum Gene Ther 18:712–725

    Article  CAS  PubMed  Google Scholar 

  • Wang X, Olszewska M, Capacio V et al (2008) Quantitative analysis of clinically relevant mutations occurring in lymphoid cells harboring gamma-retrovirus-encoded HSVTK suicide genes. Gene Ther 15:1454–1459

    Article  CAS  PubMed  Google Scholar 

  • Weijtens ME, Willemsen RA, van Krimpen BA et al (1998) Chimeric scFv/gamma receptor-mediated T-cell lysis of tumor cells is coregulated by adhesion and accessory molecules. Int J Cancer 77:181–187

    Article  CAS  PubMed  Google Scholar 

  • Westwood JA, Smyth MJ, Teng MW et al (2005) Adoptive transfer of T cells modified with a humanized chimeric receptor gene inhibits growth of Lewis-Y-expressing tumors in mice. Proc Natl Acad Sci USA 102:19051–19056

    Article  CAS  PubMed  Google Scholar 

  • Wilkie S, Picco G, Foster J et al (2008) Retargeting of human T cells to tumor-associated MUC1: the evolution of a chimeric antigen receptor. J Immunol 180:4901–4909

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Yoon SH, Lee JM, Cho HI et al (2009) Adoptive immunotherapy using human peripheral blood lymphocytes transferred with RNA encoding Her-2/neu-specific chimeric immune receptor in ovarian cancer xenograft model. Cancer Gene Ther 16:489–497

    Article  CAS  PubMed  Google Scholar 

  • Yun CO, Nolan KF, Beecham EJ et al (2000) Targeting of T lymphocytes to melanoma cells through chimeric anti-GD3 immunoglobulin T-cell receptors. Neoplasia 2:449–459

    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 

Download references

Acknowledgments

Grant support for D. M. Davies is provided by a Graduate School PhD Studentship, King’s College, London, and by a project grant awarded by the Association for International Cancer Research (08-0419). J. Maher is supported by a Breast Cancer Campaign Project Grant (2006NovPR18) and a Royal College of Pathologists/Health Foundation Senior Clinician Scientist Research Fellowship. Since submission of this review, there have been two fatalities in patients shortly after systemic administration of CAR-grafted T-cells. One of these events has been described by Morgan et al. 2010.

Author information

Authors and Affiliations

  1. King’s College London School of Medicine, Research Oncology Section, Division of Cancer Studies, Third Floor Bermondsey Wing, Guy’s Hospital Campus, St Thomas Street, London, SE1 9RT, UK

    David Marc Davies & John Maher

Authors
  1. David Marc Davies
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John Maher
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to John Maher.

About this article

Cite this article

Davies, D.M., Maher, J. Adoptive T-cell Immunotherapy of Cancer Using Chimeric Antigen Receptor-Grafted T Cells. Arch. Immunol. Ther. Exp. 58, 165–178 (2010). https://doi.org/10.1007/s00005-010-0074-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00005-010-0074-1

Keywords

Search

Navigation