Cancer Immunology, Immunotherapy

, Volume 61, Issue 1, pp 127–135 | Cite as

Muscle CARs and TcRs: turbo-charged technologies for the (T cell) masses

Focussed Research Review

Abstract

A central role for T cells in the control of cancer has been supported by both animal models and clinical observations. Accordingly, the development of potent anti-tumor T cell immunity has been a long-standing objective of immunotherapy. Emerging data from clinical trials that test T cell immune-modulatory agents and genetically engineered and re-targeted T cells have begun to realize the profound potential of T cell immunotherapy to target cancer. This review will focus on a description of recent conceptual and technological advances for the genetic engineering of T cells to enhance anti-tumor T cell immunity through the introduction of tumor-specific receptors, both Chimeric Antigen Receptors (CAR) and T cell receptors (TcR), as well as an overview of emerging data from ongoing clinical trials that highlight the potential of these approaches to effect dramatic and potent anti-tumor immunity.

Keywords

Chimeric antigen receptor T cell receptor Adoptive T cell transfer Immunotherapy Gene transfer CIMT 2011 

Notes

Acknowledgments

Effort for composing this manuscript was supported in part by funding from the University of Pennsylvania’s Institutional Clinical and Translational Science Award (CTSA), and by the Commonwealth of Pennsylvania/Pennsylvania Department of Health (grant# 4100051725).

References

  1. 1.
    Brichard V, Van Pel A, Wolfel T, Wolfel C, De Plaen E, Lethe B, Coulie P, Boon T (1993) The tyrosinase gene codes for an antigen recognized by autologous cytolytic T lymphocytes on HLA-A2 melanomas. J Exp Med 178(2):489–495PubMedCrossRefGoogle Scholar
  2. 2.
    Novellino L, Castelli C, Parmiani G (2005) A listing of human tumor antigens recognized by T cells: March 2004 update. Cancer Immunol Immunother CII 54(3):187–207CrossRefGoogle Scholar
  3. 3.
    Caballero OL, Chen YT (2009) Cancer/testis (CT) antigens: potential targets for immunotherapy. Cancer Sci 100(11):2014–2021PubMedCrossRefGoogle Scholar
  4. 4.
    Sang M, Wang L, Ding C, Zhou X, Wang B, Lian Y, Shan B (2011) Melanoma-associated antigen genes—an update. Cancer Lett 302(2):85–90PubMedCrossRefGoogle Scholar
  5. 5.
    Old LJ (2008) Cancer vaccines: an overview. Cancer Immun 8(Suppl 1):1Google Scholar
  6. 6.
    Bedognetti D, Balwit JM, Wang E, Disis ML, Britten CM, Delogu LG, Tomei S, Fox BA, Gajewski TF, Marincola FM et al. (2011) SITC/iSBTc cancer immunotherapy biomarkers resource document: online resources and useful tools—a compass in the land of biomarker discovery. J Trans Med 9:155Google Scholar
  7. 7.
    Beatty GL, Chiorean EG, Fishman MP, Saboury B, Teitelbaum UR, Sun W, Huhn RD, Song W, Li D, Sharp LL et al (2011) CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science 331(6024):1612–1616PubMedCrossRefGoogle Scholar
  8. 8.
    Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC et al (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363(8):711–723PubMedCrossRefGoogle Scholar
  9. 9.
    Klages K, Mayer CT, Lahl K, Loddenkemper C, Teng MW, Ngiow SF, Smyth MJ, Hamann A, Huehn J, Sparwasser T (2010) Selective depletion of Foxp3+ regulatory T cells improves effective therapeutic vaccination against established melanoma. Cancer Res 70(20):7788–7799PubMedCrossRefGoogle Scholar
  10. 10.
    Kline J, Gajewski TF (2010) Clinical development of mAbs to block the PD1 pathway as an immunotherapy for cancer. Curr Opin Investig Drugs 11(12):1354–1359PubMedGoogle Scholar
  11. 11.
    Rech AJ, Vonderheide RH (2009) Clinical use of anti-CD25 antibody daclizumab to enhance immune responses to tumor antigen vaccination by targeting regulatory T cells. Ann N Y Acad Sci 1174:99–106PubMedCrossRefGoogle Scholar
  12. 12.
    Lustgarten J, Dominguez AL, Cuadros C (2004) The CD8+ T cell repertoire against Her-2/neu antigens in neu transgenic mice is of low avidity with antitumor activity. Eur J Immunol 34(3):752–761PubMedCrossRefGoogle Scholar
  13. 13.
    Friedman RS, Spies AG, Kalos M (2004) Identification of naturally processed CD8 T cell epitopes from protein, a prostate tissue-specific vaccine candidate. Eur J Immunol 34(4):1091–1101PubMedCrossRefGoogle Scholar
  14. 14.
    Cole DK, Pumphrey NJ, Boulter JM, Sami M, Bell JI, Gostick E, Price DA, Gao GF, Sewell AK, Jakobsen BK (2007) Human TCR-binding affinity is governed by MHC class restriction. J Immunol 178(9):5727–5734PubMedGoogle Scholar
  15. 15.
    Kenter GG, Welters MJ, Valentijn AR, Lowik MJ, Berends-van der Meer DM, Vloon AP, Essahsah F, Fathers LM, Offringa R, Drijfhout JW et al. (2009) Vaccination against HPV-16 oncoproteins for vulvar intraepithelial neoplasia. New Eng J Med 361(19):1838–1847Google Scholar
  16. 16.
    Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, Redfern CH, Ferrari AC, Dreicer R, Sims RB et al (2010) Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 363(5):411–422PubMedCrossRefGoogle Scholar
  17. 17.
    Shang X, Wang L, Niu W, Meng G, Fu X, Ni B, Lin Z, Yang Z, Chen X, Wu Y (2009) Rational optimization of tumor epitopes using in silico analysis-assisted substitution of TCR contact residues. Eur J Immunol 39(8):2248–2258PubMedCrossRefGoogle Scholar
  18. 18.
    Jinushi M, Hodi FS, Dranoff G (2008) Enhancing the clinical activity of granulocyte-macrophage colony-stimulating factor-secreting tumor cell vaccines. Immunol Rev 222:287–298PubMedCrossRefGoogle Scholar
  19. 19.
    Chiang CL, Kandalaft LE, Coukos G (2011) Adjuvants for enhancing the immunogenicity of whole tumor cell vaccines. Int Rev Immunol 30(2–3):150–182PubMedCrossRefGoogle Scholar
  20. 20.
    Levine BL (2008) T lymphocyte engineering ex vivo for cancer and infectious disease. Expert Opin Biol Ther 8(4):475–489Google Scholar
  21. 21.
    Morgan RA, Dudley ME, Rosenberg SA (2010) Adoptive cell therapy: genetic modification to redirect effector cell specificity. Cancer J 16(4):336–341PubMedCrossRefGoogle Scholar
  22. 22.
    Tran KQ, Zhou J, Durflinger KH, Langhan MM, Shelton TE, Wunderlich JR, Robbins PF, Rosenberg SA, Dudley ME (2008) Minimally cultured tumor-infiltrating lymphocytes display optimal characteristics for adoptive cell therapy. J Immunother 31(8):742–751PubMedCrossRefGoogle Scholar
  23. 23.
    Leen AM, Christin A, Myers GD, Liu H, Cruz CR, Hanley PJ, Kennedy-Nasser AA, Leung KS, Gee AP, Krance RA (2009) Cytotoxic T lymphocyte therapy with donor T cells prevents and treats adenovirus and Epstein-Barr virus infections after haploidentical and matched unrelated stem cell transplantation. Blood 114(19):4283–4292PubMedCrossRefGoogle Scholar
  24. 24.
    Yague J, White J, Coleclough C, Kappler J, Palmer E, Marrack P (1985) The T cell receptor: the alpha and beta chains define idiotype, and antigen and MHC specificity. Cell 42(1):81–87PubMedCrossRefGoogle Scholar
  25. 25.
    Clay TM, Custer MC, Sachs J, Hwu P, Rosenberg SA, Nishimura MI (1999) Efficient transfer of a tumor antigen-reactive TCR to human peripheral blood lymphocytes confers anti-tumor reactivity. J Immunol 163(1):507–513PubMedGoogle Scholar
  26. 26.
    Cooper LJ, Kalos M, Lewinsohn DA, Riddell SR, Greenberg PD (2000) Transfer of specificity for human immunodeficiency virus type 1 into primary human T lymphocytes by introduction of T-cell receptor genes. J Virol 74(17):8207–8212PubMedCrossRefGoogle Scholar
  27. 27.
    Lustgarten J, Theobald M, Labadie C, LaFace D, Peterson P, Disis ML, Cheever MA, Sherman LA (1997) Identification of Her-2/Neu CTL epitopes using double transgenic mice expressing HLA-A2.1 and human CD.8. Hum Immunol 52(2):109–118PubMedCrossRefGoogle Scholar
  28. 28.
    Amir AL, van der Steen DM, van Loenen MM, Hagedoorn RS, de Boer R, Kester MD, de Ru AH, Lugthart GJ, van Kooten C, Hiemstra PS et al. (2011) PRAME-specific Allo-HLA-restricted T cells with potent antitumor reactivity useful for therapeutic T-cell receptor gene transfer. Clin Cancer Res 17(17):5615–5625Google Scholar
  29. 29.
    Chervin AS, Aggen DH, Raseman JM, Kranz DM (2008) Engineering higher affinity T cell receptors using a T cell display system. J Immunol Methods 339(2):175–184PubMedCrossRefGoogle Scholar
  30. 30.
    Li Y, Moysey R, Molloy PE, Vuidepot AL, Mahon T, Baston E, Dunn S, Liddy N, Jacob J, Jakobsen BK et al (2005) Directed evolution of human T-cell receptors with picomolar affinities by phage display. Nat Biotechnol 23(3):349–354PubMedCrossRefGoogle Scholar
  31. 31.
    Robbins PF, Li YF, El-Gamil M, Zhao Y, Wargo JA, Zheng Z, Xu H, Morgan RA, Feldman SA, Johnson LA (2008) Single and dual amino acid substitutions in TCR CDRs can enhance antigen-specific T cell functions. J Immunol 180(9):6116–6131PubMedGoogle Scholar
  32. 32.
    Udyavar A, Alli R, Nguyen P, Baker L, Geiger TL (2009) Subtle affinity-enhancing mutations in a myelin oligodendrocyte glycoprotein-specific TCR alter specificity and generate new self-reactivity. J Immunol 182(7):4439–4447PubMedCrossRefGoogle Scholar
  33. 33.
    Kuball J, Hauptrock B, Malina V, Antunes E, Voss RH, Wolfl M, Strong R, Theobald M, Greenberg PD (2009) Increasing functional avidity of TCR-redirected T cells by removing defined N-glycosylation sites in the TCR constant domain. J Exp Med 206(2):463–475PubMedCrossRefGoogle Scholar
  34. 34.
    Zhao Y, Bennett AD, Zheng Z, Wang QJ, Robbins PF, Yu LY, Li Y, Molloy PE, Dunn SM, Jakobsen BK 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(9):5845–5854PubMedGoogle Scholar
  35. 35.
    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(24):10024–10028PubMedCrossRefGoogle Scholar
  36. 36.
    Sadelain M, Brentjens R, Riviere I (2009) The promise and potential pitfalls of chimeric antigen receptors. Curr Opin Immunol 21(2):215–223PubMedCrossRefGoogle Scholar
  37. 37.
    Jensen MC, Popplewell L, Cooper LJ, DiGiusto D, Kalos M, Ostberg JR, Forman SJ (2010) Antitransgene rejection responses contribute to attenuated persistence of adoptively transferred CD20/CD19-specific chimeric antigen receptor redirected T cells in humans. Biol Blood Marrow Transpl 16(9):1245–1256CrossRefGoogle Scholar
  38. 38.
    Kochenderfer JN, Wilson WH, Janik JE, Dudley ME, Stetler-Stevenson M, Feldman SA, Maric I, Raffeld M, Nathan DA, Lanier BJ (2010) Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. Blood 116(20):4099–4102PubMedCrossRefGoogle Scholar
  39. 39.
    Brentjens RJ, Riviere I, Park JH, Davila ML, Wang X, Stefanski J, Taylor C, Yeh R, Bartido S, Borquez-Ojeda O et al. (2011) Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood 118(18):4817–4828Google Scholar
  40. 40.
    Kalos M, Levine BL, Porter DL, Katz S, Grupp SA, Bagg A, June CH (2011) T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Trans Med 3(95):95ra73Google Scholar
  41. 41.
    Porter DL, Levine BL, Kalos M, Bagg A, June CH (2011) Chimeric antigen receptor-modified t cells in chronic lymphoid leukemia. N Engl J Med 365(8):725–733Google Scholar
  42. 42.
    Till BG, Jensen MC, Wang J, Chen EY, Wood BL, Greisman HA, Qian X, James SE, Raubitschek A, Forman SJ et al (2008) Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T cells. Blood 112(6):2261–2271PubMedCrossRefGoogle Scholar
  43. 43.
    Kershaw MH, Westwood JA, Parker LL, Wang G, Eshhar Z, Mavroukakis SA, White DE, Wunderlich JR, Canevari S, Rogers-Freezer L et al (2006) A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer. Clin Cancer Res 12(20 Pt 1):6106–6115PubMedCrossRefGoogle Scholar
  44. 44.
    Pule MA, Savoldo B, Myers GD, Rossig C, Russell HV, Dotti G, Huls MH, Liu E, Gee AP, Mei Z et al (2008) Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma. Nat Med 14(11):1264–1270PubMedCrossRefGoogle Scholar
  45. 45.
    Morgan RA, Yang JC, Kitano M, Dudley ME, Laurencot CM, Rosenberg SA (2010) Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol Ther 18(4):843–851PubMedCrossRefGoogle Scholar
  46. 46.
    Buning H, Uckert W, Cichutek K, Hawkins RE, Abken H (2010) Do CARs need a driver’s license? Adoptive cell therapy with chimeric antigen receptor-redirected T cells has caused serious adverse events. Hum Gene Ther 21(9):1039–1042PubMedCrossRefGoogle Scholar
  47. 47.
    Amos SM, Duong CP, Westwood JA, Ritchie DS, Junghans RP, Darcy PK, Kershaw MH (2011) Autoimmunity associated with immunotherapy of cancer. Blood 118(3):499–509PubMedCrossRefGoogle Scholar
  48. 48.
    Robbins PF, Morgan RA, Feldman SA, Yang JC, Sherry RM, Dudley ME, Wunderlich JR, Nahvi AV, Helman LJ, Mackall CL et al (2011) Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J Clin Oncol 29(7):917–924PubMedCrossRefGoogle Scholar
  49. 49.
    Parkhurst MR, Yang JC, Langan RC, Dudley ME, Nathan DA, Feldman SA, Davis JL, Morgan RA, Merino MJ, Sherry RM (2011) T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis. Mol Ther 19(3):620–626PubMedCrossRefGoogle Scholar
  50. 50.
    Johnson LA, Morgan RA, Dudley ME, Cassard L, Yang JC, Hughes MS, Kammula US, Royal RE, Sherry RM, Wunderlich JR et al (2009) Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen. Blood 114(3):535–546PubMedCrossRefGoogle Scholar
  51. 51.
    Milone MC, Fish JD, Carpenito C, Carroll RG, Binder GK, Teachey D, Samanta M, Lakhal M, Gloss B, Danet-Desnoyers G et al (2009) Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo. Mol Ther 17(8):1453–1464PubMedCrossRefGoogle Scholar
  52. 52.
    Carpenito C, Milone MC, Hassan R, Simonet JC, Lakhal M, Suhoski MM, Varela-Rohena A, Haines KM, Heitjan DF, Albelda SM et al (2009) Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains. Proc Natl Acad Sci USA 106(9):3360–3365PubMedCrossRefGoogle Scholar
  53. 53.
    Brentjens RJ, Santos E, Nikhamin Y, Yeh R, Matsushita M, La Perle K, Quintas-Cardama A, Larson SM, Sadelain M (2007) Genetically targeted T cells eradicate systemic acute lymphoblastic leukemia xenografts. Clin Cancer Res 13(18 Pt 1):5426–5435PubMedCrossRefGoogle Scholar
  54. 54.
    Savoldo B, Ramos CA, Liu E, Mims MP, Keating MJ, Carrum G, Kamble RT, Bollard CM, Gee AP, Mei Z et al (2011) CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. J Clin Investig 121(5):1822–1826PubMedCrossRefGoogle Scholar
  55. 55.
    Birkholz K, Hofmann C, Hoyer S, Schulz B, Harrer T, Kampgen E, Schuler G, Dorrie J, Schaft N (2009) A fast and robust method to clone and functionally validate T-cell receptors. J Immunol Methods 346(1–2):45–54PubMedCrossRefGoogle Scholar
  56. 56.
    Seitz S, Schneider CK, Malotka J, Nong X, Engel AG, Wekerle H, Hohlfeld R, Dornmair K (2006) Reconstitution of paired T cell receptor alpha- and beta-chains from microdissected single cells of human inflammatory tissues. Proc Natl Acad Sci USA 103(32):12057–12062PubMedCrossRefGoogle Scholar
  57. 57.
    Okamoto S, Mineno J, Ikeda H, Fujiwara H, Yasukawa M, Shiku H, Kato I (2009) Improved expression and reactivity of transduced tumor-specific TCRs in human lymphocytes by specific silencing of endogenous TCR. Cancer Res 69(23):9003–9011PubMedCrossRefGoogle Scholar
  58. 58.
    Kuball J, Dossett ML, Wolfl M, Ho WY, Voss RH, Fowler C, Greenberg PD (2007) Facilitating matched pairing and expression of TCR chains introduced into human T cells. Blood 109(6):2331–2338PubMedCrossRefGoogle Scholar
  59. 59.
    Lamers CH, Willemsen R, van Elzakker P, van Steenbergen-Langeveld S, Broertjes M, Oosterwijk-Wakka J, Oosterwijk E, Sleijfer S, Debets R, Gratama JW (2011) Immune responses to transgene and retroviral vector in patients treated with ex vivo-engineered T cells. Blood 117(1):72–82PubMedCrossRefGoogle Scholar
  60. 60.
    Barrett DM, Zhao Y, Liu X, Jiang S, Carpenito C, Kalos M, Carroll RG, June CH, Grupp SA (2011) Treatment of advanced leukemia in mice with mRNA engineered T cells. Hum Gene TherGoogle Scholar
  61. 61.
    Wilson MH, Coates CJ, George AL Jr (2007) PiggyBac transposon-mediated gene transfer in human cells. Mol Ther 15(1):139–145PubMedCrossRefGoogle Scholar
  62. 62.
    Hackett PB, Largaespada DA, Cooper LJ (2010) A transposon and transposase system for human application. Mol Ther 18(4):674–683PubMedCrossRefGoogle Scholar
  63. 63.
    Marktel S, Magnani Z, Ciceri F, Cazzaniga S, Riddell SR, Traversari C, Bordignon C, Bonini C (2003) Immunologic potential of donor lymphocytes expressing a suicide gene for early immune reconstitution after hematopoietic T-cell-depleted stem cell transplantation. Blood 101(4):1290–1298PubMedCrossRefGoogle Scholar
  64. 64.
    Straathof KC, Pule MA, Yotnda P, Dotti G, Vanin EF, Brenner MK, Heslop HE, Spencer DM, Rooney CM (2005) An inducible caspase 9 safety switch for T-cell therapy. Blood 105(11):4247–4254PubMedCrossRefGoogle Scholar
  65. 65.
    Shen X, Zhou J, Hathcock KS, Robbins P, Powell DJ Jr, Rosenberg SA, Hodes RJ (2007) Persistence of tumor infiltrating lymphocytes in adoptive immunotherapy correlates with telomere length. J Immunother 30(1):123–129PubMedCrossRefGoogle Scholar
  66. 66.
    Berger C, Jensen MC, Lansdorp PM, Gough M, Elliott C, Riddell SR (2008) Adoptive transfer of effector CD8+ T cells derived from central memory cells establishes persistent T cell memory in primates. J Clin Invest 118(1):294–305PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  1. 1.Department of Pathology and Laboratory Medicine, Perelman School of Medicine, Abramson Family Cancer Research InstituteUniversity of PennsylvaniaPhiladelphiaUSA

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