Cancer immunotherapy is emerging as an effective and dependable approach to induce durable responses and survival benefit in several cancers. Two approaches, one based on antibody therapy to block immune inhibitory checkpoints and the other on the genetic engineering of T lymphocytes, have yielded dramatic clinical results in recent years, earning cancer immunotherapy the title “breakthrough of the year” by the journal in 2013. Based on the success of targeting CD19 in B cell malignancies, chimeric antigen receptors (CARs) have established themselves as a powerful means to redirect and enhance the natural properties of both CD8+ and CD4+ T lymphocyte subsets. Dual-signaling CARs not only redirect and activate T cells but also reprogram their effector, metabolic, and survival functions, enabling the rapid manufacture of tumor-specific agents for any given cancer patient. This approach marks a major shift in cell-based therapy, which previously depended on the identification and expansion of rare naturally occurring T cells with therapeutic potential, but now relies on the genetic engineering and manufacturing of optimized T cell products. Several challenges remain to tailor this approach to tackle cell tumors, which will require identifying suitable CAR targets and overcoming multiple obstacles in a complex tumor microenvironment.


Article metrics loading...

Loading full text...

Full text loading...


Literature Cited

  1. Adusumilli PS, Cherkassky L, Villena-Vargas J, Colovos C, Servais E. et al. 2014. Regional delivery of mesothelin-targeted CAR T cell therapy generates potent and long-lasting CD4-dependent tumor immunity. Sci. Transl. Med. 6:261ra151 [Google Scholar]
  2. Ahmed N, Salsman VS, Yvon E, Louis CU, Perlaky L. et al. 2009. Immunotherapy for osteosarcoma: Genetic modification of T cells overcomes low levels of tumor antigen expression. Mol. Ther. 17:1779–87 [Google Scholar]
  3. Beard RE, Zheng Z, Lagisetty KH, Burns WR, Tran E. et al. 2014. Multiple chimeric antigen receptors successfully target chondroitin sulfate proteoglycan 4 in several different cancer histologies and cancer stem cells. J. Immunother. Cancer 2:25 [Google Scholar]
  4. Beatty GL, Haas AR, Maus MV, Torigian DA, Soulen MC. et al. 2014. Mesothelin-specific chimeric antigen receptor mRNA-engineered T cells induce anti-tumor activity in solid malignancies. Cancer Immunol. Res. 2:112–20 [Google Scholar]
  5. Bonifant CL, Jackson HJ, Brentjens RJ, Curran KJ. 2016. Toxicity and management in CAR T-cell therapy. Mol. Ther. Oncolytics 3:16011 [Google Scholar]
  6. Borberg H, Oettgen HF, Choudry K, Beattie EJ Jr. 1972. Inhibition of established transplants of chemically induced sarcomas in syngeneic mice by lymphocytes from immunized donors. Int. J. Cancer 10:539–47 [Google Scholar]
  7. Brentjens RJ, Davila ML, Riviere I, Park J, Wang X. et al. 2013. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci. Transl. Med. 5:177ra38 [Google Scholar]
  8. Brentjens RJ, Latouche JB, Santos E, Marti F, Gong MC. et al. 2003. Eradication of systemic B-cell tumors by genetically targeted human T lymphocytes co-stimulated by CD80 and interleukin-15. Nat. Med. 9:279–86 [Google Scholar]
  9. Brentjens RJ, Santos E, Nikhamin Y, Yeh R, Matsushita M. et al. 2007. Genetically targeted T cells eradicate systemic acute lymphoblastic leukemia xenografts. Clin. Cancer Res. 13:5426–35 [Google Scholar]
  10. Brocker T. 2000. Chimeric Fv-ζ or Fv-ε receptors are not sufficient to induce activation or cytokine production in peripheral T cells. Blood 96:1999–2001 [Google Scholar]
  11. Brocker T, Peter A, Traunecker A, Karjalainen K. 1993. New simplified molecular design for functional T cell receptor. Eur. J. Immunol. 23:1435–39 [Google Scholar]
  12. Brudno JN, Somerville RP, Shi V, Rose JJ, Halverson DC. et al. 2016. Allogeneic T cells that express an anti-CD19 chimeric antigen receptor induce remissions of B-cell malignancies that progress after allogeneic hematopoietic stem-cell transplantation without causing graft-versus-host disease. J. Clin. Oncol. 34:1112–21 [Google Scholar]
  13. Bunnell BA, Muul LM, Donahue RE, Blaese RM, Morgan RA. 1995. High-efficiency retroviral-mediated gene transfer into human and nonhuman primate peripheral blood lymphocytes. PNAS 92:7739–43 [Google Scholar]
  14. Busch DH, Frassle SP, Sommermeyer D, Buchholz VR, Riddell SR. 2016. Role of memory T cell subsets for adoptive immunotherapy. Semin. Immunol. 28:28–34 [Google Scholar]
  15. Butturini A, Bortin MM, Gale RP. 1987. Graft-versus-leukemia following bone marrow transplantation. Bone Marrow Transplant 2:233–42 [Google Scholar]
  16. Carpenito C, Milone MC, Hassan R, Simonet JC, Lakhal M. et al. 2009. Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains. PNAS 106:3360–65 [Google Scholar]
  17. Carter RH, Fearon DT. 1992. CD19: lowering the threshold for antigen receptor stimulation of B lymphocytes. Science 256:105–7 [Google Scholar]
  18. Champlin R. 1991. Immunobiology of bone marrow transplantation as treatment for hematologic malignancies. Trans. Proc. 23:2123–27 [Google Scholar]
  19. Chinnasamy D, Yu Z, Kerkar SP, Zhang L, Morgan RA. et al. 2012. Local delivery of interleukin-12 using T cells targeting VEGF receptor-2 eradicates multiple vascularized tumors in mice. Clin. Cancer Res. 18:1672–83 [Google Scholar]
  20. Cooper LJN, Topp MS, Serrano LM, Gonzalez S, Chang WC. 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 101:1637–44 [Google Scholar]
  21. Cruz CR, Micklethwaite KP, Savoldo B, Ramos CA, Lam S. et al. 2013. Infusion of donor-derived CD19-redirected virus-specific T cells for B-cell malignancies relapsed after allogeneic stem cell transplant: a phase 1 study. Blood 122:2965–73 [Google Scholar]
  22. Davila ML, Kloss CC, Gunset G, Sadelain M. 2013. CD19 CAR-targeted T cells induce long-term remission and B cell aplasia in an immunocompetent mouse model of B cell acute lymphoblastic leukemia. PLOS ONE 8:e61338 [Google Scholar]
  23. Davila ML, Riviere I, Wang X, Bartido S, Park J. et al. 2014. Efficacy and toxicity management of. 19–28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci. Transl. Med. 6:224ra25 [Google Scholar]
  24. Davila ML, Sadelain M. 2016. The biology and clinical application of CAR T cells for B cell malignancies. Int. J. Hematol. 104:6–17 [Google Scholar]
  25. Di Stasi A, Tey SK, Dotti G, Fujita Y, Kennedy-Nasser A. et al. 2011. Inducible apoptosis as a safety switch for adoptive cell therapy. N. Engl. J. Med. 365:1673–83 [Google Scholar]
  26. Dunn GP, Old LJ, Schreiber RD. 2004. The three Es of cancer immunoediting. Annu. Rev. Immunol. 22:329–60 [Google Scholar]
  27. Engel P, Zhou LJ, Ord DC, Sato S, Koller B, Tedder TF. 1995. Abnormal B lymphocyte development, activation, and differentiation in mice that lack or overexpress the CD19 signal transduction molecule. Immunity 3:39–50 [Google Scholar]
  28. Eshhar Z, Waks T, Gross G, Schindler DG. 1993. Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the γ or ζ subunits of the immunoglobulin and T-cell receptors. PNAS 90:720–24 [Google Scholar]
  29. Eyquem J, Mansilla-Soto J, Odak A, Sadelain M. 2016. One-step generation of universal CAR T cells Presented at Am. Soc. Gene Cell Ther. Annu. Meet., 19th, Washington, DC [Google Scholar]
  30. Fedorov VD, Themeli M, Sadelain M. 2013. PD-1- and CTLA-4-based inhibitory chimeric antigen receptors (iCARs) divert off-target immunotherapy responses. Sci. Transl. Med. 5:215ra172 [Google Scholar]
  31. Ferrara JL, Levine JE, Reddy P, Holler E. 2009. Graft-versus-host disease. Lancet 373:1550–61 [Google Scholar]
  32. Gallardo HF, Tan C, Ory D, Sadelain M. 1997. Recombinant retroviruses pseudotyped with the vesicular stomatitis virus G glycoprotein mediate both stable gene transfer and pseudotransduction in human peripheral blood lymphocytes. Blood 90:952–57 [Google Scholar]
  33. Galon J, Angell HK, Bedognetti D, Marincola FM. 2013. The continuum of cancer immunosurveillance: prognostic, predictive, and mechanistic signatures. Immunity 39:11–26 [Google Scholar]
  34. Gattinoni L, Lugli E, Ji Y, Pos Z, Paulos CM. et al. 2011. A human memory T cell subset with stem cell-like properties. Nat. Med. 17:1290–97 [Google Scholar]
  35. Gee AP. 2015. Manufacturing genetically modified T cells for clinical trials. Cancer Gene Ther 22:67–71 [Google Scholar]
  36. Ghosh A, Davila ML, Young LF, Kloss C, Gunset G. et al. 2012. CD19-targeted donor T cells exert potent graft versus lymphoma activity and attenuated GVHD. Presented at Am. Soc. Hematol. Annu. Meet. Expo. 54th, Atlanta, GA [Google Scholar]
  37. Gong MC, Latouche JB, Krause A, Heston WDW, Bander NH, Sadelain M. 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 1:123–27 [Google Scholar]
  38. Gordon WR, Zimmerman B, He L, Miles LJ, Huang J. et al. 2015. Mechanical allostery: evidence for a force requirement in the proteolytic activation of Notch. Dev. Cell 33:729–36 [Google Scholar]
  39. Graef P, Buchholz VR, Stemberger C, Flossdorf M, Henkel L. et al. 2014. Serial transfer of single-cell-derived immunocompetence reveals stemness of CD8+ central memory T cells. Immunity 41:116–26 [Google Scholar]
  40. Greenberg PD. 1991. Adoptive T cell therapy of tumors: mechanisms operative in the recognition and elimination of tumor cells. Adv. Immunol. 49:281–355 [Google Scholar]
  41. Grimm EA, Mazumder A, Zhang HZ, Rosenberg SA. 1982. Lymphokine-activated killer cell phenomenon. Lysis of natural killer-resistant fresh solid tumor cells by interleukin 2–activated autologous human peripheral blood lymphocytes. J. Exp. Med. 155:1823–41 [Google Scholar]
  42. Grimm EA, Robb RJ, Roth JA, Neckers LM, Lachman LB. et al. 1983. Lymphokine-activated killer cell phenomenon. III. Evidence that IL-2 is sufficient for direct activation of peripheral blood lymphocytes into lymphokine-activated killer cells. J. Exp. Med. 158:1356–61 [Google Scholar]
  43. Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL. et al. 2013. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N. Engl. J. Med. 368:1509–18 [Google Scholar]
  44. Heslop HE, Brenner MK, Rooney CM. 1994. Donor T cells to treat EBV-associated lymphoma. N. Engl. J. Med. 331:679–80 [Google Scholar]
  45. Hinrichs CS, Restifo NP. 2013. Reassessing target antigens for adoptive T-cell therapy. Nat. Biotechnol. 31:999–1008 [Google Scholar]
  46. Ho WY, Blattman JN, Dossett ML, Yee C, Greenberg PD. 2003. Adoptive immunotherapy: engineering T cell responses as biologic weapons for tumor mass destruction. Cancer Cell 3:431–37 [Google Scholar]
  47. Hollyman D, Stefanski J, Przybylowski M, Bartido S, Borquez-Ojeda O. et al. 2009. Manufacturing validation of biologically functional T cells targeted to CD19 antigen for autologous adoptive cell therapy. J. Immunother. 32:169–80 [Google Scholar]
  48. Hombach A, Wieczarkowiecz A, Marquardt T, Heuser C, Usai L. et al. 2001. Tumor-specific T cell activation by recombinant immunoreceptors: CD3ζ signaling and CD28 costimulation are simultaneously required for efficient IL-2 secretion and can be integrated into one combined CD28/CD3ζ signaling receptor molecule. J. Immunol. 167:6123–31 [Google Scholar]
  49. Hoyos V, Savoldo B, Quintarelli C, Mahendravada A, Zhang M. et al. 2010. Engineering CD19-specific T lymphocytes with interleukin-15 and a suicide gene to enhance their anti-lymphoma/leukemia effects and safety. Leukemia 24:1160–70 [Google Scholar]
  50. Hromas R, Cornetta K, Srour E, Blanke C, Broun ER. 1994. Donor leukocyte infusion as therapy of life-threatening adenoviral infections after T-cell-depleted bone marrow transplantation. Blood 84:1689–90 [Google Scholar]
  51. Imai C, Mihara K, Andreansky M, Nicholson IC, Pui CH. et al. 2004. Chimeric receptors with 4-1BB signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia. Leukemia 18:676–84 [Google Scholar]
  52. Jensen MC, Popplewell L, Cooper LJ, DiGiusto D, Kalos M. et al. 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 Transplant. 16:1245–56 [Google Scholar]
  53. Jensen MC, Riddell SR. 2015. Designing chimeric antigen receptors to effectively and safely target tumors. Curr. Opin. Immunol. 33:9–15 [Google Scholar]
  54. Johnson LA, Scholler J, Ohkuri T, Kosaka A, Patel PR. et al. 2015. Rational development and characterization of humanized anti-EGFR variant III chimeric antigen receptor T cells for glioblastoma. Sci. Transl. Med. 7:275ra22 [Google Scholar]
  55. Kakarla S, Gottschalk S. 2014. CAR T cells for solid tumors: armed and ready to go. Cancer J 20:151–55 [Google Scholar]
  56. Kalos M, Levine BL, Porter DL, Katz S, Grupp SA. et al. 2011. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci. Transl. Med. 3:95ra73 [Google Scholar]
  57. Kim MS, Ma JS, Yun H, Cao Y, Kim JY. et al. 2015. Redirection of genetically engineered CAR-T cells using bifunctional small molecules. J. Am. Chem. Soc. 137:2832–35 [Google Scholar]
  58. Klebanoff CA, Gattinoni L, Restifo NP. 2012. Sorting through subsets: which T-cell populations mediate highly effective adoptive immunotherapy. J. Immunother. 35:651–60 [Google Scholar]
  59. Klebanoff CA, Rosenberg SA, Restifo NP. 2016. Prospects for gene-engineered T cell immunotherapy for solid cancers. Nat. Med. 22:26–36 [Google Scholar]
  60. Klein E, Kis LL, Klein G. 2007. Epstein-Barr virus infection in humans: from harmless to life endangering virus-lymphocyte interactions. Oncogene 26:1297–305 [Google Scholar]
  61. Klein G, Sjogren HO, Klein E, Hellstrom KE. 1960. Demonstration of resistance against methylcholanthrene-induced sarcomas in the primary autochthonous host. Cancer Res 20:1561–72 [Google Scholar]
  62. Kloss CC, Condomines M, Cartellieri M, Bachmann M, Sadelain M. 2013. Combinatorial antigen recognition with balanced signaling promotes selective tumor eradication by engineered T cells. Nat. Biotechnol. 31:71–75 [Google Scholar]
  63. Kochenderfer JN. 2014. Genetic engineering of T cells in leukemia and lymphoma. Clin. Adv. Hematol. Oncol. 12:190–92 [Google Scholar]
  64. Kochenderfer JN, Dudley ME, Kassim SH, Somerville RPT, Carpenter RO. et al. 2015. Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J. Clin. Oncol. 33:540–49 [Google Scholar]
  65. Kochenderfer JN, Rosenberg SA. 2013. Treating B-cell cancer with T cells expressing anti-CD19 chimeric antigen receptors. Nat. Rev. Clin. Oncol. 10:267–76 [Google Scholar]
  66. Kolb HJ, Schattenberg A, Goldman JM, Hertenstein B, Jacobsen N. et al. 1995. Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. Blood 86:2041–50 [Google Scholar]
  67. Korman AJ, Peggs KS, Allison JP. 2006. Checkpoint blockade in cancer immunotherapy. Adv. Immunol. 90:297–339 [Google Scholar]
  68. Korngold R, Sprent J. 1991. Graft-versus-host disease in experimental allogeneic bone marrow transplantation. Proc. Soc. Exp. Biol. Med. 197:12–18 [Google Scholar]
  69. Kowolik CM, Topp MS, Gonzalez S, Pfeiffer T, Olivares S. et al. 2006. CD28 costimulation provided through a CD19-specific chimeric antigen receptor enhances in vivo persistence and antitumor efficacy of adoptively transferred T cells. Cancer Res 66:10995–1004 [Google Scholar]
  70. Krause A, Guo HF, Latouche JB, Tan C, Cheung NKV, Sadelain M. 1998. Antigen-dependent CD28 signaling selectively enhances survival and proliferation in genetically modified activated human primary T lymphocytes. J. Exp. Med. 188:619–26 [Google Scholar]
  71. Kudo K, Imai C, Lorenzini P, Kamiya T, Kono K. et al. 2014. T lymphocytes expressing a CD16 signaling receptor exert antibody-dependent cancer cell killing. Cancer Res 74:93–103 [Google Scholar]
  72. Leach DR, Krummel MF, Allison JP. 1996. Enhancement of antitumor immunity by CTLA-4 blockade. Science 271:1734–36 [Google Scholar]
  73. Lebien TW, Tedder TF. 2008. B lymphocytes: how they develop and function. Blood 112:1570–80 [Google Scholar]
  74. Lee DW, Kochenderfer JN, Stetler-Stevenson M, Cui YK, Delbrook C. et al. 2015. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet 385:517–28 [Google Scholar]
  75. Leen AM, Heslop HE, Brenner MK. 2014. Antiviral T-cell therapy. Immunol. Rev. 258:12–29 [Google Scholar]
  76. Levine BL. 2015. Performance-enhancing drugs: design and production of redirected chimeric antigen receptor (CAR) T cells. Cancer Gene Ther 22:79–84 [Google Scholar]
  77. Maher J, Brentjens RJ, Gunset G, Rivière I, Sadelain M. 2002. Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRζ/CD28 receptor. Nat. Biotechnol. 20:70–75 [Google Scholar]
  78. Mahoney KM, Rennert PD, Freeman GJ. 2015. Combination cancer immunotherapy and new immunomodulatory targets. Nat. Rev. Drug Discov. 14:561–84 [Google Scholar]
  79. Markley JC, Sadelain M. 2010. IL-7 and IL-21 are superior to IL-2 and IL-15 in promoting human T cell-mediated rejection of systemic lymphoma in immunodeficient mice. Blood 115:3508–19 [Google Scholar]
  80. Maude SL, Barrett D, Teachey DT, Grupp SA. 2014a. Managing cytokine release syndrome associated with novel T cell-engaging therapies. Cancer J 20:119–22 [Google Scholar]
  81. Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM. et al. 2014b. Chimeric antigen receptor T cells for sustained remissions in leukemia. N. Engl. J. Med. 371:1507–17 [Google Scholar]
  82. Maude SL, Teachey DT, Porter DL, Grupp SA. 2015. CD19-targeted chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Blood 125:4017–23 [Google Scholar]
  83. Mavilio F, Ferrari G, Rossini S, Nobili N, Bonini C. et al. 1994. Peripheral blood lymphocytes as target cells of retroviral vector-mediated gene transfer. Blood 83:1988–97 [Google Scholar]
  84. McGranahan N, Furness AJ, Rosenthal R, Ramskov S, Lyngaa R. et al. 2016. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 351:1463–69 [Google Scholar]
  85. Melenhorst JJ, Castillo P, Hanley PJ, Keller MD, Krance RA. et al. 2015. Graft versus leukemia response without graft-versus-host disease elicited by adoptively transferred multivirus-specific T-cells. Mol. Ther. 23:179–83 [Google Scholar]
  86. Melief CJ. 1992. Tumor eradication by adoptive transfer of cytotoxic T lymphocytes. Adv. Cancer Res. 58:143–75 [Google Scholar]
  87. Mellman I, Coukos G, Dranoff G. 2011. Cancer immunotherapy comes of age. Nature 480:480–89 [Google Scholar]
  88. Menger L, Gouble A, Marzolini MA, Pachnio A, Bergerhoff K. et al. 2015. TALEN-mediated genetic inactivation of the glucocorticoid receptor in cytomegalovirus-specific T cells. Blood 126:2781–89 [Google Scholar]
  89. Mihich E. 1969. Modification of tumor regression by immunologic means. Cancer Res 29:2345–50 [Google Scholar]
  90. Miller JFAP. 1961. Immunological function of the thymus. Lancet 278:748–49 [Google Scholar]
  91. Miller JFAP. 1962. Effect of neonatal thymectomy on the immunological responsiveness of the mouse. Proc. R. Soc. Lond. B 156:415–28 [Google Scholar]
  92. Miller JFAP, Sadelain M. 2015. The journey from discoveries in fundamental immunology to cancer immunotherapy. Cancer Cell 27:439–49 [Google Scholar]
  93. Milone MC, Fish JD, Carpenito C, Carroll RG, Binder GK. et al. 2009. Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo. Mol. Ther. 17:1453–64 [Google Scholar]
  94. Mitchison NA. 1955. Studies on the immunological response to foreign tumor transplants in the mouse. I. The role of lymph node cells in conferring immunity by adoptive transfer. J. Exp. Med. 102:157–77 [Google Scholar]
  95. Moeller M, Kershaw MH, Cameron R, Westwood JA, Trapani JA. et al. 2007. Sustained antigen-specific antitumor recall response mediated by gene-modified CD4+ T helper-1 and CD8+ T cells. Cancer Res 67:11428–37 [Google Scholar]
  96. Montini E, Cesana D, Schmidt M, Sanvito F, Bartholomae CC. et al. 2009. The genotoxic potential of retroviral vectors is strongly modulated by vector design and integration site selection in a mouse model of HSC gene therapy. J. Clin. Investig. 119:964–75 [Google Scholar]
  97. Moon EK, Ranganathan R, Eruslanov E, Kim S, Newick K. et al. 2016. Blockade of programmed death 1 augments the ability of human T cells engineered to target NY-ESO-1 to control tumor growth after adoptive transfer. Clin. Cancer Res. 22:436–47 [Google Scholar]
  98. Morello A, Sadelain M, Adusumilli PS. 2016. Mesothelin-targeted CARs: driving T cells to solid tumors. Cancer Discov 6:133–46 [Google Scholar]
  99. Morgan RA, Dudley ME, Wunderlich JR, Hughes MS, Yang JC. et al. 2006. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314:126–29 [Google Scholar]
  100. Morgan RA, Johnson LA, Davis JL, Zheng Z, Woolard KD. et al. 2012. Recognition of glioma stem cells by genetically modified T cells targeting EGFRvIII and development of adoptive cell therapy for glioma. Hum. Gene Ther. 23:1043–53 [Google Scholar]
  101. 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. 18:843–51 [Google Scholar]
  102. Morsut L, Roybal KT, Xiong X, Gordley RM, Coyle SM. et al. 2016. Engineering customized cell sensing and response behaviors using synthetic notch receptors. Cell 164:780–91 [Google Scholar]
  103. Nadler SH, Moore GE. 1969. Immunotherapy of malignant disease. Arch. Surg. 99:376–81 [Google Scholar]
  104. Nishimura T, Kaneko S, Kawana-Tachikawa A, Tajima Y, Goto H. et al. 2013. Generation of rejuvenated antigen-specific T cells by reprogramming to pluripotency and redifferentiation. Cell Stem Cell 12:114–26 [Google Scholar]
  105. O'Reilly RJ, Prockop S, Hasan AN, Koehne G, Doubrovina E. 2016. Virus-specific T-cell banks for ‘off the shelf’ adoptive therapy of refractory infections. Bone Marrow Transplant 51:1163–72 [Google Scholar]
  106. Old LJ. 1992. Tumor immunology: the first century. Curr. Opin. Immunol. 4:603–7 [Google Scholar]
  107. Oliveira G, Ruggiero E, Stanghellini MT, Cieri N, D'Agostino M. et al. 2015. Tracking genetically engineered lymphocytes long-term reveals the dynamics of T cell immunological memory. Sci. Transl. Med. 7:317ra198 [Google Scholar]
  108. Page DB, Postow MA, Callahan MK, Allison JP, Wolchok JD. 2014. Immune modulation in cancer with antibodies. Annu. Rev. Med. 65:185–202 [Google Scholar]
  109. Papadopoulos EB, Ladanyi M, Emanuel D, Mackinnon S, Boulad F. et al. 1994. Infusions of donor leukocytes to treat Epstein-Barr virus-associated lymphoproliferative disorders after allogeneic bone marrow transplantation. N. Engl. J. Med. 330:1185–91 [Google Scholar]
  110. Pardoll DM. 2012. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12:252–64 [Google Scholar]
  111. Pegram HJ, Lee JC, Hayman EG, Imperato GH, Tedder TF. et al. 2012. Tumor-targeted T cells modified to secrete IL-12 eradicate systemic tumors without need for prior conditioning. Blood 119:4133–41 [Google Scholar]
  112. Pegram HJ, Park JH, Brentjens RJ. 2014. CD28z CARs and armored CARs. Cancer J 20:127–33 [Google Scholar]
  113. Perna SK, Pagliara D, Mahendravada A, Liu H, Brenner MK. et al. 2014. Interleukin-7 mediates selective expansion of tumor-redirected cytotoxic T lymphocytes (CTLs) without enhancement of regulatory T-cell inhibition. Clin. Cancer Res. 20:131–39 [Google Scholar]
  114. Poirot L, Philip B, Schiffer-Mannioui C, Le Clerre D, Chion-Sotinel I. et al. 2015. Multiplex genome-edited T-cell manufacturing platform for “off-the-shelf” adoptive T-cell immunotherapies. Cancer Res 75:3853–64 [Google Scholar]
  115. Porter DL, Hwang WT, Frey NV, Lacey SF, Shaw PA. et al. 2015. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci. Transl. Med. 7:303ra139 [Google Scholar]
  116. Prosser ME, Brown CE, Shami AF, Forman SJ, Jensen MC. 2012. Tumor PD-L1 co-stimulates primary human CD8+ cytotoxic T cells modified to express a PD1:CD28 chimeric receptor. Mol. Immunol. 51:263–72 [Google Scholar]
  117. Pule MA, Savoldo B, Myers GD, Rossig C, Russell HV. et al. 2008. Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma. Nat. Med. 14:1264–70 [Google Scholar]
  118. Pule MA, Straathof KC, Dotti G, Heslop HE, Rooney CM, Brenner MK. 2005. A chimeric T cell antigen receptor that augments cytokine release and supports clonal expansion of primary human T cells. Mol. Ther. 12:933–41 [Google Scholar]
  119. Qasim W, Persis J, Samarasinghe S, Ghorashian S, Zhan H. et al. 2015. First clinical application of Talen engineered universal CAR19 T cells in B-ALL Presented at 2015 Am. Soc. Hematol. Conf., Orlando, FL [Google Scholar]
  120. Radvanyi LG. 2015. Tumor-infiltrating lymphocyte therapy: addressing prevailing questions. Cancer J 21:450–64 [Google Scholar]
  121. Ramos CA, Savoldo B, Dotti G. 2014. CD19-CAR trials. Cancer J 20:112–18 [Google Scholar]
  122. Rickert RC, Rajewsky K, Roes J. 1995. Impairment of T-cell-dependent B-cell responses and B-1 cell development in CD19-deficient mice. Nature 376:352–55 [Google Scholar]
  123. Riddell SR, Sommermeyer D, Berger C, Liu LS, Balakrishnan A. et al. 2014. Adoptive therapy with chimeric antigen receptor-modified T cells of defined subset composition. Cancer J 20:141–44 [Google Scholar]
  124. Riese MJ, Wang LC, Moon EK, Joshi RP, Ranganathan A. et al. 2013. Enhanced effector responses in activated CD8+ T cells deficient in diacylglycerol kinases. Cancer Res 73:3566–77 [Google Scholar]
  125. Riviere I, Brose K, Mulligan RC. 1995. Effects of retroviral vector design on expression of human adenosine deaminase in murine bone marrow transplant recipients engrafted with genetically modified cells. PNAS 92:6733–37 [Google Scholar]
  126. Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V. et al. 2015. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348:124–28 [Google Scholar]
  127. Rosenberg SA, Spiess P, Lafreniere R. 1986. A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes. Science 233:1318–21 [Google Scholar]
  128. Rosenberg SA, Terry WD. 1977. Passive immunotherapy of cancer in animals and man. Adv. Cancer Res. 25:323–88 [Google Scholar]
  129. Roybal KT, Rupp LJ, Morsut L, Walker WJ, McNally KA. et al. 2016. Precision tumor recognition by T cells with combinatorial antigen-sensing circuits. Cell 164:770–79 [Google Scholar]
  130. Sabatino M, Hu J, Sommariva M, Gautam S, Fellowes V. et al. 2016. Generation of clinical-grade CD19-specific CAR-modified CD8+ memory stem cells for the treatment of human B-cell malignancies. Blood 128:519–28 [Google Scholar]
  131. Sadelain M. 2015. CAR therapy: the CD19 paradigm. J. Clin. Investig. 125:3392–400 [Google Scholar]
  132. Sadelain M. 2016a. Chimeric antigen receptors: driving immunology towards synthetic biology. Curr. Opin. Immunol. 41:68–76 [Google Scholar]
  133. Sadelain M. 2016b. From adoptive immunity to CAR therapy: an evolutionary perspective. Encyclopedia of Immunobiology MJH Ratclliffe 4560–68 New York: Academic [Google Scholar]
  134. Sadelain M, Brentjens R, Riviere I. 2013. The basic principles of chimeric antigen receptor design. Cancer Discov 3:388–98 [Google Scholar]
  135. Sadelain M, Brentjens R, Rivière I. 2009. The promise and potential pitfalls of chimeric antigen receptors. Curr. Opin. Immunol. 21:215–23 [Google Scholar]
  136. Sadelain M, Brentjens R, Riviere I, Park J. 2015. CD19 CAR therapy for acute lymphoblastic leukemia. American Society of Clinical Oncology 2015 Educational Book 35 DS Dizon e360–63 Alexandria, VA: Am. Soc. Clin. Oncol. [Google Scholar]
  137. Sadelain M, Mulligan RC. 1992. Efficient-retroviral-mediated gene transfer into murine primary lymphocytes Presented at 8th Int. Congr. Immunol., Budapest, Abstr. 34 [Google Scholar]
  138. Sadelain M, Riviere I, Brentjens R. 2003. Targeting tumours with genetically enhanced T lymphocytes. Nat. Rev. Cancer 3:35–45 [Google Scholar]
  139. Santos GW. 1979. Bone marrow transplantation. Adv. Intern. Med. 24:157–82 [Google Scholar]
  140. Savoldo B, Ramos CA, Liu E, Mims MP, Keating MJ. et al. 2011. CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. J. Clin. Investig. 121:1822–26 [Google Scholar]
  141. Schumann K, Lin S, Boyer E, Simeonov DR, Subramaniam M. et al. 2015. Generation of knock-in primary human T cells using Cas9 ribonucleoproteins. PNAS 112:10437–42 [Google Scholar]
  142. Singh H, Moyes JS, Huls MH, Cooper LJ. 2015. Manufacture of T cells using the Sleeping Beauty system to enforce expression of a CD19-specific chimeric antigen receptor. Cancer Gene Ther 22:95–100 [Google Scholar]
  143. Sommermeyer D, Hudecek M, Kosasih PL, Gogishvili T, Maloney DG. et al. 2016. Chimeric antigen receptor-modified T cells derived from defined CD8+ and CD4+ subsets confer superior antitumor reactivity in vivo. Leukemia 30:492–500 [Google Scholar]
  144. Spencer DM, Wandless TJ, Schreiber SL, Crabtree GR. 1993. Controlling signal transduction with synthetic ligands. Science 262:1019–24 [Google Scholar]
  145. Stephan MT, Ponomarev V, Brentjens RJ, Chang AH, Dobrenkov KV. et al. 2007. T cell-encoded CD80 and 4-1BBL induce auto- and transcostimulation, resulting in potent tumor rejection. Nat. Med. 13:1440–49 [Google Scholar]
  146. Sun J, Sadelain M. 2015. The quest for spatio-temporal control of CAR T cells. Cell Res 25:1281–82 [Google Scholar]
  147. Themeli M, Kloss CC, Ciriello G, Fedorov VD, Perna F. et al. 2013. Generation of tumor-targeted human T lymphocytes from induced pluripotent stem cells for cancer therapy. Nat. Biotechnol. 31:928–33 [Google Scholar]
  148. Themeli M, Riviere I, Sadelain M. 2015. New cell sources for T cell engineering and adoptive immunotherapy. Cell Stem Cell 16:357–66 [Google Scholar]
  149. Themeli M, Sadelain M. 2016. Combinatorial antigen targeting: ideal T-cell sensing and anti-tumor response. Trends Mol. Med. 22:271–73 [Google Scholar]
  150. Till BG, Jensen MC, Wang J, Qian X, Gopal AK. et al. 2012. CD20-specific adoptive immunotherapy for lymphoma using a chimeric antigen receptor with both CD28 and 4-1BB domains: pilot clinical trial results. Blood 119:3940–50 [Google Scholar]
  151. Van Der Stegen SJC, Hamieh M, Sadelain M. 2015. The pharmacology of second-generation chimeric antigen receptors. Nat. Rev. Drug Discov. 14:499–509 [Google Scholar]
  152. Vizcardo R, Masuda K, Yamada D, Ikawa T, Shimizu K. et al. 2013. Regeneration of human tumor antigen-specific T cells from iPSCs derived from mature CD8+ T cells. Cell Stem Cell 12:31–36 [Google Scholar]
  153. Wang J, Jensen M, Lin Y, Sui X, Chen E. 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. 18:712–25 [Google Scholar]
  154. Wang X, Olszewska M, Qu J, Wasielewska T, Bartido S. et al. 2015. Large-scale clinical-grade retroviral vector production in a fixed-bed bioreactor. J. Immunother. 38:127–35 [Google Scholar]
  155. Wang X, Riviere I. 2015. Manufacture of tumor- and virus-specific T lymphocytes for adoptive cell therapies. Cancer Gene Ther 22:85–94 [Google Scholar]
  156. Wang X, Riviere I. 2016. Clinical manufacturing of CAR T cells: foundation of a promising therapy. Mol. Ther. Oncolytics 3:16015 [Google Scholar]
  157. Weber JS. 2014. At the bedside: adoptive cell therapy for melanoma-clinical development. J. Leukoc. Biol. 95:875–82 [Google Scholar]
  158. Wilkie S, Burbridge SE, Chiapero-Stanke L, Pereira AC, Cleary S. et al. 2010. Selective expansion of chimeric antigen receptor-targeted T-cells with potent effector function using interleukin-4. J. Biol. Chem. 285:25538–44 [Google Scholar]
  159. Wilkie S, Picco G, Foster J, Davies DM, Julien S. et al. 2008. Retargeting of human T cells to tumor-associated MUC1: the evolution of a chimeric antigen receptor. J. Immunol. 180:4901–9 [Google Scholar]
  160. Winn HJ. 1959. The immune response and the homograft reaction. Nat. Cancer Inst. Monogr. 2:113–37 [Google Scholar]
  161. Wu CY, Roybal KT, Puchner EM, Onuffer J, Lim WA. 2015. Remote control of therapeutic T cells through a small molecule-gated chimeric receptor. Science 350:aab4077 [Google Scholar]
  162. Wu R, Forget MA, Chacon J, Bernatchez C, Haymaker C. et al. 2012. Adoptive T-cell therapy using autologous tumor-infiltrating lymphocytes for metastatic melanoma: current status and future outlook. Cancer J 18:160–75 [Google Scholar]
  163. Zhao Z, Condomines M, van der Stegen SJ, Perna F, Kloss CC. et al. 2015. Structural design of engineered costimulation determines tumor rejection kinetics and persistence of CAR T cells. Cancer Cell 28:415–28 [Google Scholar]
  164. Zhong XS, Matsushita M, Plotkin J, Riviere I, Sadelain M. 2010. Chimeric antigen receptors combining 4-1BB and CD28 signaling domains augment PI3kinase/AKT/Bcl-XL activation and CD8+ T cell-mediated tumor eradication. Mol. Ther. 18:413–20 [Google Scholar]

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error