1932
0
  1. Home
  2. A-Z Publications
  3. Annual Review of Immunology
  4. Volume 35, 2017
  5. Article

Annual Review of Immunology

Volume 35, 2017

Synthetic Immunology: Hacking Immune Cells to Expand Their Therapeutic Capabilities

Abstract

The ability of immune cells to survey tissues and sense pathologic insults and deviations makes them a unique platform for interfacing with the body and disease. With the rapid advancement of synthetic biology, we can now engineer and equip immune cells with new sensors and controllable therapeutic response programs to sense and treat diseases that our natural immune system cannot normally handle. Here we review the current state of engineered immune cell therapeutics and their unique capabilities compared to small molecules and biologics. We then discuss how engineered immune cells are being designed to combat cancer, focusing on how new synthetic biology tools are providing potential ways to overcome the major roadblocks for treatment. Finally, we give a long-term vision for the use of synthetic biology to engineer immune cells as a general sensor-response platform to precisely detect disease, to remodel disease microenvironments, and to treat a potentially wide range of challenging diseases.

Keyword(s): chimeric antigen receptors, engineered immune cells, immunotherapy, synthetic biology, synthetic Notch, T cells
Loading

Article metrics loading...

/content/journals/10.1146/annurev-immunol-051116-052302
2017-04-26
2025-04-27
Loading full text...

Full text loading...

/deliver/fulltext/immunol/35/1/annurev-immunol-051116-052302.html?itemId=/content/journals/10.1146/annurev-immunol-051116-052302&mimeType=html&fmt=ahah

Literature Cited

  1. Chovatiya R, Medzhitov R. 1.  2014. Stress, inflammation, and defense of homeostasis. Mol. Cell 542281–88 [Google Scholar]
  2. Lämmermann T, Sixt M. 2.  2008. The microanatomy of T-cell responses. Immunol. Rev. 221126–43 [Google Scholar]
  3. Spiegel DA. 3.  2010. Grand challenge commentary: synthetic immunology to engineer human immunity. Nat. Chem. Biol. 612871–72 [Google Scholar]
  4. Geering B, Fussenegger M. 4.  2015. Synthetic immunology: modulating the human immune system. Trends Biotechnol 33265–79 [Google Scholar]
  5. Thaiss CA, Zmora N, Levy M, Elinav E. 5.  2016. The microbiome and innate immunity. Nature 535761065–74 [Google Scholar]
  6. Brestoff JR, Artis D. 6.  2015. Immune regulation of metabolic homeostasis in health and disease. Cell 1611146–60 [Google Scholar]
  7. Fischbach MA, Bluestone JA, Lim WA. 7.  2013. Cell-based therapeutics: the next pillar of medicine. Sci. Transl. Med. 5179179ps7 [Google Scholar]
  8. Irvine DJ, Swartz MA, Szeto GL. 8.  2013. Engineering synthetic vaccines using cues from natural immunity. Nat. Mater. 1211978–90 [Google Scholar]
  9. Goldberg MS. 9.  2015. Immunoengineering: how nanotechnology can enhance cancer immunotherapy. Cell 1612201–4 [Google Scholar]
  10. Baumeister SH, Freeman GJ, Dranoff G, Sharpe AH. 10.  2016. Coinhibitory pathways in immunotherapy for cancer. Annu. Rev. Immunol. 34539–73 [Google Scholar]
  11. Sharma P, Allison JP. 11.  2015. Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell 1612205–14 [Google Scholar]
  12. Palucka K, Banchereau J. 12.  2012. Cancer immunotherapy via dendritic cells. Nat. Rev. Cancer 124265–77 [Google Scholar]
  13. Kalos M, Levine BL, Porter DL, Katz S, Grupp SA. 13.  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. 39595ra73 [Google Scholar]
  14. Scholler J, Brady TL, Binder-Scholl G, Hwang W-T, Plesa G. 14.  et al. 2012. Decade-long safety and function of retroviral-modified chimeric antigen receptor T cells. Sci. Transl. Med. 4132132ra53 [Google Scholar]
  15. Porter DL, Hwang W-T, Frey NV, Lacey SF, Shaw PA. 15.  et al. 2015. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci. Transl. Med. 7303303ra139 [Google Scholar]
  16. Kawakami Y, Robbins PF, Wang X, Tupesis JP, Parkhurst MR. 16.  et al. 1998. Identification of new melanoma epitopes on melanosomal proteins recognized by tumor infiltrating T lymphocytes restricted by HLA-A1, -A2, and -A3 alleles. J. Immunol. 161126985–92 [Google Scholar]
  17. Rosenberg SA, Yang JC, White DE, Steinberg SM. 17.  1998. Durability of complete responses in patients with metastatic cancer treated with high-dose interleukin-2: identification of the antigens mediating response. Ann. Surg. 2283307–19 [Google Scholar]
  18. Dudley ME, Yang JC, Sherry R, Hughes MS, Royal R. 18.  et al. 2008. Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J. Clin. Oncol. 26325233–39 [Google Scholar]
  19. Rosenberg SA, Yang JC, Sherry RM, Kammula US, Hughes MS. 19.  et al. 2011. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin. Cancer Res. 17134550–57 [Google Scholar]
  20. Gallina G, Dolcetti L, Serafini P. Santo C, Marigo I. 20. , De et al. 2006. Tumors induce a subset of inflammatory monocytes with immunosuppressive activity on CD8+ T cells. J. Clin. Investig. 116:102777–90 [Google Scholar]
  21. Gros A, Turcotte S, Wunderlich JR, Ahmadzadeh M, Dudley ME, Rosenberg SA. 21.  2012. Myeloid cells obtained from the blood but not from the tumor can suppress T-cell proliferation in patients with melanoma. Clin. Cancer Res. 18195212–23 [Google Scholar]
  22. Ahmadzadeh M, Felipe-Silva A, Heemskerk B, Powell DJ, Wunderlich JR. 22.  et al. 2008. FOXP3 expression accurately defines the population of intratumoral regulatory T cells that selectively accumulate in metastatic melanoma lesions. Blood Am. Soc. Hematol. 112134953–60 [Google Scholar]
  23. Yao X, Ahmadzadeh M, Lu Y-C, Liewehr DJ, Dudley ME. 23.  et al. 2012. Levels of peripheral CD4+FoxP3+ regulatory T cells are negatively associated with clinical response to adoptive immunotherapy of human cancer. Blood 119245688–96 [Google Scholar]
  24. Gross G, Waks T, Eshhar Z. 24.  1989. Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. PNAS 862410024–28 [Google Scholar]
  25. Irving BA, Weiss A. 25.  1991. The cytoplasmic domain of the T cell receptor zeta chain is sufficient to couple to receptor-associated signal transduction pathways. Cell 645891–901 [Google Scholar]
  26. Eshhar Z, Waks T, Gross G, Schindler DG. 26.  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. PNAS 902720–24 [Google Scholar]
  27. Finney HM, Lawson AD, Bebbington CR, Weir AN. 27.  1998. Chimeric receptors providing both primary and costimulatory signaling in T cells from a single gene product. J. Immunol. 16162791–97 [Google Scholar]
  28. Maher J, Brentjens RJ, Gunset G, Rivière I, Sadelain M. 28.  2002. Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRζ/CD28 receptor. Nat. Biotechnol. 20170–75 [Google Scholar]
  29. Milone MC, Fish JD, Carpenito C, Carroll RG, Binder GK. 29.  et al. 2009. Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo. Mol. Ther. 1781453–64 [Google Scholar]
  30. Morgan RA, Dudley ME, Wunderlich JR, Hughes MS, Yang JC. 30.  et al. 2006. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 3145796126–29 [Google Scholar]
  31. Johnson LA, Morgan RA, Dudley ME, Cassard L, Yang JC. 31.  et al. 2009. Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen. Blood 1143535–46 [Google Scholar]
  32. Parkhurst MR, Yang JC, Langan RC, Dudley ME, Nathan D-AN. 32.  et al. 2011. T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis. Mol. Ther. 193620–26 [Google Scholar]
  33. Robbins PF, Morgan RA, Feldman SA, Yang JC, Sherry RM. 33.  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. 297917–24 [Google Scholar]
  34. Morgan RA, Chinnasamy N, Abate-Daga D, Gros A, Robbins PF. 34.  et al. 2013. Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy. J. Immunother. 362133–51 [Google Scholar]
  35. Paust S, Andrian von UH. 35.  2011. Natural killer cell memory. Nat. Immunol. 126500–8 [Google Scholar]
  36. Lanier LL. 36.  2008. Up on the tightrope: natural killer cell activation and inhibition. Nat. Immunol. 95495–502 [Google Scholar]
  37. Ferlazzo G, Pack M, Thomas D, Paludan C, Schmid D. 37.  et al. 2004. Distinct roles of IL-12 and IL-15 in human natural killer cell activation by dendritic cells from secondary lymphoid organs. PNAS 1014716606–11 [Google Scholar]
  38. Koka R, Burkett P, Chien M, Chai S, Boone DL, Ma A. 38.  2004. Cutting edge: Murine dendritic cells require IL-15R alpha to prime NK cells. J. Immunol. 17363594–98 [Google Scholar]
  39. Lucas M, Schachterle W, Oberle K, Aichele P, Diefenbach A. 39.  2007. Dendritic cells prime natural killer cells by trans-presenting interleukin 15. Immunity 264503–17 [Google Scholar]
  40. Kruschinski A, Moosmann A, Poschke I, Norell H, Chmielewski M. 40.  et al. 2008. Engineering antigen-specific primary human NK cells against HER-2 positive carcinomas. PNAS 1054517481–86 [Google Scholar]
  41. Altvater B, Landmeier S, Pscherer S, Temme J, Schweer K. 41.  et al. 2009. 2B4 (CD244) signaling by recombinant antigen-specific chimeric receptors costimulates natural killer cell activation to leukemia and neuroblastoma cells. Clin. Cancer Res. 15154857–66 [Google Scholar]
  42. Chu Y, Hochberg J, Yahr A, Ayello J, van de Ven C. 42.  et al. 2015. Targeting CD20+ aggressive B-cell non–Hodgkin lymphoma by anti-CD20 CAR mRNA-modified expanded natural killer cells in vitro and in NSG mice. Cancer Immunol. Res. 34333–44 [Google Scholar]
  43. Imai C, Iwamoto S, Campana D. 43.  2005. Genetic modification of primary natural killer cells overcomes inhibitory signals and induces specific killing of leukemic cells. Blood 1061376–83 [Google Scholar]
  44. Li L, Liu LN, Feller S, Allen C, Shivakumar R. 44.  et al. 2010. Expression of chimeric antigen receptors in natural killer cells with a regulatory-compliant non-viral method. Cancer Gene Ther 173147–54 [Google Scholar]
  45. Shimasaki N, Fujisaki H, Cho D, Masselli M, Lockey T. 45.  et al. 2012. A clinically adaptable method to enhance the cytotoxicity of natural killer cells against B-cell malignancies. Cytotherapy 147830–40 [Google Scholar]
  46. Ivics Z, Izsvák Z. 46.  2010. The expanding universe of transposon technologies for gene and cell engineering. Mob. DNA 1125 [Google Scholar]
  47. Nakazawa Y, Huye LE, Dotti G, Foster AE, Vera JF. 47.  et al. 2009. Optimization of the PiggyBac transposon system for the sustained genetic modification of human T lymphocytes. J. Immunother. 328826–36 [Google Scholar]
  48. Davey NE, Travé G, Gibson TJ. 48.  2011. How viruses hijack cell regulation. Trends Biochem. Sci. 363159–69 [Google Scholar]
  49. Barrett DM, Singh N, Porter DL, Grupp SA, June CH. 49.  2014. Chimeric antigen receptor therapy for cancer. Annu. Rev. Med. 65333–47 [Google Scholar]
  50. Morsut L, Roybal KT, Xiong X, Gordley RM, Coyle SM. 50.  et al. 2016. Engineering customized cell sensing and response behaviors using synthetic Notch receptors. Cell 1644780–91 [Google Scholar]
  51. Yang Y, Jacoby E, Fry TJ. 51.  2015. Challenges and opportunities of allogeneic donor-derived CAR T cells. Curr. Opin. Hematol. 226509–15 [Google Scholar]
  52. Kochenderfer JN, Wilson WH, Janik JE, Dudley ME, Stetler-Stevenson M. 52.  et al. 2010. Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. Blood 116:204099–102 [Google Scholar]
  53. Brentjens RJ, Rivière I, Park JH, Davila ML, Wang X. 53.  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 118:184817–28 [Google Scholar]
  54. Kochenderfer JN, Dudley ME, Feldman SA, Wilson WH, Spaner DE. 54.  et al. 2012. B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells. Blood 119:122709–20 [Google Scholar]
  55. Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL. 55.  et al. 2013. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N. Engl. J. Med. 368:161509–18 [Google Scholar]
  56. Lee DW, Kochenderfer JN, Stetler-Stevenson M, Cui YK, Delbrook C. 56.  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 385:9967517–28 [Google Scholar]
  57. Kochenderfer JN, Dudley ME, Kassim SH, Somerville RPT, Carpenter RO. 57.  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. 33:6540–49 [Google Scholar]
  58. Sadelain M, Brentjens R, Rivière I. 58.  2013. The basic principles of chimeric antigen receptor design. Cancer Discov. 34388–98 [Google Scholar]
  59. Kawalekar OU, O'Connor RS, Fraietta JA, Guo L, McGettigan SE. 59.  et al. 2016. Distinct signaling of coreceptors regulates specific metabolism pathways and impacts memory development in CAR T cells. Immunity 442380–90 [Google Scholar]
  60. Brentjens RJ, Davila ML, Rivière I, Park J, Wang X. 60.  et al. 2013. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci. Transl. Med. 5177177ra38 [Google Scholar]
  61. Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM. 61.  et al. 2014. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med. 371232189–99 [Google Scholar]
  62. Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V. 62.  et al. 2015. Cancer immunology: Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer. Science 3486230124–28 [Google Scholar]
  63. Parkhurst MR, Riley JP, Dudley ME, Rosenberg SA. 63.  2011. Adoptive transfer of autologous natural killer cells leads to high levels of circulating natural killer cells but does not mediate tumor regression. Clin. Cancer Res. 17196287–97 [Google Scholar]
  64. Linette GP, Stadtmauer EA, Maus MV, Rapoport AP, Levine BL. 64.  et al. 2013. Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma. Blood 1226863–71 [Google Scholar]
  65. Kunert A, Straetemans T, Govers C, Lamers C, Mathijssen R. 65.  et al. 2013. TCR-engineered T cells meet new challenges to treat solid tumors: choice of antigen, T cell fitness, and sensitization of tumor milieu. Front. Immunol. 4363 [Google Scholar]
  66. Rapoport AP, Stadtmauer EA, Binder-Scholl GK, Goloubeva O, Vogl DT. 66.  et al. 2015. NY-ESO-1-specific TCR-engineered T cells mediate sustained antigen-specific antitumor effects in myeloma. Nat. Med. 218914–21 [Google Scholar]
  67. Chen L, Flies DB. 67.  2013. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat. Rev. Immunol. 134227–42 [Google Scholar]
  68. Narayanan P, Lapteva N, Seethammagari M, Levitt JM, Slawin KM, Spencer DM. 68.  2011. A composite MyD88/CD40 switch synergistically activates mouse and human dendritic cells for enhanced antitumor efficacy. J. Clin. Investig. 12141524–34 [Google Scholar]
  69. Fedorov VD, Themeli M, Sadelain M. 69.  2013. PD-1- and CTLA-4-based inhibitory chimeric antigen receptors (iCARs) divert off-target immunotherapy responses. Sci. Transl. Med. 5215215ra172 [Google Scholar]
  70. Hart Y, Alon U. 70.  2013. The utility of paradoxical components in biological circuits. Mol. Cell 492213–21 [Google Scholar]
  71. Hart Y, Reich-Zeliger S, Antebi YE, Zaretsky I, Mayo AE. 71.  et al. 2014. Paradoxical signaling by a secreted molecule leads to homeostasis of cell levels. Cell 15851022–32 [Google Scholar]
  72. Spangler JB, Moraga I, Mendoza JL, Garcia KC. 72.  2015. Insights into cytokine-receptor interactions from cytokine engineering. Annu. Rev. Immunol. 33139–67 [Google Scholar]
  73. Levin AM, Bates DL, Ring AM, Krieg C, Lin JT. 73.  et al. 2012. Exploiting a natural conformational switch to engineer an interleukin-2 ‘superkine’. Nature 4847395529–33 [Google Scholar]
  74. Mitra S, Ring AM, Amarnath S, Spangler JB, Li P. 74.  et al. 2015. Interleukin-2 activity can be fine tuned with engineered receptor signaling clamps. Immunity 425826–38 [Google Scholar]
  75. Kawahara M, Ueda H, Nagamune T. 75.  2010. Engineering cytokine receptors to control cellular functions. Biochem. Eng. J. 483283–94 [Google Scholar]
  76. Sogo T, Kawahara M, Tsumoto K, Kumagai I, Ueda H, Nagamune T. 76.  2008. Selective expansion of genetically modified T cells using an antibody/interleukin-2 receptor chimera. J. Immunol. Methods 337116–23 [Google Scholar]
  77. Melero I, Rouzaut A, Motz GT, Coukos G. 77.  2014. T-cell and NK-cell infiltration into solid tumors: a key limiting factor for efficacious cancer immunotherapy. Cancer Discov. 45522–26 [Google Scholar]
  78. Di Stasi A, De Angelis B, Rooney CM, Zhang L, Mahendravada A. 78.  et al. 2009. T lymphocytes coexpressing CCR4 and a chimeric antigen receptor targeting CD30 have improved homing and antitumor activity in a Hodgkin tumor model. Blood 113256392–402 [Google Scholar]
  79. Craddock JA, Lu A, Bear A, Pule M, Brenner MK. 79.  et al. 2010. Enhanced tumor trafficking of GD2 chimeric antigen receptor T cells by expression of the chemokine receptor CCR2b. J. Immunother. 338780–88 [Google Scholar]
  80. Moon EK, Carpenito C, Sun J, Wang L-CS, Kapoor V. 80.  et al. 2011. Expression of a functional CCR2 receptor enhances tumor localization and tumor eradication by retargeted human T cells expressing a mesothelin-specific chimeric antibody receptor. Clin. Cancer Res. 17144719–30 [Google Scholar]
  81. Park JS, Rhau B, Hermann A, McNally KA, Zhou C. 81.  et al. 2014. Synthetic control of mammalian-cell motility by engineering chemotaxis to an orthogonal bioinert chemical signal. PNAS 111165896–901 [Google Scholar]
  82. Conklin BR, Hsiao EC, Claeysen S, Dumuis A, Srinivasan S. 82.  et al. 2008. Engineering GPCR signaling pathways with RASSLs. Nat. Methods 58673–78 [Google Scholar]
  83. Sykes EA, Dai Q, Sarsons CD, Chen J, Rocheleau JV. 83.  et al. 2016. Tailoring nanoparticle designs to target cancer based on tumor pathophysiology. PNAS 1139E1142–51 [Google Scholar]
  84. Roybal KT, Rupp LJ, Morsut L, Walker WJ, McNally KA. 84.  et al. 2016. Precision tumor recognition by T cells with combinatorial antigen-sensing circuits. Cell 1644770–79 [Google Scholar]
  85. Schroeter EH, Kisslinger JA, Kopan R. 85.  1998. Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain. Nature 3936683382–86 [Google Scholar]
  86. Selkoe D, Kopan R. 86.  2003. Notch and Presenilin: regulated intramembrane proteolysis links development and degeneration. Annu. Rev. Neurosci. 26:565–97 [Google Scholar]
  87. Gordon WR, Vardar-Ulu D, Histen G, Sanchez-Irizarry C, Aster JC, Blacklow SC. 87.  2007. Structural basis for autoinhibition of Notch. Nat. Struct. Mol. Biol. 144295–300 [Google Scholar]
  88. Bray SJ. 88.  2006. Notch signalling: A simple pathway becomes complex. Nat. Rev. Mol. Cell Biol. 79678–89 [Google Scholar]
  89. Gordon WR, Zimmerman B, He L, Miles LJ, Huang J. 89.  et al. 2015. Mechanical allostery: evidence for a force requirement in the proteolytic activation of Notch. Dev. Cell 336729–36 [Google Scholar]
  90. Roybal KT, Williams JZ, Morsut L, Rupp LJ, Kolinko I. 90.  et al. 2016. Engineering T cells with customized therapeutic response programs using synthetic Notch receptors. Cell 167:2419–32.e16 [Google Scholar]
  91. Bonini C, Ferrari G, Verzeletti S, Servida P, Zappone E. 91.  et al. 1997. HSV-TK gene transfer into donor lymphocytes for control of allogeneic graft-versus-leukemia. Science 27653191719–24 [Google Scholar]
  92. Greco R, Oliveira G, Stanghellini MTL, Vago L, Bondanza A. 92.  et al. 2015. Improving the safety of cell therapy with the TK-suicide gene. Front. Pharmacol. 695 [Google Scholar]
  93. Riddell SR, Elliott M, Lewinsohn DA, Gilbert MJ, Wilson L. 93.  et al. 1996. T-cell mediated rejection of gene-modified HIV-specific cytotoxic T lymphocytes in HIV-infected patients. Nat. Med. 22216–23 [Google Scholar]
  94. Frank O, Rudolph C, Heberlein C, von Neuhoff N, Schröck E. 94.  et al. 2004. Tumor cells escape suicide gene therapy by genetic and epigenetic instability. Blood 104123543–49 [Google Scholar]
  95. Di Stasi A, Tey S-K, Dotti G, Fujita Y, Kennedy-Nasser A. 95.  et al. 2011. Inducible apoptosis as a safety switch for adoptive cell therapy. N. Engl. J. Med. 365181673–83 [Google Scholar]
  96. Wang X, Chang W-C, Wong CW, Colcher D, Sherman M. 96.  et al. 2011. A transgene-encoded cell surface polypeptide for selection, in vivo tracking, and ablation of engineered cells. Blood Am. Soc. Hematol. 11851255–63 [Google Scholar]
  97. Wu C-Y, Roybal KT, Puchner EM, Onuffer J, Lim WA. 97.  2015. Remote control of therapeutic T cells through a small molecule-gated chimeric receptor. Science 3506258aab4077 [Google Scholar]
  98. Bayle JH, Grimley JS, Stankunas K, Gestwicki JE, Wandless TJ, Crabtree GR. 98.  2006. Rapamycin analogs with differential binding specificity permit orthogonal control of protein activity. Chem. Biol. 13199–107 [Google Scholar]
  99. Juillerat A, Marechal A, Filhol J-M, Valton J, Duclert A. 99.  et al. 2016. Design of chimeric antigen receptors with integrated controllable transient functions. Sci. Rep 618950 [Google Scholar]
  100. Sakemura R, Terakura S, Watanabe K, Julamanee J, Takagi E. 100.  et al. 2016. A Tet-On inducible system for controlling CD19-chimeric antigen receptor expression upon drug administration. Cancer Immunol. Res. 48658–68 [Google Scholar]
  101. Klebanoff CA, Rosenberg SA, Restifo NP. 101.  2016. Prospects for gene-engineered T cell immunotherapy for solid cancers. Nat. Med. 22126–36 [Google Scholar]
  102. Gross G, Eshhar Z. 102.  2016. Therapeutic potential of T cell chimeric antigen receptors (CARs) in cancer treatment: counteracting off-tumor toxicities for safe CAR T cell therapy. Annu. Rev. Pharmacol. Toxicol. 5659–83 [Google Scholar]
  103. Wilkie S, van Schalkwyk MCI, Hobbs S, Davies DM, van der Stegen SJC. 103.  et al. 2012. Dual targeting of ErbB2 and MUC1 in breast cancer using chimeric antigen receptors engineered to provide complementary signaling. J. Clin. Immunol. 3251059–70 [Google Scholar]
  104. Kloss CC, Condomines M, Cartellieri M, Bachmann M, Sadelain M. 104.  2013. Combinatorial antigen recognition with balanced signaling promotes selective tumor eradication by engineered T cells. Nat. Biotechnol. 31171–75 [Google Scholar]
  105. Lanitis E, Poussin M, Klattenhoff AW, Song D, Sandaltzopoulos R. 105.  et al. 2013. Chimeric antigen receptor T cells with dissociated signaling domains exhibit focused antitumor activity with reduced potential for toxicity in vivo. Cancer Immunol. Res. 1143–53 [Google Scholar]
  106. Quail DF, Joyce JA. 106.  2013. Microenvironmental regulation of tumor progression and metastasis. Nat. Med. 19111423–37 [Google Scholar]
  107. Hanahan D, Coussens LM. 107.  2012. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 213309–22 [Google Scholar]
  108. Pegram HJ, Lee JC, Hayman EG, Imperato GH, Tedder TF. 108.  et al. 2012. Tumor-targeted T cells modified to secrete IL-12 eradicate systemic tumors without need for prior conditioning. Blood 119184133–41 [Google Scholar]
  109. Kerkar SP, Muranski P, Kaiser A, Boni A, Sanchez-Perez L. 109.  et al. 2010. Tumor-specific CD8+ T cells expressing interleukin-12 eradicate established cancers in lymphodepleted hosts. Cancer Res. 70176725–34 [Google Scholar]
  110. Zhang L, Kerkar SP, Yu Z, Zheng Z, Yang S. 110.  et al. 2011. Improving adoptive T cell therapy by targeting and controlling IL-12 expression to the tumor environment. Mol. Ther. 194751–59 [Google Scholar]
  111. Zhang L, Feldman SA, Zheng Z, Chinnasamy N, Xu H. 111.  et al. 2012. Evaluation of γ-retroviral vectors that mediate the inducible expression of IL-12 for clinical application. J. Immunother. 355430–39 [Google Scholar]
  112. Leonard JP, Sherman ML, Fisher GL, Buchanan LJ, Larsen G. 112.  et al. 1997. Effects of single-dose interleukin-12 exposure on interleukin-12-associated toxicity and interferon-gamma production. Blood 9072541–48 [Google Scholar]
  113. Margolin KA, Rayner AA, Hawkins MJ, Atkins MB, Dutcher JP. 113.  et al. 1989. Interleukin-2 and lymphokine-activated killer cell therapy of solid tumors: analysis of toxicity and management guidelines. J. Clin. Oncol. 74486–98 [Google Scholar]
  114. Ochoa JB, Curti B, Peitzman AB, Simmons RL, Billiar TR. 114.  et al. 1992. Increased circulating nitrogen oxides after human tumor immunotherapy: correlation with toxic hemodynamic changes. J. Natl. Cancer Inst. 8411864–67 [Google Scholar]
  115. Schwartz RN, Stover L, Dutcher J. 115.  2002. Managing toxicities of high-dose interleukin-2. Oncology 16Suppl. 1311–20 [Google Scholar]
  116. Caruana I, Savoldo B, Hoyos V, Weber G, Liu H. 116.  et al. 2015. Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T lymphocytes. Nat. Med. 215524–29 [Google Scholar]
  117. Ellebrecht CT, Bhoj VG, Nace A, Choi EJ, Mao X. 117.  et al. 2016. Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease. Science 353:6295179–84 [Google Scholar]
/content/journals/10.1146/annurev-immunol-051116-052302
Loading
Synthetic Immunology: Hacking Immune Cells to Expand Their Therapeutic Capabilities
Annual Review of Immunology 35, 229 (2017); https://doi.org/10.1146/annurev-immunol-051116-052302
/content/journals/10.1146/annurev-immunol-051116-052302
/content/journals/10.1146/annurev-immunol-051116-052302
Loading

Data & Media loading...

  • Article Type: Review Article

Most Cited Most Cited RSS feed

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