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Medical Oncology

, 35:87 | Cite as

Challenges and prospects of chimeric antigen receptor T cell therapy in solid tumors

  • Vishal JindalEmail author
  • Ena Arora
  • Sorab Gupta
Review Article

Abstract

Chimeric antigen receptor (CAR) T cell therapy is a novel and innovative immunotherapy. CAR-T cells are genetically engineered T cells, carrying MHC independent specific antigen receptor and co-stimulatory molecule which can activate an immune response to a cancer specific antigen. This therapy showed great results in hematological malignancies but were unable to prove their worth in solid tumors. Likely reasons for their failure are lack of antigens, poor trafficking, and hostile tumor microenvironment. Excessive amount of research is going on to improve the efficacy of CAR T cell therapy in solid tumors. In this article, we will discuss the challenges faced in improving the outcome of CAR T cell therapy in solid tumors and various strategies adopted to curb them.

Keywords

Chimeric antigen receptor T cell therapy Solid tumors Immunotherapy 

Notes

Acknowledgements

Special thanks to Dr. Manisha Dhananjaya.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

References

  1. 1.
    Sadelain M, Brentjens R, Rivière I. The basic principles of chimeric antigen receptor design. Cancer Discov. 2013;3:388–98.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Savoldo B, Ramos CA, Liu E, et al. CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. J Clin Invest. 2011;121:1822–6.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Zhao Y, Wang QJ, Yang S, et al. A herceptin-based chimeric antigen receptor with modified signaling domains leads to enhanced survival of transduced T lymphocytes and antitumor activity. J Immunol. 2009;183:5563–74.CrossRefPubMedGoogle Scholar
  4. 4.
    Zhong XS, Matsushita M, Plotkin J, et al. Chimeric antigen receptors combining 4-1BB and CD28 signaling domains augment PI3kinase/AKT/Bcl-XL activation and CD8* T cell-mediated tumor eradication. MolTher. 2010;18:413–20.Google Scholar
  5. 5.
    Wilkie S, Picco G, Foster J, et al. Re-targeting of human T cells to tumor-associated MUC1: the evolution of a chimeric antigen receptor. J Immunol. 2008;180:4901–9.CrossRefPubMedGoogle Scholar
  6. 6.
    Yeku OO, Brentjens RJ. Armored CAR T-cells: utilizing cytokines and pro-inflammatory ligands to enhance CAR T-cell anti-tumour efficacy. Biochem Soc Trans. 2016;44:412–8.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Suarez ER, Chang K, Sun J, et al. Chimeric antigen receptor T cells secreting anti–PD-L1 antibodies more effectively regress renal cell carcinoma in a humanized mouse model. Oncotarget. 2016;7:34341–55.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, Chew A, Gonzalez VE, Zheng Z, Lacey SF, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371:1507–17.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Porter DL, Hwang WT, Frey NV, Lacey SF, Shaw PA, Loren AW, Bagg A, Marcucci KT, Shen A, Gonzalez V, et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Med Sci Transl. 2015;7:303ra139.CrossRefGoogle Scholar
  10. 10.
    Garfall AL, Maus MV, Hwang WT, Lacey SF, Mahnke YD, Melenhorst JJ, Zheng Z, Vogl DT, Cohen AD, Weiss BM, et al. Chimeric antigen receptor T cells against CD19 for multiple myeloma. N Engl J Med. 2015;373:1040–7.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Lee DW, Kochenderfer JN, Stetler-Stevenson M, Cui YK, Delbrook C, Feldman SA, Fry TJ, Orentas R, Sabatino M, Shah NN, et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet. 2015;385:517–28.CrossRefPubMedGoogle Scholar
  12. 12.
    Yu S, Li A, Liu Q, Li T, Yuan X, Han X, et al. Chimeric antigen receptor T cells: a novel therapy for solid tumors. J Hematol Oncol 2017;10(1):78.  https://doi.org/10.1186/s13045-017-0444-9.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Hynes NE, MacDonald G. ErbB receptors and signaling pathways in cancer. Curr Opin Cell Biol. 2009;21(2):177–84.  https://doi.org/10.1016/j.ceb.2008.12.010 53.CrossRefPubMedGoogle Scholar
  14. 14.
    Hynes NE, Lane HA. ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 2005;5(5):341–54.  https://doi.org/10.1038/nrc166754.CrossRefPubMedGoogle Scholar
  15. 15.
    Olayioye MA, Neve RM, Lane HA, Hynes NE. The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J. 2000;19(13):3159–67.  https://doi.org/10.1093/emboj/19.13.3159.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Yano S, Kondo K, Yamaguchi M, Richmond G, Hutchison M, Wakeling A, et al. Distribution and function of EGFR in human tissue and the effect of EGFR tyrosine kinase inhibition. Anticancer Res. 2002;23(5A):3639–50. 56.Google Scholar
  17. 17.
    Sasada T, Azuma K, Ohtake J, Fujimoto Y. Immune responses to epidermal growth factor receptor (EGFR) and their application for cancer treatment. Front Pharmacol. 2016;7:405.  https://doi.org/10.3389/fphar.2016.0040557.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Arteaga CL. Epidermal growth factor receptor dependence in human tumors: more than just expression? Oncologist. 2002;7(Suppl 4):31–9.CrossRefPubMedGoogle Scholar
  19. 19.
    Shinojima N, Tada K, Shiraishi S, Kamiryo T, Kochi M, Nakamura H, et al. Prognostic value of epidermal growth factor receptor in patients with glio-blastomamultiforme. Cancer Res. 2003;63(20):6962–70. 59.PubMedGoogle Scholar
  20. 20.
    Frederick L, Wang X-Y, Eley G, James CD. Diversity and frequency of epider-mal growth factor receptor mutations in human glioblastomas. Cancer Res. 2000;60(5):1383–7. 60.PubMedGoogle Scholar
  21. 21.
    Wong AJ, Ruppert JM, Bigner SH, Grzeschik CH, Humphrey PA, Bigner DS, et al. Structural alterations of the epidermal growth factor receptor gene in human gliomas. Proc Natl Acad Sci USA 1992;89(7):2965–9.  https://doi.org/10.1073/pnas.89.7.2965.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Johnson LA, Scholler J, Ohkuri T, Kosaka A, Patel PR, McGettigan SE, et al. Rational development and characterization of humanized anti-EGFR variant III chimeric antigen receptor T cells for glioblastoma. Sci Transl Med. 2015;7(275):275ra22.  https://doi.org/10.1126/scitranslmed.aaa4963.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Morgan RA, Johnson LA, Davis JL, Zheng Z, Woolard KD, Reap EA, et al. Recognition of glioma stem cells by genetically modified T cells targeting EGFRvIII and development of adoptive cell therapy for glioma. Hum Gene Ther. 2012;23(10):1043–53.  https://doi.org/10.1089/hum.2012.041.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    O’Rourke DM, Nasrallah MP, Desai A, Melenhorst JJ, Mansfield K, Morrissette JJD, et al. A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma. Sci Transl Med 2017;9(399).  https://doi.org/10.1126/scitranslmed.aaa098468.
  25. 25.
    Debinski W, Gibo DM, Hulet SW, Connor JR, Gillespie GY. Receptor for inter-leukin 13 is a marker and therapeutic target for human high-grade gliomas. Clin Cancer Res. 1999;5(5):985–90. 70.PubMedGoogle Scholar
  26. 26.
    Brown CE, Warden CD, Starr R, Deng X, Badie B, Yuan YC, et al. Glioma IL13Ralpha2 is associated with mesenchymal signature gene expression and poor patient prognosis. PLoS ONE 2013;8(10):e77769.  https://doi.org/10.1371/journal.pone.007776971.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Thaci B, Brown CE, Binello E, Werbaneth K, Sampath P, Sengupta S. Significance of interleukin-13 receptor alpha 2-targeted glioblastoma therapy. Neuro Oncol. 2014;16(10):1304–12.  https://doi.org/10.1093/neuonc/nou045.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Brown CE, Alizadeh D, Starr R, Weng L, Wagner JR, Naranjo A, et al. Regression of glioblastoma after chimeric antigen receptor T-cell therapy. N Engl J Med. 2016;375(26):2561–9.  https://doi.org/10.1056/NEJMoa1610497.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Bielamowicz K, Fousek K, Byrd TT, Samaha H, Mukherjee M, Aware N, et al. Trivalent CAR T-cells overcome interpatient antigenic variability in glioblastoma. Neuro Oncol. 2017.  https://doi.org/10.1093/neuonc/nox182.CrossRefPubMedCentralGoogle Scholar
  30. 30.
    Park JR, DiGiusto DL, Slovak M, Wright C, Naranjo A, Wagner J, et al. Adoptive transfer of chimeric antigen receptor re-directed cytolytic T lym-phocyte clones in patients with neuroblastoma. Mol Ther. 2007;15(4):825–33.  https://doi.org/10.1038/sj.mt.6300104.CrossRefPubMedGoogle Scholar
  31. 31.
    Kershaw MH, Westwood JA, Parker LL, Wang G, Eshhar Z, Mavroukakis SA, et al. A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer. Clin Cancer Res 2006;12(20):6106–15.  https://doi.org/10.1158/1078-0432.CCR-06-1183.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Riese MJ, Wang LC, Moon EK, Joshi RP, Ranganathan A, June CH, et al. Enhanced effector responses in activated CD8 + T cells deficient in diacy-lglycerol kinases. Cancer Res 2013;73(12):3566–77.  https://doi.org/10.1158/0008-5472.CAN-12-3874.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Shen H, Laird PW. Interplay between the cancer genome and epigenome. Cell. 2013;153:38–55.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Grada Z, Hegde M, Byrd T, Shaffer DR, Ghazi A, Brawley VS, et al. TanCAR: a novel bispecific chimeric antigen receptor for cancer immunotherapy. Mol Ther Nucleic Acids 2013;9(2):32.  https://doi.org/10.1038/mtna.2013.3224.CrossRefGoogle Scholar
  35. 35.
    Chinnasamy D, Tran E, Yu Z, Morgan RA, Restifo NP, Rosenberg SA. Simultaneous targeting of tumor antigens and the tumor vasculature using T lymphocyte transfer synergize to induce regression of established tumors in mice. Cancer Res. 2013;73(11):3371–80.  https://doi.org/10.1158/0008-5472. CAN-12-3913.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Wilkie S, van Schalkwyk MC, Hobbs S, Davies DM, van der Stegen SJ, Pereira ACP, et al. Dual targeting of ErbB2 and MUC1 in breast cancer using chimeric antigen receptors engineered to provide complementary signaling. J Clin Immunol. 2012;32:1059–70.CrossRefPubMedGoogle Scholar
  37. 37.
    Kloss CC, Condomines M, Cartellieri M, Bachmann M, Sadelain M. Combinatorial antigen recognition with balanced signaling promotes selective tumor eradication by engineered T cells. Nat Biotechnol. 2013;31:71 – 5.CrossRefPubMedGoogle Scholar
  38. 38.
    Caruso HG, Hurton LV, Najjar A, Rushworth D, Ang S, Olivares S, et al. Tuning sensitivity of CAR to EGFR density limits recognition of normal tissue while maintaining potent antitumor activity. Cancer Res. 2015;75:3505–18.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Jones BS, Lamb LS, Goldman F, Di Stasi A. Improving the safety of cell therapy products by suicide gene transfer. Front Pharmacol. 2014;5.Google Scholar
  40. 40.
    Gargett T, Brown MP. The inducible caspase-9 suicide gene system as a “safety switch” to limit on-target, off-tumor toxicities of chimeric antigen receptor T cells. Front Pharmacol. 2014;5.Google Scholar
  41. 41.
    Ciceri F, Bonini C, Stanghellini MTL, Bondanza A, Traversari C, Salomoni M, et al. Infusion of suicide-gene-engineered donor lymphocytes after family haploidenticalhaemopoietic stem-cell transplantation for leukaemia (the TK007 trial): a non-randomised phase I–II study. Lancet Oncol. 2009;10:489–500.CrossRefPubMedGoogle Scholar
  42. 42.
    Slaney CY, Kershaw MH, Darcy PK. Trafficking of T Cells into Tumors. Cancer Res. 2014;74:7168–74.CrossRefPubMedGoogle Scholar
  43. 43.
    Brown CE, Vishwanath RP, Aguilar B, Starr R, Najbauer J, Aboody KS, et al. Tumor-derived chemokine MCP-1/CCL2 is sufficient for mediating tumor tropism of adoptively transferred T cells. J Immunol. 2007;179(5):3332–41.  https://doi.org/10.4049/jimmunol.179.5.3332.CrossRefPubMedGoogle Scholar
  44. 44.
    Craddock JA, Lu A, Bear A, Pule M, Brenner MK, Rooney CM, et al. Enhanced tumor trafficking of GD2 chimeric antigen receptor T cells by expression of the chemokine receptor CCR2b. J Immunother (Hagerstown:1997). 2010;33:780.CrossRefGoogle Scholar
  45. 45.
    Di Stasi A, De Angelis B, Rooney CM, Zhang L, Mahendravada A, Foster AE, et al. T lymphocytes coexpressing CCR4 and a chimeric antigen receptor targeting CD30 have improved homing and antitumor activity in a Hodgkin tumor model. Blood. 2009;113:6392 – 402.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Moon EK, Carpenito C, Sun J, Wang L-CS, Kapoor V, Predina J, et al. 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. 2011;17(14):4719–30.  https://doi.org/10.1158/1078-0432.CCR-11-0351.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Di Stasi A, De Angelis B, Rooney CM, Zhang L, Mahendravada A, Foster AE, et al. T lymphocytes coexpressing CCR4 and a chimeric antigen receptor targeting CD30 have improved homing and antitumor activity in a Hodgkin tumor model. Blood 2009;113(25):6392–402.  https://doi.org/10.1182/blood-2009-03-209650.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Craddock JA, Lu A, Bear A, Pule M, Brenner MK, Rooney CM, et al. Enhanced tumor trafficking of GD2 chimeric antigen receptor T cells by expression of the chemokine receptor CCR2b. J Immunother. 2010;33(8):780–8.  https://doi.org/10.1097/CJI.0b013e3181ee6675.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Parato KA, Senger D, Forsyth PA, Bell JC. Recent progress in the battle between oncolytic viruses and tumours. Nat Rev Cancer. 2005.  https://doi.org/10.1038/nrc1750. 5:965 – 76; PMID ;.PubMedCrossRefGoogle Scholar
  50. 50.
    Nishio N, Dotti G. Oncolytic virus expressing RANTES and IL-15 enhances function of CAR-modified T cells in solid tumors. Oncoimmunology. 2015;4(2):e988098.  https://doi.org/10.4161/21505594.2014.988098.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Nishio N, Diaconu I, Liu H, Cerullo V, Caruana I, Hoyos V, et al. Armed oncolytic virus enhances immune functions of chimeric antigen receptor– modified T cells in solid tumors. Cancer Res. 2014;74(18):5195–205.  https://doi.org/10.1158/0008-5472.CAN-14-0697.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Bernfield M, et al. Functions of cell surface heparan sulfate proteoglycans. Annu Rev Biochem. 1999;68:729–77.CrossRefPubMedGoogle Scholar
  53. 53.
    de Mestre AM, Staykova MA, Hornby JR, Willenborg DO, Hulett MD. Expression of the heparan sulfate-degrading enzyme heparanase is induced in infiltrating CD4 + T cells in experimental autoimmune encephalomyelitis and regulated at the level of transcription by early growth response gene 1. J Leukoc Biol. 2007;82:1289–300.CrossRefPubMedGoogle Scholar
  54. 54.
    Vlodavsky I, Ilan N, Naggi A, Casu B. Heparanase: structure, biological functions, and inhibition by heparin-derived mimetics of heparan sulfate. Curr Pharm Des. 2007;13:2057–73. 14.CrossRefPubMedGoogle Scholar
  55. 55.
    Yurchenco PD, Schittny JC. Molecular architecture of basement membranes. FASEB J. 1990;4:1577–90.CrossRefPubMedGoogle Scholar
  56. 56.
    Caruana I, Savoldo B, Hoyos V, Weber G, Liu H, Kim ES, et al. Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T lym-phocytes. Nat Med. 2015;21(5):524–9.  https://doi.org/10.1038/nm.3833.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Yaghoubi SS, Jensen MC, Satyamurthy N, Paik D, Czernin J, Gambh SS. Non-invasive detection of therapeutic cytolytic T Cells in patients with [18-F]FHBG positron emission tomography in a glioma patient.Nat. Clin Pract Oncol. 2009;6:53–8.CrossRefGoogle Scholar
  58. 58.
    Brown CE, Badie B, Barish ME, Weng L, Julie R, Chang W, Naranjo A, Starr R, Wagner J, Wright C, et al. Bioactivity and safety of IL13Ra2-redirected chimeric antigen receptor CD8 + T cells inpatients with recurrent glioblastoma. Clin Cancer Res. 2016;21:4062–72.CrossRefGoogle Scholar
  59. 59.
    Brown CE, Alizadeh D, Ostberg JR, Blanchard MS, Kilpatrick J, Simpson J, Kurien A, Priceman SJ, Wang X, et al. Regression of glioblastoma after chimeric antigen receptor T-cell therapy. N Engl J Med. 2016;375:2561–9.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Katz SC, Burga RA, Mccormack E, Wang LJ, Mooring W, Point G, Khare PD, Thorn M, Ma Q, Stainken BF, et al. Phase I hepatic immunotherapy for metastases study of intra-arterial chimeric antigenreceptor modified T cell therapy for CEA + liver metastases. Clin Cancer Res. 2015;21:3149–59.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Dannenberg AJ, Subbaramaiah K. Targeting cyclooxygenase-2 in humanneoplasia: rationale and promise. Cancer Cell. 2003;4:431–6.CrossRefPubMedGoogle Scholar
  62. 62.
    Sitkovsky MV, Lukashev D, Apasov S, Kojima H, Koshiba M, Caldwell C, Ohta A, Thiel M. Physiological control of immune response and inflammatorytissue damage by hypoxia-inducible factors and adenosine A2A receptors. Annu Rev Immunol. 2004;22:657–82.CrossRefPubMedGoogle Scholar
  63. 63.
    Newick K, O’Brien S, Sun J, Kapoor V, Maceyko S, Lo A, et al. Augmentation of CAR T-cell trafficking and antitumor efficacy by blocking protein kinase A localization. Cancer Immunol Res. 2016;4(6):541–51.  https://doi.org/10.1158/2326-6066. CIR-15-0263.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Toyokuni S, Okamoto K, Yodoi J, Hiai H. Persistent oxidative stress in cancer. FEBS Lett. 1995;358:1–3.CrossRefPubMedGoogle Scholar
  65. 65.
    Ligtenberg MA, Mougiakakos D, Mukhopadhyay M, Witt K, Lladser A, Chmielewski M, et al. Coexpressed catalase protects chimeric antigen receptor–redirected T cells as well as bystander cells from oxidative stress-induced loss of antitumor activity. J Immunol. 2016;196(2):759–66.  https://doi.org/10.4049/jimmunol.1401710.CrossRefPubMedGoogle Scholar
  66. 66.
    Hirata F, Ohnishi T, Hayaishi O. Indoleamine 2,3-dioxygenase. Characterization and properties of enzyme. O2- complex. J BiolChem. 1977;252(13):4637–42.Google Scholar
  67. 67.
    Friberg M, Jennings R, Alsarraj M, et al. Indoleamine 2,3-dioxygenase contributes to tumor cell evasion of T cell-mediated rejection. Int J Cancer. 2002;101(2):151–5.CrossRefPubMedGoogle Scholar
  68. 68.
    Frumento G, Rotondo R, Tonetti M, Damonte G, Benatti U, Ferrara GB. Tryptophan-derived catabolites are responsible for inhibition of T and natural killer cell proliferation induced by indoleamine 2,3-dioxygenase. J Exp Med. 2002;196(4):459–68.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Opitz CA, Litzenburger UM, Sahm F, et al. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature. 2011;478(7368):197–203.CrossRefPubMedGoogle Scholar
  70. 70.
    Ninomiya S, Hara T, Tsurumi H, et al. Indoleamine 2,3-dioxygenase in tumor tissue indicates prognosis in patients with diffuse large B-cell lymphoma treated with R-CHOP. Ann Hematol. 2011;90(4):409–16.CrossRefPubMedGoogle Scholar
  71. 71.
    Ninomiya S, Hara T, Tsurumi H, et al. Indoleamine 2,3-dioxygenase expression and serum kynurenine concentrations in patients with diffuse large B-cell lymphoma. Leuk Lymphoma. 2012;53(6):1143–5.CrossRefPubMedGoogle Scholar
  72. 72.
    Ninomiya S, Narala N, Huye L, Yagyu S, Savoldo B, Dotti G, Heslop HE, Brenner MK, Rooney CM, Ramos CA. Tumor indoleamine 2,3-dioxygenase (IDO) inhibits CD19-CAR T cells and is downregulated by lymphodepletingdrugs. Blood. 2015;125(25):3905–16.  https://doi.org/10.1182/blood-2015-01-621474.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Schönbeck U, Libby P. The CD40/CD154 receptor/ligand dyad. Cell Mol Life Sci. 2001;58:4–43.CrossRefPubMedGoogle Scholar
  74. 74.
    Cella M, Scheidegger D, Palmer-Lehmann K, Lane P, Lanzavecchia A, Alber G. Ligation of CD40 on dendritic cells triggers production of high levels of interleukin-12 and enhances T cell stimulatory capacity: T-T help via APC activation. J Exp Med. 1996;184:747–52.CrossRefPubMedGoogle Scholar
  75. 75.
    Clarke SR. The critical role of CD40/CD40L in the CD4-dependent generation of CD8 + T cell immunity. J Leukoc Biol. 2000;67:607–14.CrossRefPubMedGoogle Scholar
  76. 76.
    Cayabyab M, Phillips JH, Lanier LL. CD40 preferentially costimulates activation of CD4 + T lymphocytes. J Immunol. 1994;152:1523–31.PubMedGoogle Scholar
  77. 77.
    Peng X, Kasran A, Warmerdam PA, de Boer M, Ceuppens JL. Accessory signaling by CD40 for T cell activation: induction of Th1 and Th2 cytokines and synergy with interleukin-12 for interferon-gamma production. Eur J Immunol. 1996;26:1621–7.CrossRefPubMedGoogle Scholar
  78. 78.
    Curran KJ, Seinstra BA, Nikhamin Y, et al. Enhancing antitumor efficacy of chimeric antigen receptor T cells through constitutive CD40L expression. Mol Ther. 2015;23(4):769–78.  https://doi.org/10.1038/mt.2015.4.CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Leivonen SK, Kahari VM. Transforming growth factor-beta signaling in cancer invasion and metastasis. Int J Cancer. 2007;121(10):2119–24.  https://doi.org/10.1002/ijc.23113.CrossRefPubMedGoogle Scholar
  80. 80.
    Rubtsov YP, Rudensky AY. TGFbetasignalling in control of T-cell-mediated self-reactivity. Nat Rev Immunol. 2007;7(6):443–53.  https://doi.org/10.1038/nri2095.CrossRefPubMedGoogle Scholar
  81. 81.
    Chen ML, et al. Regulatory T cells suppress tumor-specific CD8 T cell cytotoxicity through TGF-beta signals in vivo. Proc Natl Acad Sci USA. 2005;102(2):419–24.  https://doi.org/10.1073/pnas.0408197102.CrossRefPubMedGoogle Scholar
  82. 82.
    Li MO, Sanjabi S, Flavell RA. Transforming growth factor-beta controls development, homeostasis, and tolerance of T cells by regulatory T cell-dependent and -independent mechanisms. Immunity. 2006;25(3):455–71.  https://doi.org/10.1016/j.immuni.2006.07.011.CrossRefPubMedGoogle Scholar
  83. 83.
    Lacuesta K, et al. Assessing the safety of cytotoxic T lymphocytes transduced with a dominant negative transforming growth factor-beta receptor. J Immunother. 2006;29(3):250–60.  https://doi.org/10.1097/01.cji.0000192104.24583.CrossRefPubMedGoogle Scholar
  84. 84.
    Wang L, et al. Immunotherapy for human renal cell carcinoma by adoptive transfer of autologous transforming growth factor beta-insensitive CD8 + T cells. Clin Cancer Res. 2010;16(1):164–73.  https://doi.org/10.1158/1078-0432.CCR-09-1758.CrossRefPubMedGoogle Scholar
  85. 85.
    Quatromoni JG, Wang Y, Vo DD, et al. T cell receptor (TCR)-transgenic CD8 lymphocytes rendered insensitive to transforming growth factor beta (TGFβ) signaling mediate superior tumor regression in an animal model of adoptive cell therapy. J Transl Med. 2012;10:127.  https://doi.org/10.1186/1479-5876-10-127.CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Scanlan MJ, Mohan Raj BK, Calvo B, Garin-Chesa P, Sanz-Moncasi MP, Healey JH, et al. Molecular cloning of fibroblast activtion proteinα, a member of the serine protease family selectively expressed in stromal fibroblasts of epithelial cancers. Proc Natl Acad Sci USA. 1994;91:5657–61.CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Garin-Chesa P, Old LJ, Rettig WJ. Cell surface glycoprotein of reactive stromal fibroblasts as a potential antibody target in human epithelial cancers. Proc Natl Acad Sci USA. 1990;87:7235–9.CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Tran E, Chinnasamy D, Yu Z, Morgan RA, Lee CC, Restifo NP, et al. Immune targeting of fibroblast activation protein triggers recognition of multipotent bone marrow stromal cells and cachexia. J Exp Med. 2013;210:1125–35.CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Kakarla S, Chow KKH, Mata M, Shaffer DR, Song XT, Wu MF, et al. Antitumor effects of chimeric receptor engineered human T cells directed to tumor stroma. Mol Ther. 2013;21:1611–20.CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Schuberth PC, Hagedorn C, Jenesen SM, Gulati P, van den Broek M, Mischo A, et al. Treatment of malignant pleural mesothelioma by fibroblast activation protein-specific re-directed T cells. J Transl Med. 2013;11:187.CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Wang LC, Lo A, Scholler J, Sun J, Majumdar RS, Kapoor V, Antzis M, Cotner CE, Johnson LA, Durham AC, et al. Targeting fibroblast activation protein intumor stroma with chimeric antigen receptor T cells can inhibit tumorgrowth and augment host immunity without severe toxicity. Cancer Immunol Res. 2014;2:154–66.CrossRefPubMedGoogle Scholar
  92. 92.
    Lo A, Wang LC, Scholler J, Monslow J, Avery D, Newick K, O’Brien S, Evans RA, Bajor DJ, Clendenin C, et al. Tumor-promoting desmoplasia is disruptedby depleting FAP-expressing stromal cells. Cancer Res. 2015;75:2800–10.CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    John LB, Devaud C, Duong CP, Yong CS, Beavis PA, Haynes NM, Chow MT, Smyth MJ, Kershaw MH, Darcy PK. Anti-PD-1 antibody therapy potentlenhances the eradication of established tumors by gene-modified T cells.Clin. Cancer Res. 2013;19:5636–46.Google Scholar
  94. 94.
    Moon EK, Wang LC, Dolfi DV, Wilson CB, Ranganathan R, Sun J, Kapoor V, Scholler J, Pure E, Milone MC, et al. Multifactorial T-cell hypofunction that isreversible can limit the efficacy of chimeric antigen receptor-transducedhuman T cells in solid tumors. Clin Cancer Res. 2014;20:4262–73.CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Liu X, Ranganathan R, Jiang S, Fang C, Sun J, Kim S, Newick K, Lo A, June CH, Zhao Y, Moon EK. A chimeric switch-receptor targeting PD1 augmentsthe efficacy of second-generation CAR T cells in advanced solid tumors. Cancer Res. 2016;76:1578–90.CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Prosser ME, Brown CE, Shami AF, Forman SJ, Jensen MC. Tumor PD-L1 costimulatesprimary human CD8(+) cytotoxic T cells modified to express aPD1:CD28 chimeric receptor. Mol Immunol. 2012;51:263–72.CrossRefPubMedGoogle Scholar
  97. 97.
    Mohammed S, Sukumaran S, Bajgain P, Watanabe N, Heslop HE, Rooney CM, et al. Improving chimeric antigen receptor-modified T cell function by reversing the immunosuppressive tumor microenvironment of pancreatic cancer. Mol Ther. 2017;25(1):249–58.  https://doi.org/10.1016/j.ymthe.2016.10.016.CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Zhang X, Sun S, Hwang I, Tough DF, Sprent J. Potent and selective stimulation of memory-phenotype CD8 + T cells in vivo by IL-15. Immunity. 1998;8(5):591–9.CrossRefPubMedGoogle Scholar
  99. 99.
    Teague RM, et al. Interleukin-15 rescues tolerant CD8 + T cells for use in adoptive immunotherapy of established tumors. Nat Med. 2006;12(3):335–41.CrossRefPubMedGoogle Scholar
  100. 100.
    Klebanoff CA, et al. IL-15 enhances the in vivo antitumor activity of tumor-reactive CD8 + T cells. Proc Natl Acad Sci USA. 2004;101(7):1969–74.CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    Hurton LV, Singh H, Najjar AM, et al. Tethered IL-15 augments antitumor activity and promotes a stem-cell memory subset in tumor-specific T cells. Proc Natl Acad Sci USA. 2016;113(48):E7788-E7797.  https://doi.org/10.1073/pnas.1610544113.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Internal MedicineSaint Vincent HospitalWorcesterUSA
  2. 2.Department of Internal MedicineGovernment Medical CollegeChandigarhIndia
  3. 3.Department of Hematology and OncologyEinstein Healthcare NetworkPhiladelphiaUSA

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