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Targeting cancer cells: from historic methods to modern chimeric antigen receptor (CAR) T-Cell strategies

1 Fırat University, Faculty of Science, Department of Biology, Elazığ 23200, Turkey
2 Erbil Polytechnic University, Koya Technical Institute, Department of Community Health, Erbil, Iraq

Topical Section: Tumor Immunology

Cancer therapy and diagnosis have long been challenges for humans. Despite accumulated knowledge and information, there are many complications and difficulties with cancer therapy and diagnosis. The challenges of cancer treatment are modified according to the new forms that have been discovered by researchers. Each stage of development has involved new techniques for cancer therapy, culminating in the modern immunotherapy approach using chimeric antigen receptor (CAR) cytotoxic T lymphocytes. This strategy is an example of the latest version of cancer cell therapy. Chimeric antigen receptor T-cell therapy drew interest soon after its implementation by researchers as a new strategy to control various types of cancer cells, and it is considered a living drug in the body that detects and destroys cancer cells in a long-term manner, with CAR T-cells remaining as memory cells. CAR T-cell therapy has shown remarkable effects against both primary acute lymphoblastic leukemia (ALL) and relapsed ALL, with a high remission rate observed in adults and children (approximately 90%). Although the use of CAR T-cell therapy for solid tumors has encountered obstacles associated with the microenvironment and immunosuppression, researchers are poised to improve effective CAR T-cell therapy for solid tumors. In this mini review, we describe some attempts that have applied CAR T-cells from the past and present; in addition, it contains many aspects of new anticancer strategies featuring CAR T-cells, especially CAR T-cell killing mechanisms.
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Keywords cancer; immunotherapy; chimeric antigen receptor T-cell

Citation: Kochar Khasro Saleh, Semih Dalkiliç, Lütfiye Kadioğlu Dalkiliç, Bahra Radhaa Hamarashid, Sevda Kirbağ. Targeting cancer cells: from historic methods to modern chimeric antigen receptor (CAR) T-Cell strategies. AIMS Allergy and Immunology, 2020, 4(2): 32-49. doi: 10.3934/Allergy.2020004


  • 1. Storm HH, Michelsen EV, Clemmensen IH, et al. (1997) The Danish Cancer Registry-history, content, quality and use. Dan Med Bull 44: 535–538.
  • 2. Vieira CMP, Fragoso M, Ferreira M, et al. (2019) The history of cancer pain and bone-targeted agents: 10 most commonly asked questions. Cancer Manag Res 11: 37.
  • 3. Taylor AM, Shih J, Ha G, et al. (2018) Genomic and functional approaches to understanding cancer aneuploidy. Cancer Cell 33: 676–689.    
  • 4. Kastan MB, Bartek J (2004) Cell-cycle checkpoints and cancer. Nature 432: 316–323.    
  • 5. Bredenkamp N, Stirparo GG, Nichols J, et al. (2019) The cell-surface marker Sushi containing domain 2 facilitates establishment of human naive pluripotent stem cells. Stem Cell Rep 12: 1212–1222.    
  • 6. Gielen B, Remacle A, Mertens R (2010) Patterns of health care use and expenditure during the last 6 months of life in Belgium: differences between age categories in cancer and non-cancer patients. Health Policy 97: 53–61.    
  • 7. Tamargo J, Caballero R, Delpón E (2015) Cancer chemotherapy and cardiac arrhythmias: a review. Drug Saf 38: 129–152.    
  • 8. Sui Q, Jiang W, Wu X, et al. (2019) A frameshift mutation in exon 19 of MLH1 in a Chinese Lynch syndrome family: a pedigree study. J Zhejiang Univ Sci B 20: 105.    
  • 9. Lord CJ, Ashworth A (2012) The DNA damage response and cancer therapy. Nature 481: 287–294.    
  • 10. Alfano RR, Liu CH, Glassman WS (1993) Method for determining if a tissue is a malignant tumor tissue, a benign tumor tissue, or a normal or benign tissue using Raman spectroscopy. U.S. Patent 5261410 A.
  • 11. Boldrini R, De Pasquale MD, Melaiu O, et al. (2019) Tumor-infiltrating T cells and PD-L1 expression in childhood malignant extracranial germ-cell tumors. OncoImmunology 8: e1542245.    
  • 12. Hughes-Parry HE, Cross RS, Jenkins MR (2020) The Evolving Protein Engineering in the Design of Chimeric Antigen Receptor T Cells. Int J Mol Sci 21: 204.
  • 13. Mirzaei HR, Pourghadamyari H, Rahmati M, et al. (2018) Gene-knocked out chimeric antigen receptor (CAR) T cells: tuning up for the next generation cancer immunotherapy. Cancer Lett 423: 95–104.    
  • 14. Wicha MS, Liu S, Dontu G (2006) Cancer stem cells: an old idea-a paradigm shift. Cancer Res 66: 1883–1890.    
  • 15. Guilford FT, Yu S (2019) Antiparasitic and antifungal medications for targeting cancer cells literature review and case studies. Synth 9: 11.
  • 16. Elinder CG, Kjellstrom T (2019) Carcinogenic and genetic effects, In: Friberg LT, Elinder GG, Kjellstrom T, et al., Cadmium and Health: A Toxicological and Epidemiological Appraisal: Volume 2: Effects and Response, 1st Ed., Boca Raton: CRC Press, 35.
  • 17. Ernst E (1998) The prevalence of complementary/alternative medicine in cancer: a systematic review. Cancer Interdiscipl Int J Am Cancer Soc 83: 777–782.
  • 18. Chen S, Giannakou A, Wyman S, et al. (2018) Cancer-associated fibroblasts suppress SOX2-induced dysplasia in a lung squamous cancer coculture. P Natl Acad Sci Usa 115: E11671–E11680.    
  • 19. Couzin-Frankel J (2013) Cancer immunotherapy. Science 342: 1432–1433.    
  • 20. Bystrom LM, Rivella S (2015) Cancer cells with irons in the fire. Free Radical Bio Med 79: 337–342.    
  • 21. Saleh KK, Kakey ES (2018) Some molecular characterization of β-thalassemia major in Koya City. International Conference on Pure and Applied Sciences, 4: 64–68.
  • 22. Kershaw MH, Westwood JA, Parker LL, et al. (2006) A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer. Clin Cancer Res 12: 6106–6115.    
  • 23. Vaissière T, Sawan C, Herceg Z (2008) Epigenetic interplay between histone modifications and DNA methylation in gene silencing. Mutat Res-Rev Mutat 659: 40–48.    
  • 24. Siegel RL, Miller KD, Jemal A (2016) Cancer statistics, 2016. CA Cancer J Clin 66: 7–30.    
  • 25. Sudhakar A, Boosani CS (2008) Inhibition of tumor angiogenesis by tumstatin: insights into signaling mechanisms and implications in cancer regression. Pharm Res 25: 2731.    
  • 26. Li WW, Li VW, Hutnik M, et al. (2012) Tumor angiogenesis as a target for dietary cancer prevention. Int J Oncol 2012: 879623.
  • 27. Kirkpatrick DB (1984) The first primary brain-tumor operation. J Neurosurg 61: 809–813.    
  • 28. Xu FM, Zhang Y, Xu JH, et al. (2017) Operation and tumor metastasis. J Int Onc 44: 376–379.
  • 29. Sehouli J, Richter R, Braicu EI, et al. (2010) Role of secondary cytoreductive surgery in ovarian cancer relapse: who will benefit? A systematic analysis of 240 consecutive patients. J Surg Oncol 102: 656–662.
  • 30. Depierre A, Milleron B, Moro-Sibilot D, et al. (2002) Preoperative chemotherapy followed by surgery compared with primary surgery in resectable stage I (except T1N0), II, and IIIa non–small-cell lung cancer. J Clin Oncol 20: 247–253.
  • 31. Hentschel B, Oehler W, Strauß D, et al. (2011) Definition of the CTV prostate in CT and MRI by using CT–MRI image fusion in IMRT planning for prostate cancer. Strahlenther Onkol 187: 183–190.    
  • 32. Keshavarzi M, Darijani M, Momeni F, et al. (2017) Molecular imaging and oral cancer diagnosis and therapy. J Cell Biochem 118: 3055–3060.    
  • 33. Saadatpour Z, Bjorklund G, Chirumbolo S, et al. (2016) Molecular imaging and cancer gene therapy. Cancer Gene Ther: 1–5.
  • 34. Jafari SH, Saadatpour Z, Salmaninejad A, et al. (2018) Breast cancer diagnosis: Imaging techniques and biochemical markers. J Cell Physiol 233: 5200–5213.    
  • 35. Chabner BA, Roberts TG (2005) Chemotherapy and the war on cancer. Nat Rev Cancer 5: 65–72.    
  • 36. Thomas A, Teicher BA, Hassan R (2016) Antibody–drug conjugates for cancer therapy. Lancet Oncol 17: e254–e262.    
  • 37. Lam JS, Leppert JT, Vemulapalli SN, et al. (2006) Secondary hormonal therapy for advanced prostate cancer. J Urol 175: 27–34.
  • 38. Yan D, Vicini F, Wong J, et al. (1997) Adaptive radiation therapy. Phys Med Biol 42: 123.    
  • 39. Dawson LA, Jaffray DA (2007) Advances in image-guided radiation therapy. J Clin Oncol 25: 938–946.    
  • 40. Mirzaei HR, Sahebkar A, Salehi R, et al. (2016) Boron neutron capture therapy: Moving toward targeted cancer therapy. J Cancer Res Ther 12: 520.    
  • 41. Seifert HS (2018) Above and beyond watson and crick: Guanine quadruplex structures and microbes. Annu Rev Microbiol 72: 49–69.    
  • 42. Turner KM, Deshpande V, Beyter D, et al. (2017) Extrachromosomal oncogene amplification drives tumour evolution and genetic heterogeneity. Nature 543: 122–125.    
  • 43. Friedberg EC (2016) A history of the DNA repair and mutagenesis field: The discovery of base excision repair. DNA repair 37: A35–A39.    
  • 44. Zhu K, Liu Q, Zhou Y, et al. (2015) Oncogenes and tumor suppressor genes: comparative genomics and network perspectives. BMC genomics 16: S8.
  • 45. Ratcliffe CD, Sahgal P, Parachoniak CA, et al. (2016) Regulation of cell migration and β1 integrin trafficking by the endosomal adaptor GGA3. Traffic 17: 670–688.    
  • 46. Li D, Kang N, Ji J, et al. (2015) BRCA1 regulates transforming growth factor-β (TGF-β1) signaling through Gadd45a by enhancing the protein stability of Smad4. Mol Oncol 9: 1655–1666.    
  • 47. Bernstein L (2002) Epidemiology of endocrine-related risk factors for breast cancer. J Mammary Gland Biol Neoplasia 7: 3–15.    
  • 48. Chen X, Duan N, Zhang C, et al. (2016) Survivin and tumorigenesis: molecular mechanisms and therapeutic strategies. J Cancer 7: 314.    
  • 49. Fodde R (2002) The APC gene in colorectal cancer. Eur J Cancer 38: 867–871.    
  • 50. Akavia UD, Litvin O, Kim J, et al. (2010) An integrated approach to uncover drivers of cancer. Cell 143: 1005–1017.    
  • 51. Mirzaei H, Sahebkar A, Sichani LS, et al. (2018) Therapeutic application of multipotent stem cells. J Cell Physiol 233: 2815–2823.    
  • 52. West NR, McCuaig S, Franchini F, et al. (2015) Emerging cytokine networks in colorectal cancer. Nat Rev Immunol 15: 615–629.    
  • 53. Lu J, Wu J, Tian J, et al. (2018) Role of T cell-derived exosomes in immunoregulation. Immunol Res 66: 313–322.    
  • 54. Born W, White J, O'Brien R, et al. (1988) Development of T cell receptor expression: studies using T cell hybridomas. Immunol Res 7: 279–291.    
  • 55. Mirzaei H, Salehi H, Oskuee RK, et al. (2018) The therapeutic potential of human adipose-derived mesenchymal stem cells producing CXCL10 in a mouse melanoma lung metastasis model. Cancer Lett 419: 30–39.    
  • 56. Zhao L, Cao YJ (2019) Engineered T Cell Therapy for Cancer in the Clinic. Front Immunol 10: 2250.    
  • 57. Schlessinger J, Ullrich A (1992) Growth factor signaling by receptor tyrosine kinases. Neuron 9: 383–391.    
  • 58. Iwamoto M, Saso W, Sugiyama R, et al. (2019) Epidermal growth factor receptor is a host-entry cofactor triggering hepatitis B virus internalization. P Natl Acad Sci Usa 116: 8487–8492.    
  • 59. Moradian Tehrani R, Verdi J, Noureddini M, et al. (2018) Mesenchymal stem cells: A new platform for targeting suicide genes in cancer. J Cell Physiol 233: 3831–3845.    
  • 60. Mirzaei H, Sahebkar A, Avan A, et al. (2016) Application of mesenchymal stem cells in melanoma: a potential therapeutic strategy for delivery of targeted agents. Curr Med Chem 23: 455–463.    
  • 61. Pichlmair A, Schulz O, Tan CP, et al. (2006) RIG-I-mediated antiviral responses to single-stranded RNA bearing 5'-phosphates. Science 314: 997–1001.    
  • 62. Grossman JD, Grossman W (2019) Angiogenesis. Rev Cardiovasc Med 3: 138–144.
  • 63. Hashemi Goradel N, Ghiyami-Hour F, Jahangiri S, et al. (2018) Nanoparticles as new tools for inhibition of cancer angiogenesis. J Cell Physiol 233: 2902–2910.    
  • 64. Ning S, Laird D, Cherrington JM, et al. (2002) The antiangiogenic agents SU5416 and SU6668 increase the antitumor effects of fractionated irradiation. Radiat Res 157: 45–51.    
  • 65. Ye W (2016) The complexity of translating anti-angiogenesis therapy from basic science to the clinic. Dev Cell 37: 114–125.    
  • 66. Sudhakar A (2009) History of Cancer, Ancient and Modern Treatment Methods. J Cancer Res Sci Ther 1: 1–4.
  • 67. Wood AK, Sehgal CM (2015) A review of low-intensity ultrasound for cancer therapy. Ultrasound Med Biol 41: 905–928.    
  • 68. Romero P, Banchereau J, Bhardwaj N, et al. (2016) The Human Vaccines Project: A roadmap for cancer vaccine development. Sci Transl Med 8: 334ps339–334ps339.
  • 69. Paez JG, Jänne PA, Lee JC, et al. (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304: 1497–1500.    
  • 70. Zeitoun G, Sissy C, Kirilovsky A, et al. (2019) The immunoscore in the clinical practice of patients with colon and rectal cancers. Chirurgia (Bucur) 114: 152–161.    
  • 71. Fridman WH, Pagès F, Sautes-Fridman C, et al. (2012) The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer 12: 298–306.    
  • 72. Rodríguez PC, Rodríguez G, González G, et al. (2010) Clinical development and perspectives of CIMAvax EGF, Cuban vaccine for non-small-cell lung cancer therapy. MEDICC Rev 12: 17–23.
  • 73. Perez CA, Santos ES, Raez LE (2011) Active immunotherapy for non-small-cell lung cancer: moving toward a reality. Expert Rev Anticancer Ther 11: 1599–1605.    
  • 74. Gattinoni L, Powell DJ, Rosenberg SA, et al. (2006) Adoptive immunotherapy for cancer: building on success. Nat Rev Immunol 6: 383–393.    
  • 75. Mahoney KM, Rennert PD, Freeman GJ (2015) Combination cancer immunotherapy and new immunomodulatory targets. Nat Rev Drug Discov 14: 561–584.    
  • 76. Restifo NP, Dudley ME, Rosenberg SA (2012) Adoptive immunotherapy for cancer: harnessing the T cell response. Nat Rev Immunol 12: 269–281.    
  • 77. Mirzaei HR, Mirzaei H, Lee SY, et al. (2016) Prospects for chimeric antigen receptor (CAR) γδ T cells: A potential game changer for adoptive T cell cancer immunotherapy. Cancer Lett 380: 413–423.    
  • 78. Han X, Wang Y, Han WD (2018) Chimeric antigen receptor modified T-cells for cancer treatment. Chronic Dis Transl Med 4: 225–243.
  • 79. Weng J, Lai P, Qin L, et al. (2018) A novel generation 1928zT2 CAR T cells induce remission in extramedullary relapse of acute lymphoblastic leukemia. J Hematol Oncol 11: 25.    
  • 80. Turtle CJ, Hanafi LA, Berger C, et al. (2016) CD19 CAR–T cells of defined CD4+: CD8+ composition in adult B cell ALL patients. J Clin Invest 126: 2123–2138.    
  • 81. Wang Y, Zhang W, Han Q, et al. (2014) Effective response and delayed toxicities of refractory advanced diffuse large B-cell lymphoma treated by CD20-directed chimeric antigen receptor-modified T cells. Clin Immunol 155: 160–175.    
  • 82. Fry TJ, Shah NN, Orentas RJ, et al. (2018) CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy. Nat Med 24: 20.    
  • 83. Ramos CA, Ballard B, Zhang H, et al. (2017) Clinical and immunological responses after CD30-specific chimeric antigen receptor–redirected lymphocytes. J Clin Invest 127: 3462–3471.    
  • 84. Levine BL, Miskin J, Wonnacott K, et al. (2017) Global Manufacturing of CAR T Cell Therapy. Mol Ther-Meth Clin D 4: 92–101.    
  • 85. Mirzaei HR, Mirzaei H, Namdar A, et al. (2019) Predictive and therapeutic biomarkers in chimeric antigen receptor T-cell therapy: A clinical perspective. J Cell Physiol 234: 5827–5841.    
  • 86. Newick K, O'Brien S, Moon E, et al. (2017) CAR T cell therapy for solid tumors. Annu Rev Med 68: 139–152.    
  • 87. Eshhar Z (2008) The T-body approach: redirecting T cells with antibody specificity, In: Chernajovsky Yuti, Nissim Ahuva, Therapeutic Antibodies, 1st Ed., Heidelberg: Springer, 329–342.
  • 88. Curran KJ, Pegram HJ, Brentjens RJ (2012) Chimeric antigen receptors for T cell immunotherapy: current understanding and future directions. J Gene Med 14: 405–415.
  • 89. Del Nagro CJ, Otero DC, Anzelon AN, et al. (2005) CD 19 function in central and peripheral B-cell development. Immunol Res 31: 119–131.    
  • 90. Mirzaei HR, Jamali A, Jafarzadeh L, et al. (2019) Construction and functional characterization of a fully human anti-CD19 chimeric antigen receptor (huCAR)-expressing primary human T cells. J Cell Physiol 234: 9207–9215.    
  • 91. Feng K, Guo Y, Dai H, et al. (2016) Chimeric antigen receptor-modified T cells for the immunotherapy of patients with EGFR-expressing advanced relapsed/refractory non-small cell lung cancer. Sci China Life Sci 59: 468–479.
  • 92. O'Rourke DM, Nasrallah MP, Desai A, et al. (2017) 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 9: eaaa0984.    
  • 93. Lamers CH, Sleijfer S, Van Steenbergen S, et al. (2013) Treatment of metastatic renal cell carcinoma with CAIX CAR-engineered T cells: clinical evaluation and management of on-target toxicity. Mol Ther 21: 904–912.    
  • 94. Thistlethwaite FC, Gilham DE, Guest RD, et al. (2017) The clinical efficacy of first-generation carcinoembryonic antigen (CEACAM5)-specific CAR T cells is limited by poor persistence and transient pre-conditioning-dependent respiratory toxicity. Cancer Immunol Immun 66: 1425–1436.    
  • 95. Savoldo B, Ramos CA, Liu E, et al. (2011) CD28 costimulation improves expansion and persistence of chimeric antigen receptor–modified T cells in lymphoma patients. J Clin Invest 121: 1822–1826.    
  • 96. Hartmann J, Schüßler-Lenz M, Bondanza A, et al. (2017) Clinical development of CAR T cells-challenges and opportunities in translating innovative treatment concepts. EMBO Mol Med 9: 1183–1197.    
  • 97. Srivastava S, Riddell SR (2015) Engineering CAR-T cells: design concepts. Trends Immunol 36: 494–502.    
  • 98. Linehan DC, Goedegebuure PS (2005) CD25+ CD4+ regulatory T-cells in cancer. Immunol Res 32: 155–168.    
  • 99. Frey NV, Porter DL (2016) The promise of chimeric antigen receptor T-cell therapy. Oncology-Basel 30.
  • 100. Maude SL, Frey N, Shaw PA, et al. (2014) Chimeric antigen receptor T cells for sustained remissions in leukemia. New Engl J Med 371: 1507–1517.    
  • 101. Turtle CJ, Berger C, Sommermeyer D, et al. (2015) Anti-CD19 chimeric antigen receptor-modified T cell therapy for B cell non-Hodgkin lymphoma and chronic lymphocytic leukemia: fludarabine and cyclophosphamide lymphodepletion improves in vivo expansion and persistence of CAR-T cells and clinical outcomes. Blood 126: 184.    
  • 102. Zhao Z, Chen Y, Francisco NM, et al. (2018) The application of CAR-T cell therapy in hematological malignancies: advantages and challenges. Acta Pharm Sin B 8: 539–551.    
  • 103. Carpenter RO, Evbuomwan MO, Pittaluga S, et al. (2013) B-cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma. Clin Cancer Res 19: 2048–2060.    


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