Targeting cancer stem cells by using chimeric antigen receptor-modified T cells: a potential and curable approach for cancer treatment

Abstract

Cancer stem cells (CSCs), a subpopulation of tumor cells, have self-renewal and multi-lineage differentiation abilities that play an important role in cancer initiation, maintenance, and metastasis. An accumulation of evidence indicates that CSCs can cause conventional therapy failure and cancer recurrence because of their treatment resistance and self-regeneration characteristics. Therefore, approaches that specifically and efficiently eliminate CSCs to achieve a durable clinical response are urgently needed. Currently, treatments with chimeric antigen receptor-modified T (CART) cells have shown successful clinical outcomes in patients with hematologic malignancies, and their safety and feasibility in solid tumors was confirmed. In this review, we will discuss in detail the possibility that CART cells inhibit CSCs by specifically targeting their cell surface markers, which will ultimately improve the clinical response for patients with various types of cancer. A number of viewpoints were summarized to promote the application of CSC-targeted CART cells in clinical cancer treatment. This review covers the key aspects of CSC-targeted CART cells against cancers in accordance with the premise of the model, from bench to bedside and back to bench.

Key words： cancer stem cells; chimeric antigen receptor; immunotherapy; translational medicine; response evaluation criterion

References

1 Ades F, Yamaguchi N (2015) WHO, RECIST, and immune-related response criteria: is it time to revisit pembrolizumab results? Ecancermedicalscience 9:604

2 Ahmed N, Brawley VS, Hegde M (2015) Human epidermal growth factor receptor 2 (HER2)-specific chimeric antigen receptor-modified Tcells for the immunotherapy of HER2-positive sarcoma. J Clin Oncol 33:1688–1696

3 Alamgeer M, Peacock CD, Matsui W (2013) Cancer stem cells in lung cancer: Evidence and controversies. Respirology 18:757–764

4 Al-Hajj M, Wicha MS, Benito-Hernandez A (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 100:3983–3988

5 Ang W, Li Z, Chi Z (2017) Intraperitoneal immunotherapy with T cells stably and transiently expressing anti-EpCAM CAR in xenograft models of peritoneal carcinomatosis. Oncotarget.

6 Baba T, Convery PA, Matsumura N (2009) Epigenetic regulation of CD133 and tumorigenicity of CD133+ ovarian cancer cells. Oncogene 28:209–218

7 Bakalova R, Ohba H, Zhelev Z (2004) Quantum dots as photosensitizers? Nat Biotechnol 22:1360–1361

8 Bidlingmaier S, Zhu X, Liu B (2008) The utility and limitations of glycosylated human CD133 epitopes in defining cancer stem cells. J Mol Med (Berl). 86:1025–1032

9 Bonnet D, Dick JE (1997) Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 3:730–737

10 Bruce WR, Van Der Gaag HA (1963) Quantitative assay for the number of murine lymphoma cells capable of proliferation in vivo. Nature 199:79–80

11 Budde LE, Berger C, Lin Y (2013) Combining a CD20 chimeric antigen receptor and an inducible caspase 9 suicide switch to improve the efficacy and safety of T cell adoptive immunotherapy for lymphoma. PLoS ONE 8:e82742

12 Chao MP, Tang C, Pachynski RK (2011a) Extranodal dissemination of non-Hodgkin lymphoma requires CD47 and is inhibited by anti-CD47 antibody therapy. Blood 118:4890–4901

13 Chao MP, Alizadeh AA, Tang C (2011b) Therapeutic antibody targeting of CD47 eliminates human acute lymphoblastic leukemia. Cancer Res 71:1374–1384

14 Chen Y,Song J, Jiang Y (2015) Predictive value of CD44 and CD24 for prognosis and chemotherapy response in invasive breast ductal carcinoma. Int J Clin Exp Pathol 8:11287–11295

15 Collins AT, Berry PA, Hyde C (2005) Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res 65:10946–10951

16 Corbeil D, Marzesco AM, Wilsch-Brauninger M (2010) The intriguing links between prominin-1 (CD133), cholesterol-based membrane microdomains, remodeling of apical plasma membrane protrusions, extracellular membrane particles, and (neuro) epithelial cell differentiation. FEBS Lett 584:1659–1664

17 Dai H, Zhang W, Li X (2015) Tolerance and efficacy of autologous or donor-derived T cells expressing CD19 chimeric antigen receptors in adult B-ALL with extramedullary leukemia. Oncoimmunology 4:e1027469

18 Deng Z, Wu Y, Ma W (2015) Adoptive T-cell therapy of prostate cancer targeting the cancer stem cell antigen EpCAM. BMC Immunol 16:1

19 Dragu DL, Necula LG, Bleotu C (2015) Therapies targeting cancer stem cells: Current trends and future challenges. World J Stem Cells 26:1185–1201

20 Edris B, Weiskopf K, Volkmer AK (2012) Antibody therapy targeting the CD47 protein is effective in a model of aggressive metastatic leiomyosarcoma. Proc Natl Acad Sci USA 109:6656–6661

21 Feldmann G, Dhara S, Fendrich V (2007) Blockade of hedgehog signaling inhibits pancreatic cancer invasion and metastases: a new paradigm for combinationtherapy in solid cancers. Cancer Res 67:2187–2196

22 Feng K, Guo Y, Dai H (2016) Chimeric antigen receptormodified T cells for the immunotherapy of patients with EGFRexpressing advanced relapsed/refractory non-small cell lung cancer. Sci China Life Sci 59:468–479

23 Feng K, Guo Y, Liu Y(2017) Cocktail treatment with EGFRspecific and CD133-specific chimeric antigen receptor-modified T cells in a patient with advanced cholangiocarcinoma. J Hematol Oncol 10:4

24 Focosi D, Bestagno M, Burrone O (2010) CD57+ T lymphocytes and functional immune deficiency. J Leukoc Biol 87:107–116

25 Frank NY, Schatton T, Frank MH (2010) The therapeutic promise of the cancer stem cell concept. J Clin Invest 120:41–50

26 Fukuda K, Saikawa Y, Ohashi M (2009) Tumor initiating potential of side population cells in human gastric cancer. Int J Oncol 34:1201–1207

27 Garfall AL, Maus MV, Hwang WT (2015) Chimeric antigen receptor Tcells against CD19 for multiple myeloma. N Engl J Med 373:1040–1047

28 Ginestier C, Hur MH, Charafe-Jauffret E (2007) ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 1:555–567

29 Gires O, Klein CA, Baeuerle PA (2009) On the abundance of EpCAM on cancer stem cells. Nat Rev Cancer 9:143

30 Grada Z, Hegde M, Byrd T (2013) TanCAR: a novel bispecific chimeric antigen receptor for cancer immunotherapy. Mol Ther Nucleic Acids 2:e105

31 Gross G, Waks T, Eshhar Z (1989) Expression of immunoglobulin-Tcell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc Natl Acad Sci USA 86:10024–10028

32 Grupp SA, Kalos M, Barrett D (2013) Chimeric antigen receptormodified T cells for acute lymphoid leukemia. N Engl J Med 368:1509–1518

33 Gupta PB, Chaffer CL, Weinberg RA (2009) Cancer stem cells: mirage or reality? Nat Med 15:1010–1012

34 Hemmati HD, Nakano I, Lazareff JA (2003) Cancerous stem cells can arise from pediatric brain tumors. Proc Natl Acad Sci USA 100:15178–15183

35 Hibi K, Sakata M, Kitamura YH (2010) Demethylation of the CD133 gene is frequently detected in early gastric carcinoma. Anticancer Res 30:1201–1203

36 Hodi FS, O’Day SJ, McDermott DF (2010) Improved survivalwith ipilimumab in patientswithmetastaticmelanoma. N Engl J Med 363:711–723

37 Hong IS, Jang GB, Lee HY (2015) Targeting cancer stem cells by using the nanoparticles. Int J Nanomed 10(Spec Iss):251–260

38 Hoos A, Eggermont AM, Janetzki S (2010) Improved endpoints for cancer immunotherapy trials. J Natl Cancer Inst 102:1388–1397

39 Hoos A, Wolchok JD, Humphrey RW (2015) CCR 20th anniversary commentary: immune-related response criteria-capturing clinical activity in immuno-oncology. Clin Cancer Res 21:4989–4991

40 Jain A, Jain SK (2008) In vitro and cell uptake studies for targeting of ligand anchored nanoparticles for colon tumors. Eur J Pharm Sci 35:404–416

41 Jain A, Jain SK, Ganesh N (2010) Design and development of ligand-appended polysaccharidic nanoparticles for the delivery of oxaliplatin in colorectal cancer. Nanomedicine 6:179–190

42 Jensen MC, Riddell SR (2015) Designing chimeric antigen receptors to effectively and safely target tumors. Curr Opin Immunol 33:9–15

43 Julien S,Merino-Trigo A, Lacroix L (2012) Characterization of a large panel of patient-derived tumor xenografts representing the clinical heterogeneity of human colorectal cancer. Clin Cancer Res 18(19):5314–5328

44 Kastan MB, Schlaffer E, Russo JE (1990) Direct demonstration of elevated aldehyde dehydrogenase in human hematopoietic progenitor cells. Blood 75:1947–1950

45 Kershaw MH, Westwood JA, Darcy PK (2013) Gene-engineered T cells for cancer therapy. Nat Rev Cancer 13:525–541

46 Khaleghi S, Rahbarizadeh F, Ahmadvand D (2012) A caspase 8-based suicide switch induces apoptosis in nanobody-directed chimeric receptor expressing T cells. Int J Hematol 95:434–444

47 Khan N, Mukhtar H (2015) Dietary agents for prevention and treatment of lung cancer. Cancer Lett 359:155–164

48 Kim D, Wang J, Willingham SB (2012) Anti-CD47 antibodies promote phagocytosis and inhibit the growth of human myeloma cells. Leukemia 26:2538–2545

49 Kim MS, Ma JS, Yun H (2015) Redirection of genetically engineered CAR-T cells using bifunctional small molecules. J Am Chem Soc 137:2832–2835

50 Kochenderfer JN, Dudley ME, Kassim SH (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 33:540–549

51 Lamers CH, Sleijfer S, van Steenbergen S (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

52 Lapidot T, Sirard C, Vormoor J (1994) A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367:645–648

53 Lee DW, Gardner R, Porter DL (2014) Current concepts in the diagnosis and management of cytokine release syndrome. Blood 124:188–195

54 Li C, Heidt DG, Dalerba P (2007) Identification of pancreatic cancer stem cells. Cancer Res 67:1030–1037

55 Lingala S, Cui YY, Chen X (2010) Immunohistochemical staining of cancer stem cell markers in hepatocellular carcinoma. Exp Mol Pathol 89:27–35

56 Liu J, Jiang G (2006) CD44 and hematologic malignancies. Cell Mol Immunol 3:359–365

57 Lu JW, Chang JG, Yeh KT (2011) Overexpression of Thy1/CD90 in human hepatocellular carcinoma is associated with HBV infection and poor prognosis. Acta Histochem 113:833–838

58 Ma S, Chan KW, Hu L (2007) Identification and characterization of tumorigenic liver cancer stem/progenitor cells. Gastroenterology 132:2542–2556

59 Ma ZL, Chen YP, Song JL (2015) Knock-down of CD24 inhibits proliferation, invasion and sensitizes breast cancer MCF-7 cells to tamoxifen in vitro. Eur Rev Med Pharmacol Sci 19:2394–2399

60 Majeti R, Chao MP, Alizadeh AA (2009) CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell 138:286–299

61 Marchitti SA, Brocker C, Stagos D (2008) Non-P450 aldehyde oxidizing enzymes: the aldehyde dehydrogenase superfamily. Expert Opin Drug Metab Toxicol 4:697–720

62 Maude SL, Frey N, Shaw PA (2014) Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 371:1507

63 Mitra M, Kandalam M, Verma RS (2010) Genome-wide changes accompanying the knockdown of Ep-CAM in retinoblastoma. Mol Vis 16:828–842

64 Morgan RA, Yang JC, Kitano M (2010) Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol Ther 18:843–851

65 Munz M, Baeuerle PA, Gires O (2009) The emerging role of EpCAM in cancer and stem cell signaling. Cancer Res 69:5627–5629

66 Naujokat C (2012) Targeting human cancer stem cells with monoclonal antibodies. J Clin Cell Immunol S5:7

67 O’Brien CA, Pollett A, Gallinger S (2007) A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445:106–110

68 Ogura E, Senzaki H, Yoshizawa K (1998) Immunohistochemical localization of epithelial glycoprotein EGP-2 and carcinoembryonic antigen in normal colonic mucosa and colorectal tumors. Anticancer Res 18:3669–3675

69 Osta WA, Chen Y, Mikhitarian K (2004) EpCAM is overexpressed inbreast cancer and is a potential target for breast cancer gene therapy. Cancer Res 64:5818–5824

70 Pan Q, Li Q, Liu S (2015) Concise review: targeting cancer stem cells using immunologic approaches. Stem Cells 33:2085–2092

71 Porter DL, Levine BL, Kalos M (2011) Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med 365:725–733

72 Rege TA, Hagood JS (2006) Thy-1 as a regulator of cell-cell and cellmatrix interactions in axon regeneration, apoptosis, adhesion, migration, cancer, and fibrosis. FASEB J 20:1045–1054

73 Reya T, Morrison SJ, Clarke MF (2001) Stem cells, cancer, and cancer stem cells. Nature 414:105–111

74 Ricci-Vitiani L, Lombardi DG, Pilozzi E (2007) Identification and expansion of human colon-cancer-initiating cells. Nature 445:111–115

75 Rosfjord E, Lucas J, Li G (2014) Advances in patient-derived tumor xenografts: From target identification to predicting clinical response rates in oncology. Biochem Pharmacol 91(2):135–143

76 Sadelain M, Brentjens R, Riviere I (2013) The basic principles of chimeric antigen receptor design. Cancer Discov 3:388–398

77 Salomon J, Goulet O, Canioni D (2014) Genetic characterization of congenital tufting enteropathy: epcam associated phenotype and involvement of SPINT2 in the syndromic form. Hum Genet 133:299–310

78 Savona MR, Malcovati L, Komrokji R (2015) An international consortium proposal of uniform response criteria for myelodysplastic/myeloproliferative neoplasms (mds/mpn) in adults. Blood 125:1857–1865

79 Schmidt M, Scheulen ME, Dittrich C (2010) An open-label, randomized phase II study of adecatumumab, a fully human anti-EpCAM antibody, as monotherapy in patients with metastatic breast cancer. Ann Oncol 21:275–282

80 Shigdar S, Lin J, Yu Y, Pastuovic M (2011) RNA aptamer against a cancer stem cell marker epithelial cell adhesion molecule. Cancer Sci 102:991–998

81 Shmelkov SV, St Clair R, Lyden D (2005) AC133/CD133/Prominin-1. Int J Biochem Cell Biol 37:715–719

82 Skubitz AP, Taras EP, Boylan KL (2013) Targeting CD133 in an in vivo ovarian cancer model reduces ovarian cancer progression. Gynecol Oncol 130:579–587

83 Smith LM, Nesterova A, Ryan MC (2008) CD133/prominin-1 is a potential therapeutic target for antibody-drug conjugates in hepatocellular and gastric cancers. Br J Cancer 99:100–109

84 Song G, Liao X, Zhou L (2004) HI44a, an anti-CD44 monoclonal antibody, induces differentiation and apoptosis of human acute myeloid leukemia cells. Leuk Res 28:1089–1096

85 Song Y, Zhu Z, An Y (2013) Selection of DNA aptamers against epithelial cell adhesion molecule for cancer cell imaging and circulating tumor cell capture. Anal Chem 85:4141–4149

86 Stewart BW, Wild C, International Agency for Research on Cancer and World Health Organization (2014) World cancer report 2014. International Agency for Research on Cancer WHO Press, Lyon, France/Geneva, Switzerland

87 Strioga M, Pasukoniene V, Characiejus D (2011) CD8+ CD28- and CD8+CD57+ T cells and their role in health and disease. Immunology 134:17–32

88 Su YJ, Lin WH, Chang YW (2015) Polarized cell migration induces cancer type-specific CD133/integrin/Src/Akt/GSK3β/β-catenin signaling required for maintenance of cancer stem cell properties. Oncotarget 6:38029–38045

89 Sukowati CH, Anfuso B, Torre G (2013) The expression of CD90/Thy-1 in hepatocellular carcinoma: an in vivo and in vitro study. PLoS ONE 8:e76830

90 Swaminathan SK, Roger E, Toti U (2013) CD133-targeted paclitaxel delivery inhibits local tumor recurrence in a mouse model of breast cancer. J Control Release 171:280–287

91 Tang KH, Dai YD, Tong M (2013) A CD90(+) tumor-initiating cell population with an aggressive signature and metastatic capacity in esophageal cancer. Cancer Res 73:2322–2332

92 Till BG, Jensen MC, Wang J (2012) CD20-specific adoptive immunotherapy for lymphoma using a chimeric antigen receptor with both CD28 and 4-1BB domains: pilot clinical trial results. Blood 119:3940–3950

93 Van der Gun BT, Melchers LJ, Ruiters MH (2010) EpCAM in carcinogenesis: the good, the bad or the ugly. Carcinogenesis 31:1913–1921

94 Visus C, Wang Y, Lozano-Leon A (2011) Targeting ALDH bright human carcinoma-initiating cells with ALDH1A1-Specific CD8+ T cells. Clin Cancer Res 17:6174–6184

95 Visvader JE, Lindeman GJ (2008) Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer 8:755–768

96 Wang L, Su W, Liu Z (2012) CD44 antibody-targeted liposomal nanoparticles for molecular imaging and therapy of hepatocellular carcinoma. Biomaterials 33:5107–5114

97 Wang Y, Zhang WY, Han QW (2014) Effective response and delayed toxicities of refractory advanced diffuse large B-cell lymphoma treated by CD20-directed chimeric antigen receptormodified T cells. Clin Immunol 155:160–175

98 Wang QS, Wang Y, Lv HY (2015a) Treatment of CD33-directed chimeric antigen receptor-modified T cells in one patient with relapsed and refractory acute myeloid leukemia. Mol Ther 23:184–191

99 Wang X, Liu Y, Zhou K (2015b) Isolation and characterization of CD105+/CD90+ subpopulation in breast cancer MDA-MB-231 cell line. Int J Clin Exp Pathol 8:5105–5112

100 Willingham SB, Volkmer JP, Gentles AJ (2012) The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proc Natl Acad Sci USA 109:6662–6667

101 Wolchok JD, Hoos A, O’Day S (2009) Guidelines for the evaluation of immune therapy activity in solid tumors: immunerelated response criteria. Clin Cancer Res 15:7412–7420

102 Woo SR, Oh YT, An JY (2015) Glioblastoma specific antigens, GD2 and CD90, are not involved in cancer stemness. Anat Cell Biol 48:44–53

103 Wu RC, Liu S, Chacon JA (2012) Detection and characterization of a novel subset of CD8(+)CD57(+) T cells in metastatic melanoma with an incompletely differentiated phenotype. Clin Cancer Res 18:2465–2477

104 Wu CY, Roybal KT, Puchner EM (2015) Remote control of therapeutic T cells through a small molecule-gated chimeric receptor. Science 350:4077

105 Yamashita T, Wang XW (2013) Cancer stem cells in the development of liver cancer. J Clin Invest 123:1911–1918

106 Yee C, Thompson JA, Byrd D (2002) Adoptive T cell therapy using antigen-specific CD8+ T cell clones for the treatment of patients with metastatic melanoma: in vivo persistence, migration, and antitumor effect of transferred T cells. Proc Natl Acad Sci USA 99:16168–16173

107 Yi JM, Tsai HC, Glöckner SC (2008) Abnormal DNA methylation of CD133 in colorectal and glioblastoma tumors. Cancer Res 68:8094–8103

108 Yin AH, Miraglia S, Zanjani ED (1997) AC133, a novel marker for human hematopoietic stem and progenitor cells. Blood 90:5002–5012

109 Zhang Q, Shi S, Yen Y (2010) A subpopulation of CD133(+) cancer stem-like cells characterized in human oral squamous cell carcinoma confer resistance to chemotherapy. Cancer Lett 289:151–160

110 Zhang C, Zhou C, Wu XJ (2014a) Human CD133-positive hematopoietic progenitor cells initiate growth and metastasis of colorectal cancer cells. Carcinogenesis 35:2771–2777

111 Zhang YH, Wang ZY, Hao FYl (2014b) Cluster of differentiation 24 monoclonal antibody induces apoptosis in the osteosarcoma cells. Eur Rev Med Pharmacol Sci 18:2038–2041

112 Zhao L, Yang Y, Zhou P (2015) Targeting CD133 high colorectal cancer cells in vitro and in vivo with an asymmetric bispecific antibody. J Immunother 38:217–228

113 Zhu J, Thakolwiboon S, Liu X (2014) Overexpression of CD90 (Thy-1) in pancreatic adenocarcinoma present in the tumor microenvironment. PLoS ONE 9:e115507

114 Zhu X, Prasad S, Gaedicke Sl (2015) Patient-derived glioblastoma stem cells are killed by CD133-specific CAR T cells but induce the T cell aging marker CD57. Oncotarget 6:171–184