Digestive system cancers, including hepatocellular carcinoma, colorectal and gastric tumors, are characterized by high rates of incidence and mortality. Digestive cancers are difficult to diagnose during the early stages, and the side effects of chemotherapy are often severe and may outweigh the therapeutic benefits. Chimeric antibody chimeric antigen receptor T cell (CAR-T) therapy, a novel immunotherapy, has achieved excellent results for the treatment of hematological tumors. However, CAR-T treatment of solid tumors has struggled due to a lack of target specificity, a difficult tumor microenvironment, and T cell homing. Despite the challenges, CAR-T treatment of digestive cancers is progressing. Combining CAR-T with other targets and/or modifying the CAR may represent the most promising approaches for future treatment of digestive cancers.
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References
1.
BrayF, FerlayJ, SoerjomataramI, et al.Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2018; 68:394.
2.
ThomasS, PrendergastGC. Cancer vaccines: A brief overview. Methods Mol Biol, 2016; 1403:755.
3.
MartinezM, MoonEK. CAR T cells for solid tumors: New strategies for finding, infiltrating, and surviving in the tumor microenvironment. Front Immunol, 2019; 10:128.
4.
BrahmerJR, TykodiSS, ChowLQ, et al.Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med, 2012; 366:2455.
5.
LipsonEJ, DrakeCG. Ipilimumab: An anti-CTLA-4 antibody for metastatic melanoma. Clin Cancer Res, 2011; 17:6958.
6.
PalSK, MillerMJ, AgarwalN, et al.Clinical cancer advances 2019: Annual report on progress against cancer from the American Society of Clinical Oncology. J Clin Oncol, 2019; 37:834.
7.
HouB, TangY, LiW, et al.Efficiency of CAR-T therapy for treatment of solid tumor in clinical trials: A meta-analysis. Dis Markers, 2019; 2019:3425291.
8.
PangY, HouX, YangC, et al.Advances on chimeric antigen receptor-modified T-cell therapy for oncotherapy. Mol Cancer, 2018; 17:91.
9.
KochenderferJN, RosenbergSA. Treating B-cell cancer with T cells expressing anti-CD19 chimeric antigen receptors. Nat Rev Clin Oncol, 2013; 10:267.
10.
ZhaiB, ShiD, GaoH, et al.A phase I study of anti-GPC3 chimeric antigen receptor modified T cells (GPC3 CAR-T) in Chinese patients with refractory or relapsed GPC3+ hepatocellular carcinoma (r/r GPC3+ HCC). J Clin Oncol, 2017; 35:3049.
11.
RamosCA, DottiG. Chimeric antigen receptor (CAR)-engineered lymphocytes for cancer therapy. Expert Opin Biol Ther, 2011; 11:855.
12.
Lipowska-BhallaG, GilhamDE, HawkinsRE, RothwellDG. Targeted immunotherapy of cancer with CAR T cells: Achievements and challenges. Cancer Immunol Immunother, 2012; 61:953.
13.
GrossG, WaksT, EshharZ. Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc Natl Acad Sci U S A, 1989; 86:10024.
14.
FrigaultMJ, LeeJ, BasilMC, et al.Identification of chimeric antigen receptors that mediate constitutive or inducible proliferation of T cells. Cancer Immunol Res, 2015; 3:356.
15.
FinneyHM, AkbarAN, LawsonAD. Activation of resting human primary T cells with chimeric receptors: Costimulation from CD28, inducible costimulator, CD134, and CD137 in series with signals from the TCR zeta chain. J Immunol, 2004; 172:104.
16.
EshharZ.The T-body approach: Redirecting T cells with antibody specificity. Handb Exp Pharmacol, 2008:329.
17.
WangJ, JensenM, LinY, et al.Optimizing adoptive polyclonal T cell immunotherapy of lymphomas, using a chimeric T cell receptor possessing CD28 and CD137 costimulatory domains. Hum Gene Ther, 2007; 18:712.
18.
ChoJH, CollinsJJ, WongWW. Universal chimeric antigen receptors for multiplexed and logical control of T cell responses. Cell, 2018; 173:1426.
19.
WuY, LiuH, DingH. GPC-3 in hepatocellular carcinoma: Current perspectives. J Hepatocell Carcinoma, 2016; 3:63.
20.
HsuHC, ChengW, LaiPL. Cloning and expression of a developmentally regulated transcript MXR7 in hepatocellular carcinoma: Biological significance and temporospatial distribution. Cancer Res, 1997; 57:5179.
21.
ZhuZW, FriessH, WangL, et al.Enhanced glypican-3 expression differentiates the majority of hepatocellular carcinomas from benign hepatic disorders. Gut, 2001; 48:558.
22.
YamauchiN, WatanabeA, HishinumaM, et al.The glypican 3 oncofetal protein is a promising diagnostic marker for hepatocellular carcinoma. Mod Pathol, 2005; 18:1591.
23.
FilmusJ, CapurroM. Glypican-3: A marker and a therapeutic target in hepatocellular carcinoma. FEBS J, 2013; 280:2471.
24.
JiangZ, JiangX, ChenS, et al.Anti-GPC3-CAR T cells suppress the growth of tumor cells in patient-derived xenografts of hepatocellular carcinoma. Front Immunol, 2016; 7:690.
25.
WuX, LuoH, ShiB, et al.Combined antitumor effects of sorafenib and GPC3-CAR T cells in mouse models of hepatocellular carcinoma. Mol Ther, 2019; 27:1483.
26.
GuoX, JiangH, ShiB, et al.Disruption of PD-1 enhanced the anti-tumor activity of chimeric antigen receptor T cells against hepatocellular carcinoma. Front Pharmacol, 2018; 9:1118.
27.
AdachiK, KanoY, NagaiT, et al.IL-7 and CCL19 expression in CAR-T cells improves immune cell infiltration and CAR-T cell survival in the tumor. Nat Biotechnol, 2018; 36:346.
28.
ChenC, LiK, JiangH, et al.Development of T cells carrying two complementary chimeric antigen receptors against glypican-3 and asialoglycoprotein receptor 1 for the treatment of hepatocellular carcinoma. Cancer Immunol Immunother, 2017; 66:475.
29.
PanZ, DiS, ShiB, et al.Increased antitumor activities of glypican-3-specific chimeric antigen receptor-modified T cells by coexpression of a soluble PD1-CH3 fusion protein. Cancer Immunol Immunother, 2018; 67:1621.
30.
DudichE, SemenkovaL, DudichI, et al.alpha-fetoprotein causes apoptosis in tumor cells via a pathway independent of CD95, TNFR1 and TNFR2 through activation of caspase-3-like proteases. Eur J Biochem, 1999; 266:750.
31.
DeutschHF. Chemistry and biology of alpha-fetoprotein. Adv Cancer Res, 1991; 56:253.
32.
GaoF, ZhuHK, ZhuYB, et al.Predictive value of tumor markers in patients with recurrent hepatocellular carcinoma in different vascular invasion pattern. Hepatobiliary Pancreat Dis Int, 2016; 15:371.
33.
JohnsonPJ. Role of alpha-fetoprotein in the diagnosis and management of hepatocellular carcinoma. J Gastroenterol Hepatol, 1999; 14(Suppl.):S32.
34.
EngelhardtNV, GoussevAI, ShipovaLJ, AbelevGI. Immunofluorescent study of alpha-foetoprotein (alpha-fp) in liver and liver liver tumours. I. Technique of alpha-fp localization in tissue sections. Int J Cancer, 1971; 7:198.
35.
LuoP, WuS, YuY, et al.Current status and perspective biomarkers in AFP negative HCC: Towards screening for and diagnosing hepatocellular carcinoma at an earlier stage. Pathol Oncol Res, 2020; 26:599.
36.
BeiR, MizejewskiGJ. Alpha fetoprotein is more than a hepatocellular cancer biomarker: From spontaneous immune response in cancer patients to the development of an AFP-based cancer vaccine. Curr Mol Med, 2011; 11:564.
37.
LiuH, XuY, XiangJ, et al.Targeting alpha-fetoprotein (AFP)-MHC complex with CAR T-cell therapy for liver cancer. Clin Cancer Res, 2017; 23:478.
38.
YiFT, LuQP. Mucin 1 promotes radioresistance in hepatocellular carcinoma cells through activation of JAK2/STAT3 signaling. Oncol Lett, 2017; 14:7571.
39.
KasprzakA, AdamekA. Mucins: The old, the new and the promising factors in hepatobiliary carcinogenesis. Int J Mol Sci, 2019; 20.
40.
NathS, MukherjeeP. MUC1: A multifaceted oncoprotein with a key role in cancer progression. Trends Mol Med, 2014; 20:332.
41.
YouF, JiangL, ZhangB, et al.Phase 1 clinical trial demonstrated that MUC1 positive metastatic seminal vesicle cancer can be effectively eradicated by modified Anti-MUC1 chimeric antigen receptor transduced T cells. Sci China Life Sci, 2016; 59:386.
42.
ZhouR, YazdanifarM, RoyLD, et al.CAR T cells targeting the tumor MUC1 glycoprotein reduce triple-negative breast cancer growth. Front Immunol, 2019; 10:1149.
43.
MaYD, WangZ, GongRZ, et al.Specific cytotoxicity of MUC1 chimeric antigen receptor-engineered Jurkat T cells against hepatocellular carcinoma. Acad J Second Milit Med Univ, 2014; 35:1177.
44.
ZhangJ, BasherF, WuJD. NKG2D ligands in tumor immunity: Two sides of a coin. Front Immunol, 2015; 6:97.
45.
LiuH, WangS, XinJ, et al.Role of NKG2D and its ligands in cancer immunotherapy. Am J Cancer Res, 2019; 9:2064.
46.
SunB, YangD, DaiH, et al.Eradication of hepatocellular carcinoma by NKG2D-based CAR-T cells. Cancer Immunol Res, 2019; 7:1813.
47.
SokerS, TakashimaS, MiaoHQ, et al.Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell, 1998; 92:735.
48.
BergeM, AllanicD, BonninP, et al.Neuropilin-1 is upregulated in hepatocellular carcinoma and contributes to tumour growth and vascular remodelling. J Hepatol, 2011; 55:866.
49.
ZhangY, LiuP, JiangY, et al.High expression of neuropilin-1 associates with unfavorable clinicopathological features in hepatocellular carcinoma. Pathol Oncol Res, 2016; 22:367.
50.
LinJ, ZhangY, WuJ, et al.Neuropilin 1 (NRP1) is a novel tumor marker in hepatocellular carcinoma. Clin Chim Acta, 2018; 485:158.
51.
RohdeC, YamaguchiR, MukhinaS, et al.Comparison of Claudin 18.2 expression in primary tumors and lymph node metastases in Japanese patients with gastric adenocarcinoma. Jpn J Clin Oncol, 2019; 49:870.
52.
WollS, SchlitterAM, DhaeneK, et al.Claudin 18.2 is a target for IMAB362 antibody in pancreatic neoplasms. Int J Cancer, 2014; 134:731.
53.
TureciO, KoslowskiM, HelftenbeinG, et al.Claudin-18 gene structure, regulation, and expression is evolutionary conserved in mammals. Gene, 2011; 481:83.
54.
SinghP, ToomS, HuangY. Anti-claudin 18.2 antibody as new targeted therapy for advanced gastric cancer. J Hematol Oncol, 2017; 10:105.
55.
SanadaY, OueN, MitaniY, et al.Down-regulation of the claudin-18 gene, identified through serial analysis of gene expression data analysis, in gastric cancer with an intestinal phenotype. J Pathol, 2006; 208:633.
56.
JiangH, ShiZ, WangP, et al.Claudin18.2-specific chimeric antigen receptor engineered T cells for the treatment of gastric cancer. J Natl Cancer Inst, 2019; 111:409.
57.
ReinhardK, RengstlB, OehmP, et al.An RNA vaccine drives expansion and efficacy of claudin-CAR-T cells against solid tumors. Science, 2020; 367:446.
58.
Xianbao ZhanBW, ZonghaiLi, JieLi, et al.Phase I trial of Claudin 18.2-specific chimeric antigen receptor T cells for advanced gastric and pancreatic adenocarcinoma. Journal of Clinical Oncology, 2019; 37:2509.
59.
OlayioyeMA, NeveRM, LaneHA, HynesNE. The ErbB signaling network: Receptor heterodimerization in development and cancer. EMBO J, 2000; 19:3159.
60.
YardenY, SchlessingerJ. Self-phosphorylation of epidermal growth factor receptor: Evidence for a model of intermolecular allosteric activation. Biochemistry, 1987; 26:1434.
61.
OlayioyeMA. Update on HER-2 as a target for cancer therapy: Intracellular signaling pathways of ErbB2/HER-2 and family members. Breast Cancer Res, 2001; 3:385.
62.
FisherSB, FisherKE, SquiresMH, et al.HER2 in resected gastric cancer: Is there prognostic value?. J Surg Oncol, 2014; 109:61.
63.
HanY, LiuC, LiG, et al.Antitumor effects and persistence of a novel HER2 CAR T cells directed to gastric cancer in preclinical models. Am J Cancer Res, 2018; 8:106.
64.
SongY, TongC, WangY, et al.Effective and persistent antitumor activity of HER2-directed CAR-T cells against gastric cancer cells in vitro and xenotransplanted tumors in vivo. Protein Cell, 2018; 9:867.
65.
ZhangD, ChenY, FanD. MG7 mimotope-based DNA vaccination for gastric cancer. Expert Rev Vaccines, 2006; 5:223.
66.
ScarfoI, MausMV. Current approaches to increase CAR T cell potency in solid tumors: Targeting the tumor microenvironment. J Immunother Cancer, 2017; 5:28.
67.
GuoDL, DongM, WangL, et al.Expression of gastric cancer-associated MG7 antigen in gastric cancer, precancerous lesions and H. pylori -associated gastric diseases. World J Gastroenterol, 2002; 8:1009.
68.
RenJ, ChenZ, JuanSJ, et al.Detection of circulating gastric carcinoma-associated antigen MG7-Ag in human sera using an established single determinant immuno-polymerase chain reaction technique. Cancer, 2000; 88:280.
69.
LiZ, ZuoXL, LiCQ, et al.In vivo molecular imaging of gastric cancer by targeting MG7 antigen with confocal laser endomicroscopy. Endoscopy, 2013; 45:79.
70.
Yuan J; Shanghai Genechem Co. L, Shanghai, China. Abstract 3766: MG7-car, a first-in-class T-cell therapy for gastric cancer. Cancer Res, 2017; 77:3766.
71.
Yuan J; Shanghai Genechem Co. L, Shanghai, China. Abstract CT056: The first-in-human clinical trial of MG7-CART for metastasis colon cancer. Cancer Res, 2018; 78(13 Suppl.):CT056.
72.
ZhangC, WangZ, YangZ, et al.Phase I escalating-dose trial of CAR-T therapy targeting CEA(+) metastatic colorectal cancers. Mol Ther, 2017; 25:1248.
73.
RajD, YangMH, RodgersD, et al.Switchable CAR-T cells mediate remission in metastatic pancreatic ductal adenocarcinoma. Gut, 2019; 68:1052.
74.
HegeKM, BergslandEK, FisherGA, et al.Safety, tumor trafficking and immunogenicity of chimeric antigen receptor (CAR)-T cells specific for TAG-72 in colorectal cancer. J Immunother Cancer, 2017; 5:22.
75.
CarrithersSL, BarberMT, BiswasS, et al.Guanylyl cyclase C is a selective marker for metastatic colorectal tumors in human extraintestinal tissues. Proc Natl Acad Sci U S A, 1996; 93:14827.
76.
FulleHJ, GarbersDL. Guanylyl cyclases: A family of receptor-linked enzymes. Cell Biochem Funct, 1994; 12:157.
77.
BirbeR, PalazzoJP, WaltersR, et al.Guanylyl cyclase C is a marker of intestinal metaplasia, dysplasia, and adenocarcinoma of the gastrointestinal tract. Hum Pathol, 2005; 36:170.
78.
BucE, VartanianMD, DarchaC, et al.Guanylyl cyclase C as a reliable immunohistochemical marker and its ligand Escherichia coli heat-stable enterotoxin as a potential protein-delivering vehicle for colorectal cancer cells. Eur J Cancer, 2005; 41:1618.
79.
LinJE, LiP, SnookAE, et al.The hormone receptor GUCY2C suppresses intestinal tumor formation by inhibiting AKT signaling. Gastroenterology, 2010; 138:241.
80.
AkaAA, RappaportJA, PattisonAM, et al.Guanylate cyclase C as a target for prevention, detection, and therapy in colorectal cancer. Expert Rev Clin Pharmacol, 2017; 10:549.
81.
BaybuttTR, AkaAA, SnookAE. The heat-stable enterotoxin receptor, guanylyl cyclase C, as a pharmacological target in colorectal cancer immunotherapy: A bench-to-bedside current report. Toxins (Basel), 2017; 9:282.
82.
MageeMS, KraftCL, AbrahamTS, et al.GUCY2C-directed CAR-T cells oppose colorectal cancer metastases without autoimmunity. Oncoimmunology, 2016; 5:e1227897.
83.
MageeMS, AbrahamTS, BaybuttTR, et al.Human GUCY2C-targeted chimeric antigen receptor (CAR)-expressing T cells eliminate colorectal cancer metastases. Cancer Immunol Res, 2018; 6:509.
84.
GoldP, FreedmanSO. Specific carcinoembryonic antigens of the human digestive system. J Exp Med, 1965; 122:467.
85.
FicheraA, MichelassiF, ArenasRB. Selective expression of carcinoembryonic antigen promoter in cancer cell lines: Targeting strategy for gene therapy in colorectal cancer. Dis Colon Rectum, 1998; 41:747.
86.
BeaucheminN, ArabzadehA. Carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) in cancer progression and metastasis. Cancer Metastasis Rev, 2013; 32:643.
87.
LongAH, HasoWM, ShernJF, et al.4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nat Med, 2015; 21:581.
88.
WangL, MaN, OkamotoS, et al.Efficient tumor regression by adoptively transferred CEA-specific CAR-T cells associated with symptoms of mild cytokine release syndrome. Oncoimmunology, 2016; 5:e1211218.
89.
OtaniT, NakamuraS, TokiM, et al.Identification of IFN-gamma-producing cells in IL-12/IL-18-treated mice. Cell Immunol, 1999; 198:111.
90.
ChiX, YangP, ZhangE, et al.Significantly increased anti-tumor activity of carcinoembryonic antigen-specific chimeric antigen receptor T cells in combination with recombinant human IL-12. Cancer Med, 2019; 8:4753.
WangY, LuoF, YangJ, et al.New chimeric antigen receptor design for solid tumors. Front Immunol, 2017; 8:1934.
93.
MajznerRG, MackallCL. Tumor antigen escape from CAR T-cell therapy. Cancer Discov, 2018; 8:1219.
94.
O'RourkeDM, NasrallahMP, DesaiA, 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:eaaa0984.
95.
LiJ, LiW, HuangK, et al.Chimeric antigen receptor T cell (CAR-T) immunotherapy for solid tumors: Lessons learned and strategies for moving forward. J Hematol Oncol, 2018; 11:22.
96.
InagumaY, AkahoriY, MurayamaY, et al.Construction and molecular characterization of a T-cell receptor-like antibody and CAR-T cells specific for minor histocompatibility antigen HA-1H. Gene Ther, 2014; 21:575.
97.
IrelandL, SantosA, AhmedMS, et al.Chemoresistance in pancreatic cancer is driven by stroma-derived insulin-like growth factors. Cancer Res, 2016; 76:6851.
98.
CaruanaI, SavoldoB, HoyosV, et al.Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T lymphocytes. Nat Med, 2015; 21:524.
99.
DavilaML, RiviereI, WangX, et al.Efficacy and toxicity management of 19–28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med, 2014; 6:224ra25.
100.
KlampatsaA, AchkovaDY, DaviesDM, et al.Intracavitary ‘T4 immunotherapy’ of malignant mesothelioma using pan-ErbB re-targeted CAR T-cells. Cancer Lett, 2017; 393:52.
101.
MausMV, HaasAR, BeattyGL, et al.T cells expressing chimeric antigen receptors can cause anaphylaxis in humans. Cancer Immunol Res, 2013; 1:26.
102.
ThistlethwaiteFC, GilhamDE, GuestRD, et al.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 Immunother, 2017; 66:1425.
103.
SpringuelL, LonezC, AlexandreB, et al.Chimeric antigen receptor-T cells for targeting solid tumors: Current challenges and existing strategies. BioDrugs, 2019; 33:515.
104.
ClinicalTrials.gov. Online document at https://clinicaltrials.gov/ct2/home Accessed on May30, 2020.
105.
MaX, ShouP, SmithC, et al.Interleukin-23 engineering improves CAR T cell function in solid tumors. Nat Biotechnol, 2020; 38:1.
106.
RafiqS, YekuOO, JacksonHJ, et al.Targeted delivery of a PD-1-blocking scFv by CAR-T cells enhances anti-tumor efficacy in vivo. Nat Biotechnol, 2018; 36:847.
107.
CoonME, StephanSB, GuptaV, et al.Nitinol thin films functionalized with CAR-T cells for the treatment of solid tumours. Nat Biomed Eng, 2020; 4:195.
XieYJ, DouganM, JailkhaniN, et al.Nanobody-based CAR T cells that target the tumor microenvironment inhibit the growth of solid tumors in immunocompetent mice. Proc Natl Acad Sci U S A, 2019; 116:7624.
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