Novel immunotherapeutic approaches for hepatocellular carcinoma treatment

References

• Llovet JM, Zucman-Rossi J, Pikarsky E, et al. Hepatocellular carcinoma. Nat Rev Dis Primer. 2016;2:16018.
   PubMed Web of Science ®Google Scholar
• European Association For The Study Of The Liver, European Organisation For Research And Treatment Of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2012;56:908–943.
   PubMed Web of Science ®Google Scholar
• Lumsden AB, Henderson JM, Kutner MH. Endotoxin levels measured by a chromogenic assay in portal, hepatic and peripheral venous blood in patients with cirrhosis. Hepatology. 1988;8:232–236.
   PubMed Web of Science ®Google Scholar
• Jenne CN, Kubes P. Immune surveillance by the liver. Nat Immunol. 2013;14:996–1006.
   PubMed Web of Science ®Google Scholar
• Protzer U, Maini MK, Knolle PA. Living in the liver: hepatic infections. Nat Rev Immunol. 2012;12:201–213.
   PubMed Web of Science ®Google Scholar
• Robinson MW, Harmon C, O’Farrelly C. Liver immunology and its role in inflammation and homeostasis. Cell Mol Immunol. 2016;13:267–276.
   PubMed Web of Science ®Google Scholar
• Heymann F, Peusquens J, Ludwig-Portugall I, et al. Liver inflammation abrogates immunological tolerance induced by Kupffer cells. Hepatology. 2015;62:279–291.
   PubMed Web of Science ®Google Scholar
• Daher S, Massarwa M, Benson AA, et al. Current and future treatment of hepatocellular carcinoma: an updated comprehensive review. J Clin Transl Hepatol. 2018;6:69–78.
   PubMed Web of Science ®Google Scholar
• El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet Lond Engl. 2017;389:2492–2502.
   PubMed Web of Science ®Google Scholar
• Cancer Genome Atlas Research Network. Electronic address: [email protected], Cancer Genome Atlas Research Network. Comprehensive and integrative genomic characterization of hepatocellular carcinoma. Cell. 2017;169:1327–1341.
   PubMed Web of Science ®Google Scholar
• Ringelhan M, Pfister D, O’Connor T, et al. The immunology of hepatocellular carcinoma. Nat Immunol. 2018;19:222–232.
   PubMed Web of Science ®Google Scholar
• Ishiguro T, Sugimoto M, Kinoshita Y, et al. Anti-glypican 3 antibody as a potential antitumor agent for human liver cancer. Cancer Res. 2008;68:9832–9838.
   PubMed Web of Science ®Google Scholar
• Yong CSM, Dardalhon V, Devaud C, et al. CAR T-cell therapy of solid tumors. Immunol Cell Biol. 2017;95:356–363.
   PubMed Web of Science ®Google Scholar
• Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378:439–448.
   PubMed Web of Science ®Google Scholar
• Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large b-cell lymphoma. N Engl J Med. 2017;377:2531–2544.
   PubMed Web of Science ®Google Scholar
• Hu Z, Ott PA, Wu CJ. Towards personalized, tumour-specific, therapeutic vaccines for cancer. Nat Rev Immunol. 2017;18:168–182.
   PubMed Web of Science ®Google Scholar
• Consortium HEPAVAC, Buonaguro L. Developments in cancer vaccines for hepatocellular carcinoma. Cancer Immunol Immunother. 2016;65:93–99.
   PubMed Web of Science ®Google Scholar
• Buonaguro L, Mayer-Mokler A, Accolla R, et al. HepaVac-101 first-in-man therapeutic cancer vaccine phase I/II clinical trial for hepatocellular carcinoma patients. Cancer Immunol Immunother. 2018;36:TPS3135–TPS3135.
   Google Scholar
• Weiner GJ. Building better monoclonal antibody-based therapeutics. Nat Rev Cancer. 2015;15:361–370.
   PubMed Web of Science ®Google Scholar
• Xu F, Jin T, Zhu Y, et al. Immune checkpoint therapy in liver cancer. J Exp Clin Cancer Res. 2018;37:110.
   PubMed Web of Science ®Google Scholar
• Bhandaru M, Rotte A. Blockade of programmed cell death protein-1 pathway for the treatment of melanoma. J Dermatol Res Ther. 2017;1:1–11.
   Google Scholar
• Iñarrairaegui M, Melero I, Sangro B. Immunotherapy of hepatocellular carcinoma: facts and hopes. Clin Cancer Res. 2018;24:1518–1524.
   PubMed Web of Science ®Google Scholar
• Stone JD, Chervin AS, Kranz DM. T-cell receptor binding affinities and kinetics: impact on T-cell activity and specificity. Immunology. 2009;126:165–176.
   PubMed Web of Science ®Google Scholar
• Krummel MF, Allison JP. CTLA-4 engagement inhibits IL-2 accumulation and cell cycle progression upon activation of resting T cells. J Exp Med. 1996;183:2533–2540.
   PubMed Web of Science ®Google Scholar
• Chambers CA, Kuhns MS, Egen JG, et al. CTLA-4-mediated inhibition in regulation of T cell responses: mechanisms and manipulation in tumor immunotherapy. Annu Rev Immunol. 2001;19:565–594.
   PubMed Web of Science ®Google Scholar
• Collins AV, Brodie DW, Gilbert RJC, et al. The interaction properties of costimulatory molecules revisited. Immunity. 2002;17:201–210.
   PubMed Web of Science ®Google Scholar
• Fallarino F, Fields PE, Gajewski TF. B7–1 engagement of cytotoxic T lymphocyte antigen 4 inhibits T cell activation in the absence of CD28. J Exp Med. 1998;188:205–210.
   PubMed Web of Science ®Google Scholar
• Masteller EL, Chuang E, Mullen AC, et al. Structural analysis of CTLA-4 function in vivo. J Immunol. 2000;164:5319–5327.
   PubMed Web of Science ®Google Scholar
• Krummel MF, Allison JP. CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J Exp Med. 1995;182:459–465.
   PubMed Web of Science ®Google Scholar
• Balzano C, Buonavista N, Rouvier E, et al. CTLA-4 and CD28: similar proteins, neighbouring genes. Int J Cancer. 1992;7:28–32.
   Google Scholar
• Read S, Malmström V, Powrie F. Cytotoxic T lymphocyte–associated antigen 4 plays an essential role in the function of cd25+cd4+ regulatory cells that control intestinal inflammation. J Exp Med. 2000;192:295–302.
   PubMed Web of Science ®Google Scholar
• Linsley PS, Bradshaw J, Greene J, et al. Intracellular trafficking of CTLA-4 and focal localization towards sites of TCR engagement. Immunity. 1996;4:535–543.
   PubMed Web of Science ®Google Scholar
• Fife BT, Bluestone JA. Control of peripheral T-cell tolerance and autoimmunity via the CTLA-4 and PD-1 pathways. Immunol Rev. 2008;224:166–182.
   PubMed Web of Science ®Google Scholar
• Egen JG, Kuhns MS, Allison JP. CTLA-4: new insights into its biological function and use in tumor immunotherapy. Nat Immunol. 2002;3:611–618.
   PubMed Web of Science ®Google Scholar
• Schneider H, Downey J, Smith A, et al. Reversal of the TCR stop signal by CTLA-4. Science. 2006;313:1972–1975.
   PubMed Web of Science ®Google Scholar
• Han Y, Chen Z, Yang Y, et al. Human CD14+CTLA‐4+ regulatory dendritic cells suppress T‐cell response by cytotoxic T‐lymphocyte antigen‐4‐dependent IL‐10 and indoleamine‐2,3‐dioxygenase production in hepatocellular carcinoma. Hepatology. 2014;59:567–579.
   PubMed Web of Science ®Google Scholar
• Ishida Y, Agata Y, Shibahara K, et al. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. Embo J. 1992;11:3887–3895.
   PubMed Web of Science ®Google Scholar
• Keir ME, Butte MJ, Freeman GJ, et al. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677–704.
   PubMed Web of Science ®Google Scholar
• Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. Immunol Rev. 2010;236:219–242.
   PubMed Web of Science ®Google Scholar
• Cheng X, Veverka V, Radhakrishnan A, et al. Structure and interactions of the human programmed cell death 1 receptor. J Biol Chem. 2013;288:11771–11785.
   PubMed Web of Science ®Google Scholar
• Hui E, Cheung J, Zhu J, et al. T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition. Science. 2017;355:1428–1433.
   PubMed Web of Science ®Google Scholar
• Rotte A, Jin JY, Lemaire V. Mechanistic overview of immune checkpoints to support the rational design of their combinations in cancer immunotherapy. Ann Oncol. 2018;29:71–83.
   PubMed Web of Science ®Google Scholar
• Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2001;2:261–268.
   PubMed Web of Science ®Google Scholar
• Francisco LM, Salinas VH, Brown KE, et al. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med. 2009;206:3015–3029.
   PubMed Web of Science ®Google Scholar
• Butte MJ, Keir ME, Phamduy TB, et al. Programmed death-1 ligand 1 interacts specifically with the B7–1 costimulatory molecule to inhibit T cell responses. Immunity. 2007;27:111–122.
   PubMed Web of Science ®Google Scholar
• Wherry EJ. T cell exhaustion. Nat Immunol. 2011;12:492–499.
   PubMed Web of Science ®Google Scholar
• Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12:252–264.
   PubMed Web of Science ®Google Scholar
• Patel SP, Kurzrock R. PD-L1 expression as a predictive biomarker in cancer immunotherapy. Mol Cancer Ther. 2015;14:847–856.
   PubMed Web of Science ®Google Scholar
• Wu K, Kryczek I, Chen L, Zou W, Welling TH. Kupffer cell suppression of CD8+ T cells in human hepatocellular carcinoma is mediated by B7-H1/PD-1 interactions. Cancer Res. 2009;69:8067–8075.
   PubMed Web of Science ®Google Scholar
• Semaan A, Dietrich D, Bergheim D, et al. CXCL12 expression and PD-L1 expression serve as prognostic biomarkers in HCC and are induced by hypoxia. Virchows Arch. 2017;470:185–196.
   PubMed Web of Science ®Google Scholar
• Dai X, Xue J, Hu J, et al. Positive expression of programmed death ligand 1 in peritumoral liver tissue is associated with poor survival after curative resection of hepatocellular carcinoma. Transl Oncol. 2017;10:511–517.
   PubMed Web of Science ®Google Scholar
• Parry RV, Chemnitz JM, Frauwirth KA, et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol. 2005;25:9543–9553.
   PubMed Web of Science ®Google Scholar
• Dunn GP, Old LJ, Schreiber RD. The immunobiology of cancer immunosurveillance and immunoediting. Immunity. 2004;21:137–148.
   PubMed Web of Science ®Google Scholar
• Morse MA. Technology evaluation: ipilimumab, Medarex/Bristol-Myers Squibb. Curr Opin Mol Ther. 2005;7:588–597.
   PubMed Web of Science ®Google Scholar
• Jain S, Clark JI. Ipilimumab for the treatment of melanoma. Melanoma Manag. 2015;2:33–39.
   PubMed Web of Science ®Google Scholar
• Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–723.
   PubMed Web of Science ®Google Scholar
• Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364:2517–2526.
   PubMed Web of Science ®Google Scholar
• Eggermont AMM, Chiarion-Sileni V, Grob -J-J, et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2015;16:522–530.
   PubMed Web of Science ®Google Scholar
• Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373:23–34.
   PubMed Web of Science ®Google Scholar
• Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378:1277–1290.
   PubMed Web of Science ®Google Scholar
• Kaseb AO, Carmagnani Pestana R, Vence LM, et al. Randomized, open-label, perioperative phase II study evaluating nivolumab alone versus nivolumab plus ipilimumab in patients with resectable HCC. J Clin Oncol. 2019;37:185.
   Web of Science ®Google Scholar
• Hanson DC, Canniff PC, Primiano MJ, et al. Preclinical in vitro characterization of anti-CTLA4 therapeutic antibody CP-675,206. Cancer Res. 2004;64:877.
   Google Scholar
• ClinicalTrials.gov [Internet]. [ cited 2019 Mar 18]. Available from: https://clinicaltrials.gov/ct2/results?cond=&term=tremelimumab&cntry=&state=&city=&dist
   Google Scholar
• Sangro B, Gomez-Martin C, de la Mata M, et al. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J Hepatol. 2013;59:81–88.
   PubMed Web of Science ®Google Scholar
• Duffy AG, Ulahannan SV, Makorova-Rusher O, et al. Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma. J Hepatol. 2017;66:545–551.
   PubMed Web of Science ®Google Scholar
• Kelley RK, Abou-Alfa GK, Bendell JC, et al. Phase I/II study of durvalumab and tremelimumab in patients with unresectable hepatocellular carcinoma (HCC): phase I safety and efficacy analyses. J Clin Oncol. 2017;35:4073.
   Web of Science ®Google Scholar
• Floudas CS, Xie C, Brar G, et al. Combined immune checkpoint inhibition (ICI) with tremelimumab and durvalumab in patients with advanced hepatocellular carcinoma (HCC) or biliary tract carcinomas (BTC). J Clin Oncol. 2019;37:336.
   PubMed Web of Science ®Google Scholar
• Brahmer JR, Drake CG, Wollner I, et al. Phase I study of single-agent anti–programmed death-1 (mdx-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010;28:3167–3175.
   PubMed Web of Science ®Google Scholar
• fda.gov. Approved drugs - FDA grants accelerated approval to nivolumab for HCC previously treated with sorafenib [Internet]. [ cited 2019 Mar 18]. Available from: https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm577166.htm
   Google Scholar
• Esteve M, Saro C, González-Huix F, et al. Chronic hepatitis B reactivation following infliximab therapy in Crohn’s disease patients: need for primary prophylaxis. Gut. 2004;53:1363–1365.
   PubMed Web of Science ®Google Scholar
• Patnaik A, Kang SP, Rasco D, et al. Phase I Study of pembrolizumab (MK-3475; anti–PD-1 monoclonal antibody) in patients with advanced solid tumors. Clin Cancer Res. 2015;21:4286–4293.
   PubMed Web of Science ®Google Scholar
• fda.gov. Drugs@FDA: FDA approved drug products [Internet]. [ cited 2019 Mar 18]. Available from: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&applno=125514
   Google Scholar
• Robert C, Ribas A, Wolchok JD, et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014;384:1109–1117.
   PubMed Web of Science ®Google Scholar
• fda.gov. Approved drugs - FDA approves pembrolizumab for advanced cervical cancer with disease progression during or after chemotherapy [Internet]. [ cited 2019 Mar 18]. Available from: https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm610572.htm
   Google Scholar
• fda.gov. Approved drugs - FDA grants accelerated approval to pembrolizumab for hepatocellular carcinoma [Internet]. [ cited 2019 Mar 18]. Available from: https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm625705.htm
   Google Scholar
• Zhu AX, Finn RS, Edeline J, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol. 2018;19:940–952.
   PubMed Web of Science ®Google Scholar
• Ikeda M, Sung MW, Kudo M, et al. A phase 1b trial of lenvatinib (LEN) plus pembrolizumab (PEM) in patients (pts) with unresectable hepatocellular carcinoma (uHCC). J Clin Oncol. 2018;36:4076.
   Web of Science ®Google Scholar
• Chung VM, Kos F, Hardwick N, et al. A phase 1 study of p53MVA vaccine in combination with pembrolizumab. J Clin Oncol. 2018;36:206.
   Web of Science ®Google Scholar
• Gangadhar TC, Hamid O, Smith DC, et al. Preliminary results from a Phase I/II study of epacadostat (incb024360) in combination with pembrolizumab in patients with selected advanced cancers. J Immunother Cancer. 2015;3:O7.
   PubMed Web of Science ®Google Scholar
• Friedlander M, Meniawy T, Markman B, et al. A phase 1b study of the anti-PD-1 monoclonal antibody BGB-A317 (A317) in combination with the PARP inhibitor BGB-290 (290) in advanced solid tumors. J Clin Oncol. 2018;36:48.
   Web of Science ®Google Scholar
• Zhang T, Song X, Xu L, et al. The binding of an anti-PD-1 antibody to FcγRΙ has a profound impact on its biological functions. Cancer Immunol Immunother. 2018;67:1079–1090.
   PubMed Web of Science ®Google Scholar
• Li Y, Li F, Jiang F, et al. A mini-review for cancer immunotherapy: molecular understanding of pd-1/pd-l1 pathway & translational blockade of immune checkpoints. Int J Mol Sci. 2016;17:1151.
   PubMed Web of Science ®Google Scholar
• Xu J, Zhang Y, Jia R, et al. Anti-PD-1 antibody shr-1210 combined with apatinib for advanced hepatocellular carcinoma, gastric, or esophagogastric junction cancer: an open-label, dose escalation and expansion study. Clin Cancer Res. 2019;25:515–523.
   PubMed Web of Science ®Google Scholar
• Stewart R, Morrow M, Hammond SA, et al. Identification and characterization of MEDI4736, an antagonistic anti–PD-L1 monoclonal antibody. Cancer Immunol Res. 2015;3:1052–1062.
   PubMed Web of Science ®Google Scholar
• Karzai F, VanderWeele D, Madan RA, et al. Activity of durvalumab plus olaparib in metastatic castration-resistant prostate cancer in men with and without DNA damage repair mutations. J Immunother Cancer. 2018;6:141.
   PubMed Web of Science ®Google Scholar
• Powles T, O’Donnell PH, Massard C, et al. Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma: updated results from a phase 1/2 open-label study. JAMA Oncol. 2017;3:e172411.
   PubMed Web of Science ®Google Scholar
• fda.gov. Approved drugs - durvalumab (imfinzi) [Internet]. [ cited 2019 Mar 18]. Available from: https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm555930.htm
   Google Scholar
• Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after chemoradiotherapy in stage iii non-small-cell lung cancer. N Engl J Med. 2017;377:1919–1929.
   PubMed Web of Science ®Google Scholar
• fda.gov. Approved Drugs - FDA approves durvalumab after chemoradiation for unresectable stage III NSCLC [Internet]. [ cited 2019 Mar 18]. Available from: https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm597248.htm
   Google Scholar
• Boyerinas B, Jochems C, Fantini M, et al. Antibody-dependent cellular cytotoxicity activity of a novel anti–PD-L1 antibody avelumab (MSB0010718C) on human tumor cells. Cancer Immunol Res. 2015;3:1148–1157.
   PubMed Web of Science ®Google Scholar
• Kaufman HL, Russell J, Hamid O, et al. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. Lancet Oncol. 2016;17:1374–1385.
   PubMed Web of Science ®Google Scholar
• fda.gov. Approved drugs - avelumab (BAVENCIO) [Internet]. [ cited 2019 Mar 18]. Available from: https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm547965.htm
   Google Scholar
• Apolo AB, Infante JR, Balmanoukian A, et al. Avelumab, an anti–programmed death-ligand 1 antibody, in patients with refractory metastatic urothelial carcinoma: results from a multicenter, phase ib study. J Clin Oncol. 2017;35:2117–2124.
   PubMed Web of Science ®Google Scholar
• fda.gov. Approved drugs - FDA grants accelerated approval to avelumab for urothelial carcinoma [Internet]. [ cited 2019 Mar 18]. Available from: https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm557162.htm
   Google Scholar
• Shah NJ, Kelly WJ, Liu SV, et al. Product review on the Anti-PD-L1 antibody atezolizumab. Hum Vaccines Immunother. 2018;14:269–276.
   PubMed Web of Science ®Google Scholar
• Herbst RS, Soria J-C, Kowanetz M, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014;515:563–567.
   PubMed Web of Science ®Google Scholar
• fda.gov. Press announcements - FDA approves new, targeted treatment for bladder cancer [Internet]. [ cited 2019 Mar 18]. Available from: https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm501762.htm
   Google Scholar
• Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet Lond Engl. 2016;387:1909–1920.
   PubMed Web of Science ®Google Scholar
• fda.gov. Approved drugs - FDA approves atezolizumab with chemotherapy and bevacizumab for first-line treatment of metastatic non-squamous NSCLC [Internet]. [ cited 2019 Mar 18]. Available from: https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm627874.htm
   Google Scholar
• Yamashita T, Forgues M, Wang W, et al. EpCAM and alpha-fetoprotein expression defines novel prognostic subtypes of hepatocellular carcinoma. Cancer Res. 2008;68:1451–1461.
   PubMed Web of Science ®Google Scholar
• Abelev GI. Alpha-fetoprotein in ontogenesis and its association with malignant tumors. Adv Cancer Res. 1971;14:295–358.
   PubMedGoogle Scholar
• Thimme R, Neagu M, Boettler T, et al. Comprehensive analysis of the alpha-fetoprotein-specific CD8+ T cell responses in patients with hepatocellular carcinoma. Hepatology. 2008;48:1821–1833.
   PubMed Web of Science ®Google Scholar
• Korangy F, Ormandy LA, Bleck JS, et al. Spontaneous tumor-specific humoral and cellular immune responses to NY-ESO-1 in hepatocellular carcinoma. Clin Cancer Res. 2004;10:4332–4341.
   PubMed Web of Science ®Google Scholar
• Bricard G, Bouzourene H, Martinet O, et al. Naturally acquired MAGE-A10- and SSX-2-specific CD8+ T cell responses in patients with hepatocellular carcinoma. J Immunol. 2005;174:1709–1716.
   PubMed Web of Science ®Google Scholar
• Kerzerho J, Adotevi O, Castelli FA, et al. The angiogenic growth factor and biomarker midkine is a tumor-shared antigen. J Immunol. 2010;185:418–423.
   PubMed Web of Science ®Google Scholar
• Jia H-L, Ye Q-H, Qin L-X, et al. Gene expression profiling reveals potential biomarkers of human hepatocellular carcinoma. Clin Cancer Res. 2007;13:1133–1139.
   PubMed Web of Science ®Google Scholar
• Lin Y-S, Jung S-M, Yeh C-N, et al. MUC1, MUC2 and MUC5AC expression in hepatocellular carcinoma with cardiac metastasis. Mol Med Rep. 2009;2:291–294.
   PubMed Web of Science ®Google Scholar
• Yuan S-F, Li K-Z, Wang L, et al. Expression of MUC1 and its significance in hepatocellular and cholangiocarcinoma tissue. World J Gastroenterol. 2005;11:4661–4666.
   PubMed Web of Science ®Google Scholar
• Sawabu N, Wakabayashi T, Ozaki K, et al. Serum tumor markers in patients with hepatocellular carcinoma: diagnosis of alpha-fetoprotein -low or -negative patients. Gastroenterol Jpn. 1985;20:209–215.
   PubMedGoogle Scholar
• Yoshikawa M, Morine Y, Ikemoto T, et al. Elevated preoperative serum CEA level is associated with poor prognosis in patients with hepatocellular carcinoma through the epithelial-mesenchymal transition. Anticancer Res. 2017;37:1169–1175.
   PubMed Web of Science ®Google Scholar
• Ogawa K, Tanaka S, Matsumura S, et al. EpCAM-targeted therapy for human hepatocellular carcinoma. Ann Surg Oncol. 2014;21:1314–1322.
   PubMedGoogle Scholar
• Yamashita T, Ji J, Budhu A, et al. EpCAM-positive hepatocellular carcinoma cells are tumor-initiating cells with stem/progenitor cell features. Gastroenterology. 2009;136:1012–1024.
   PubMed Web of Science ®Google Scholar
• Ross JS, Sheehan CE, Fisher HAG, et al. Correlation of primary tumor prostate-specific membrane antigen expression with disease recurrence in prostate cancer. Clin Cancer Res. 2003;9:6357–6362.
   PubMed Web of Science ®Google Scholar
• Capurro M, Wanless IR, Sherman M, et al. Glypican-3: a novel serum and histochemical marker for hepatocellular carcinoma. Gastroenterology. 2003;125:89–97.
   PubMed Web of Science ®Google Scholar
• Zhu Z-W, Friess H, Wang L, et al. Enhanced glypican-3 expression differentiates the majority of hepatocellular carcinomas from benign hepatic disorders. Gut. 2001;48:558–564.
   PubMed Web of Science ®Google Scholar
• Hsu HC, Cheng W, Lai PL. Cloning and expression of a developmentally regulated transcript MXR7 in hepatocellular carcinoma: biological significance and temporospatial distribution. Cancer Res. 1997;57:5179–5184.
   PubMed Web of Science ®Google Scholar
• Anatelli F, Chuang S-T, Yang XJ, et al. Value of glypican 3 immunostaining in the diagnosis of hepatocellular carcinoma on needle biopsy. Am J Clin Pathol. 2008;130:219–223.
   PubMed Web of Science ®Google Scholar
• Zhang L, Liu H, Sun L, et al. Glypican-3 as a potential differential diagnosis marker for hepatocellular carcinoma: a tissue microarray-based study. Acta Histochem. 2012;114:547–552.
   PubMed Web of Science ®Google Scholar
• Yamauchi N, Watanabe A, Hishinuma M, et al. The glypican 3 oncofetal protein is a promising diagnostic marker for hepatocellular carcinoma. Mod Pathol. 2005;18:1591–1598.
   PubMed Web of Science ®Google Scholar
• Valdez Y, Maia M, Conway EM. CD248: reviewing its role in health and disease. Curr Drug Targets. 2012;13:432–439.
   PubMed Web of Science ®Google Scholar
• Tomkowicz B, Rybinski K, Foley B, et al. Interaction of endosialin/TEM1 with extracellular matrix proteins mediates cell adhesion and migration. Proc Natl Acad Sci U S A. 2007;104:17965–17970.
   PubMed Web of Science ®Google Scholar
• Becker R, Lenter MC, Vollkommer T, et al. Tumor stroma marker endosialin (Tem1) is a binding partner of metastasis-related protein Mac-2 BP/90K. FASEB J. 2008;22:3059–3067.
   PubMed Web of Science ®Google Scholar
• Nanda A, Karim B, Peng Z, et al. Tumor endothelial marker 1 (Tem1) functions in the growth and progression of abdominal tumors. Proc Natl Acad Sci U S A. 2006;103:3351–3356.
   PubMed Web of Science ®Google Scholar
• Lee JH, Lee S-W. The roles of carcinoembryonic antigen in liver metastasis and therapeutic approaches. Gastroenterol Res Pract. 2017;2017:7521987.
   PubMedGoogle Scholar
• Sasikumar A, Joy A, Nanabala R, et al. (68)Ga-PSMA PET/CT imaging in primary hepatocellular carcinoma. Eur J Nucl Med Mol Imaging. 2016;43:795–796.
   PubMedGoogle Scholar
• Huang HL, Zhen Loh TJ, Hoe Chow PK. A case of well-differentiated hepatocellular carcinoma identified on gallium-68 prostate-specific membrane antigen positron emission tomography/computed tomography. World J Nucl Med. 2018;17:102–105.
   PubMedGoogle Scholar
• Frigerio B, Fracasso G, Luison E, et al. A single-chain fragment against prostate specific membrane antigen as a tool to build theranostic reagents for prostate cancer. Eur J Cancer Oxf Engl 1990. 2013;49:2223–2232.
   PubMed Web of Science ®Google Scholar
• Zuccolotto G, Fracasso G, Merlo A, et al. PSMA-specific CAR-engineered T cells eradicate disseminated prostate cancer in preclinical models. PloS One. 2014;9:e109427.
   PubMed Web of Science ®Google Scholar
• Filmus J, Capurro M, Rast J. Glypicans. Genome Biol. 2008;9:224.
   PubMed Web of Science ®Google Scholar
• De Cat B, Muyldermans S-Y, Coomans C, et al. Processing by proprotein convertases is required for glypican-3 modulation of cell survival, Wnt signaling, and gastrulation movements. J Cell Biol. 2003;163:625–635.
   PubMed Web of Science ®Google Scholar
• Filmus J. Glypicans in growth control and cancer. Glycobiology. 2001;11:19R–23R.
   PubMed Web of Science ®Google Scholar
• Filmus J, Selleck SB. Glypicans: proteoglycans with a surprise. J Clin Invest. 2001;108:497–501.
   PubMed Web of Science ®Google Scholar
• Gallagher JT. Heparan sulfate: growth control with a restricted sequence menu. J Clin Invest. 2001;108:357–361.
   PubMed Web of Science ®Google Scholar
• Capurro MI, Xu P, Shi W, et al. Glypican-3 inhibits Hedgehog signaling during development by competing with patched for Hedgehog binding. Dev Cell. 2008;14:700–711.
   PubMed Web of Science ®Google Scholar
• Capurro MI, Xiang -Y-Y, Lobe C, et al. Glypican-3 promotes the growth of hepatocellular carcinoma by stimulating canonical Wnt signaling. Cancer Res. 2005;65:6245–6254.
   PubMed Web of Science ®Google Scholar
• Song HH, Shi W, Xiang -Y-Y, et al. the loss of glypican-3 induces alterations in Wnt signaling. J Biol Chem. 2005;280:2116–2125.
   PubMed Web of Science ®Google Scholar
• Zittermann SI, Capurro MI, Shi W, et al. Soluble glypican 3 inhibits the growth of hepatocellular carcinoma in vitro and in vivo. Int J Cancer. 2010;126:1291–1301.
   PubMed Web of Science ®Google Scholar
• Capurro M, Martin T, Shi W, et al. Glypican-3 binds to Frizzled and plays a direct role in the stimulation of canonical Wnt signaling. J Cell Sci. 2014;127:1565–1575.
   PubMed Web of Science ®Google Scholar
• Liu H. Diagnostic value of glypican-3 in serum and liver for primary hepatocellular carcinoma. World J Gastroenterol. 2010;16:4410.
   PubMed Web of Science ®Google Scholar
• Christian S, Ahorn H, Koehler A, et al. Molecular cloning and characterization of endosialin, a C-type lectin-like cell surface receptor of tumor endothelium. J Biol Chem. 2001;276:7408–7414.
   PubMed Web of Science ®Google Scholar
• Christian S, Winkler R, Helfrich I, et al. Endosialin (Tem1) is a marker of tumor-associated myofibroblasts and tumor vessel-associated mural cells. Am J Pathol. 2008;172:486–494.
   PubMed Web of Science ®Google Scholar
• Bagley RG, Weber W, Rouleau C, et al. Human mesenchymal stem cells from bone marrow express tumor endothelial and stromal markers. Int J Oncol. 2009;34:619–627.
   PubMed Web of Science ®Google Scholar
• Bagley RG, Rouleau C, St Martin T, et al. Human endothelial precursor cells express tumor endothelial marker 1/endosialin/CD248. Mol Cancer Ther. 2008;7:2536–2546.
   PubMed Web of Science ®Google Scholar
• Rettig WJ, Garin-Chesa P, Healey JH, et al. Identification of endosialin, a cell surface glycoprotein of vascular endothelial cells in human cancer. Proc Natl Acad Sci U S A. 1992;89:10832–10836.
   PubMed Web of Science ®Google Scholar
• Zhu AX, Gold PJ, El-Khoueiry AB, et al. First-in-man phase I study of GC33, a novel recombinant humanized antibody against glypican-3, in patients with advanced hepatocellular carcinoma. Clin Cancer Res. 2013;19:920–928.
   PubMed Web of Science ®Google Scholar
• Abou-Alfa GK, Puig O, Daniele B, et al. Randomized phase II placebo controlled study of codrituzumab in previously treated patients with advanced hepatocellular carcinoma. J Hepatol. 2016;65:289–295.
   PubMed Web of Science ®Google Scholar
• Abou-Alfa GK, Yen C-J, Hsu C-H, et al. Phase Ib study of codrituzumab in combination with sorafenib in patients with non-curable advanced hepatocellular carcinoma (HCC). Cancer Chemother Pharmacol. 2017;79:421–429.
   PubMed Web of Science ®Google Scholar
• Phung Y, Gao W, Man Y-G, et al. High-affinity monoclonal antibodies to cell surface tumor antigen glypican-3 generated through a combination of peptide immunization and flow cytometry screening. mAbs. 2012;4:592–599.
   PubMed Web of Science ®Google Scholar
• Zhang Y-F, Ho M. Humanization of high-affinity antibodies targeting glypican-3 in hepatocellular carcinoma. Sci Rep. 2016;6:33878.
   PubMed Web of Science ®Google Scholar
• Feng M, Gao W, Wang R, et al. Therapeutically targeting glypican-3 via a conformation-specific single-domain antibody in hepatocellular carcinoma. Proc Natl Acad Sci U S A. 2013;110:E1083–91.
   PubMed Web of Science ®Google Scholar
• Diaz LA, Coughlin CM, Weil SC, et al. A first-in-human phase I study of MORAb-004, a monoclonal antibody to endosialin in patients with advanced solid tumors. Clin Cancer Res. 2015;21:1281–1288.
   PubMed Web of Science ®Google Scholar
• Doi T, Aramaki T, Yasui H, et al. A phase I study of ontuxizumab, a humanized monoclonal antibody targeting endosialin, in Japanese patients with solid tumors. Invest New Drugs. 2019.
   Web of Science ®Google Scholar
• Hoseini SS, Cheung N-KV. Immunotherapy of hepatocellular carcinoma using chimeric antigen receptors and bispecific antibodies. Cancer Lett. 2017;399:44–52.
   PubMed Web of Science ®Google Scholar
• Mackall CL, Merchant MS, Fry TJ. Immune-based therapies for childhood cancer. Nat Rev Clin Oncol. 2014;11:693–703.
   PubMed Web of Science ®Google Scholar
• Yu S, Li A, Liu Q, et al. Recent advances of bispecific antibodies in solid tumors. J Hematol Oncol. 2017;10:155.
   PubMed Web of Science ®Google Scholar
• May C, Sapra P, Gerber H-P. Advances in bispecific biotherapeutics for the treatment of cancer. Biochem Pharmacol. 2012;84:1105–1112.
   PubMed Web of Science ®Google Scholar
• Suryadevara CM, Gedeon PC, Sanchez-Perez L, et al. Are BiTEs the “missing link” in cancer therapy? OncoImmunology. 2015;4:e1008339.
   PubMed Web of Science ®Google Scholar
• Löffler A, Kufer P, Lutterbüse R, et al. A recombinant bispecific single-chain antibody, CD19 × CD3, induces rapid and high lymphoma-directed cytotoxicity by unstimulated T lymphocytes. Blood. 2000;95:2098–2103.
   PubMed Web of Science ®Google Scholar
• Wu J, Fu J, Zhang M, et al. Blinatumomab: a bispecific T cell engager (BiTE) antibody against CD19/CD3 for refractory acute lymphoid leukemia. J Hematol Oncol. 2015;8:104.
   PubMed Web of Science ®Google Scholar
• fda.gov. Approved Drugs - FDA grants regular approval to blinatumomab and expands indication to include Philadelphia chromosome-positive B cell [Internet]. [ cited 2019 Mar 18]. Available from: https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm566708.htm
   Google Scholar
• fda.gov. Approved drugs - FDA granted accelerated approval to blinatumomab (Blincyto, Amgen Inc.) for the treatment of adult and pediatric patients with B-cell precursor acute lymphoblastic leukemia [Internet]. [ cited 2019 Mar 18]. Available from: https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm603171.htm
   Google Scholar
• Goéré D, Flament C, Rusakiewicz S, et al. Potent immunomodulatory effects of the trifunctional antibody catumaxomab. Cancer Res. 2013;73:4663–4673.
   PubMed Web of Science ®Google Scholar
• ema.europa.eu. Removab [Internet]. 2018 [cited 2019 Mar 18]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/removab
   Google Scholar
• Ishiguro T, Sano Y, Komatsu S, et al. An anti–glypican 3/CD3 bispecific T cell–redirecting antibody for treatment of solid tumors. Sci Transl Med. 2017;9:eaal4291.
   PubMed Web of Science ®Google Scholar
• Hedvat M, Bonzon C, Bernett MJ, et al. Abstract 2784: simultaneous checkpoint-checkpoint or checkpoint-costimulatory receptor targeting with bispecific antibodies promotes enhanced human T cell activation. Cancer Res. 2018;78:2784.
   Web of Science ®Google Scholar
• Yamashita T, Budhu A, Forgues M, et al. Activation of hepatic stem cell marker EpCAM by Wnt–β-catenin signaling in hepatocellular carcinoma. Cancer Res. 2007;67:10831–10839.
   PubMed Web of Science ®Google Scholar
• Zhang P, Shi B, Gao H, et al. An EpCAM/CD3 bispecific antibody efficiently eliminates hepatocellular carcinoma cells with limited galectin-1 expression. Cancer Immunol Immunother. 2014;63:121–132.
   PubMed Web of Science ®Google Scholar
• Beck A, Goetsch L, Dumontet C, et al. Strategies and challenges for the next generation of antibody–drug conjugates. Nat Rev Drug Discov. 2017;16:315–337.
   PubMed Web of Science ®Google Scholar
• Lambert JM, Morris CQ. Antibody–drug conjugates (ADCs) for personalized treatment of solid tumors: a review. Adv Ther. 2017;34:1015–1035.
   PubMed Web of Science ®Google Scholar
• Fu Y, Urban DJ, Nani RR, et al. Glypican-3-specific antibody drug conjugates targeting hepatocellular carcinoma. Hepatology. 2018. Epub ahead of print.
   Google Scholar
• fda.gov. Approved Drugs - FDA approves inotuzumab ozogamicin for relapsed or refractory B-cell precursor ALL [Internet]. [ cited 2019 Mar 18]. Available from: https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm572133.htm
   Google Scholar
• Cardillo TM, Govindan SV, Sharkey RM, et al. Humanized anti-trop-2 IgG-SN-38 conjugate for effective treatment of diverse epithelial cancers: preclinical studies in human cancer xenograft models and monkeys. Clin Cancer Res. 2011;17:3157–3169.
   PubMed Web of Science ®Google Scholar
• Pastan I, Hassan R, FitzGerald DJ, et al. Immunotoxin therapy of cancer. Nat Rev Cancer. 2006;6:559–565.
   PubMed Web of Science ®Google Scholar
• Batra JK, Kasprzyk PG, Bird RE, et al. Recombinant anti-erbB2 immunotoxins containing Pseudomonas exotoxin. Proc Natl Acad Sci U S A. 1992;89:5867–5871.
   PubMed Web of Science ®Google Scholar
• Hassan R, Alewine C, Pastan I. New life for immunotoxin cancer therapy. Clin Cancer Res. 2016;22:1055–1058.
   PubMed Web of Science ®Google Scholar
• Weldon JE, Xiang L, Zhang J, et al. A recombinant immunotoxin against the tumor-associated antigen mesothelin reengineered for high activity, low off-target toxicity, and reduced antigenicity. Mol Cancer Ther. 2013;12:48–57.
   PubMed Web of Science ®Google Scholar
• Liu W, Onda M, Lee B, et al. Recombinant immunotoxin engineered for low immunogenicity and antigenicity by identifying and silencing human B-cell epitopes. Proc Natl Acad Sci U S A. 2012;109:11782–11787.
   PubMed Web of Science ®Google Scholar
• Onda M, Nagata S, FitzGerald DJ, et al. Characterization of the B cell epitopes associated with a truncated form of pseudomonas exotoxin (PE38) used to make immunotoxins for the treatment of cancer patients. J Immunol. 2006;177:8822–8834.
   PubMed Web of Science ®Google Scholar
• Schmohl JU, Todhunter D, Oh S, et al. Mutagenic deimmunization of diphtheria toxin for use in biologic drug development. Toxins (Basel). 2015;7:4067–4082.
   PubMed Web of Science ®Google Scholar
• Schmohl JU, Todhunter D, Taras E, et al. Development of a deimmunized bispecific immunotoxin dDT2219 against B-cell malignancies. Toxins (Basel). 2018;10:32.
   Web of Science ®Google Scholar
• Mazor R, Zhang J, Xiang L, et al. Recombinant immunotoxin with T cell epitope mutations that greatly reduce immunogenicity for treatment of mesothelin expressing tumors. Mol Cancer Ther. 2015;14:2789–2796.
   PubMed Web of Science ®Google Scholar
• Kreitman RJ, Pastan I. Accumulation of a recombinant immunotoxin in a tumor in vivo: fewer than 1000 molecules per cell are sufficient for complete responses. Cancer Res. 1998;58:968–975.
   PubMed Web of Science ®Google Scholar
• Alewine C, Xiang L, Yamori T, et al. Efficacy of RG7787, a next generation mesothelin-targeted immunotoxin, against triple-negative breast and gastric cancers. Mol Cancer Ther. 2014;13:2653–2661.
   PubMed Web of Science ®Google Scholar
• Hollevoet K, Mason-Osann E, Liu X, et al. In vitro and in vivo activity of the low-immunogenic anti-mesothelin immunotoxin RG7787 in pancreatic cancer. Mol Cancer Ther. 2014;13:2040–2049.
   PubMed Web of Science ®Google Scholar
• Moskowitz CH, Nademanee A, Masszi T, et al. Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin’s lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2015;385:1853–1862.
   PubMed Web of Science ®Google Scholar
• Pai-Scherf LH, Villa J, Pearson D, et al. Hepatotoxicity in cancer patients receiving erb-38, a recombinant immunotoxin that targets the erbb2 receptor. Clin Cancer Res. 1999;5:2311–2315.
   PubMed Web of Science ®Google Scholar
• Gao W, Tang Z, Zhang Y, et al. Immunotoxin targeting glypican-3 regresses liver cancer via dual inhibition of Wnt signaling and protein synthesis. Nat Commun. 2015;6:6536.
   PubMed Web of Science ®Google Scholar
• Wang C, Gao W, Feng M, et al. Construction of an immunotoxin, HN3-mPE24, targeting glypican-3 for liver cancer therapy. Oncotarget. 2016;8:32450–32460.
   Google Scholar
• Weldon JE, Xiang L, Chertov O, et al. A protease-resistant immunotoxin against CD22 with greatly increased activity against CLL and diminished animal toxicity. Blood. 2009;113:3792–3800.
   PubMed Web of Science ®Google Scholar
• June CH, O’Connor RS, Kawalekar OU, et al. CAR T cell immunotherapy for human cancer. Science. 2018;359:1361–1365.
   PubMed Web of Science ®Google Scholar
• Pang Y, Hou X, Yang C, et al. Advances on chimeric antigen receptor-modified T-cell therapy for oncotherapy. Mol Cancer. 2018;17:91.
   PubMed Web of Science ®Google Scholar
• Kalos M, June CH. Adoptive T cell transfer for cancer immunotherapy in the era of synthetic biology. Immunity. 2013;39:49–60.
   PubMed Web of Science ®Google Scholar
• fda.gov. Approved Drugs - FDA approves tisagenlecleucel for B-cell ALL and tocilizumab for cytokine release syndrome [Internet]. [ cited 2019 Mar 18]. Available from: https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm574154.htm
   Google Scholar
• Milone MC, Fish JD, Carpenito C, et al. Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of t cells and increased antileukemic efficacy in vivo. Mol Ther. 2009;17:1453–1464.
   PubMed Web of Science ®Google Scholar
• Kochenderfer JN, Feldman SA, Zhao Y, et al. Construction and preclinical evaluation of an anti-CD19 chimeric antigen receptor. J Immunother. 1997;2009(32):689–702.
   Google Scholar
• fda.gov. Approved drugs - FDA approves axicabtagene ciloleucel for large B-cell lymphoma [Internet]. [ cited 2019 Mar 18]. Available from: https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm581296.htm
   Google Scholar
• Gao H, Li K, Tu H, et al. Development of T cells redirected to glypican-3 for the treatment of hepatocellular carcinoma. Clin Cancer Res. 2014;20:6418–6428.
   PubMed Web of Science ®Google Scholar
• Burga RA, Thorn M, Point GR, et al. Liver myeloid-derived suppressor cells expand in response to liver metastases in mice and inhibit the anti-tumor efficacy of anti-CEA CAR-T. Cancer Immunol Immunother. 2015;64:817–829.
   PubMed Web of Science ®Google Scholar
• Katz SC, Burga RA, McCormack E, et al. Phase I Hepatic Immunotherapy for Metastases study of intra-arterial chimeric antigen receptor modified T cell therapy for CEA+ liver metastases. Clin Cancer Res. 2015;21:3149–3159.
   PubMed Web of Science ®Google Scholar
• Jiang Z, Jiang X, Chen S, 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.
   PubMed Web of Science ®Google Scholar
• Zhang Q, Zhang Z, Peng M, et al. CAR-T cell therapy in gastrointestinal tumors and hepatic carcinoma: from bench to bedside. Oncoimmunology. 2016;5:e1251539.
   PubMed Web of Science ®Google Scholar
• Li K, Lan Y, Wang J, et al. Chimeric antigen receptor–engineered T cells for liver cancers, progress and obstacles. Tumor Biol. 2017;39:1010428317692229.
   Google Scholar
• Zhai B, Shi D, Gao H, 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.
   Web of Science ®Google Scholar
• Guo C, Manjili MH, Subjeck JR, et al. Therapeutic cancer vaccines: past, present and future. Adv Cancer Res. 2013;119:421–475.
   PubMed Web of Science ®Google Scholar
• Boisguérin V, Castle JC, Loewer M, et al. Translation of genomics-guided RNA-based personalised cancer vaccines: towards the bedside. Br J Cancer. 2014;111:1469–1475.
   PubMed Web of Science ®Google Scholar
• Prieto J, Melero I, Sangro B. Immunological landscape and immunotherapy of hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2015;12:681–700.
   PubMed Web of Science ®Google Scholar
• cancer.gov. Definition of mRNA-based personalized cancer vaccine NCI-4650 - NCI drug dictionary - national cancer institute [Internet]. [ cited 2019 Mar 18]. Available from: https://www.cancer.gov/publications/dictionaries/cancer-drug/def/795447
   Google Scholar
• Schlom J. Therapeutic cancer vaccines: current status and moving forward. J Natl Cancer Inst. 2012;104:599–613.
   PubMed Web of Science ®Google Scholar
• Niethammer AG, Xiang R, Becker JC, et al. A DNA vaccine against VEGF receptor 2 prevents effective angiogenesis and inhibits tumor growth. Nat Med. 2002;8:1369–1375.
   PubMed Web of Science ®Google Scholar
• Ishizaki H, Tsunoda T, Wada S, et al. Inhibition of tumor growth with antiangiogenic cancer vaccine using epitope peptides derived from human vascular endothelial growth factor receptor 1. Clin Cancer Res. 2006;12:5841–5849.
   PubMed Web of Science ®Google Scholar
• Wada S, Tsunoda T, Baba T, et al. Rationale for antiangiogenic cancer therapy with vaccination using epitope peptides derived from human vascular endothelial growth factor receptor 2. Cancer Res. 2005;65:4939–4946.
   PubMed Web of Science ®Google Scholar
• Tang J, Yu JX, Hubbard-Lucey VM, et al. Trial watch: the clinical trial landscape for PD1/PDL1 immune checkpoint inhibitors. Nat Rev Drug Discov. 2018;17:854–855.
   PubMedGoogle Scholar
• Gajewski TF, Schreiber H, Fu Y-X. Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol. 2013;14:1014–1022.
   PubMed Web of Science ®Google Scholar
• Onyshchenko M. The puzzle of predicting response to immune checkpoint blockade. EBioMedicine. 2018;33:18–19.
   PubMed Web of Science ®Google Scholar