Engineering T cells for immunotherapy of primary human hepatocellular carcinoma

Leidy D. Caraballo Galva; Lun Cai; Yanxia Shao; Yukai He

doi:10.1016/j.jgg.2020.01.002

Volume 47 Issue 1

Jan. 2020

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Article Navigation > Journal of Genetics and Genomics > 2020 > 47(1): 1-15

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Engineering T cells for immunotherapy of primary human hepatocellular carcinoma

doi: 10.1016/j.jgg.2020.01.002

a
Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA
b
Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA

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Corresponding author: E-mail address: yhe@augusta.edu (Yukai He)
Publish Date: 2020-01-25

Abstract

Abstract

Liver cancers, majority of which are primary hepatocellular carcinoma (HCC), continue to be on the rise in the world. Furthermore, due to the lack of effective treatments, liver cancer ranks the 4^th most common cause of male cancer deaths. Novel therapies are urgently needed. Over the last few years, immunotherapies, especially the checkpoint blockades and adoptive cell therapies of engineered T cells, have demonstrated a great potential for treating malignant tumors including HCC. In this review, we summarize the current ongoing research of antigen-specific immunotherapies including cancer vaccines and adoptive cell therapies for HCC. We briefly discuss the HCC cancer vaccine and then focus on the antigen-specific T cells genetically engineered with the T cell receptor genes (TCRTs) and the chimeric antigen receptor genes (CARTs). We first review the current options of TCRTs and CARTs immunotherapies for HCC, and then analyze the factors and parameters that may help to improve the design of TCRTs and CARTs to enhance their antitumor efficacy and safety. Our goals are to render readers a panoramic view of the current stand of HCC immunotherapies and provide some strategies to design better TCRTs and CARTs to achieve more effective and durable antitumor effects.
- Immunotherapy,
- Hepatocellular carcinoma,
- T cell receptor,
- Chimeric antigen receptor,
- T cell engineering,
- Gene transfer

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References(166)

References

[1]	Abou-Alfa, G.K., Puig, O., Daniele, B., Kudo, M., Merle, P., Park, J.W., Ross, P., Peron, J.M., Ebert, O., Chan, S., Poon, T.P., Colombo, M., Okusaka, T., Ryoo, B.Y., Minguez, B., Tanaka, T., Ohtomo, T., Ukrainskyj, S., Boisserie, F., Rutman, O., Chen, Y.C., Xu, C., Shochat, E., Jukofsky, L., Reis, B., Chen, G., Di Laurenzio, L., Lee, R., Yen, C.J., 2016. Randomized phase II placebo controlled study of codrituzumab in previously treated patients with advanced hepatocellular carcinoma. J Hepatol 65, 289-295.
[2]	Adachi, K., Kano, Y., Nagai, T., Okuyama, N., Sakoda, Y., Tamada, K., 2018. IL-7 and CCL19 expression in CAR-T cells improves immune cell infiltration and CAR-T cell survival in the tumor. Nat Biotechnol 36, 346-351.
[3]	Alizadeh, D., Wong, R.A., Yang, X., Wang, D., Pecoraro, J.R., Kuo, C.F., Aguilar, B., Qi, Y., Ann, D.K., Starr, R., Urak, R., Wang, X., Forman, S.J., Brown, C.E., 2019. IL15 enhances CAR-T cell antitumor activity by reducing mTORC1 activity and preserving their stem cell memory phenotype. Cancer Immunol Res 7, 759-772.
[4]	Bailey, S.R., Nelson, M.H., Majchrzak, K., Bowers, J.S., Wyatt, M.M., Smith, A.S., Neal, L.R., Shirai, K., Carpenito, C., June, C.H., Zilliox, M.J., Paulos, C.M., 2017. Human CD26(high) T cells elicit tumor immunity against multiple malignancies via enhanced migration and persistence. Nat Commun 8, 1961.
[5]	Berger, C., Jensen, M.C., Lansdorp, P.M., Gough, M., Elliott, C., Riddell, S.R., 2008. Adoptive transfer of effector CD8+ T cells derived from central memory cells establishes persistent T cell memory in primates. J Clin Invest 118, 294-305.
[6]	Border, E.C., Sanderson, J.P., Weissensteiner, T., Gerry, A.B., Pumphrey, N.J., 2019. Affinity-enhanced T-cell receptors for adoptive T-cell therapy targeting MAGE-A10: strategy for selection of an optimal candidate. Oncoimmunology 8, e1532759.
[7]	Bowers, J.S., Nelson, M.H., Majchrzak, K., Bailey, S.R., Rohrer, B., Kaiser, A.D., Atkinson, C., Gattinoni, L., Paulos, C.M., 2017. Th17 cells are refractory to senescence and retain robust antitumor activity after long-term ex vivo expansion. JCI Insight 2, e90772.
[8]	Brar, G., Greten, T.F., Brown, Z.J., 2018. Current frontline approaches in the management of hepatocellular carcinoma: the evolving role of immunotherapy. Therap Adv Gastroenterol 11, 1756284818808086.
[9]	Brichard, V.G., Louahed, J., Clay, T.M., 2013. Cancer regression and neurological toxicity cases after anti-MAGE-A3 TCR gene therapy. J Immunother 36, 79-81.
[10]	Bridgeman, J.S., Hawkins, R.E., Bagley, S., Blaylock, M., Holland, M., Gilham, D.E., 2010. The optimal antigen response of chimeric antigen receptors harboring the CD3zeta transmembrane domain is dependent upon incorporation of the receptor into the endogenous TCR/CD3 complex. J Immunol 184, 6938-6949.
[11]	Buonaguro, L., Mauriello, A., Cavalluzzo, B., Petrizzo, A., Tagliamonte, M., 2019. Immunotherapy in hepatocellular carcinoma. Ann Hepatol 18, 291-297.
[12]	Burns, W.R., Zhao, Y., Frankel, T.L., Hinrichs, C.S., Zheng, Z., Xu, H., Feldman, S.A., Ferrone, S., Rosenberg, S.A., Morgan, R.A., 2010. A high molecular weight melanoma-associated antigen-specific chimeric antigen receptor redirects lymphocytes to target human melanomas. Cancer Res 70, 3027-3033.
[13]	Butterfield, L.H., Koh, A., Meng, W., Vollmer, C.M., Ribas, A., Dissette, V., Lee, E., Glaspy, J.A., McBride, W.H., Economou, J.S., 1999. Generation of human T-cell responses to an HLA-A2.1-restricted peptide epitope derived from alpha-fetoprotein. Cancer Res 59, 3134-3142.
[14]	Butterfield, L.H., Meng, W.S., Koh, A., Vollmer, C.M., Ribas, A., Dissette, V.B., Faull, K., Glaspy, J.A., McBride, W.H., Economou, J.S., 2001. T cell responses to HLA-A*0201-restricted peptides derived from human alpha fetoprotein. J Immunol 166, 5300-5308.
[15]	Butterfield, L.H., Ribas, A., Dissette, V.B., Lee, Y., Yang, J.Q., De la Rocha, P., Duran, S.D., Hernandez, J., Seja, E., Potter, D.M., McBride, W.H., Finn, R., Glaspy, J.A., Economou, J.S., 2006. A phase I/II trial testing immunization of hepatocellular carcinoma patients with dendritic cells pulsed with four alpha-fetoprotein peptides. Clin Cancer Res 12, 2817-2825.
[16]	Caballero, O.L., Chen, Y.T., 2009. Cancer/testis (CT) antigens: potential targets for immunotherapy. Cancer Sci 100, 2014-2021.
[17]	Cameron, B.J., Gerry, A.B., Dukes, J., Harper, J.V., Kannan, V., Bianchi, F.C., Grand, F., Brewer, J.E., Gupta, M., Plesa, G., Bossi, G., Vuidepot, A., Powlesland, A.S., Legg, A., Adams, K.J., Bennett, A.D., Pumphrey, N.J., Williams, D.D., Binder-Scholl, G., Kulikovskaya, I., Levine, B.L., Riley, J.L., Varela-Rohena, A., Stadtmauer, E.A., Rapoport, A.P., Linette, G.P., June, C.H., Hassan, N.J., Kalos, M., Jakobsen, B.K., 2013. Identification of a Titin-derived HLA-A1-presented peptide as a cross-reactive target for engineered MAGE A3-directed T cells. Sci Transl Med 5, 197ra103.
[18]	Chang, M.H., You, S.L., Chen, C.J., Liu, C.J., Lee, C.M., Lin, S.M., Chu, H.C., Wu, T.C., Yang, S.S., Kuo, H.S., Chen, D.S., Taiwan Hepatoma Study, G., 2009. Decreased incidence of hepatocellular carcinoma in hepatitis B vaccinees: a 20-year follow-up study. J Natl Cancer Inst 101, 1348-1355.
[19]	Chang, Z.L., Silver, P.A., Chen, Y.Y., 2015. Identification and selective expansion of functionally superior T cells expressing chimeric antigen receptors. J Transl Med 13, 161.
[20]	Chen, C., Li, K., Jiang, H., Song, F., Gao, H., Pan, X., Shi, B., Bi, Y., Wang, H., Wang, H., Li, Z., 2017. 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 66, 475-489.
[21]	Chen, J., Lopez-Moyado, I.F., Seo, H., Lio, C.J., Hempleman, L.J., Sekiya, T., Yoshimura, A., Scott-Browne, J.P., Rao, A., 2019. NR4A transcription factors limit CAR T cell function in solid tumours. Nature 567, 530-534.
[22]	Cho, J.H., Collins, J.J., Wong, W.W., 2018. Universal chimeric antigen receptors for multiplexed and logical control of T cell responses. Cell 173, 1426-1438 e1411.
[23]	D'Angelo, S.P., Melchiori, L., Merchant, M.S., Bernstein, D., Glod, J., Kaplan, R., Grupp, S., Tap, W.D., Chagin, K., Binder, G.K., Basu, S., Lowther, D.E., Wang, R., Bath, N., Tipping, A., Betts, G., Ramachandran, I., Navenot, J.M., Zhang, H., Wells, D.K., Van Winkle, E., Kari, G., Trivedi, T., Holdich, T., Pandite, L., Amado, R., Mackall, C.L., 2018. Antitumor activity associated with prolonged persistence of adoptively transferred NY-ESO-1 (c259)T cells in synovial sarcoma. Cancer Discov 8, 944-957.
[24]	Dargel, C., Bassani-Sternberg, M., Hasreiter, J., Zani, F., Bockmann, J.H., Thiele, F., Bohne, F., Wisskirchen, K., Wilde, S., Sprinzl, M.F., Schendel, D.J., Krackhardt, A.M., Uckert, W., Wohlleber, D., Schiemann, M., Stemmer, K., Heikenwalder, M., Busch, D.H., Richter, G., Mann, M., Protzer, U., 2015. T cells engineered to express a T-cell receptor specific for glypican-3 to recognize and kill hepatoma cells in vitro and in mice. Gastroenterology 149, 1042-1052.
[25]	De Munter, S., Ingels, J., Goetgeluk, G., Bonte, S., Pille, M., Weening, K., Kerre, T., Abken, H., Vandekerckhove, B., 2018. Nanobody Based Dual Specific CARs. Int J Mol Sci 19.
[26]	Desplancq, D., King, D.J., Lawson, A.D., Mountain, A., 1994. Multimerization behaviour of single chain Fv variants for the tumour-binding antibody B72.3. Protein Eng 7, 1027-1033.
[27]	Docta, R.Y., Ferronha, T., Sanderson, J.P., Weissensteiner, T., Pope, G.R., Bennett, A.D., Pumphrey, N.J., Ferjentsik, Z., Quinn, L.L., Wiedermann, G.E., Anderson, V.E., Saini, M., Maroto, M., Norry, E., Gerry, A.B., 2019. Tuning T-cell receptor affinity to optimize clinical risk-benefit when targeting alpha-fetoprotein-positive liver cancer. Hepatology 69, 2061-2075.
[28]	El-Serag, H.B., Tran, T., Everhart, J.E., 2004. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology 126, 460-468.
[29]	Ellis, J., 2005. Silencing and variegation of gammaretrovirus and lentivirus vectors. Hum Gene Ther 16, 1241-1246.
[30]	Eyquem, J., Mansilla-Soto, J., Giavridis, T., van der Stegen, S.J., Hamieh, M., Cunanan, K.M., Odak, A., Gonen, M., Sadelain, M., 2017. Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection. Nature 543, 113-117.
[31]	Feng, M., Ho, M., 2014. Glypican-3 antibodies: a new therapeutic target for liver cancer. FEBS Lett 588, 377-382.
[32]	Feucht, J., Sun, J., Eyquem, J., Ho, Y.J., Zhao, Z., Leibold, J., Dobrin, A., Cabriolu, A., Hamieh, M., Sadelain, M., 2019. Calibration of CAR activation potential directs alternative T cell fates and therapeutic potency. Nat Med 25, 82-88.
[33]	Filmus, J., Capurro, M., 2013. Glypican-3: a marker and a therapeutic target in hepatocellular carcinoma. FEBS J 280, 2471-2476.
[34]	Fraietta, J.A., Nobles, C.L., Sammons, M.A., Lundh, S., Carty, S.A., Reich, T.J., Cogdill, A.P., Morrissette, J.J.D., DeNizio, J.E., Reddy, S., Hwang, Y., Gohil, M., Kulikovskaya, I., Nazimuddin, F., Gupta, M., Chen, F., Everett, J.K., Alexander, K.A., Lin-Shiao, E., Gee, M.H., Liu, X., Young, R.M., Ambrose, D., Wang, Y., Xu, J., Jordan, M.S., Marcucci, K.T., Levine, B.L., Garcia, K.C., Zhao, Y., Kalos, M., Porter, D.L., Kohli, R.M., Lacey, S.F., Berger, S.L., Bushman, F.D., June, C.H., Melenhorst, J.J., 2018. Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells. Nature 558, 307-312.
[35]	Frigault, M.J., Lee, J., Basil, M.C., Carpenito, C., Motohashi, S., Scholler, J., Kawalekar, O.U., Guedan, S., McGettigan, S.E., Posey, A.D., Jr., Ang, S., Cooper, L.J., Platt, J.M., Johnson, F.B., Paulos, C.M., Zhao, Y., Kalos, M., Milone, M.C., June, C.H., 2015. Identification of chimeric antigen receptors that mediate constitutive or inducible proliferation of T cells. Cancer Immunol Res 3, 356-367.
[36]	Gacerez, A.T., Sentman, C.L., 2018. T-bet promotes potent antitumor activity of CD4+CAR T cells. Cancer Gene Ther 25, 117-128.
[37]	Gao, H., Li, K., Tu, H., Pan, X., Jiang, H., Shi, B., Kong, J., Wang, H., Yang, S., Gu, J., Li, Z., 2014. Development of T cells redirected to glypican-3 for the treatment of hepatocellular carcinoma. Clin Cancer Res 20, 6418-6428.
[38]	Gao, Q., Wang, X.Y., Qiu, S.J., Yamato, I., Sho, M., Nakajima, Y., Zhou, J., Li, B.Z., Shi, Y.H., Xiao, Y.S., Xu, Y., Fan, J., 2009. Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma. Clin Cancer Res 15, 971-979.
[39]	Gargett, T., Brown, M.P., 2014. The inducible caspase-9 suicide gene system as a "safety switch" to limit on-target, off-tumor toxicities of chimeric antigen receptor T cells. Front Pharmacol 5, 235.
[40]	Gattinoni, L., Lugli, E., Ji, Y., Pos, Z., Paulos, C.M., Quigley, M.F., Almeida, J.R., Gostick, E., Yu, Z., Carpenito, C., Wang, E., Douek, D.C., Price, D.A., June, C.H., Marincola, F.M., Roederer, M., Restifo, N.P., 2011. A human memory T cell subset with stem cell-like properties. Nat Med 17, 1290-1297.
[41]	Gehring, A.J., Xue, S.A., Ho, Z.Z., Teoh, D., Ruedl, C., Chia, A., Koh, S., Lim, S.G., Maini, M.K., Stauss, H., Bertoletti, A., 2011. Engineering virus-specific T cells that target HBV infected hepatocytes and hepatocellular carcinoma cell lines. J Hepatol 55, 103-110.
[42]	Ghassemi, S., Nunez-Cruz, S., O'Connor, R.S., Fraietta, J.A., Patel, P.R., Scholler, J., Barrett, D.M., Lundh, S.M., Davis, M.M., Bedoya, F., Zhang, C., Leferovich, J., Lacey, S.F., Levine, B.L., Grupp, S.A., June, C.H., Melenhorst, J.J., Milone, M.C., 2018. Reducing ex vivo culture improves the antileukemic activity of chimeric antigen receptor (CAR) T cells. Cancer Immunol Res 6, 1100-1109.
[43]	Global Burden of Disease Cancer, C., Fitzmaurice, C., Allen, C., Barber, R.M., Barregard, L., Bhutta, Z.A., Brenner, H., Dicker, D.J., Chimed-Orchir, O., Dandona, R., Dandona, L., Fleming, T., Forouzanfar, M.H., Hancock, J., Hay, R.J., Hunter-Merrill, R., Huynh, C., Hosgood, H.D., Johnson, C.O., Jonas, J.B., Khubchandani, J., Kumar, G.A., Kutz, M., Lan, Q., Larson, H.J., Liang, X., Lim, S.S., Lopez, A.D., MacIntyre, M.F., Marczak, L., Marquez, N., Mokdad, A.H., Pinho, C., Pourmalek, F., Salomon, J.A., Sanabria, J.R., Sandar, L., Sartorius, B., Schwartz, S.M., Shackelford, K.A., Shibuya, K., Stanaway, J., Steiner, C., Sun, J., Takahashi, K., Vollset, S.E., Vos, T., Wagner, J.A., Wang, H., Westerman, R., Zeeb, H., Zoeckler, L., Abd-Allah, F., Ahmed, M.B., Alabed, S., Alam, N.K., Aldhahri, S.F., Alem, G., Alemayohu, M.A., Ali, R., Al-Raddadi, R., Amare, A., Amoako, Y., Artaman, A., Asayesh, H., Atnafu, N., Awasthi, A., Saleem, H.B., Barac, A., Bedi, N., Bensenor, I., Berhane, A., Bernabe, E., Betsu, B., Binagwaho, A., Boneya, D., Campos-Nonato, I., Castaneda-Orjuela, C., Catala-Lopez, F., Chiang, P., Chibueze, C., Chitheer, A., Choi, J.Y., Cowie, B., Damtew, S., das Neves, J., Dey, S., Dharmaratne, S., Dhillon, P., Ding, E., Driscoll, T., Ekwueme, D., Endries, A.Y., Farvid, M., Farzadfar, F., Fernandes, J., Fischer, F., TT, G.H., Gebru, A., Gopalani, S., Hailu, A., Horino, M., Horita, N., Husseini, A., Huybrechts, I., Inoue, M., Islami, F., Jakovljevic, M., James, S., Javanbakht, M., Jee, S.H., Kasaeian, A., Kedir, M.S., Khader, Y.S., Khang, Y.H., Kim, D., Leigh, J., Linn, S., Lunevicius, R., El Razek, H.M.A., Malekzadeh, R., Malta, D.C., Marcenes, W., Markos, D., Melaku, Y.A., Meles, K.G., Mendoza, W., Mengiste, D.T., Meretoja, T.J., Miller, T.R., Mohammad, K.A., Mohammadi, A., Mohammed, S., Moradi-Lakeh, M., Nagel, G., Nand, D., Le Nguyen, Q., Nolte, S., Ogbo, F.A., Oladimeji, K.E., Oren, E., Pa, M., Park, E.K., Pereira, D.M., Plass, D., Qorbani, M., Radfar, A., Rafay, A., Rahman, M., Rana, S.M., Soreide, K., Satpathy, M., Sawhney, M., Sepanlou, S.G., Shaikh, M.A., She, J., Shiue, I., Shore, H.R., Shrime, M.G., So, S., Soneji, S., Stathopoulou, V., Stroumpoulis, K., Sufiyan, M.B., Sykes, B.L., Tabares-Seisdedos, R., Tadese, F., Tedla, B.A., Tessema, G.A., Thakur, J.S., Tran, B.X., Ukwaja, K.N., Uzochukwu, B.S.C., Vlassov, V.V., Weiderpass, E., Wubshet Terefe, M., Yebyo, H.G., Yimam, H.H., Yonemoto, N., Younis, M.Z., Yu, C., Zaidi, Z., Zaki, M.E.S., Zenebe, Z.M., Murray, C.J.L., Naghavi, M., 2017. Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-years for 32 Cancer Groups, 1990 to 2015: A systematic analysis for the global burden of disease study. JAMA Oncol 3, 524-548.
[44]	Gnjatic, S., Nishikawa, H., Jungbluth, A.A., Gure, A.O., Ritter, G., Jager, E., Knuth, A., Chen, Y.T., Old, L.J., 2006. NY-ESO-1: review of an immunogenic tumor antigen. Adv Cancer Res 95, 1-30.
[45]	Gomes-Silva, D., Mukherjee, M., Srinivasan, M., Krenciute, G., Dakhova, O., Zheng, Y., Cabral, J.M.S., Rooney, C.M., Orange, J.S., Brenner, M.K., Mamonkin, M., 2017. Tonic 4-1BB costimulation in chimeric antigen receptors impedes T cell survival and is vector-dependent. Cell Rep 21, 17-26.
[46]	Grange, M., Buferne, M., Verdeil, G., Leserman, L., Schmitt-Verhulst, A.M., Auphan-Anezin, N., 2012. Activated STAT5 promotes long-lived cytotoxic CD8+ T cells that induce regression of autochthonous melanoma. Cancer Res 72, 76-87.
[47]	Guedan, S., Calderon, H., Posey, A.D., Jr., Maus, M.V., 2019. Engineering and design of chimeric antigen receptors. Mol Ther Methods Clin Dev 12, 145-156.
[48]	Guedan, S., Posey, A.D., Jr., Shaw, C., Wing, A., Da, T., Patel, P.R., McGettigan, S.E., Casado-Medrano, V., Kawalekar, O.U., Uribe-Herranz, M., Song, D., Melenhorst, J.J., Lacey, S.F., Scholler, J., Keith, B., Young, R.M., June, C.H., 2018. Enhancing CAR T cell persistence through ICOS and 4-1BB costimulation. JCI Insight 3.
[49]	Guest, R.D., Hawkins, R.E., Kirillova, N., Cheadle, E.J., Arnold, J., O'Neill, A., Irlam, J., Chester, K.A., Kemshead, J.T., Shaw, D.M., Embleton, M.J., Stern, P.L., Gilham, D.E., 2005. The role of extracellular spacer regions in the optimal design of chimeric immune receptors: evaluation of four different scFvs and antigens. J Immunother 28, 203-211.
[50]	Han, X., Wang, Y., Han, W., 2019. Multi-antigen-targeted chimeric antigen receptor T cells for cancer therapy. J Hematol Oncol 12, 128.
[51]	Hashimoto, M., Kamphorst, A.O., Im, S.J., Kissick, H.T., Pillai, R.N., Ramalingam, S.S., Araki, K., Ahmed, R., 2018. CD8 T Cell Exhaustion in Chronic Infection and Cancer: Opportunities for Interventions. Annu Rev Med 69, 301-318.
[52]	Hato, T., Goyal, L., Greten, T.F., Duda, D.G., Zhu, A.X., 2014. Immune checkpoint blockade in hepatocellular carcinoma: current progress and future directions. Hepatology 60, 1776-1782.
[53]	He, Y., Zhang, J., Mi, Z., Robbins, P., Falo, L.D., Jr., 2005. Immunization with lentiviral vector-transduced dendritic cells induces strong and long-lasting T cell responses and therapeutic immunity. J Immunol 174, 3808-3817.
[54]	Hombach, A.A., Schildgen, V., Heuser, C., Finnern, R., Gilham, D.E., Abken, H., 2007. T cell activation by antibody-like immunoreceptors: the position of the binding epitope within the target molecule determines the efficiency of activation of redirected T cells. J Immunol 178, 4650-4657.
[55]	Hong, Y., Peng, Y., Guo, Z.S., Guevara-Patino, J., Pang, J., Butterfield, L.H., Mivechi, N.F., Munn, D.H., Bartlett, D.L., He, Y., 2014. Epitope-optimized alpha-fetoprotein genetic vaccines prevent carcinogen-induced murine autochthonous hepatocellular carcinoma. Hepatology 59, 1448-1458.
[56]	Hou, B., Tang, Y., Li, W., Zeng, Q., Chang, D., 2019. Efficiency of CAR-T therapy for treatment of solid tumor in clinical trials: a meta-analysis. Dis Markers 2019, 3425291.
[57]	Hudecek, M., Lupo-Stanghellini, M.T., Kosasih, P.L., Sommermeyer, D., Jensen, M.C., Rader, C., Riddell, S.R., 2013. Receptor affinity and extracellular domain modifications affect tumor recognition by ROR1-specific chimeric antigen receptor T cells. Clin Cancer Res 19, 3153-3164.
[58]	Hudecek, M., Sommermeyer, D., Kosasih, P.L., Silva-Benedict, A., Liu, L., Rader, C., Jensen, M.C., Riddell, S.R., 2015. The nonsignaling extracellular spacer domain of chimeric antigen receptors is decisive for in vivo antitumor activity. Cancer Immunol Res 3, 125-135.
[59]	Hurton, L.V., Singh, H., Najjar, A.M., Switzer, K.C., Mi, T., Maiti, S., Olivares, S., Rabinovich, B., Huls, H., Forget, M.A., Datar, V., Kebriaei, P., Lee, D.A., Champlin, R.E., Cooper, L.J., 2016. Tethered IL-15 augments antitumor activity and promotes a stem-cell memory subset in tumor-specific T cells. Proc Natl Acad Sci U S A 113, E7788-E7797.
[60]	Hwang, S., Cobb, D.A., Bhadra, R., Youngblood, B., Khan, I.A., 2016. Blimp-1-mediated CD4 T cell exhaustion causes CD8 T cell dysfunction during chronic toxoplasmosis. J Exp Med 213, 1799-1818.
[61]	James, S.E., Greenberg, P.D., Jensen, M.C., Lin, Y., Wang, J., Till, B.G., Raubitschek, A.A., Forman, S.J., Press, O.W., 2008. Antigen sensitivity of CD22-specific chimeric TCR is modulated by target epitope distance from the cell membrane. J Immunol 180, 7028-7038.
[62]	Jaspers, J.E., Brentjens, R.J., 2017. Development of CAR T cells designed to improve antitumor efficacy and safety. Pharmacol Ther 178, 83-91.
[63]	Jensen, M.C., Riddell, S.R., 2014. Design and implementation of adoptive therapy with chimeric antigen receptor-modified T cells. Immunol Rev 257, 127-144.
[64]	Jiang, Z., Jiang, X., Chen, S., Lai, Y., Wei, X., Li, B., Lin, S., Wang, S., Wu, Q., Liang, Q., Liu, Q., Peng, M., Yu, F., Weng, J., Du, X., Pei, D., Liu, P., Yao, Y., Xue, P., Li, P., 2016. Anti-GPC3-CAR T Cells Suppress the Growth of Tumor Cells in Patient-Derived Xenografts of Hepatocellular Carcinoma. Front Immunol 7, 690.
[65]	Jin, L., Tao, H., Karachi, A., Long, Y., Hou, A.Y., Na, M., Dyson, K.A., Grippin, A.J., Deleyrolle, L.P., Zhang, W., Rajon, D.A., Wang, Q.J., Yang, J.C., Kresak, J.L., Sayour, E.J., Rahman, M., Bova, F.J., Lin, Z., Mitchell, D.A., Huang, J., 2019. CXCR1- or CXCR2-modified CAR T cells co-opt IL-8 for maximal antitumor efficacy in solid tumors. Nat Commun 10, 4016.
[66]	Jonnalagadda, M., Mardiros, A., Urak, R., Wang, X., Hoffman, L.J., Bernanke, A., Chang, W.C., Bretzlaff, W., Starr, R., Priceman, S., Ostberg, J.R., Forman, S.J., Brown, C.E., 2015. Chimeric antigen receptors with mutated IgG4 Fc spacer avoid fc receptor binding and improve T cell persistence and antitumor efficacy. Mol Ther 23, 757-768.
[67]	Kao, W.Y., Su, C.W., Chau, G.Y., Lui, W.Y., Wu, C.W., Wu, J.C., 2011. A comparison of prognosis between patients with hepatitis B and C virus-related hepatocellular carcinoma undergoing resection surgery. World J Surg 35, 858-867.
[68]	Khan, O., Giles, J.R., McDonald, S., Manne, S., Ngiow, S.F., Patel, K.P., Werner, M.T., Huang, A.C., Alexander, K.A., Wu, J.E., Attanasio, J., Yan, P., George, S.M., Bengsch, B., Staupe, R.P., Donahue, G., Xu, W., Amaravadi, R.K., Xu, X., Karakousis, G.C., Mitchell, T.C., Schuchter, L.M., Kaye, J., Berger, S.L., Wherry, E.J., 2019. TOX transcriptionally and epigenetically programs CD8(+) T cell exhaustion. Nature 571, 211-218.
[69]	Klebanoff, C.A., Scott, C.D., Leonardi, A.J., Yamamoto, T.N., Cruz, A.C., Ouyang, C., Ramaswamy, M., Roychoudhuri, R., Ji, Y., Eil, R.L., Sukumar, M., Crompton, J.G., Palmer, D.C., Borman, Z.A., Clever, D., Thomas, S.K., Patel, S., Yu, Z., Muranski, P., Liu, H., Wang, E., Marincola, F.M., Gros, A., Gattinoni, L., Rosenberg, S.A., Siegel, R.M., Restifo, N.P., 2016. Memory T cell-driven differentiation of naive cells impairs adoptive immunotherapy. J Clin Invest 126, 318-334.
[70]	Kloss, C.C., Lee, J., Zhang, A., Chen, F., Melenhorst, J.J., Lacey, S.F., Maus, M.V., Fraietta, J.A., Zhao, Y., June, C.H., 2018. Dominant-negative TGF-beta receptor enhances PSMA-targeted human CAR T cell proliferation and augments prostate cancer eradication. Mol Ther 26, 1855-1866.
[71]	Knolle, P.A., Thimme, R., 2014. Hepatic immune regulation and its involvement in viral hepatitis infection. Gastroenterology 146, 1193-1207.
[72]	Kobayashi, E., Mizukoshi, E., Kishi, H., Ozawa, T., Hamana, H., Nagai, T., Nakagawa, H., Jin, A., Kaneko, S., Muraguchi, A., 2013. A new cloning and expression system yields and validates TCRs from blood lymphocytes of patients with cancer within 10 days. Nat Med 19, 1542-1546.
[73]	Komori, H., Nakatsura, T., Senju, S., Yoshitake, Y., Motomura, Y., Ikuta, Y., Fukuma, D., Yokomine, K., Harao, M., Beppu, T., Matsui, M., Torigoe, T., Sato, N., Baba, H., Nishimura, Y., 2006. Identification of HLA-A2- or HLA-A24-restricted CTL epitopes possibly useful for glypican-3-specific immunotherapy of hepatocellular carcinoma. Clin Cancer Res 12, 2689-2697.
[74]	Koneru, M., O'Cearbhaill, R., Pendharkar, S., Spriggs, D.R., Brentjens, R.J., 2015a. A phase I clinical trial of adoptive T cell therapy using IL-12 secreting MUC-16(ecto) directed chimeric antigen receptors for recurrent ovarian cancer. J Transl Med 13, 102.
[75]	Koneru, M., Purdon, T.J., Spriggs, D., Koneru, S., Brentjens, R.J., 2015b. IL-12 secreting tumor-targeted chimeric antigen receptor T cells eradicate ovarian tumors in vivo. Oncoimmunology 4, e994446.
[76]	Korangy, F., Ormandy, L.A., Bleck, J.S., Klempnauer, J., Wilkens, L., Manns, M.P., Greten, T.F., 2004. Spontaneous tumor-specific humoral and cellular immune responses to NY-ESO-1 in hepatocellular carcinoma. Clin Cancer Res 10, 4332-4341.
[77]	Krenciute, G., Prinzing, B.L., Yi, Z., Wu, M.F., Liu, H., Dotti, G., Balyasnikova, I.V., Gottschalk, S., 2017. Transgenic expression of IL15 improves antiglioma activity of IL13Ralpha2-CAR T cells but results in antigen loss variants. Cancer Immunol Res 5, 571-581.
[78]	Lawrence, M.S., Stojanov, P., Polak, P., Kryukov, G.V., Cibulskis, K., Sivachenko, A., Carter, S.L., Stewart, C., Mermel, C.H., Roberts, S.A., Kiezun, A., Hammerman, P.S., McKenna, A., Drier, Y., Zou, L., Ramos, A.H., Pugh, T.J., Stransky, N., Helman, E., Kim, J., Sougnez, C., Ambrogio, L., Nickerson, E., Shefler, E., Cortes, M.L., Auclair, D., Saksena, G., Voet, D., Noble, M., DiCara, D., Lin, P., Lichtenstein, L., Heiman, D.I., Fennell, T., Imielinski, M., Hernandez, B., Hodis, E., Baca, S., Dulak, A.M., Lohr, J., Landau, D.A., Wu, C.J., Melendez-Zajgla, J., Hidalgo-Miranda, A., Koren, A., McCarroll, S.A., Mora, J., Crompton, B., Onofrio, R., Parkin, M., Winckler, W., Ardlie, K., Gabriel, S.B., Roberts, C.W.M., Biegel, J.A., Stegmaier, K., Bass, A.J., Garraway, L.A., Meyerson, M., Golub, T.R., Gordenin, D.A., Sunyaev, S., Lander, E.S., Getz, G., 2013. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 499, 214-218.
[79]	Lee, J.S., 2015. The mutational landscape of hepatocellular carcinoma. Clin Mol Hepatol 21, 220-229.
[80]	Lee, J.H., Lee, J.H., Lim, Y.S., Yeon, J.E., Song, T.J., Yu, S.J., Gwak, G.Y., Kim, K.M., Kim, Y.J., Lee, J.W., Yoon, J.H., 2015. Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma. Gastroenterology 148, 1383-1391 e1386.
[81]	Leen, A.M., Sukumaran, S., Watanabe, N., Mohammed, S., Keirnan, J., Yanagisawa, R., Anurathapan, U., Rendon, D., Heslop, H.E., Rooney, C.M., Brenner, M.K., Vera, J.F., 2014. Reversal of tumor immune inhibition using a chimeric cytokine receptor. Mol Ther 22, 1211-1220.
[82]	Li, D., Li, N., Zhang, Y., Fu, H., Torres, M.B., Wang, Q., Greten, T.F., Ho, M., 2018. Abstract 2549: Development of CAR T-cell therapy targeting glypican-3 in liver cancer. Cancer Res. 78, 2549-2549.
[83]	Li, J., Stagg, N.J., Johnston, J., Harris, M.J., Menzies, S.A., DiCara, D., Clark, V., Hristopoulos, M., Cook, R., Slaga, D., Nakamura, R., McCarty, L., Sukumaran, S., Luis, E., Ye, Z., Wu, T.D., Sumiyoshi, T., Danilenko, D., Lee, G.Y., Totpal, K., Ellerman, D., Hotzel, I., James, J.R., Junttila, T.T., 2017a. Membrane-proximal epitope facilitates efficient T cell synapse formation by anti-FcRH5/CD3 and is a requirement for myeloma cell killing. Cancer Cell 31, 383-395.
[84]	Li, L.P., Lampert, J.C., Chen, X., Leitao, C., Popovic, J., Muller, W., Blankenstein, T., 2010. Transgenic mice with a diverse human T cell antigen receptor repertoire. Nat Med 16, 1029-1034.
[85]	Li, W., Guo, L., Rathi, P., Marinova, E., Gao, X., Wu, M.F., Liu, H., Dotti, G., Gottschalk, S., Metelitsa, L.S., Heczey, A., 2017b. Redirecting T Cells to Glypican-3 with 4-1BB Zeta Chimeric Antigen Receptors Results in Th1 Polarization and Potent Antitumor Activity. Hum Gene Ther 28, 437-448.
[86]	Li, Y., Moysey, R., Molloy, P.E., Vuidepot, A.L., Mahon, T., Baston, E., Dunn, S., Liddy, N., Jacob, J., Jakobsen, B.K., Boulter, J.M., 2005. Directed evolution of human T-cell receptors with picomolar affinities by phage display. Nat Biotechnol 23, 349-354.
[87]	Linette, G.P., Stadtmauer, E.A., Maus, M.V., Rapoport, A.P., Levine, B.L., Emery, L., Litzky, L., Bagg, A., Carreno, B.M., Cimino, P.J., Binder-Scholl, G.K., Smethurst, D.P., Gerry, A.B., Pumphrey, N.J., Bennett, A.D., Brewer, J.E., Dukes, J., Harper, J., Tayton-Martin, H.K., Jakobsen, B.K., Hassan, N.J., Kalos, M., June, C.H., 2013. Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma. Blood 122, 863-871.
[88]	Liu, H., Xu, Y., Xiang, J., Long, L., Green, S., Yang, Z., Zimdahl, B., Lu, J., Cheng, N., Horan, L.H., Liu, B., Yan, S., Wang, P., Diaz, J., Jin, L., Nakano, Y., Morales, J.F., Zhang, P., Liu, L.X., Staley, B.K., Priceman, S.J., Brown, C.E., Forman, S.J., Chan, V.W., Liu, C., 2017. Targeting Alpha-Fetoprotein (AFP)-MHC Complex with CAR T-Cell Therapy for Liver Cancer. Clin Cancer Res 23, 478-488.
[89]	Liu, X., Jiang, S., Fang, C., Yang, S., Olalere, D., Pequignot, E.C., Cogdill, A.P., Li, N., Ramones, M., Granda, B., Zhou, L., Loew, A., Young, R.M., June, C.H., Zhao, Y., 2015. Affinity-Tuned ErbB2 or EGFR Chimeric Antigen Receptor T Cells Exhibit an Increased Therapeutic Index against Tumors in Mice. Cancer Res 75, 3596-3607.
[90]	Liu, Y., Di, S., Shi, B., Zhang, H., Wang, Y., Wu, X., Luo, H., Wang, H., Li, Z., Jiang, H., 2019. Armored Inducible Expression of IL-12 Enhances Antitumor Activity of Glypican-3-Targeted Chimeric Antigen Receptor-Engineered T Cells in Hepatocellular Carcinoma. J Immunol 203, 198-207.
[91]	Liu, Y., Peng, Y., Mi, M., Guevara-Patino, J., Munn, D.H., Fu, N., He, Y., 2009. Lentivector immunization stimulates potent CD8 T cell responses against melanoma self-antigen tyrosinase-related protein 1 and generates antitumor immunity in mice. J Immunol 182, 5960-5969.
[92]	Long, A.H., Haso, W.M., Shern, J.F., Wanhainen, K.M., Murgai, M., Ingaramo, M., Smith, J.P., Walker, A.J., Kohler, M.E., Venkateshwara, V.R., Kaplan, R.N., Patterson, G.H., Fry, T.J., Orentas, R.J., Mackall, C.L., 2015. 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nat Med 21, 581-590.
[93]	Louis, C.U., Savoldo, B., Dotti, G., Pule, M., Yvon, E., Myers, G.D., Rossig, C., Russell, H.V., Diouf, O., Liu, E., Liu, H., Wu, M.F., Gee, A.P., Mei, Z., Rooney, C.M., Heslop, H.E., Brenner, M.K., 2011. Antitumor activity and long-term fate of chimeric antigen receptor-positive T cells in patients with neuroblastoma. Blood 118, 6050-6056.
[94]	Luo, G., Huang, S., Xie, X., Stockert, E., Chen, Y.T., Kubuschok, B., Pfreundschuh, M., 2002. Expression of cancer-testis genes in human hepatocellular carcinomas. Cancer Immun 2, 11.
[95]	Lynn, R.C., Weber, E.W., Gennert, D., Sotillo, E., Xu, P., Good, Z., Anbunathan, H., Jones, R., Tieu, V., Granja, J., DeBourcy, C., Majzner, R., Satpathy, A.T., Quake, S.R., Chang, H., Mackall, C.L., 2019. c-Jun overexpressing CAR-T cells are exhaustion-resistant and mediate enhanced antitumor activity. bioRxiv, 653725.
[96]	Ma, L., Dichwalkar, T., Chang, J.Y.H., Cossette, B., Garafola, D., Zhang, A.Q., Fichter, M., Wang, C., Liang, S., Silva, M., Kumari, S., Mehta, N.K., Abraham, W., Thai, N., Li, N., Wittrup, K.D., Irvine, D.J., 2019. Enhanced CAR-T cell activity against solid tumors by vaccine boosting through the chimeric receptor. Science 365, 162-168.
[97]	Makarova-Rusher, O.V., Medina-Echeverz, J., Duffy, A.G., Greten, T.F., 2015. The yin and yang of evasion and immune activation in HCC. J Hepatol 62, 1420-1429.
[98]	Manus, M., Haas, A., Beatty, G., Albelda, S., Levine, B., Liu, X., Zhao, Y., Kalos, M., June, C., 2014. Cancer Immunol Res.
[99]	Martinez, M., Moon, E.K., 2019. CAR T Cells for solid tumors: new strategies for finding, infiltrating, and surviving in the tumor microenvironment. Front Immunol 10, 128.
[100]	Maruta, M., Ochi, T., Tanimoto, K., Azuma, T., Fujiwara, H., Yasukawa, M., 2017. Development of T-cell therapy by exploiting modified antibodies specific for A2/NY-ESO-1 for refractory myeloma. Blood 130, 1913-1913.
[101]	Mestermann, K., Giavridis, T., Weber, J., Rydzek, J., Frenz, S., Nerreter, T., Mades, A., Sadelain, M., Einsele, H., Hudecek, M., 2019. The tyrosine kinase inhibitor dasatinib acts as a pharmacologic on/off switch for CAR T cells. Sci Transl Med 11, 11, pii: eaau5907.
[102]	Milone, M.C., Fish, J.D., Carpenito, C., Carroll, R.G., Binder, G.K., Teachey, D., Samanta, M., Lakhal, M., Gloss, B., Danet-Desnoyers, G., Campana, D., Riley, J.L., Grupp, S.A., June, C.H., 2009. Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo. Mol Ther 17, 1453-1464.
[103]	Mizukoshi, E., Kaneko, S., 2019. Immune cell therapy for hepatocellular carcinoma. J Hematol Oncol 12, 52.
[104]	Mizukoshi, E., Nakagawa, H., Kitahara, M., Yamashita, T., Arai, K., Sunagozaka, H., Fushimi, K., Kobayashi, E., Kishi, H., Muraguchi, A., Kaneko, S., 2015. Immunological features of T cells induced by human telomerase reverse transcriptase-derived peptides in patients with hepatocellular carcinoma. Cancer Lett 364, 98-105.
[105]	Mizukoshi, E., Nakamoto, Y., Marukawa, Y., Arai, K., Yamashita, T., Tsuji, H., Kuzushima, K., Takiguchi, M., Kaneko, S., 2006a. Cytotoxic T cell responses to human telomerase reverse transcriptase in patients with hepatocellular carcinoma. Hepatology 43, 1284-1294.
[106]	Mizukoshi, E., Nakamoto, Y., Tsuji, H., Yamashita, T., Kaneko, S., 2006b. Identification of alpha-fetoprotein-derived peptides recognized by cytotoxic T lymphocytes in HLA-A24+ patients with hepatocellular carcinoma. Int J Cancer 118, 1194-1204.
[107]	Morgan, R.A., Yang, J.C., Kitano, M., Dudley, M.E., Laurencot, C.M., Rosenberg, S.A., 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.
[108]	Morita, D., Nishio, N., Saito, S., Tanaka, M., Kawashima, N., Okuno, Y., Suzuki, S., Matsuda, K., Maeda, Y., Wilson, M.H., Dotti, G., Rooney, C.M., Takahashi, Y., Nakazawa, Y., 2018. Enhanced expression of anti-CD19 chimeric antigen receptor in piggyBac transposon-engineered T cells. Mol Ther Methods Clin Dev 8, 131-140.
[109]	Nakagawa, H., Mizukoshi, E., Kobayashi, E., Tamai, T., Hamana, H., Ozawa, T., Kishi, H., Kitahara, M., Yamashita, T., Arai, K., Terashima, T., Iida, N., Fushimi, K., Muraguchi, A., Kaneko, S., 2017. Association between high-avidity T-cell receptors, induced by alpha-fetoprotein-derived peptides, and anti-tumor effects in patients with hepatocellular carcinoma. Gastroenterology 152, 1395-1406 e1310.
[110]	Nakatsura, T., Kageshita, T., Ito, S., Wakamatsu, K., Monji, M., Ikuta, Y., Senju, S., Ono, T., Nishimura, Y., 2004a. Identification of glypican-3 as a novel tumor marker for melanoma. Clin Cancer Res 10, 6612-6621.
[111]	Nakatsura, T., Komori, H., Kubo, T., Yoshitake, Y., Senju, S., Katagiri, T., Furukawa, Y., Ogawa, M., Nakamura, Y., Nishimura, Y., 2004b. Mouse homologue of a novel human oncofetal antigen, glypican-3, evokes T-cell-mediated tumor rejection without autoimmune reactions in mice. Clin Cancer Res 10, 8630-8640.
[112]	Obenaus, M., Leitao, C., Leisegang, M., Chen, X., Gavvovidis, I., van der Bruggen, P., Uckert, W., Schendel, D.J., Blankenstein, T., 2015. Identification of human T-cell receptors with optimal affinity to cancer antigens using antigen-negative humanized mice. Nat Biotechnol 33, 402-407.
[113]	Orentas, R.J., Sindiri, S., Duris, C., Wen, X., He, J., Wei, J.S., Jarzembowski, J., Khan, J., 2017. Paired Expression Analysis of Tumor Cell Surface Antigens. Front Oncol 7, 173.
[114]	Ott, P.A., Hu, Z., Keskin, D.B., Shukla, S.A., Sun, J., Bozym, D.J., Zhang, W., Luoma, A., Giobbie-Hurder, A., Peter, L., Chen, C., Olive, O., Carter, T.A., Li, S., Lieb, D.J., Eisenhaure, T., Gjini, E., Stevens, J., Lane, W.J., Javeri, I., Nellaiappan, K., Salazar, A.M., Daley, H., Seaman, M., Buchbinder, E.I., Yoon, C.H., Harden, M., Lennon, N., Gabriel, S., Rodig, S.J., Barouch, D.H., Aster, J.C., Getz, G., Wucherpfennig, K., Neuberg, D., Ritz, J., Lander, E.S., Fritsch, E.F., Hacohen, N., Wu, C.J., 2017. An immunogenic personal neoantigen vaccine for patients with melanoma. Nature 547, 217-221.
[115]	Palmer, D.H., Midgley, R.S., Mirza, N., Torr, E.E., Ahmed, F., Steele, J.C., Steven, N.M., Kerr, D.J., Young, L.S., Adams, D.H., 2009. A phase II study of adoptive immunotherapy using dendritic cells pulsed with tumor lysate in patients with hepatocellular carcinoma. Hepatology 49, 124-132.
[116]	Paszkiewicz, P.J., Frassle, S.P., Srivastava, S., Sommermeyer, D., Hudecek, M., Drexler, I., Sadelain, M., Liu, L., Jensen, M.C., Riddell, S.R., Busch, D.H., 2016. Targeted antibody-mediated depletion of murine CD19 CAR T cells permanently reverses B cell aplasia. J Clin Invest 126, 4262-4272.
[117]	Pez, F., Lopez, A., Kim, M., Wands, J.R., Caron de Fromentel, C., Merle, P., 2013. Wnt signaling and hepatocarcinogenesis: molecular targets for the development of innovative anticancer drugs. J Hepatol 59, 1107-1117.
[118]	Philip, M., Fairchild, L., Sun, L., Horste, E.L., Camara, S., Shakiba, M., Scott, A.C., Viale, A., Lauer, P., Merghoub, T., Hellmann, M.D., Wolchok, J.D., Leslie, C.S., Schietinger, A., 2017. Chromatin states define tumour-specific T cell dysfunction and reprogramming. Nature 545, 452-456.
[119]	Prieto, J., Melero, I., Sangro, B., 2015. Immunological landscape and immunotherapy of hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 12, 681-700.
[120]	Qasim, W., Brunetto, M., Gehring, A.J., Xue, S.A., Schurich, A., Khakpoor, A., Zhan, H., Ciccorossi, P., Gilmour, K., Cavallone, D., Moriconi, F., Farzhenah, F., Mazzoni, A., Chan, L., Morris, E., Thrasher, A., Maini, M.K., Bonino, F., Stauss, H., Bertoletti, A., 2015. Immunotherapy of HCC metastases with autologous T cell receptor redirected T cells, targeting HBsAg in a liver transplant patient. J Hepatol 62, 486-491.
[121]	Rafiq, S., Purdon, T.J., Daniyan, A.F., Koneru, M., Dao, T., Liu, C., Scheinberg, D.A., Brentjens, R.J., 2017. Optimized T-cell receptor-mimic chimeric antigen receptor T cells directed toward the intracellular Wilms Tumor 1 antigen. Leukemia 31, 1788-1797.
[122]	Rapoport, A.P., Stadtmauer, E.A., Binder-Scholl, G.K., Goloubeva, O., Vogl, D.T., Lacey, S.F., Badros, A.Z., Garfall, A., Weiss, B., Finklestein, J., Kulikovskaya, I., Sinha, S.K., Kronsberg, S., Gupta, M., Bond, S., Melchiori, L., Brewer, J.E., Bennett, A.D., Gerry, A.B., Pumphrey, N.J., Williams, D., Tayton-Martin, H.K., Ribeiro, L., Holdich, T., Yanovich, S., Hardy, N., Yared, J., Kerr, N., Philip, S., Westphal, S., Siegel, D.L., Levine, B.L., Jakobsen, B.K., Kalos, M., June, C.H., 2015. NY-ESO-1-specific TCR-engineered T cells mediate sustained antigen-specific antitumor effects in myeloma. Nat Med 21, 914-921.
[123]	Richman, S.A., Nunez-Cruz, S., Moghimi, B., Li, L.Z., Gershenson, Z.T., Mourelatos, Z., Barrett, D.M., Grupp, S.A., Milone, M.C., 2018. High-affinity GD2-specific CAR T cells induce fatal encephalitis in a preclinical neuroblastoma model. Cancer Immunol Res 6, 36-46.
[124]	Rizvi, N.A., Hellmann, M.D., Snyder, A., Kvistborg, P., Makarov, V., Havel, J.J., Lee, W., Yuan, J., Wong, P., Ho, T.S., Miller, M.L., Rekhtman, N., Moreira, A.L., Ibrahim, F., Bruggeman, C., Gasmi, B., Zappasodi, R., Maeda, Y., Sander, C., Garon, E.B., Merghoub, T., Wolchok, J.D., Schumacher, T.N., Chan, T.A., 2015. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348, 124-128.
[125]	Robbins, P.F., Kassim, S.H., Tran, T.L., Crystal, J.S., Morgan, R.A., Feldman, S.A., Yang, J.C., Dudley, M.E., Wunderlich, J.R., Sherry, R.M., Kammula, U.S., Hughes, M.S., Restifo, N.P., Raffeld, M., Lee, C.C., Li, Y.F., El-Gamil, M., Rosenberg, S.A., 2015. A pilot trial using lymphocytes genetically engineered with an NY-ESO-1-reactive T-cell receptor: long-term follow-up and correlates with response. Clin Cancer Res 21, 1019-1027.
[126]	Robbins, P.F., Li, Y.F., El-Gamil, M., Zhao, Y., Wargo, J.A., Zheng, Z., Xu, H., Morgan, R.A., Feldman, S.A., Johnson, L.A., Bennett, A.D., Dunn, S.M., Mahon, T.M., Jakobsen, B.K., Rosenberg, S.A., 2008. Single and dual amino acid substitutions in TCR CDRs can enhance antigen-specific T cell functions. J Immunol 180, 6116-6131.
[127]	Rosati, S.F., Parkhurst, M.R., Hong, Y., Zheng, Z., Feldman, S.A., Rao, M., Abate-Daga, D., Beard, R.E., Xu, H., Black, M.A., Robbins, P.F., Schrump, D.A., Rosenberg, S.A., Morgan, R.A., 2014. A novel murine T-cell receptor targeting NY-ESO-1. J Immunother 37, 135-146.
[128]	Saeidi, A., Zandi, K., Cheok, Y.Y., Saeidi, H., Wong, W.F., Lee, C.Y.Q., Cheong, H.C., Yong, Y.K., Larsson, M., Shankar, E.M., 2018. T-cell exhaustion in chronic infections: reversing the state of exhaustion and reinvigorating optimal protective immune responses. Front Immunol 9, 2569.
[129]	Sahin, U., Derhovanessian, E., Miller, M., Kloke, B.P., Simon, P., Lower, M., Bukur, V., Tadmor, A.D., Luxemburger, U., Schrors, B., Omokoko, T., Vormehr, M., Albrecht, C., Paruzynski, A., Kuhn, A.N., Buck, J., Heesch, S., Schreeb, K.H., Muller, F., Ortseifer, I., Vogler, I., Godehardt, E., Attig, S., Rae, R., Breitkreuz, A., Tolliver, C., Suchan, M., Martic, G., Hohberger, A., Sorn, P., Diekmann, J., Ciesla, J., Waksmann, O., Bruck, A.K., Witt, M., Zillgen, M., Rothermel, A., Kasemann, B., Langer, D., Bolte, S., Diken, M., Kreiter, S., Nemecek, R., Gebhardt, C., Grabbe, S., Holler, C., Utikal, J., Huber, C., Loquai, C., Tureci, O., 2017. Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature 547, 222-226.
[130]	Sawada, Y., Yoshikawa, T., Nobuoka, D., Shirakawa, H., Kuronuma, T., Motomura, Y., Mizuno, S., Ishii, H., Nakachi, K., Konishi, M., Nakagohri, T., Takahashi, S., Gotohda, N., Takayama, T., Yamao, K., Uesaka, K., Furuse, J., Kinoshita, T., Nakatsura, T., 2012. Phase I trial of a glypican-3-derived peptide vaccine for advanced hepatocellular carcinoma: immunologic evidence and potential for improving overall survival. Clin Cancer Res 18, 3686-3696.
[131]	Schmueck-Henneresse, M., Omer, B., Shum, T., Tashiro, H., Mamonkin, M., Lapteva, N., Sharma, S., Rollins, L., Dotti, G., Reinke, P., Volk, H.D., Rooney, C.M., 2017. Comprehensive approach for identifying the T cell subset origin of CD3 and CD28 antibody-activated chimeric antigen receptor-modified T cells. J Immunol 199, 348-362.
[132]	Schulze, K., Imbeaud, S., Letouze, E., Alexandrov, L.B., Calderaro, J., Rebouissou, S., Couchy, G., Meiller, C., Shinde, J., Soysouvanh, F., Calatayud, A.L., Pinyol, R., Pelletier, L., Balabaud, C., Laurent, A., Blanc, J.F., Mazzaferro, V., Calvo, F., Villanueva, A., Nault, J.C., Bioulac-Sage, P., Stratton, M.R., Llovet, J.M., Zucman-Rossi, J., 2015. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat Genet 47, 505-511.
[133]	Seo, H., Chen, J., Gonzalez-Avalos, E., Samaniego-Castruita, D., Das, A., Wang, Y.H., Lopez-Moyado, I.F., Georges, R.O., Zhang, W., Onodera, A., Wu, C.J., Lu, L.F., Hogan, P.G., Bhandoola, A., Rao, A., 2019. TOX and TOX2 transcription factors cooperate with NR4A transcription factors to impose CD8+ T cell exhaustion. Proc Natl Acad Sci U S A 116, 12410-12415.
[134]	Shimizu, Y., Suzuki, T., Yoshikawa, T., Tsuchiya, N., Sawada, Y., Endo, I., Nakatsura, T., 2018. Cancer immunotherapy-targeted glypican-3 or neoantigens. Cancer Sci 109, 531-541.
[135]	Singh, H., Figliola, M.J., Dawson, M.J., Olivares, S., Zhang, L., Yang, G., Maiti, S., Manuri, P., Senyukov, V., Jena, B., Kebriaei, P., Champlin, R.E., Huls, H., Cooper, L.J., 2013. Manufacture of clinical-grade CD19-specific T cells stably expressing chimeric antigen receptor using Sleeping Beauty system and artificial antigen presenting cells. PLoS One 8, e64138.
[136]	Sommermeyer, D., Hudecek, M., Kosasih, P.L., Gogishvili, T., Maloney, D.G., Turtle, C.J., Riddell, S.R., 2016. Chimeric antigen receptor-modified T cells derived from defined CD8+ and CD4+ subsets confer superior antitumor reactivity in vivo. Leukemia 30, 492-500.
[137]	Spear, T.T., Callender, G.G., Roszkowski, J.J., Moxley, K.M., Simms, P.E., Foley, K.C., Murray, D.C., Scurti, G.M., Li, M., Thomas, J.T., Langerman, A., Garrett-Mayer, E., Zhang, Y., Nishimura, M.I., 2016. TCR gene-modified T cells can efficiently treat established hepatitis C-associated hepatocellular carcinoma tumors. Cancer Immunol Immunother 65, 293-304.
[138]	Srivastava, S., Riddell, S.R., 2015. Engineering CAR-T cells: Design concepts. Trends Immunol 36, 494-502.
[139]	Stadtmauer, E.A., Faitg, T.H., Lowther, D.E., Badros, A.Z., Chagin, K., Dengel, K., Iyengar, M., Melchiori, L., Navenot, J.M., Norry, E., Trivedi, T., Wang, R., Binder, G.K., Amado, R., Rapoport, A.P., 2019. Long-term safety and activity of NY-ESO-1 SPEAR T cells after autologous stem cell transplant for myeloma. Blood Adv 3, 2022-2034.
[140]	Stoiber, S., Cadilha, B.L., Benmebarek, M.R., Lesch, S., Endres, S., Kobold, S., 2019. Limitations in the design of chimeric antigen receptors for cancer Therapy. Cells 8.
[141]	Suryadevara, C.M., Desai, R., Farber, S.H., Choi, B.D., Swartz, A.M., Shen, S.H., Gedeon, P.C., Snyder, D.J., Herndon, J.E., 2nd, Healy, P., Reap, E.A., Archer, G.E., Fecci, P.E., Sampson, J.H., Sanchez-Perez, L., 2019. Preventing Lck activation in CAR T cells confers Treg resistance but requires 4-1BB signaling for them to persist and treat solid tumors in nonlymphodepleted hosts. Clin Cancer Res 25, 358-368.
[142]	Turtle, C.J., Hanafi, L.A., Berger, C., Gooley, T.A., Cherian, S., Hudecek, M., Sommermeyer, D., Melville, K., Pender, B., Budiarto, T.M., Robinson, E., Steevens, N.N., Chaney, C., Soma, L., Chen, X., Yeung, C., Wood, B., Li, D., Cao, J., Heimfeld, S., Jensen, M.C., Riddell, S.R., Maloney, D.G., 2016a. CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J Clin Invest 126, 2123-2138.
[143]	Turtle, C.J., Hanafi, L.A., Berger, C., Hudecek, M., Pender, B., Robinson, E., Hawkins, R., Chaney, C., Cherian, S., Chen, X., Soma, L., Wood, B., Li, D., Heimfeld, S., Riddell, S.R., Maloney, D.G., 2016b. Immunotherapy of non-Hodgkin's lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells. Sci Transl Med 8, 355ra116.
[144]	Wang, D., Aguilar, B., Starr, R., Alizadeh, D., Brito, A., Sarkissian, A., Ostberg, J.R., Forman, S.J., Brown, C.E., 2018. Glioblastoma-targeted CD4+ CAR T cells mediate superior antitumor activity. JCI Insight 3.
[145]	Wang, X., Berger, C., Wong, C.W., Forman, S.J., Riddell, S.R., Jensen, M.C., 2011. Engraftment of human central memory-derived effector CD8+ T cells in immunodeficient mice. Blood 117, 1888-1898.
[146]	Wang, Y., Jiang, H., Luo, H., Sun, Y., Shi, B., Sun, R., Li, Z., 2019. An IL-4/21 Inverted Cytokine Receptor Improving CAR-T Cell Potency in Immunosuppressive Solid-Tumor Microenvironment. Front Immunol 10, 1691.
[147]	Welzel, T.M., Graubard, B.I., Quraishi, S., Zeuzem, S., Davila, J.A., El-Serag, H.B., McGlynn, K.A., 2013. Population-attributable fractions of risk factors for hepatocellular carcinoma in the United States. Am J Gastroenterol 108, 1314-1321.
[148]	Wherry, E.J., 2011. T cell exhaustion. Nat Immunol 12, 492-499.
[149]	Wu, C.Y., Roybal, K.T., Puchner, E.M., Onuffer, J., Lim, W.A., 2015. Remote control of therapeutic T cells through a small molecule-gated chimeric receptor. Science 350, aab4077.
[150]	Xiong, W., Chen, Y., Kang, X., Chen, Z., Zheng, P., Hsu, Y.H., Jang, J.H., Qin, L., Liu, H., Dotti, G., Liu, D., 2018. Immunological synapse predicts effectiveness of chimeric antigen receptor cells. Mol Ther 26, 963-975.
[151]	Xu, Y., Dotti, G., 2016. Selection bias: maintaining less-differentiated T cells for adoptive immunotherapy. J Clin Invest 126, 35-37.
[152]	Xu, Y., Yang, Z., Horan, L.H., Zhang, P., Liu, L., Zimdahl, B., Green, S., Lu, J., Morales, J.F., Barrett, D.M., Grupp, S.A., Chan, V.W., Liu, H., Liu, C., 2018. A novel antibody-TCR (AbTCR) platform combines Fab-based antigen recognition with gamma/delta-TCR signaling to facilitate T-cell cytotoxicity with low cytokine release. Cell Discov 4, 62.
[153]	Xu, Y., Zhang, M., Ramos, C.A., Durett, A., Liu, E., Dakhova, O., Liu, H., Creighton, C.J., Gee, A.P., Heslop, H.E., Rooney, C.M., Savoldo, B., Dotti, G., 2014. Closely related T-memory stem cells correlate with in vivo expansion of CAR.CD19-T cells and are preserved by IL-7 and IL-15. Blood 123, 3750-3759.
[154]	Yan, L., Liu, B., 2019. Critical factors in chimeric antigen receptor-modified T-cell (CAR-T) therapy for solid tumors. Onco Targets Ther 12, 193-204.
[155]	Yanez, L., Sanchez-Escamilla, M., & Perales, M. A. , 2019. CAR T cell toxicity: current management and future directions. HemaSphere 3.
[156]	Yang, Y., Kohler, M.E., Chien, C.D., Sauter, C.T., Jacoby, E., Yan, C., Hu, Y., Wanhainen, K., Qin, H., Fry, T.J., 2017. TCR engagement negatively affects CD8 but not CD4 CAR T cell expansion and leukemic clearance. Sci Transl Med 9.
[157]	Yao, S., Johnson, C., Hu, Q., Yan, L., Liu, B., Ambrosone, C.B., Wang, J., Liu, S., 2016. Differences in somatic mutation landscape of hepatocellular carcinoma in Asian American and European American populations. Oncotarget 7, 40491-40499.
[158]	Yu, M., Luo, H., Fan, M., Wu, X., Shi, B., Di, S., Liu, Y., Pan, Z., Jiang, H., Li, Z., 2018. Development of GPC3-Specific Chimeric Antigen Receptor-Engineered Natural Killer Cells for the Treatment of Hepatocellular Carcinoma. Mol Ther 26, 366-378.
[159]	Zhang, H.H., Mei, M.H., Fei, R., Liao, W.J., Wang, X.Y., Qin, L.L., Wang, J.H., Wei, L., Chen, H.S., 2010. Regulatory T cell depletion enhances tumor specific CD8 T-cell responses, elicited by tumor antigen NY-ESO-1b in hepatocellular carcinoma patients, in vitro. Int J Oncol 36, 841-848.
[160]	Zhang, J., Wang, L., 2019. The Emerging World of TCR-T Cell Trials Against Cancer: A Systematic Review. Technol Cancer Res Treat 18, 1533033819831068.
[161]	Zhang, T., Wu, M.R., Sentman, C.L., 2012. An NKp30-based chimeric antigen receptor promotes T cell effector functions and antitumor efficacy in vivo. J Immunol 189, 2290-2299.
[162]	Zhao, Z., Condomines, M., van der Stegen, S.J.C., Perna, F., Kloss, C.C., Gunset, G., Plotkin, J., Sadelain, M., 2015. Structural design of Engineered Costimulation Determines Tumor Rejection Kinetics and Persistence of CAR T Cells. Cancer Cell 28, 415-428.
[163]	Zhou, Q., Xiao, H., Liu, Y., Peng, Y., Hong, Y., Yagita, H., Chandler, P., Munn, D.H., Mellor, A., Fu, N., He, Y., 2010. Blockade of programmed death-1 pathway rescues the effector function of tumor-infiltrating T cells and enhances the antitumor efficacy of lentivector immunization. J Immunol 185, 5082-5092.
[164]	Zhou, X., Zhu, H., Lu, J., 2015. PTEN and hTERT gene expression and the correlation with human hepatocellular carcinoma. Pathol Res Pract 211, 316-319.
[165]	Zhu, W., Peng, Y., Wang, L., Hong, Y., Jiang, X., Li, Q., Liu, H., Huang, L., Wu, J., Celis, E., Merchen, T., Kruse, E., He, Y., 2018. Identification of alpha-fetoprotein-specific T-cell receptors for hepatocellular carcinoma immunotherapy. Hepatology 68, 574-589.
[166]	Zucman-Rossi, J., Villanueva, A., Nault, J.C., Llovet, J.M., 2015. Genetic landscape and biomarkers of hepatocellular carcinoma. Gastroenterology 149, 1226-1239 e1224.