Efficacy and biomarker analysis of CD133-directed CAR T cells in advanced hepatocellular carcinoma: a single-arm, open-label, phase II trial

Hanren Dai, Chuan Tong, Daiwei Shi, Meixia Chen, Yelei Guo, Deyun Chen, Xiao Han, Hua Wang, Yao Wang, Pingping Shen, Hanren Dai, Chuan Tong, Daiwei Shi, Meixia Chen, Yelei Guo, Deyun Chen, Xiao Han, Hua Wang, Yao Wang, Pingping Shen

Abstract

Expressed by cancer stem cells of various epithelial cell origins and hepatocellular carcinoma (HCC), CD133 is an attractive therapeutic target for HCC. The marker CD133 is highly expressed in endothelial progenitor cells (EPC). EPCs circulate in increased numbers in the peripheral blood of patients with highly vascularized HCC and contribute to angiogenesis and neovascularization. This phase II study investigated CD133-directed chimeric antigen receptor (CAR) T (CART-133) cells in adults with HCC. Patients with histologically confirmed and measurable advanced HCC and adequate hematologic, hepatic, and renal functions received CART-133 cell infusions. The primary endpoints were safety in phase I and progression-free survival (PFS) and overall survival (OS) in phase II. Other endpoints included biomarkers for CART-133 T cell therapy. Between June 1, 2015, and September 1, 2017, this study enrolled 21 patients who subsequently received CART-133 T cells across phases I and II. The median OS was 12 months (95% CI, 9.3-15.3 months) and the median PFS was 6.8 months (95% CI, 4.3-8.4 months). Of 21 evaluable patients, 1 had a partial response, 14 had stable disease for 2 to 16.3 months, and 6 progressed after T-cell infusion. The most common high-grade adverse event was hyperbilirubinemia. Outcome was correlated with the baseline levels of vascular endothelial growth factor (VEGF), soluble VEGF receptor 2 (sVEGFR2), stromal cell-derived factor (SDF)-1, and EPC counts. Changes in EPC counts, VEGF, SDF-1, sVEGFR2, and interferon (IFN)-γ after cell infusion were associated with survival. In patients with previously treated advanced HCC, CART-133 cell therapy demonstrates promising antitumor activity and a manageable safety profile. We identified early changes in circulating molecules as potential biomarkers of response to CART-133 cells. The predictive value of these proangiogenic and inflammatory factors as potential biomarkers of CART-133 cell therapy in HCC will be explored in prospective trials. This study is registered at ClinicalTrials.gov (NCT02541370).

Keywords: CD133; Hepatocellular carcinoma; biomarker; chimeric antigen receptor.

© 2020 The Author(s). Published with license by Taylor & Francis Group, LLC.

Figures

Figure 1.
Figure 1.
Kaplan-Meier estimates of progression-free and overall survival

References

    1. F. Bray, J. Ferlay, I. Soerjomataram, R.L. Siegel, L.A. Torre, A. Jemal. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–8. doi:10.3322/caac.21492.
    1. 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(4):908–943. doi:10.1016/j.jhep.2011.12.001.
    1. G.K. Abou-Alfa, T. Meyer, A.L. Cheng, A.B. El-Khoueiry, L. Rimassa, B.Y. Ryoo, I. Cicin, P. Merle, Y. Chen, J.W. Park, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med. 2018;379(1):54–63. doi:10.1056/NEJMoa1717002.
    1. J.M. Llovet, S. Ricci, V. Mazzaferro, P. Hilgard, E. Gane, J.F. Blanc, A.C. de Oliveira, A. Santoro, J.L. Raoul, A. Forner, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378–390. doi:10.1056/NEJMoa0708857.
    1. M. Kudo, R.S. Finn, S. Qin, K.H. Han, K. Ikeda, F. Piscaglia, A. Baron, J.W. Park, G. Han, J. Jassem, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391(10126):1163–1173. doi:10.1016/S0140-6736(18)30207-1.
    1. J. Bruix, S. Qin, P. Merle, A. Granito, Y.H. Huang, G. Bodoky, M. Pracht, O. Yokosuka, O. Rosmorduc, V. Breder, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389(10064):56–66. doi:10.1016/S0140-6736(16)32453-9.
    1. A.B. El-Khoueiry, B. Sangro, T. Yau, T.S. Crocenzi, M. Kudo, C. Hsu, T.Y. Kim, S.P. Choo, J. Trojan, T.H.R. Welling, 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. 2017;389(10088):2492–2502. doi:10.1016/S0140-6736(17)31046-2.
    1. de Visser KE, Eichten A, Coussens LM.. Paradoxical roles of the immune system during cancer development. Nat Rev Cancer. 2006;6(1):24–37. doi:10.1038/nrc1782.
    1. Murdoch C, Muthana M, Coffelt SB, Lewis CE. The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer. 2008;8:618–631.
    1. De Palma M, Venneri MA, Roca C, Naldini L. Targeting exogenous genes to tumor angiogenesis by transplantation of genetically modified hematopoietic stem cells. Nat Med. 2003;9(6):789–795. doi:10.1038/nm871.
    1. F. Shojaei, X. Wu, A.K. Malik, C. Zhong, M.E. Baldwin, S. Schanz, G. Fuh, H.P. Gerber, N. Ferrara. Tumor refractoriness to anti-VEGF treatment is mediated by CD11b+Gr1+ myeloid cells. Nat Biotechnol. 2007;25(8):911–920. doi:10.1038/nbt1323.
    1. Ribatti D. The involvement of endothelial progenitor cells in tumor angiogenesis. J Cell Mol Med. 2004;8(3):294–300. doi:10.1111/j.1582-4934.2004.tb00319.x.
    1. J.W. Ho, R.W. Pang, C. Lau, C.K. Sun, W.C. Yu, S.T. Fan, R.T. Poon. Significance of circulating endothelial progenitor cells in hepatocellular carcinoma. Hepatology. 2006;44(4):836–843. doi:10.1002/hep.21353.
    1. D. Gao, D.J. Nolan, A.S. Mellick, K. Bambino, K. McDonnell, V. Mittal. Endothelial progenitor cells control the angiogenic switch in mouse lung metastasis. Science. 2008;319(5860):195–198. doi:10.1126/science.1150224.
    1. Y. Shaked, E. Henke, J.M. Roodhart, P. Mancuso, M.H. Langenberg, M. Colleoni, L.G. Daenen, S. Man, P. Xu, U. Emmenegger, T. Tang, et al. Rapid chemotherapy-induced acute endothelial progenitor cell mobilization: implications for antiangiogenic drugs as chemosensitizing agents. Cancer Cell. 2008;14(3):263–273. doi:10.1016/j.ccr.2008.08.001.
    1. D. Yu, X. Sun, Y. Qiu, J. Zhou, Y. Wu, L. Zhuang, J. Chen, Y. Ding. Identification and clinical significance of mobilized endothelial progenitor cells in tumor vasculogenesis of hepatocellular carcinoma. Clin Cancer Res. 2007;13(13):3814–3824. doi:10.1158/1078-0432.CCR-06-2594.
    1. X.T. Sun, X.W. Yuan, H.T. Zhu, Z.M. Deng, D.C. Yu, X. Zhou, Y.T. Ding. Endothelial precursor cells promote angiogenesis in hepatocellular carcinoma. World J Gastroenterol. 2012;18(35):4925–4933. doi:10.3748/wjg.v18.i35.4925.
    1. W. Song, H. Li, K. Tao, R. Li, Z. Song, Q. Zhao, F. Zhang, K. Dou. Expression and clinical significance of the stem cell marker CD133 in hepatocellular carcinoma. Int J Clin Pract. 2008;62(8):1212–1218. doi:10.1111/j.1742-1241.2008.01777.x.
    1. C. Won, B.H. Kim, E.H. Yi, K.J. Choi, E.K. Kim, J.M. Jeong, J.H. Lee, J.J. Jang, J.H. Yoon, W.I. Jeong, et al. Signal transducer and activator of transcription 3-mediated CD133 up-regulation contributes to promotion of hepatocellular carcinoma. Hepatology. 2015;62(4):1160–1173. doi:10.1002/hep.27968.
    1. L.M. Smith, A. Nesterova, M.C. Ryan, S. Duniho, M. Jonas, M. Anderson, R.F. Zabinski, M.K. Sutherland, H.P. Gerber, K.L. Van Orden, et al. CD133/prominin-1 is a potential therapeutic target for antibody-drug conjugates in hepatocellular and gastric cancers. Br J Cancer. 2008;99(1):100–109. doi:10.1038/sj.bjc.6604437.
    1. K. Kohga, T. Tatsumi, T. Takehara, H. Tsunematsu, S. Shimizu, M. Yamamoto, A. Sasakawa, T. Miyagi, N. Hayashi. Expression of CD133 confers malignant potential by regulating metalloproteinases in human hepatocellular carcinoma. J Hepatol. 2010;52(6):872–879. doi:10.1016/j.jhep.2009.12.030.
    1. X.R. Yang, Y. Xu, B. Yu, J. Zhou, S.J. Qiu, G.M. Shi, B.H. Zhang, W.Z. Wu, Y.H. Shi, B. Wu, G.H. Yang, et al. High expression levels of putative hepatic stem/progenitor cell biomarkers related to tumour angiogenesis and poor prognosis of hepatocellular carcinoma. Gut. 2010;59(7):953–962. doi:10.1136/gut.2008.176271.
    1. Hristov M, Weber C. Endothelial progenitor cells: characterization, pathophysiology, and possible clinical relevance. J Cell Mol Med. 2004;8(4):498–508. doi:10.1111/j.1582-4934.2004.tb00474.x.
    1. M. Peichev, A.J. Naiyer, D. Pereira, Z. Zhu, W.J. Lane, M. Williams, M.C. Oz, D.J. Hicklin, L. Witte, M.A. Moore, S. Rafii. Expression of VEGFR-2 and AC133 by circulating human CD34(+) cells identifies a population of functional endothelial precursors. Blood. 2000;95:952–958.
    1. Y. Duan, S. Yu, P. Xu, X. Wang, X. Feng, Z. Mao, C. Gao. Co-immobilization of CD133 antibodies, vascular endothelial growth factors, and REDV peptide promotes capture, proliferation, and differentiation of endothelial progenitor cells. Acta Biomater. 2019;96:137–148. doi:10.1016/j.actbio.2019.07.004.
    1. Schmohl JU, Vallera DA. CD133, selectively targeting the root of cancer.
    1. Y. Wang, M. Chen, Z. Wu, C. Tong, H. Dai, Y. Guo, Y. Liu, J. Huang, H. Lv, C. Luo, et al. CD133-directed CAR T cells for advanced metastasis malignancies: A phase I trial. Oncoimmunology. 2018;7(7):e1440169. doi:10.1080/2162402X.2018.1440169.
    1. Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, Grupp SA, Mackall CL. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014;124(2):188–195. doi:10.1182/blood-2014-05-552729.
    1. S.G. Kalathil, A.A. Lugade, R. Iyer, A. Miller, Y. Thanavala. Endothelial progenitor cell number and ERK phosphorylation serve as predictive and prognostic biomarkers in advanced hepatocellular carcinoma patients treated with sorafenib. Oncoimmunology. 2016;5(10):e1226718. doi:10.1080/2162402X.2016.1226718.
    1. F.C. Thistlethwaite, D.E. Gilham, R.D. Guest, D.G. Rothwell, M. Pillai, D.J. Burt, A.J. Byatte, N. Kirillova, J.W. Valle, S.K. Sharma, et al. The clinical efficacy of first-generation carcinoembryonic antigen (CEACAM5)-specific CAR T cells is limited by poor persistence and transient pre-conditioning-dependent respiratory toxicity. Cancer Immunol Immunother. 2017;66(11):1425–1436. doi:10.1007/s00262-017-2034-7.
    1. S.C. Katz, R.A. Burga, E. McCormack, L.J. Wang, W. Mooring, G.R. Point, P.D. Khare, M. Thorn, Q. Ma, B.F. Stainken, 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(14):3149–3159. doi:10.1158/1078-0432.CCR-14-1421.
    1. Y.T. Shih, M.C. Wang, J. Zhou, H.H. Peng, D.Y. Lee, J.J. Chiu. Endothelial progenitors promote hepatocarcinoma intrahepatic metastasis through monocyte chemotactic protein-1 induction of microRNA-21. Gut. 2015;64:1132–1147.
    1. Ramjiawan RR, Griffioen AW, Duda DG. Anti-angiogenesis for cancer revisited: is there a role for combinations with immunotherapy? Angiogenesis. 2017;20:185–204.
    1. J.R. van Beijnum, P. Nowak-Sliwinska, E.J. Huijbers, V.L. Thijssen, A.W. Griffioen. The great escape; the hallmarks of resistance to antiangiogenic therapy. Pharmacol Rev. 2015;67:441–461.
    1. Y.J. Xie, M. Dougan, N. Jailkhani, J. Ingram, T. Fang, L. Kummer, N. Momin, N. Pishesha, S. Rickelt, R.O. Hynes, H. Ploegh. Nanobody-based CAR T cells that target the tumor microenvironment inhibit the growth of solid tumors in immunocompetent mice. Proc Natl Acad Sci U S A. 2019;116(16):7624–7631. doi:10.1073/pnas.1817147116.
    1. Akbari P, Huijbers EJM, Themeli M, Griffioen AW, van Beijnum JR. The tumor vasculature an attractive CAR T cell target in solid tumors. Angiogenesis. 2019;22(4):473–475. doi:10.1007/s10456-019-09687-9.
    1. D. Shi, Y. Shi, A.O. Kaseb, X. Qi, Y. Zhang, J. Chi, Q. Lu, H. Gao, H. Jiang, H. Wang, et al. Chimeric antigen receptor-glypican-3 T-Cell therapy for advanced hepatocellular carcinoma: results of phase I trials. Clin Cancer Res. 2020;26(15):3979–3989. doi:10.1158/1078-0432.CCR-19-3259.
    1. D. Li, N. Li, Y.F. Zhang, H. Fu, M. Feng, D. Schneider, L. Su, X. Wu, J. Zhou, S. Mackay, et al. Persistent polyfunctional chimeric antigen receptor T cells that target glypican 3 eliminate orthotopic hepatocellular carcinomas in mice. Gastroenterology. 2020;158(8):2250–2265 e2220. doi:10.1053/j.gastro.2020.02.011.
    1. Huang M, Deng J, Gao L, Zhou J. Innovative strategies to advance CAR T cell therapy for solid tumors. Am J Cancer Res. 2020;10:1979–1992.
    1. N. Ahmed, V.S. Brawley, M. Hegde, C. Robertson, A. Ghazi, C. Gerken, E. Liu, O. Dakhova, A. Ashoori, A. Corder, et al. Human epidermal growth factor receptor 2 (her2) -specific chimeric antigen receptor-modified T cells for the immunotherapy of HER2-positive sarcoma. J Clin Oncol. 2015;33(15):1688–1696. doi:10.1200/JCO.2014.58.0225.
    1. N. Ahmed, V. Brawley, M. Hegde, K. Bielamowicz, M. Kalra, D. Landi, C. Robertson, T.L. Gray, O. Diouf, A. Wakefield, et al. HER2-specific chimeric antigen receptor-modified virus-specific T cells for progressive glioblastoma: a phase 1 dose-escalation trial. JAMA Oncol. 2017;3(8):1094–1101. doi:10.1001/jamaoncol.2017.0184.
    1. D.L. Porter, B.L. Levine, M. Kalos, A. Bagg and C.H. June. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011;365(8):725–733. doi:10.1056/NEJMoa1103849.
    1. B. Savoldo, C.A. Ramos, E. Liu, M.P. Mims, M.J. Keating, G. Carrum, R.T. Kamble, C.M. Bollard, A.P. Gee, Z. Mei, et al. CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. J Clin Invest. 2011;121(5):1822–1826. doi:10.1172/JCI46110.
    1. Weigmann A, Corbeil D, Hellwig A, Huttner WB. Prominin, a novel microvilli-specific polytopic membrane protein of the apical surface of epithelial cells, is targeted to plasmalemmal protrusions of non-epithelial cells. Proc Natl Acad Sci U S A. 1997;94(23):12425–12430. doi:10.1073/pnas.94.23.12425.
    1. A.H. Yin, S. Miraglia, E.D. Zanjani, G. Almeida-Porada, M. Ogawa, A.G. Leary, J. Olweus, J. Kearney, D.W. Buck. AC133, a novel marker for human hematopoietic stem and progenitor cells. Blood. 1997;90(12):5002–5012. doi:10.1182/blood.V90.12.5002.
    1. L. Mauge, A. Mejean, L. Fournier, H. Pereira, M.C. Etienne-Grimaldi, E. Levionnois, A. Caty, S. Abadie-Lacourtoisie, S. Culine, S. Le Moulec, et al. Sunitinib prior to planned nephrectomy in metastatic renal cell carcinoma: angiogenesis biomarkers predict clinical outcome in the prospective phase II PREINSUT trial. Clin Cancer Res. 2018;24(22):5534–5542. doi:10.1158/1078-0432.CCR-18-1045.
    1. Batchelor TT, Duda DG, Di Tomaso E, et al. Phase II study of cediranib, an oral pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. J Clin Oncol. 2010;28(17):2817–2823. doi:10.1200/JCO.2009.26.3988.
    1. P. Federico, A. Petrillo, P. Giordano, D. Bosso, A. Fabbrocini, M. Ottaviano, M. Rosanova, A. Silvestri, A. Tufo, A. Cozzolino, B. Daniele. Immune checkpoint inhibitors in hepatocellular carcinoma: current status and novel perspectives. Cancers (Basel). 2020;12.
    1. Nishida N, Kudo M. Immune checkpoint blockade for the treatment of human hepatocellular carcinoma. Hepatol Res. 2018;48(8):622–634. doi:10.1111/hepr.13191.
    1. Yoon DH, Osborn MJ, Tolar J, Kim CJ. Incorporation of immune checkpoint blockade into chimeric antigen receptor T cells (CAR-Ts): combination or built-in CAR-T. Int J Mol Sci. 2018 January24;19(2):340. doi:10.3390/ijms19020340.
    1. Galon J, Bruni D. Approaches to treat immune hot, altered and cold tumours with combination immunotherapies. Nat Rev Drug Discov. 2019;18:197–218.
    1. M. Hilmi, C. Neuzillet, J. Calderaro, F. Lafdil, J.M. Pawlotsky, B. Rousseau. Angiogenesis and immune checkpoint inhibitors as therapies for hepatocellular carcinoma: current knowledge and future research directions. J Immunother Cancer. 2019;7(1):333. doi:10.1186/s40425-019-0824-5.

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner