Phase I study of chimeric antigen receptor modified T cells in treating HER2-positive advanced biliary tract cancers and pancreatic cancers

Abstract

This phase I clinical trial (NCT01935843) is to evaluate the safety, feasibility, and activity of chimeric antigen receptor-engineered T cell (CART) immunotherapy targeting human epidermal growth factor receptor 2 (HER2) in patients with advanced biliary tract cancers (BTCs) and pancreatic cancers (PCs). Eligible patients with HER2-positive (>50%) BTCs and PCs were enrolled in the trial. Well cultured CART-HER2 cells were infused following the conditioning treatment composed of nabpaclitaxel (100–200 mg/m²) and cyclophosphamide (15–35 mg/kg). CAR transgene copy number in the peripheral blood was serially measured to monitor the expansion and persistence of CART-HER2 cells in vivo. Eleven enrolled patients received 1 to 2-cycle CARTHER2 cell infusion (median CAR⁺ T cell 2.1 × 10⁶/kg). The conditioning treatment resulted in mild-to-moderate fatigue, nausea/vomiting, myalgia/arthralgia, and lymphopenia. Except one grade-3 acute febrile syndrome and one abnormal elevation of transaminase (>9 ULN), adverse events related to the infusion of CART-HER2 cells were mild-to-moderate. Post-infusion toxicities included one case of reversible severe upper gastrointestinal hemorrhage which occurred in a patient with gastric antrum invaded by metastasis 11 days after the CART-HER2 cell infusion, and 2 cases of grade 1–2 delayed fever, accompanied by the release of C-reactive protein and interleukin-6. All patients were evaluable for assessment of clinical response, among which 1 obtained a 4.5-months partial response and 5 achieved stable disease. The median progression free survival was 4.8 months (range, 1.5–8.3 months). Finally, data from this study demonstrated the safety and feasibility of CART-HER2 immunotherapy, and showed encouraging signals of clinical activity.

Keywords

HER2 / CART / biliary tract cancers / pancreatic cancers / clinical trial

References

[1] Abken H (2015) Adoptive therapy with CAR redirected T cells: the challenges in targeting solid tumors. Immunotherapy 7(5):535–544

[2] Ahmed N, Salsman VS, Kew Y, Shaffer D, Powell S, Zhang YJ, Grossman RG, Heslop HE, Gottschalk S (2010) HER2-specific T cells target primary glioblastoma stem cells and induce regression of autologous experimental tumors. Clin Cancer Res. 16 (2):474–485

[3] Ahmed N, Brawley VS, Hegde M, Robertson C, Ghazi A, Gerken C, Liu E, Dakhova O, Ashoori A, Corder A (2015) Human epidermal growth factor receptor 2 (HER2)-specific chimeric antigen receptor-modified T cells for the immunotherapy of HER2-positive sarcoma. J Clin Oncol 33(15):1688–1696

[4] Beatty GL, O’Hara M (2016) Chimeric antigen receptor-modified T cells for the treatment of solid tumors: defining the challenges and next steps. Pharmacol Ther 166:30–39

[5] Cardinale V, Wang Y, Carpino G, Mendel G, Alpini G, Gaudio E, Reid LM, Alvaro D (2012) The biliary tree-a reservoir of multipotent stem cells. Nat Rev Gastroenterol Hepatol 9(4):231–240

[6] Chan E, Berlin J (2015) Biliary tract cancers: understudied and poorly understood. J Clin Oncol 33(16):1845–1848

[7] Cho HS, Mason K, Ramyar KX, Stanley AM, Gabelli SB, Denney DW Jr, Leahy DJ (2003) Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab. Nature 421 (6924):756–760

[8] Dai H, Zhang W, Li X, Han Q, Guo Y, Zhang Y, Wang Y, Wang C, Shi F, Zhang Y (2015) Tolerance and efficacy of autologous or donor derived T cells expressing CD19 chimeric antigen receptors in adult B-ALL with extramedullary leukemia. Oncoimmunology 4(11):e1027469

[9] Dudley ME, Wunderlich JR, Robbins PF, Yang JC, Hwu P, Schwartzentruber DJ, Topalian SL, Sherry R, Restifo NP, Hubicki AM (2002) Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 298(5594):850–854

[10] Hoos A, Eggermont AM, Janetzki S, Hodi FS, Ibrahim R, Anderson A, Humphrey R, Blumenstein B, Old L, Wolchok J (2010) Improved endpoints for cancer immunotherapy trials. J Natl Cancer Inst 102(18):1388–1397

[11] Hynes NE, Lane HA (2005) ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 5(5):341–354

[12] Johnson LA, June CH (2017) Driving gene-engineered T cell immunotherapy of cancer. Cell Res 27(1):38–58

[13] Klebanoff CA, Rosenberg SA, Restifo NP (2016) Prospects for gene-engineered T cell immunotherapy for solid cancers. Nat Med 22(1):26–36

[14] Kochenderfer JN, Dudley ME, Kassim SH, Somerville RP, Carpenter RO, Stetler-Stevenson M, Yang JC, Phan GQ, Hughes MS, Sherry RM (2015) Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J Clin Oncol 33(6):540–549

[15] Liu X, Jiang S, Fang C, Yang S, Olalere D, Pequignot EC, Cogdill AP, Li N, Ramones M, Granda B (2015) Affinity-Tuned ErbB2 or EGFR chimeric antigen receptor T cells exhibit an increased therapeutic index against tumors in mice. Cancer Res 75 (17):3596–3607

[16] Marks EI, Yee NS (2016) Molecular genetics and targeted therapeutics in biliary tract carcinoma. World J Gastroenterol 22 (4):1335–1347

[17] Maus MV, June CH (2016) Making better chimeric antigen receptors for adoptive T-cell therapy. Clin Cancer Res 22(8):1875–1884

[18] Mendelsohn J, Baselga J (2000) The EGF receptor family as targets for cancer therapy. Oncogene 19(56):6550–6565

[19] Morgan RA, Yang JC, Kitano M, Dudley ME, Laurencot CM, Rosenberg SA (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(4):843–851

[20] Nakazawa Y, Huye LE, Salsman VS, Leen AM, Ahmed N, Rollins L, Dotti G, Gottschalk SM, Wilson MH, Rooney CM (2011) PiggyBac-mediated cancer immunotherapy using EBV-specific cytotoxic T-cells expressing HER2-specific chimeric antigen receptor. Mol Ther 19(12):2133–2143

[21] Nam AR, Kim JW, Cha Y,Ha H, Park JE, Bang JH, Jin MH, Lee KH, Kim TY, Han SW (2016) Oncotarget 7(36):58007–58021

[22] Ogo Y, Nio Y, Yano S, Toga T, Koike M, Hashimoto K, Itakura M, Maruyama R (2006) Immunohistochemical expression of HER-1 and HER-2 in extrahepatic biliary carcinoma. Anticancer Res 26 (1B):763–770

[23] Park JH, Geyer MB, Brentjens RJ (2016) CD19-targeted CAR T-cell therapeutics for hematologic malignancies: interpreting clinical outcomes to date. Blood 127(26):3312–3320

[24] Porter DL, Hwang WT, Frey NV, Lacey SF, Shaw PA, Loren AW, Bagg A, Marcucci KT, Shen A, Gonzalez V (2015) Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med 7(303):303139

[25] Ryan DP, Hong TS, Bardeesy N (2014) Pancreatic adenocarcinoma. N Engl J Med 371(11):1039–1049

[26] Song YJ, Tong C, Wang Y, Gao YH, Dai HR, Guo Y, Zhao XD, Wang Y,Wang ZZ, Han WD (2017) Effective and persistent antitumor activity of HER2-directed CAR-T cells against gastric cancer cells in vitro and xenotransplanted tumors in vivo. Protein Cell.

[27] Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J,Jemal A (2015) Global cancer statistics 2012. CA Cancer J Clin 65(2):87–108

[28] Von Hoff DD, Ramanathan RK, Borad MJ, Laheru DA, Smith LS, Wood TE, Korn RL, Desai N, Trieu V, Iglesias JL (2011) Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol 29(34):4548–4554

[29] Wang Y, Bo J, Dai HR, Lu XC, Lv HY, Yang B, Wang T, Han WD (2013) CIK cells from recurrent or refractory AML patients can be efficiently expanded in vitro and used for reduction of leukemic blasts in vivo. Exp Hematol 41(241–252):e243

[30] Wang Y, Zhang WY, Han QW, Liu Y, Dai HR, Guo YL, Bo J, Fan H, Zhang Y, Zhang YJ (2014) Effective response and delayed toxicities of refractory advanced diffuse large B-cell lymphoma treated by CD20-directed chimeric antigen receptor-modified T cells. Clin Immunol 155(2):160–175

[31] Wolchok JD, Hoos A, O’Day S, Weber JS, Hamid O, Lebbé C, Maio M, Binder M, Bohnsack O, Nichol G (2009) Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res 15 (23):7412–7420

[32] Yan M, Schwaederle M, Arguello D, Millis SZ, Gatalica Z, Kurzrock R (2015) HER2 expression status in diverse cancers: review of results from 37,992 patients. Cancer Metastasis Rev 34(1):157–164

[33] Zhang Y, Banerjee S, Wang Z, Xu H, Zhang L, Mohammad R, Aboukameel A, Adsay NV, Che M, Abbruzzese JL (2006) Antitumor activity of epidermal growth factor receptor-related protein is mediated by inactivation of ErbB receptors and nuclear factor-kappaB in pancreatic cancer. Cancer Res 66(2):1025–1032

[34] Zhang Z, Oyesanya RA, Campbell DJ, Almenara JA, Dewitt JL, Sirica AE (2010) Preclinical assessment of simultaneous targeting of epidermal growth factor receptor (ErbB1) and ErbB2 as a strategy for cholangiocarcinoma therapy. Hepatology 52(3):975–986

RIGHTS & PERMISSIONS

2017 The Author(s) 2017. This article is an open access publication