Anti-KIT designer T cells for the treatment of gastrointestinal stromal tumor

Journal of Translational Medicine

Richard P Junghans²  Jonathan A Fletcher³  N Joseph Espat¹  Cang T Nguyen¹  Doreen Osgood¹  Mitchell Thorn¹  Lauren A Licata¹  Seema Naheed¹  Rachel A Burga¹  Steven C Katz¹ 

[1] Roger Williams Medical Center, Department of Surgery, Providence, RI/Boston University School of Medicine, Boston, MA, USA;Roger Williams Medical Center, Department of Medicine, Providence, RI/Boston University School of Medicine, Boston, MA, USA;Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA

关键词: and Designer T cells;    Immunotherapy;    Adoptive cell therapy;    GIST;   

Others  :  828030
DOI  :  10.1186/1479-5876-11-46

 received in 2012-12-10, accepted in 2013-02-08,  发布年份 2013

【 摘 要 】

Background

Imatinib mesylate is an effective treatment for metastatic gastrointestinal stromal tumor (GIST). However, most patients eventually develop resistance and there are few other treatment options. Immunotherapy using genetically modified or designer T cells (dTc) has gained increased attention for several malignancies in recent years. The aims of this study were to develop and test novel anti-KIT dTc engineered to target GIST cells.

Methods

Human anti-KIT dTc were created by retroviral transduction with novel chimeric immune receptors (CIR). The gene for stem cell factor (SCF), the natural ligand for KIT, was cloned into 1^st generation (SCF-CD3ζ, 1st gen) and 2^nd generation (SCF-CD28-CD3ζ, 2nd gen) CIR constructs. In vitro dTc proliferation and tumoricidal capacity in the presence of KIT+ tumor cells were measured. In vivo assessment of dTc anti-tumor efficacy was performed by treating immunodeficient mice harboring subcutaneous GIST xenografts with dTc tail vein infusions.

Results

We successfully produced the 1^st and 2^nd gen anti-KIT CIR and transduced murine and human T cells. Average transduction efficiencies for human 1^st and 2^nd gen dTc were 50% and 42%. When co-cultured with KIT+ tumor cells, both 1^st and 2^nd gen dTc proliferated and produced IFNγ. Human anti-KIT dTc were efficient at lysing GIST in vitro compared to untransduced T cells. In mice with established GIST xenografts, treatment with either 1^st or 2^nd gen human anti-KIT dTc led to significant reductions in tumor growth rates.

Conclusions

We have constructed a novel anti-KIT CIR for production of dTc that possess specific activity against KIT+ GIST in vitro and in vivo. Further studies are warranted to evaluate the therapeutic potential and safety of anti-KIT dTc.

【 授权许可】

   
2013 Katz et al; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Katz SC, DeMatteo RP: Gastrointestinal stromal tumors and leiomyosarcomas. J Surg Oncol 2008, 97:350-359.
• [2]Parkkila S, Lasota J, Fletcher JA, Ou WB, Kivela AJ, Nuorva K, Parkkila AK, Ollikainen J, Sly WS, Waheed A: Carbonic anhydrase II. A novel biomarker for gastrointestinal stromal tumors. Mod Pathol 2010, 23:743-750.
• [3]Dematteo RP, Ballman KV, Antonescu CR, Maki RG, Pisters PW, Demetri GD, Blackstein ME, Blanke CD, von Mehren M, Brennan MF: Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial. Lancet 2009, 373:1097-1104.
• [4]Janicke RU, Engels IH, Dunkern T, Kaina B, Schulze-Osthoff K, Porter AG: Ionizing radiation but not anticancer drugs causes cell cycle arrest and failure to activate the mitochondrial death pathway in MCF-7 breast carcinoma cells. Oncogene 2001, 20:5043-5053.
• [5]Rosenberg SA, Spiess P, Lafreniere R: A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes. Science 1986, 233:1318-1321.
• [6]Rosenberg SA, Restifo NP, Yang JC, Morgan RA, Dudley ME: Adoptive cell transfer: a clinical path to effective cancer immunotherapy. Nat Rev Cancer 2008, 8:299-308.
• [7]Emtage PC, Lo AS, Gomes EM, Liu DL, Gonzalo-Daganzo RM, Junghans RP: Second-generation anti-carcinoembryonic antigen designer T cells resist activation-induced cell death, proliferate on tumor contact, secrete cytokines, and exhibit superior antitumor activity in vivo: a preclinical evaluation. Clin Cancer Res 2008, 14:8112-8122.
• [8]Sadelain M, Riviere I, Brentjens R: Targeting tumours with genetically enhanced T lymphocytes. Nat Rev Cancer 2003, 3:35-45.
• [9]Schumacher TN: T-cell-receptor gene therapy. Nat Rev Immunol 2002, 2:512-519.
• [10]Stauss HJ, Cesco-Gaspere M, Thomas S, Hart DP, Xue SA, Holler A, Wright G, Perro M, Little AM, Pospori C: Monoclonal T-cell receptors: new reagents for cancer therapy. Mol Ther 2007, 15:1744-1750.
• [11]Porter DL, Levine BL, Kalos M, Bagg A, June CH: Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med 2011, 365:725-733.
• [12]Robbins PF, Morgan RA, Feldman SA, Yang JC, Sherry RM, Dudley ME, Wunderlich JR, Nahvi AV, Helman LJ, Mackall CL: Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J Clin Oncol 2011, 29:917-924.
• [13]Tuveson DA, Willis NA, Jacks T, Griffin JD, Singer S, Fletcher CD, Fletcher JA, Demetri GD: STI571 inactivation of the gastrointestinal stromal tumor c-KIT oncoprotein: biological and clinical implications. Oncogene 2001, 20:5054-5058.
• [14]Bauer S, Yu LK, Demetri GD, Fletcher JA: Heat shock protein 90 inhibition in imatinib-resistant gastrointestinal stromal tumor. Cancer Res 2006, 66:9153-9161.
• [15]Muhlenberg T, Zhang Y, Wagner AJ, Grabellus F, Bradner J, Taeger G, Lang H, Taguchi T, Schuler M, Fletcher JA, Bauer S: Inhibitors of deacetylases suppress oncogenic KIT signaling, acetylate HSP90, and induce apoptosis in gastrointestinal stromal tumors. Cancer Res 2009, 69:6941-6950.
• [16]Takagi S, Saito Y, Hijikata A, Tanaka S, Watanabe T, Hasegawa T, Mochizuki S, Kunisawa J, Kiyono H, Koseki H: Membrane-bound human SCF/KL promotes in vivo human hematopoietic engraftment and myeloid differentiation. Blood 2012, 119:2768-2777.
• [17]Thornton AM, Shevach EM: CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J Exp Med 1998, 188:287-296.
• [18]Balachandran VP, Cavnar MJ, Zeng S, Bamboat ZM, Ocuin LM, Obaid H, Sorenson EC, Popow R, Ariyan C, Rossi F: Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido. Nat Med 2011, 17:1094-1100.
• [19]Ley K, Bullard DC, Arbones ML, Bosse R, Vestweber D, Tedder TF, Beaudet AL: Sequential contribution of L- and P-selectin to leukocyte rolling in vivo. J Exp Med 1995, 181:669-675.
• [20]Yoshida R, Nagira M, Kitaura M, Imagawa N, Imai T, Yoshie O: Secondary lymphoid-tissue chemokine is a functional ligand for the CC chemokine receptor CCR7. J Biol Chem 1998, 273:7118-7122.
• [21]Pouw N, Treffers-Westerlaken E, Kraan J, Wittink F, ten Hagen T, Verweij J, Debets R: Combination of IL-21 and IL-15 enhances tumour-specific cytotoxicity and cytokine production of TCR-transduced primary T cells. Cancer Immunol Immunother 2010, 59:921-931.
• [22]Krause A, Guo HF, Latouche JB, Tan C, Cheung NK, Sadelain M: Antigen-dependent CD28 signaling selectively enhances survival and proliferation in genetically modified activated human primary T lymphocytes. J Exp Med 1998, 188:619-626.
• [23]Lo AS, Ma Q, Liu DL, Junghans RP: Anti-GD3 chimeric sFv-CD28/T-cell receptor zeta designer T cells for treatment of metastatic melanoma and other neuroectodermal tumors. Clin Cancer Res 2010, 16:2769-2780.
• [24]Shevach EM: Mechanisms of foxp3+ T regulatory cell-mediated suppression. Immunity 2009, 30:636-645.
• [25]Broudy VC: Stem cell factor and hematopoiesis. Blood 1997, 90:1345-1364.