Abstract
Melanoma tumors are known to harbor a high number of mutations leading to the expression of neo-antigens which can be recognized by the patient adaptive immune system. In this regard, immunotherapies involving adoptive cell transfer (ACT) of tumor-specific T-cells constitute a promising approach to treat melanoma. However, these cells do not always preexist in the patient or are difficult to isolate and/or expand. Thus, as the specificity of T-lymphocytes is determined by their T-cell receptor (TCR), it is possible to convert peripheral T-cells into cancer specific lymphocytes by transducing them to express a receptor that recognizes a defined tumor epitope. To this end, retroviral vectors can be used to efficiently transduce actively dividing cells such as proliferating T cells, while being relatively safe to the user. As we show herein, this approach is powerful and can be easily implemented, paving the way to the development of advanced research tools and potent clinical immunotherapeutic strategies.
References
Vogelstein B et al (2013) Cancer genome landscapes. Science 339:1546–1558
Tran E et al (2014) Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science 344:641–645
Robbins PF et al (2013) Mining exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumor-reactive T cells. Nat Med 19:747–752
Vigneron N, Stroobant V, Van den Eynde BJ, van der Bruggen P (2013) Database of T cell-defined human tumor antigens: the 2013 update. Cancer Immun 13:15
Dudley ME et al (2005) Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol 23:2346–2357
Haga-Friedman A, Horovitz-Fried M, Cohen CJ (2012) Incorporation of transmembrane hydrophobic mutations in the TCR enhance its surface expression and T cell functional avidity. J Immunol 1950(188):5538–5546
Tal Y et al (2014) An NCR1-based chimeric receptor endows T-cells with multiple anti-tumor specificities. Oncotarget 5
Ankri C, Shamalov K, Horovitz-Fried M, Mauer S, Cohen CJ (1950) Human T (2013) cells engineered to express a programmed death 1/28 costimulatory retargeting molecule display enhanced antitumor activity. J Immunol 191:4121–4129
Warnock JN, Daigre C, Al-Rubeai M (2011) Introduction to viral vectors. Methods Mol Biol 737:1–25
Hu WS, Pathak VK (2000) Design of retroviral vectors and helper cells for gene therapy. Pharmacol Rev 52:493–511
Wargo JA et al (2009) Recognition of NY-ESO-1+ tumor cells by engineered lymphocytes is enhanced by improved vector design and epigenetic modulation of tumor antigen expression. Cancer Immunol Immunother 58:383–394
Merhavi-Shoham E, Haga-Friedman A, Cohen CJ (2012) Genetically modulating T-cell function to target cancer. Semin Cancer Biol 22:14–22
Morgan RA et al (2006) Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314:126–129
Tsukamoto T et al (1999) Isolation of oncogenes from rat mammary tumors by a highly efficient retrovirus expression cloning system. Biochem Biophys Res Commun 265:7–12
Schaft N et al (2003) Peptide fine specificity of anti-glycoprotein 100 CTL is preserved following transfer of engineered TCR alpha beta genes into primary human T lymphocytes. J Immunol 1950(170):2186–2194
Kerkar SP et al (2001) Genetic engineering of murine CD8+ and CD4+ T cells for preclinical adoptive immunotherapy studies. J Immunother 34:343–352
Daniel-Meshulam I, Horovitz-Fried M, Cohen CJ (2013) Enhanced antitumor activity mediated by human 4-1BB-engineered T cells. Int J Cancer 133:2903–2913
Kimizuka F et al (1991) Production and characterization of functional domains of human fibronectin expressed in Escherichia coli. J Biochem (Tokyo) 110:284–291
Moritz T et al (1996) Fibronectin improves transduction of reconstituting hematopoietic stem cells by retroviral vectors: evidence of direct viral binding to chymotryptic carboxy-terminal fragments. Blood 88:855–862
Acknowledgments
This work was supported by the Israel Science foundation (1457/12) and the Israel ministry of Health.
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Weizman, E., Cohen, C.J. (2015). Engineering T-Cell Specificity Genetically to Generate Anti-melanoma Reactivity. In: Methods in Molecular Biology. Humana Press. https://doi.org/10.1007/7651_2015_297
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DOI: https://doi.org/10.1007/7651_2015_297
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