Exploiting T cell receptor genes for cancer immunotherapy

Abstract

SummaryAdoptive antigen-specific immunotherapy is an attractive concept for the treatment of cancer because it does not require immunocompetence of patients, and the specificity of transferred lymphocytes can be targeted against tumour-associated antigens that are poorly immunogenic and thus fail to effectively trigger autologous T cell responses. As the isolation and in vitro expansion of antigen-specific lymphocytes is difficult, 'conventional' adoptive T cell therapy can only be carried out in specialized centres in small numbers of patients. However, T cell receptor (

Enhanced Antitumor Activity of Murine-Human Hybrid T-Cell Receptor (TCR) in Human Lymphocytes Is Associated with Improved Pairing and TCR/CD3 Stability

“…We sought to determine if the enhanced surface expression of TCRs with murine constant regions was correlated with a higher biological activity. OKT-3-stimulated human PBLs were electroporated with the TCR a and h chains from the original and hybrid forms of the anti-p53 TCR or the anti-MART-1 TCR and cocultured overnight with T2 cells that were pulsed with specific (p53 264-272 or MART-1/27L [26][27][28][29][30][31][32][33][34][35] peptide, respectively) and nonspecific peptides. Although both forms of the p53 or MART TCR mediated antigen-specific IFN-g release, the original p53-MM mediated secretion of more than twice the amount of IFN-g compared with the humanized p53-MH (57,800 versus 25,600 pg/mL).…”

“…The sequences of the peptide used in this study are as follows: p53 264-272 (LLGRNSFEV), MART-1/27L [26][27][28][29][30][31][32][33][34][35] (ELAGIGILTV), gp100 210 M 209-217 (IMDQVPFSV), gp100 280-288 (YLEPGPVTA), HBVc 23Y [18][19][20][21][22][23][24][25][26][27] (FLPSDYFPSV), Flu-MP 58-66 (GILGFVFTL), and NY-ESO-1 161-180 (WITQCFLPVFLAQPPSGQRA).…”

Transfer of mRNA encoding recombinant immunoreceptors reprograms CD4+ and CD8+ T cells for use in the adoptive immunotherapy of cancer

“…1,2 However, the peripheral T-cell repertoire is usually devoid of high-avidity tumor-specific CTLs due to thymic selection. 3 Tumor-specific CTLs are moreover often anergic or exhibit a limited life span. [3][4][5] Transgenic expression of a T-cell receptor (TCR) aims to circumvent these constraints.…”

“…3 Tumor-specific CTLs are moreover often anergic or exhibit a limited life span. [3][4][5] Transgenic expression of a T-cell receptor (TCR) aims to circumvent these constraints. Ex vivo T cells from the peripheral blood of healthy donors, as well as of cancer patients, can be retrovirally transduced to express a TCR to reprogram the T cell with a new specificity.…”

Direct and indirect antitumor effects by human peripheral blood lymphocytes expressing both chimeric immune receptor and interleukin-2 in ovarian cancer xenograft model

“…5 The peripheral T-cell repertoire is usually without high-avidity tumor-specific cytotoxic T lymphocytes due to thymic selection. 6 Moreover, tumor-specific cytotoxic T lymphocytes are often anergic or show a limited life span. 3,7 Even if T cells with high avidity for antigens are generated, adoptive immunotherapy cannot be guaranteed to be successful because of the uncertainty of its persistency and reactivity in vivo.…”