38 research outputs found
Future perspectives in melanoma research: meeting report from the "Melanoma Bridge", Napoli, December 5th-8th 2013
Exposure to Melan-A/MART-126-35 tumor epitope specific CD8+T cells reveals immune escape by affecting the ubiquitin-proteasome system (UPS)
c-Myc and EBV–LMP1: two opposing regulators of the HLA class I antigen presentation machinery in epithelial cells
Effect of oral anticoagulant therapy on mortality in end-stage renal disease patients with atrial fibrillation: a prospective study
JAK1 truncating mutations in gynecologic cancer define new role of cancer-associated protein tyrosine kinase aberrations
Preclinical development of T-cell receptor-engineered T-cell therapy targeting the 5T4 tumor antigen on renal cell carcinoma
5T4 (trophoblast glycoprotein, TPBG) is a transmembrane tumor antigen expressed on more than 90% of primary renal cell carcinomas (RCC) and a wide range of human carcinomas but not on most somatic adult tissues. The favorable expression pattern has encouraged the development and clinical testing of 5T4-targeted antibody and vaccine therapies. 5T4 also represents a compelling and unexplored target for T-cell receptor (TCR)-engineered T-cell therapy. Our group has previously isolated high-avidity CD8
+
T-cell clones specific for an HLA-A2-restricted 5T4 epitope (residues 17–25; 5T4
p17
). In this report, targeted single-cell RNA sequencing was performed on 5T4
p17
-specific T-cell clones to sequence the highly variable complementarity-determining region 3 (
CDR3
) of T-cell receptor α chain (
TRA
) and β chain (
TRB
) genes. Full-length
TRA
and
TRB
sequences were cloned into lentiviral vectors and transduced into CD8
+
T-cells from healthy donors. Redirected effector T-cell function against 5T4
p17
was measured by cytotoxicity and cytokine release assays. Seven unique
TRA
-
TRB
pairs were identified. All seven TCRs exhibited high expression on CD8
+
T-cells with transduction efficiencies from 59 to 89%. TCR-transduced CD8
+
T-cells demonstrated redirected cytotoxicity and cytokine release in response to 5T4
p17
on target-cells and killed 5T4
+
/HLA-A2
+
kidney-, breast-, and colorectal-tumor cell lines as well as primary RCC tumor cells in vitro. TCR-transduced CD8
+
T-cells also detected presentation of 5T4
p17
in
TAP1/2
-deficient T2 target-cells. TCR-transduced T-cells redirected to recognize the 5T4
p17
epitope from a broadly shared tumor antigen are of interest for future testing as a cellular immunotherapy strategy for HLA-A2
+
subjects with 5T4
+
tumors