Preclinical development of T-cell receptor-engineered T-cell therapy targeting the 5T4 tumor antigen on renal cell carcinoma

Abstract

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; 5T4p17). In this report, targeted single-cell RNA sequencing was performed on 5T4p17-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 5T4p17 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 5T4p17 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 5T4p17 in TAP1/2-deficient T2 target-cells. TCR-transduced T-cells redirected to recognize the 5T4p17 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.Electronic supplementary materialThe online version of this article (10.1007/s00262-019-02419-4) contains supplementary material, which is available to authorized users.

Comprehensive Analysis of the Potential Immune-Related Biomarker Transporter Associated With Antigen Processing 1 That Inhibits Metastasis and Invasion of Ovarian Cancer Cells

“…Seliger et al reported that miR-200a-5p reduced HLA-I expression on the membrane of melanoma tumor cells by downregulating the level of TAP1, causing the tumor cells to escape the immune system and reducing the survival time of tumor patients (Lazaridou et al, 2020). In this study, we analyzed the data derived from TCGA database and GTEx database and found that TAP1 expression was elevated in lung cancer, breast cancer, pancreatic cancer, renal cell carcinoma, and other tumors and was correlated with the survival state of patients, which was consistent with the findings reported previously (Xu et al, 2013;Xu et al, 2019). Moreover, our results showed that TAP1 expression levels were increased in gynecological tumors, including OC, CC, and endometrial cancer.…”

Current status of antigen-specific T-cell immunotherapy for advanced renal-cell carcinoma

“…Our group has sequenced the TCRs from seven high avidity CTL clones recognizing a defined HLA-A2 presented 5T4 epitope. 151 CD8 + T-cells from healthy donors transduced with these 5T4-specific TCRs recognized 5T4-expressing tumor lines and primary RCC tumors, but not normal renal tubular epithelial cells. Clinical testing of TCR engineered T-cells redirected to target 5T4 would closely parallel the emerging success with engineered T-cells targeting single cancer-testis class antigens NY-ESO-1 and MAGE-A4 in other solid tumors.…”

T-Cell Gene Therapy in Cancer Immunotherapy: Why It Is No Longer Just CARs on The Road

“…However, efficacy against solid cancers is still unknown, so the results of these clinical trials will be invaluable. There is evidence in some solid cancers of CAR immune infiltrations at tumour sites including a phase I/II trial with HER2-targeting CARs in sarcoma [ 22 ], a preclinical study of WT4-targeting CARs in renal cell carcinoma [ 23 ] and a xenogeneic model targeting glypican-1 in multiple solid tumours [ 24 ], a potential sign that CARs may be beneficial even in some solid cancers. Indeed, the development of TRUCKs ( Figure 2 ) is one method to improve solid tumour efficacy, by site-directed release of cytokine in order to improve survival of CAR TILs by changing the tumour microenvironment [ 25 ].…”