Cancer targeting by TCR gene-engineered T cells directed against Kita-Kyushu Lung Cancer Antigen-1

Abstract

T cell receptor (TCR) gene-engineered T cells have shown promise in the treatment of melanoma and synovial cell sarcoma, but their application to epithelial cancers has been limited. The identification of novel therapeutic TCRs for the targeting of these tumors is important for the development of new treatments. Here, we describe the preclinical characterization of a TCR directed against Kita-Kyushu Lung Cancer Antigen-1 (KK-LC-1, encoded by CT83 ), a cancer germline antigen with frequent expression in human epithelial malignancies including gastric cancer, breast cancer, and lung cancer. Gene-engineered T cells expressing the KK-LC-1 TCR (KK-LC-1 TCR-Ts) demonstrated recognition of CT83 + tumor lines in vitro and mediated regression of established CT83+ xenograft tumors in immunodeficient mouse models. Cross-reactivity studies based on experimental determination of the recognition motifs for the target epitope did not demonstrate cross-reactivity against other human proteins. CT83 gene expression studies in 51 non-neural tissues and 24 neural tissues showed expression restricted exclusively to germ cells. CT83 was however expressed by a range of epithelial cancers, with the highest expression noted in gastric cancer. Collectively, these findings support the further investigation and clinical testing of KK-LC-1 TCR-Ts for gastric cancer and possibly other malignancies. Electronic supplementary material The online version of this article (10.1186/s40425-019-0678-x) contains supplementary material, which is available to authorized users.

An Innovative Prognostic Model Based on Four Genes in Asian Patient with Gastric Cancer

“…[27][28][29]. Based on this feature, Marcinkowski et al believe that CT83 may become an attractive target antigen for chimeric antigen receptor T-cell immunotherapy (CAR-T) [27]. In our results, the expression level of CT83 in the low-risk group was significantly higher than that in the highrisk group.…”

“…All rights reserved. [27][28][29]. Based on this feature, Marcinkowski et al believe that CT83 may become an attractive target antigen for chimeric antigen receptor T-cell immunotherapy (CAR-T) [27].…”

CAR T-Cell Cancer Therapy Targeting Surface Cancer/Testis Antigens

“…CT83 is also expressed in multiple cancers, such as breast, gastric, and lung cancers, and the expression can be upregulated by DNMTis ( 62 – 67 ). CT83 as a target for TCR-based therapies has shown promising results ( 64 , 68 ), but the potential of the antigen as a target for CAR T-cell therapy remains unexplored. Similarly, CAR T-cell therapy or alternative antibody therapy has not been pursued for SLO6A1 and PLAC1 despite interesting potential.…”

Enhance transgene responses through improving cellular uptake and intracellular trafficking by bio-inspired non-viral vectors

“…Gene therapy is a kind of biomedical treatment, showing a promising therapeutic prospect for inherited and acquired diseases, such as cancer, viral infection, diabetes and AIDS [1][2][3][4][5][6][7]. Given the easy preparation, high gene loading efficiency and low immunogenicity, non-viral delivery vectors have attracted considerable attention in the gene therapy compared with viral delivery vectors [1,8,9]. However, the poor intracellular bioavailability and rapid degradation of the gene in the blood circulation, endosome or lysosome hinder their clinical application.…”