Abstract B04: Study on screening of new targets, specific recognition, and intervention of bladder cancer

Abstract

Abstract Bladder cancer is one of the most common malignant tumors in the urinary system. According to NIH statistics, the 5-year survival rate of bladder cancer patients has not improved since the last three decades. Tumor immunotherapy, such as PD-L1, CAR-T, and TCR-T, brings dawn to these patients. However, there are numerous factors affecting the clinical applications and trials, such as genetic variation, drug resistance, off-target, and the low specificity of recognition and intervention of bladder cancer. We aimed to identify new targets for the specific recognition and intervention of bladder cancer and introduce single target or target combination into immune cells to develop new technologies and products for early diagnosis and clinical treatment of bladder cancer. By using large-scale sequencing technology, our team identified 21 new genes, including UTX, MLL-MLL3, and CHD6, which were highly mutated in the tumorigenesis of bladder cancer, as well as the highest-ever-found mutated gene TERT. Based on CRISPR-Cas9 system, we constructed the “AND” gate genetic circuits for bladder cancer, which integrated intracellular information from two promoters as inputs and activated the output signals only when both inputs were activated simultaneously. Furthermore, some tumor-suppressor genes can be designed as output to achieve specific inhibition or killing of bladder cancer cells. The “Artificial Nucleic Acid Aptamer” tool was used to engineer the CRISPR-Cas9 system under the control of specific signaling molecules to complete the quantitative regulation of downstream gene transcription, achieving the effect of connecting two originally unrelated signaling pathways. By combining multiple signal conductors, the oncogenic signaling could activate the downstream tumor suppressor pathway, initiating cell apoptosis and specific killing of tumor cells. Therefore, this modified system could provide insight into precision medicine in cancer treatment. The design of a series of synthetic RNA components into signal connectors could interconnect two different signals at the translation level to inhibit or enhance the expression of target genes. It could also connect the internal and external signals, reshape the gene regulation network, and redirect the oncogenic signaling to the cell apoptosis. Based on these results, our team developed CAR-T and TCR-T engineered cells for the clinical trial of bladder cancer. The effective rate of CAR-T therapy on solid and nonsolid tumors reached 60% and 87.5%, respectively. The effective rate of TCR-T therapy for NY-ESO-1 positive bladder cancer patients reached 50%, of which 2 cases were completely alleviated. In summary, our team completed a full-chain study from original discoveries to clinical applications, significantly improving the specific recognition and intervention of bladder cancer and making an important contribution to increasing 5-year survival rate and quality of life of bladder cancer patients. Note: This abstract was not presented at the conference. Citation Format: Zhiming Cai. Study on screening of new targets, specific recognition, and intervention of bladder cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr B04.