▎WuXi AppTec Content Team Report

July 1 News: Hengrui Yuanzheng (Shanghai) Biotechnology Co., Ltd. announced that the company's R&D teamNature CommunicationsResearch paper published in the journal,The research and development process, mechanism of action, and preclinical efficacy and toxicology studies of HRYZ-T101, the company's first TCR-T product to enter the clinical stage, were introduced in detail.

Research confirms that over 95% of cervical cancers are associated with the human papillomavirus (HPV) related, with types 16 and 18 being the most common.In addition, HPV infection can also lead to various head and neck cancers and anogenital tumors.Tumor cells that undergo carcinogenesis after HPV infection continuously overexpress the E7 viral protein, which is not expressed in normal tissues and represents a potential target for TCR-T and other targeted therapies.。HRYZ-T101 is a TCR-T product targeting HPV18-positive solid tumors.The ProductUnder DevelopmentFor the treatment of HPV18-positive solid tumors,1The first patient infusion has been completed in the registered clinical trial.。

In this study, the research team successfully developed from a patient based on the TCR reverse gene engineering (ReGET) platform technology.Patients Benefiting from Early Multi-Antigen Autologous Immune Cell Therapy (MASCT)Cloning of TCR molecules (10F04 TCR) targeting HPV18 E7 tumor antigen in vivo. The patient was diagnosed with HPV-positive advanced metastatic squamous cell carcinoma of the cervix in 2011 and relapsed after conventional treatments such as surgery, chemotherapy, and radiotherapy.Since 2014, the patient has achieved gradual tumor regression and long-term remission after multiple courses of MASCT treatment and has survived cancer-free for over nine years to date.The long-term presence of specific T cells targeting multiple tumor antigens such as HPV18 E7 in the patient's body is a possible reason for the patient's clinical benefit.

According to the press release from Hengrui Yuanzheng (Shanghai) Biotechnology Co., Ltd., the study results confirmed that the 10F04 TCR specifically recognizes the HPV18 E7 antigen peptide presented by the HLA-DRB1*09:01 molecule, a high-frequency HLA-II molecule in the Chinese population. It demonstrated potent anti-tumor activity both in vitro and in mouse models. The results showed,10F04 TCR can simultaneously mediate the recognition and direct killing of antigen-positive tumor cells in both CD4+ and CD8+ T cells, while releasing anti-tumor cytokines such as IFNγ, TNFα, IL2, and Granzyme B, further inducing tumor cell apoptosis and promoting the expansion of TCR-T cells.At the same time, the IFNγ cytokines secreted by activated TCR-T cells can also induce the upregulation of HLA molecule expression on the tumor surface, making them more sensitive to TCR-T recognition.

In recent years, an increasing number of clinical research results have shown that CD4+ tumor-recognizing T cells play a crucial role in tumor treatment by directly killing tumor cells, assisting CD8+ T cells in their cytotoxic effects and long-term persistence, and secreting cytokines to activate dendritic cells (DCs), macrophages, and other components of the innate immune system to achieve anti-tumor effects against tumors.The 10F04 TCR molecule reported in this study can simultaneously activate CD4+ and CD8+ T cells and secrete multiple cytokines.; At the same time, this study also conducted cross-recognition validation on the human proteome and major HLA molecules, and no off-target risk was found for 10F04 TCR.