Oncology and Autoimmune Diseases

T601Indication——Advanced malignant solid tumors of digestive tract

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Product Introduction

T601 is a dual-effect recombinant oncolytic virus vaccine that is intended to treat advanced malignant solid tumors of digestive tract, including esophageal cancer, gastric cancer, liver cancer,pancreatic cancer and colorectal cancer. T601 uses the recombinant vaccinia virus (“rVV”) strain Copenhagen, where the thymidine kinase gene and the ribonucleotide reductase gene are deleted (“TK-RR-”), as the vector to carry the gene encoding the prodrug-converting enzyme, i.e. FCU1. T601 was initially developed by Transgene. After the establishment of Transgene Tasly, Transgene transferred and licensed certain intellectual properties relating to T601 to Transgene Tasly while retaining some intellectual properties of its own. Currently, Transgene is implementing international simultaneous R&D of TG6002, a counterpart of T601 in France.We conduct the research and development of T601 in China through Transgene Tasly and have the right to manufacture and distribute T601 in China upon its commercialization. Transgene Tasly are currently conducting Phase I/IIa clinical trials of T601 in China .
Mechanism of Action
 
(1) killing tumor cells directly through selective lysis of tumor cells: By knocking out the TK-RR-gene, T601 can selectively proliferate in tumor cells and lyse tumor cells;
(2) Induce immune response: In the process of tumor cell lysis, T601 lyses tumor cells and releases tumor antigens to activate the body’s specific immune response, thereby enhancing the systemic anti-tumor effectiveness;
(3) Targeted chemotherapy: T601 carries the prodrug invertase gene (FCU1) and expresses its unique FCU1 gene in infected tumor cells to locally transform the non-cytotoxic prodrug 5-formylcytosine (5-FC) into the extensively used cancer chemotherapeutic 5-fluorouracil (5-FU). Meanwhile, the FCU1 enzyme can transform 5-FU into 5-fluorouracil monophosphate (5-FUMP) to further enhance its cytotoxic effect. Therefore, the combination of T601 and 5-FC can achieve the mode of action of targeted chemotherapy.
The mechanism of action of T601 targeted chemotherapy is as illustrated in the diagram below:
 

In addition, T601 can also be used in combination therapy with immune checkpoint inhibitors, including PD-1/PD-L1 inhibitors. T601 can make tumor tissues sensitive to the immune system, turning “cold” tumors into “hot” tumors, while PD-1/PD-L1 inhibitors can activate the immune system to attack tumor cells. The preclinical pharmacodynamics studies of the combination therapy of T601 and PD-1 immune checkpoint inhibitors are currently ongoing.

Potential Advantages
 
(1)Dual mechanism of action to achieve tumor killing: T601 has both the oncolytic mechanism and the targeted chemotherapy mechanism, which can selectively lyse tumor cells and convert 5-FC into 5-FU and 5-FUMP to play the role of targeted chemotherapy;
(2)Enhanced tumor selectivity: T601 is a recombinant oncolytic virus with double-gene knockout of TK and RR, and has better tumor selectivity than oncolytic virus with single-gene knock out of TK;
(3)Reducing the toxic side effects of chemotherapy: Compared with traditional chemotherapy, T601 has high affinity to tumor cells and achieve targeted chemotherapy, which reduces its toxicity to non-tumor tissues;
(4)Rapid progress in R&D: The international development of T601 is advancing smoothly, which will facilitate the progress of the clinical trial in China. Specifically, Transgene is conducting a Phase I/II clinical study on gastrointestinal stromal tumors for TG6002—a counterpart of T601—in France, Italy, Spain and the UK, and part of the Phase I study results will be published in the third quarter of 2020. In the meanwhile, Transgene is also conducting a Phase I/II clinical study on colorectal liver metastase in the UK, and the dosing for the first enrolled subject was completed in February 2020; Furthermore, Transgene is also conducting a clinical study on brain gliomas in France, and this clinical trial is currently ongoing.

 Clinical Progress

Through Transgene Tasly, Tasly Biopharma initiated the preclinical research of T601 in January 2016, submitted an investigational new drug (IND) application in April 2018, and obtained IND approval in April 2019. The phase I/IIa clinical trials for T601 was initiated in October 2019, which currently is still ongoing.