Team:SYSU-Medicine
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M1
Oncolytic virus therapy is a therapeutic approach to cancer treatment that utilizes native or genetically modified viruses that selectively replicate within tumor cells. M1, as a strain of alphavirus that was isolated from mosquitoes collected on Hainan Island of China, possesses selective and potent antitumor activity through intravenous infusion.
TAICHI
Therefore, we came up with the idea to combine them together! We engineered M1 to specifically encode enzymes that could convert prodrugs into active therapeutic metabolites and utilized riboswitch to enhance the dynamic regulation of the system, which can significantly increase the targeting of chemotherapy drugs and reduce its side effects. Thus, it is called “Target-Activated In situ Cancer Hijack system”, or “TAICHI” for short.
Chemotherapy Drugs
Chemotherapy, as the classical method and cornerstone of tumor treatment, has been widely used in clinic, but also has serious problems. Take Actinomycin D as an example, it causes severe side effects in the bone marrow, lymphoid tissues, and intestinal epithelium.
A Nitroreductase is inserted into the genome of the oncolytic virus M1 to reduce some kinds of prodrugs to thousands more cytotoxic intermediates.
Modified M1 and prodrugs are injected intravenously at the same time, reaching normal tissue in the body. Non-functional prodrugs cannot work effectively, while M1's selective infection mechanism also prevents it from acting on normal cells.
However, in insensitive tumor tissues (such as lung cancer), a small amount of M1 infects tumor cells and expresses nitroreductase in their cytoplasm. Meanwhile, prodrugs transport across cell membrane, converting into their active form by those enzymes.
The active drugs diffuse in the tumor, together with M1 cause a bystander effect while synergistically killing tumor cells, recruiting more immune cells to remove residual tumors.
At the same time, drugs transformed into active forms by prodrug enzymes can in turn enhance the infection rate of M1, leading to more virus production and release, forming a cascading amplification effect.
At the same time, drugs transformed into active forms by prodrug enzymes can in turn enhance the infection rate of M1, leading to more virus production and release, forming a cascading amplification effect.
What's more, three riboswitches have also been inserted into the UTR regions of M1.
After the tumor has been jointly destroyed, theophylline is injected externally to bind the aptamer on riboswitches, preventing expression of M1, therefore stopping its infection.
Due to M1's selective infection of tumor cells and the exquisitely-designed prodrug/enzyme collocation, the system has both high lethality and targeting ability, which is why we named it "Target-Activated In situ Cancer HIjack system". Abbreviated as "TAICHI", it is also a metaphor for the complementary role of M1 and actinomycin D.
