Microorganisms programmed to produce immune modulators and anti-cancer therapeutics in tumor cells
Genetically programmed microorganisms, such as bacteria or virus, pharmaceutical compositions thereof, and methods of modulating and treating cancers are disclosed.
1. A genetically engineered bacterium comprising at least one non-native gene sequence encoding an enzyme capable of producing a stimulator of interferon gene (STING) agonist, wherein the non-native gene sequence is a dacA (diadenylate cyclase) gene, wherein the dacA gene is operatively linked to an inducible promoter, and wherein the bacterium is an auxotroph in dapA (4-hydroxy-tetrahydrodipicolinate synthase) and thyA (thymidylate synthase).
2. The genetically engineered bacterium of claim 1 , wherein the STING agonist is c-di-AMP.
3. The genetically engineered bacterium of claim 1 , wherein the dacA gene sequence is integrated into a chromosome of the bacterium or is present on a plasmid in the bacterium.
4. The genetically engineered bacterium of claim 1 , wherein inducible promoter is induced by low-oxygen or anaerobic conditions.
5. The genetically engineered bacterium of claim 1 , wherein inducible promoter is induced by a hypoxic environment of a tumor.
6. The genetically engineered bacterium of claim 1 , wherein the bacterium is non-pathogenic.
7. The genetically engineered bacterium of claim 6 , wherein the bacterium is Escherichia coli Nissle.
8. A pharmaceutical composition comprising the genetically engineered bacterium of claim 1 and a pharmaceutically acceptable carrier.
9. A method of treating cancer in a subject, the method comprising administering the pharmaceutical composition of claim 8 to the subject, thereby treating cancer in the subject.
10. The method of claim 9 , wherein the administering is via intratumoral injection.