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 non-pathogenic microorganism for intratumoral administration comprising a gene sequence for producing kynureninase, wherein the gene sequence is operably linked to an inducible promoter, and wherein the bacterium further comprises an aroP, tnaB, or mtr gene sequence encoding a transporter for importing kynurenine into the bacterium; and wherein the bacterium is an auxotroph comprising a deletion in a thyA, dapD, or dapA gene.
2. The genetically engineered bacterium of claim 1 ,
i) wherein the bacterium is a Gram-negative bacterium or a Gram-positive bacterium;
ii) wherein the bacterium is an obligate anaerobic bacterium, or a facultative anaerobic bacterium, or an aerobic bacterium;
iii) wherein the bacterium is a tumor-targeting bacterium; and/or
iv) wherein the bacterium is selected from E. coli Nissle, Clostridium novyi NT, Clostridium butyricum , and E. coli K-12.
3. The genetically engineered bacterium of claim 1 ,
wherein the inducible promoter is induced by low-oxygen or anaerobic conditions,
wherein the inducible promoter is induced by the hypoxic environment of a tumor;
wherein the inducible promoter is a temperature sensitive promoter; and/or
wherein the inducible promoter is selected from a FNR-inducible promoter, an ANR-inducible promoter, a DNR-inducible promoter.
4. The genetically engineered bacterium of claim 1 ,
wherein the bacterium comprises a kill switch.
5. A pharmaceutically acceptable composition comprising the bacterium of claim 1 and a pharmaceutically acceptable carrier, wherein the composition is formulated for intratumoral administration.
6. A method of treating or modulating cancer in a subject in need thereof comprising the step of administering to the subject the composition of claim 1 .
7. The method of claim 6 , further comprising administering to the subject a checkpoint inhibitor.