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 - 136 . (canceled)
137 . A genetically engineered bacterium comprising at least one non-native gene encoding an enzyme capable of producing a stimulator of interferon gene (STING) agonist, wherein the STING agonist is c-di-AMP,
wherein the non-native gene is a dacA (diadenylate cyclase) gene and encodes a polypeptide comprising a sequence that has at least 90% identity to SEQ ID NO: 1209,
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).
138 . The genetically engineered bacterium of claim 137 , wherein the polypeptide comprises a sequence that has at least 95% identity to SEQ ID NO: 1209.
139 . The genetically engineered bacterium of claim 138 , wherein the polypeptide comprises a sequence that has at least 97% identity to SEQ ID NO: 1209.
140 . The genetically engineered bacterium of claim 139 , wherein the polypeptide comprises a sequence that has at least 99% identity to SEQ ID NO: 1209.
141 . The genetically engineered bacterium of claim 137 , wherein the dacA gene is integrated into a chromosome of the bacterium or is present on a plasmid in the bacterium.
142 . The genetically engineered bacterium of claim 137 , wherein the inducible promoter is induced by low-oxygen or anaerobic conditions, or wherein the inducible promoter is induced by a hypoxic environment of a tumor.
143 . The genetically engineered bacterium of claim 137 , wherein the bacterium is non-pathogenic.
144 . The genetically engineered bacterium of claim 143 , wherein the bacterium is Escherichia coli Nissle.
145 . A pharmaceutical composition comprising the genetically engineered bacterium of claim 137 and a pharmaceutically acceptable carrier.
146 . A method of treating cancer in a subject, the method comprising administering the pharmaceutical composition of claim 145 to the subject, thereby treating cancer in the subject.
147 . The method of claim 146 , wherein the administering is via intratumoral injection.
148 . A genetically engineered bacterium comprising at least one non-native gene encoding an enzyme capable of producing a stimulator of interferon gene (STING) agonist, wherein the STING agonist is c-di-AMP,
wherein the non-native gene is a dacA (diadenylate cyclase) gene that comprises a sequence having at least 90% identity to SEQ ID NO: 1210,
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).
149 . The genetically engineered bacterium of claim 148 , wherein the dacA gene is integrated into a chromosome of the bacterium or is present on a plasmid in the bacterium.
150 . The genetically engineered bacterium of claim 148 , wherein the inducible promoter is induced by low-oxygen or anaerobic conditions, or wherein the inducible promoter is induced by a hypoxic environment of a tumor.
151 . The genetically engineered bacterium of claim 148 , wherein the bacterium is non-pathogenic.
152 . The genetically engineered bacterium of claim 151 , wherein the bacterium is Escherichia coli Nissle.
153 . A pharmaceutical composition comprising the genetically engineered bacterium of claim 148 and a pharmaceutically acceptable carrier.
154 . A method of treating cancer in a subject, the method comprising administering the pharmaceutical composition of claim 153 to the subject, thereby treating cancer in the subject.
155 . The method of claim 154 , wherein the administering is via intratumoral injection.