Compositions and methods for treatment of cancer using bacteria
Provided herein are compositions comprising substantially non-viable Gram-negative bacterial organisms that have a substantial reduction in endotoxin activity and/or pyrogenicity and methods for treating a cancer using the same. Also provided are methods for treating cancer provided herein, comprising administering to a mammal diagnosed with cancer, substantially non-viable Gram-negative bacteria having a substantial reduction in endotoxin activity and/or pyrogenicity, in an amount sufficient to inhibit growth or metastasis of the cancer. An additional method is provided comprising administering viable or non-viable Gram-negative bacterial organisms that have a genetic defect that results in a substantial loss of lipopolysaccharide within the outer membrane of the bacteria. Further provided are methods for reducing endotoxin activity and/or pyrogenicity in Gram-negative bacteria comprising treatment with polymyxin and glutaraldehyde.
1. A method of treating a cancer in a mammalian cancer patient comprising administering to the patient an amount of intact and substantially non-viable Gram-negative bacterial cells that are treated with polymyxin B or polymyxin E and glutaraldehyde under conditions to maintain the integrity of the Gram-negative bacterial cells, to reduce the viability and pyrogenicity of the Gram-negative bacterial cells, wherein the Gram-negative bacterial cells so treated have at least 80% reduction in pyrogenicity compared to corresponding wild-type Gram-negative bacterial cells and wherein the amount administered is sufficient to inhibit growth or metastasis of the cancer.
2. The method of claim 1 , wherein the cancer is a solid tumor.
3. The method of claim 1 , wherein the mammalian cancer patient is further administered an antagonist of an immune function inhibiting T-cell receptor or T-cell receptor ligand selected from the group consisting of CTLA-4, PD-1, PD-L1 and PD-L2.
4. The method of claim 1 , wherein the mammalian cancer patient is further administered an agonist of an immune function stimulating T-cell receptor selected from the group consisting of GITR, 4-1BB, CD40 and 0X40.
5. The method of claim 1 , wherein the mammal is further administered a chemotherapeutic agent.
6. The method of claim 5 , wherein the chemotherapeutic agent is cyclophosphamide.
7. The method of claim 1 , wherein the mammal is further administered a cytokine.
8. The method of claim 1 , wherein the Gram-negative bacterial cells are Salmonella cells.
9. The method of claim 1 , wherein the Gram-negative bacterial cells are Escherichia cells.
10. The method of claim 1 , wherein the reduction of the pyrogenicity is as measured by in vitro Limulus amebocyte lysate (LAL) assay.
11. The method of claim 1 , wherein the reduction of the pyrogenicity is as measured by in vivo rabbit test.
12. The method of claim 1 , wherein 100% of the Gram-negative bacterial cells are non-viable.