Compositions and methods for treatment of cancer using bacteria
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Publication Number
US-10052371-B2
Publication Date
2018-08-21
Expiration Date
Abstract
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.
Core Innovation
The invention relates to cancer-treatment compositions and methods using Gram-negative bacterial cells that are rendered intact and substantially non-viable while reducing endotoxin activity and pyrogenicity. The problem addressed is the use of Gram-negative bacterial cells in cancer treatment while reducing viability and pyrogenicity, including reducing endotoxin activity and pyrogenicity of Gram-negative bacterial cells.
Cancer therapy is provided by administering an amount of intact and substantially non-viable Gram-negative bacterial cells treated with polymyxin B or polymyxin E and glutaraldehyde under conditions to maintain bacterial integrity, to reduce bacterial viability and pyrogenicity. The treated Gram-negative bacterial cells have at least 80% reduction in pyrogenicity compared to corresponding wild-type Gram-negative bacterial cells, and the administered amount is sufficient to inhibit growth or metastasis of the cancer.
The document also discloses genetically defective Gram-negative bacterial cells having substantial loss of lipopolysaccharide, including disruptions related to KDO2–Lipid IV_A biosynthesis or reduced O-acylation, and optional combinations with immune modulators and other therapeutic agents. The disclosed immune modulators include antagonists of CTLA-4, PD-1, PD-L1, and PD-L2, as well as agonists including GITR, 4-1BB, CD40, and OX40, with additional optional agents including chemotherapeutics and cytokines.
Claims Coverage
The partial claims set provides one independent claim. It contains a quantitative pyrogenicity reduction requirement of at least 80% compared to corresponding wild-type, and a sufficiency requirement for inhibiting cancer growth or metastasis, together with treatment of intact and substantially non-viable Gram-negative bacterial cells using polymyxin B or polymyxin E and glutaraldehyde under conditions to maintain integrity.
Treating cancer with intact substantially non-viable Gram-negative bacterial cells treated with polymyxin B or polymyxin E and glutaraldehyde while maintaining bacterial integrity
A method of treating a cancer in a mammalian cancer patient comprising administering 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.
Across the independent claim and its dependent matter described in the partial content, the core inventive concept is cancer treatment using intact, substantially non-viable Gram-negative bacterial cells treated with polymyxin B or polymyxin E and glutaraldehyde to maintain integrity while achieving at least an 80% reduction in pyrogenicity, with the administered amount sufficient to inhibit cancer growth or metastasis.
Stated Advantages
At least 80% reduction in pyrogenicity compared to corresponding wild-type Gram-negative bacterial cells.
Reduced viability and pyrogenicity of administered Gram-negative bacterial cells while maintaining integrity.
Inhibition of growth or metastasis of the cancer by the administered amount.
Documented Applications
Treating a cancer in a mammalian cancer patient by administering intact, substantially non-viable Gram-negative bacterial cells treated with polymyxin B or polymyxin E and glutaraldehyde.
Optional use in combination with immune modulators targeting T-cell receptor or its ligands selected from CTLA-4, PD-1, PD-L1, and PD-L2, and agonists including GITR, 4-1BB, CD40, and OX40.
Optional combination with chemotherapeutics, including cyclophosphamide, and cytokines.
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