Compositions and methods for treatment of cancer using bacteria
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Publication Number
US-11045504-B2
Publication Date
2021-06-29
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 disclosure describes cancer treatment using substantially non-viable or viability-reduced Gram-negative bacteria or viable bacteria with LPS-loss genetic defects, with the goal of inhibiting tumor growth or metastasis while substantially reducing endotoxin activity and pyrogenicity. Endotoxin activity and pyrogenicity reduction are addressed by treating bacteria in a way that reduces at least part of LPS-mediated activity while aiming to maintain the bacterial cells intact, including treatment with polymyxin B or polymyxin E together with glutaraldehyde under conditions intended to preserve bacterial integrity. The disclosure also describes alternative approaches that reduce LPS-mediated endotoxin activity, including antibiotics or genetic defects that disrupt KDO/Lipid IVA or O-acylation of LPS, such as msbB/lpxM pathways.
Claims Coverage
The provided content includes one independent claim. The claim combines killing Gram-negative bacterial cells with reducing LPS-mediated endotoxin activity while keeping the bacterial cells intact, using polymyxin and glutaraldehyde to achieve at least an 80% reduction compared with untreated cells.
Polymyxin plus glutaraldehyde with integrity-maintaining conditions
Treating live Gram-negative bacterial cells with a polymyxin and glutaraldehyde under conditions to maintain the integrity of the Gram-negative bacterial cells while reducing at least 80% of the LPS-mediated endotoxin activity compared to corresponding untreated cells.
Polymyxin B or polymyxin E
Using polymyxin B or polymyxin E as the polymyxin in the treatment of live Gram-negative bacterial cells together with glutaraldehyde under integrity-maintaining conditions.
At least 80% reduction in LPS-mediated endotoxin activity while killing cells
Reducing at least 80% of the LPS-mediated endotoxin activity of the Gram-negative bacterial cells compared to corresponding untreated Gram-negative bacterial cells while killing the Gram-negative bacterial cells.
Keeping bacterial cells intact while killing and reducing endotoxin activity
Keeping the bacterial cells intact during the method while killing Gram-negative bacterial cells and simultaneously reducing LPS-mediated endotoxin activity.
The inventive scope centers on killing Gram-negative bacterial cells while maintaining bacterial integrity and substantially reducing LPS-mediated endotoxin activity by treatment with polymyxin B or polymyxin E and glutaraldehyde under conditions that preserve integrity and achieve at least an 80% reduction versus untreated cells.
Stated Advantages
Substantially reduces LPS-mediated endotoxin activity of Gram-negative bacterial cells while killing the cells and keeping them intact.
Reduces pyrogenicity and endotoxin activity as described in the disclosure’s supporting data.
Documented Applications
Cancer treatment by inhibiting tumor growth or metastasis using substantially non-viable or viability-reduced Gram-negative bacteria or viable bacteria with LPS-loss genetic defects, including tumor models described for B16F10 melanoma and CT26 colorectal carcinoma.
Use of treated bacteria in combination with cyclophosphamide and an anti-CTLA-4 antibody in the provided disclosure context.
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