Compositions and methods for treatment of cancer using bacteria
Inventors
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-10195259-B2
Publication Date
2019-02-05
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 relates to cancer treatment using substantially non-viable Gram-negative bacterial cells that are intact and retain anti-tumor effects while exhibiting reduced endotoxin activity and reduced pyrogenicity. The problem addressed is the toxicity and pyrogenicity associated with lipopolysaccharide (LPS) from Gram-negative bacteria in the context of treatment, where maintaining anti-tumor activity together with reduced toxicity is needed.
The core concept is to use Gram-negative organisms whose endotoxin activity and pyrogenicity are reduced by addressing LPS. In one preparation approach, substantially non-viable and intact Gram-negative bacterial cells are made by treating live Gram-negative bacterial cells with polymyxin B or polymyxin E and with glutaraldehyde (GA), and the resulting compositions achieve at least an 80% reduction of LPS-mediated endotoxin activity compared to corresponding wild-type Gram-negative bacterial cells.
The disclosure further includes Gram-negative bacteria having genetic defects that reduce LPS, exemplified by disruption or loss related to KDO2-Lipid IV_A or loss of outer membrane LPS components. The document links reduced endotoxin activity and pyrogenicity to decreased toxicity while maintaining anti-tumor activity, and supports this linkage with characterization and testing related to endotoxin activity, pyrogenicity, bacterial integrity, and anti-cancer growth inhibition.
Claims Coverage
The partial content provides one independent claim (clm-00001). It contains inventive features centered on a pharmaceutical composition of substantially non-viable but intact Gram-negative bacterial cells achieving a specified reduction in LPS-mediated endotoxin activity versus wild-type cells, with the composition being prepared using polymyxin (polymyxin B or polymyxin E) and glutaraldehyde under defined ranges, and with intactness maintained.
Substantially non-viable and intact Gram-negative bacterial cells with reduced LPS-mediated endotoxin activity
A pharmaceutical composition comprising substantially non-viable and intact Gram-negative bacterial cells having at least 80% reduction of lipopolysaccharide (LPS)-mediated endotoxin activity as compared to the corresponding wild-type Gram-negative bacterial cells.
Preparation by polymyxin treatment and glutaraldehyde treatment
The substantially non-viable and intact Gram-negative bacterial cells are prepared by treating live Gram-negative bacterial cells with polymyxin and with glutaraldehyde.
Polymyxin selection and preparation ranges
The polymyxin is selected from the group consisting of polymyxin B or polymyxin E, and the treatment is carried out using specified polymyxin amounts relative to live cells per mL within the claimed ranges and at a temperature range of 2°C. to 10°C.
Glutaraldehyde concentration
Glutaraldehyde is used at a concentration of from 0.5% to 2.0%.
Across the single independent claim, the inventive thrust is a pharmaceutical composition comprising substantially non-viable and intact Gram-negative bacterial cells that achieve at least an 80% reduction in LPS-mediated endotoxin activity versus corresponding wild-type cells, where the cells are prepared by polymyxin (polymyxin B or polymyxin E) treatment and glutaraldehyde treatment under the claimed temperature and concentration ranges.
Stated Advantages
Reduced LPS-mediated endotoxin activity (at least 80% reduction compared to corresponding wild-type Gram-negative bacterial cells).
Reduced pyrogenicity while maintaining anti-tumor effects.
Documented Applications
Cancer treatment using substantially non-viable Gram-negative bacterial cells with reduced endotoxin activity and reduced pyrogenicity, including reported inhibition of murine melanoma and colorectal carcinoma growth.
Combination or co-administration contexts including cyclophosphamide and immune checkpoint pathway modulators (CTLA-4 and PD-1/PD-L1/PD-L2) and cytokines.
Interested in licensing this patent?