Immunomodulatory and oncolytic minicells and methods of use
Inventors
Assignees
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Publication Number
US-11167008-B2
Publication Date
2021-11-09
Expiration Date
Abstract
Disclosed herein are compositions comprising immunomodulatory and oncolytic eubacterial minicells, and the use of the composition in immunomodulatory therapies for cancer. In some embodiments, the minicells are used in combination of immune checkpoint inhibitors in treating cancer.
Core Innovation
The disclosure relates to immunomodulatory and oncolytic eubacterial minicells comprising engineered delivery vehicles for treating cancer by stimulating tumor-specific innate-to-adaptive immune responses, including in situ vaccination. The minicells described include achromosomal, membrane-encapsulated bacterial minicells such as VAX014 and VAX-IP.
The approach combines oncolytic and immune-stimulating minicell therapy with immune checkpoint inhibitor immunotherapies, including one or more immune checkpoint inhibitors that are antibodies directed to targets such as PD-1/PD-L1/CTLA-4 and additional listed immune checkpoints. The disclosure presents a synergy rationale in which oncolysis releases tumor neoantigens while checkpoint blockade sustains T-cell and NK-cell activity.
The disclosure further describes minicell composition and targeting concepts including invasin and perfringolysin O (PFO), and includes D-trehalose in the minicell pharmaceutical composition. Representative targeting strategies include invasin, including invasin from Yersinia pseudotuberculosis, and antibody-based targeting.
Claims Coverage
The provided claim set includes one independent claim. It covers a two-stage cancer treatment regimen using a bacterial minicell composition with defined minicell components and excipient, followed by a second composition comprising an antibody immune checkpoint inhibitor.
Two-stage minicell plus antibody checkpoint inhibition regimen
Administering a first pharmaceutical composition comprising bacterial minicells comprising invasin and perfringolysin O (PFO) and comprising D-trehalose, and administering a second pharmaceutical composition comprising one or more immune checkpoint inhibitors that are antibodies.
Defined minicell composition components
The bacterial minicells comprise invasin and perfringolysin O (PFO) and the first pharmaceutical composition comprises D-trehalose.
Antibody immune checkpoint inhibitor selection
The immune checkpoint inhibitor is an antibody.
The core inventive coverage is the combination of a bacterial minicell composition comprising invasin and PFO with D-trehalose and a second composition containing antibody-based immune checkpoint inhibition.
Stated Advantages
Improved cancer treatment outcomes are reported, including survival and tumor rechallenge rejection associated with VAX014 plus anti-PD-L1 combination therapy.
The disclosure describes sustaining T-cell and NK-cell activity via checkpoint blockade in combination with neoantigen release associated with oncolysis.
Documented Applications
Treating cancer using an immunomodulatory and oncolytic eubacterial minicell approach, including in situ vaccination, in combination with immune checkpoint inhibitor antibody immunotherapy.
VAX014 combined with anti-PD-L1 antibody in example tumor models, including reporting survival and tumor rechallenge rejection outcomes.
Assessment of tumor PD-L1 expression following VAX014 single-agent failure, including PD-L1 immunohistochemistry described in the disclosure.
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