Combination of rose bengal and systemic immunomodulative therapies for enhanced treatment of cancer
Inventors
Eagle, Craig J. • Dees, H. Craig • Wachter, Eric A. • Singer, Jamie
Assignees
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Publication Number
US-9839688-B2
Publication Date
2017-12-12
Expiration Date
Abstract
A method for the treatment of cancer comprising administration of a therapeutically effective amount of an intralesional chemoablative pharmaceutical composition, or variant of said composition, in combination with a therapeutically effective amount of a systemic immunomodulatory anticancer agent. A further method for the treatment of cancer comprising administration of a therapeutically effective amount of an intralesional chemoablative pharmaceutical composition, or variant of said composition, in combination with a therapeutically effective amount of a systemic targeted anticancer agent. The present invention is further directed to pharmaceutical compositions for treatment of cancer. The intralesional chemoablative pharmaceutical composition can comprise an IL chemoablative agent comprising primarily a halogenated xanthene.
Core Innovation
The patent describes cancer treatment in a human using a combination of an intralesional chemoablative pharmaceutical composition and a systemic immunomodulatory anticancer agent. The intralesional component elicits ablation of at least one cancerous tumor by administering an intralesional chemoablative agent that comprises rose bengal, and the systemic component comprises anti-CTLA-4 antibodies, anti-PD-L1 antibodies, or anti-PD-1 antibodies, or interferon-gamma, for treating cancer together with the intralesional ablation.
The patent identifies melanoma and primary or metastatic liver cancer as particular disease settings for the same combination concept. The intralesional chemoablative pharmaceutical composition is defined as a 0.1% (w/v) or higher concentration aqueous solution of rose bengal, or a physiologically acceptable salt of rose bengal, and the intralesional administration is specified into the tumor at about 0.1 mL/cc lesion volume to about 2 mL/cc lesion volume.
A mechanistic rationale is provided that the intralesional chemoablation supports enhanced antitumor immunity through rapid tumor antigen release and a bystander effect. The patent also specifies formulation constraints for the intralesional rose bengal chemoablative composition, including a hydrophilic vehicle and ranges related to rose bengal concentration, electrolyte ions and concentration, osmolality, and pH.
Claims Coverage
The independent claims are directed to a cancer treatment pharmaceutical composition that combines intralesional rose bengal chemoablation with a systemic immunomodulatory anticancer agent. Across the independent claims, the inventive scope centers on three inventive features.
Intralesional rose bengal chemoablation for ablation of at least one tumor
A therapeutically effective amount of an intralesional chemoablative pharmaceutical composition to elicit ablation of at least one cancerous tumor, wherein the intralesional chemoablative agent comprises rose bengal in a 0.1% (w/v) or higher aqueous solution, or a physiologically acceptable salt of rose bengal, and is administered intralesionally into the at least one cancerous tumor at about 0.1 mL/cc lesion volume to about 2 mL/cc lesion volume.
Systemic immunomodulatory anticancer agent with checkpoint antibodies and/or interferon-gamma
A therapeutically effective amount of a systemic immunomodulatory anticancer agent that comprises anti-CTLA-4 antibodies, anti-PD-L1 antibodies, or anti-PD-1 antibodies, or interferon-gamma, administered in combination with the intralesional chemoablation.
Melanoma and primary or metastatic liver cancer combination treatment
A therapeutically effective amount of an intralesional chemoablative pharmaceutical composition to elicit ablation of at least one melanoma, or primary or metastatic liver cancerous tumor, and a therapeutically effective amount of a systemic immunomodulatory anticancer agent comprising anti-CTLA-4 antibodies, anti-PD-L1 antibodies or anti-PD-1 antibodies, wherein the intralesional chemoablative pharmaceutical composition comprises rose bengal and is administered intralesionally at about 0.1 mL/cc lesion volume to about 2 mL/cc lesion volume.
Across the independent claims, coverage centers on combining intralesional rose bengal chemoablation with systemic immunomodulatory anticancer agents. The systemic agents are anti-CTLA-4, anti-PD-L1, and anti-PD-1 antibodies, and one claim further includes interferon-gamma; separate claim scope explicitly ties the combination to melanoma or primary or metastatic liver cancer, while another applies to a cancerous tumor in a human.
Stated Advantages
Enhanced antitumor immunity through rapid tumor antigen release and a bystander effect.
Documented Applications
Treatment of melanoma in a human using intralesional rose bengal chemoablative pharmaceutical composition with systemic immunomodulatory anticancer agent comprising anti-CTLA-4, anti-PD-L1, or anti-PD-1 antibodies.
Treatment of primary or metastatic liver cancer in a human using intralesional rose bengal chemoablative pharmaceutical composition with systemic immunomodulatory anticancer agent comprising anti-CTLA-4, anti-PD-L1, or anti-PD-1 antibodies.
Treatment of cancer in a human using intralesional rose bengal chemoablative pharmaceutical composition with systemic immunomodulatory anticancer agent comprising anti-CTLA-4 and/or anti-PD-L1 and/or anti-PD-1 antibodies, or interferon-gamma.
Treatment of a cancerous tumor in a human using intralesional rose bengal chemoablative pharmaceutical composition with systemic immunomodulatory anticancer agent selected from anti-CTLA-4, anti-PD-L1, or anti-PD-1 antibodies.
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