Combination of local 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-10471144-B2
Publication Date
2019-11-12
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 invention provides a method of treatment of a solid tumor cancer in a human in a combination therapeutic regime that separately administers an intralesional chemoablative pharmaceutical composition and a systemic immunomodulatory anticancer agent. The intralesional composition is administered intralesionally into at least one cancerous tumor to elicit ablation of the cancerous tumor(s), while the systemic agent is administered in a therapeutically effective amount as a systemic inhibitor of immune system down-regulation or a systemic enhancer of immune system up-regulation.
The intralesional chemoablative pharmaceutical composition comprises an intralesional (IL) chemoablative agent selected from rose bengal or a halogenated xanthene, including physiologically acceptable salt forms. Rose bengal is identified as 4,5,6,7-tetrachloro-2′,4′,5′,7′-tetraiodofluorescein, optionally as rose bengal disodium, and the halogenated xanthene is provided in an appropriate pharmaceutical composition, including an aqueous solution or a physiologically acceptable salt.
Formulation and dosing-related limitations are defined for the intralesional chemoablative pharmaceutical composition, including aqueous rose bengal concentration of about 0.1% (w/v) up to about 20% (w/v), and administration at about 0.1 mL/cc lesion volume to about 2 mL/cc lesion volume. Additional formulation parameters are further specified in dependent claims, including electrolyte content with selected cations and anions, osmolality thresholds, and pH ranges, together with systemic immunomodulatory anticancer agents such as anti-CTLA-4 antibodies, anti-PD-L1 antibodies, and anti-PD-1 antibodies.
Claims Coverage
The document includes three independent claims. Across these claims, the inventive features are directed to a combination regime of separate intralesional chemoablation with a rose bengal or halogenated xanthene formulation and systemic immunomodulation using immune down-regulation inhibitors or immune up-regulation enhancers, with further specification of antibody types and formulation ranges in dependent claims.
Separate intralesional chemoablation and systemic immunomodulation
A method of treatment of a solid tumor cancer in a human comprising separately administering a therapeutically effective amount of an intralesional chemoablative pharmaceutical composition to elicit ablation of at least one cancerous tumor, and a therapeutically effective amount of a systemic immunomodulatory anticancer agent that is a systemic inhibitor of immune system down-regulation or a systemic enhancer of immune system up-regulation in a combination therapeutic regime.
Rose bengal intralesional chemoablative agent with defined aqueous concentration range
The intralesional chemoablative pharmaceutical composition comprises an intralesional (IL) chemoablative agent comprising rose bengal in an appropriate pharmaceutical composition, including a 0.1% (w/v) up to about 20% (w/v) aqueous solution of rose bengal, or a physiologically acceptable salt of rose bengal.
Systemic immunomodulatory anticancer agent defined by immune down-regulation inhibition antibodies
A method of treatment of a solid tumor cancer in a human comprising administering a therapeutically effective amount of an intralesional chemoablative pharmaceutical composition to elicit ablation of at least one cancerous tumor, and a therapeutically effective amount of a systemic immunomodulatory anticancer agent that is a systemic inhibitor of immune system down-regulation comprising anti-CTLA-4 antibodies, anti-PD-L1 antibodies, or anti-PD-1 antibodies, in a combination therapeutic regimen.
Halogenated xanthene intralesional chemoablative agent in aqueous solution range
A method of treatment of a solid tumor cancer in a human comprising separately administering a therapeutically effective amount of an intralesional chemoablative pharmaceutical composition to elicit ablation of at least one cancerous tumor, and 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, wherein said intralesional chemoablative pharmaceutical composition comprises an intralesional (IL) chemoablative agent comprising a halogenated xanthene in an appropriate pharmaceutical composition, including a 0.1% (w/v) up to about 20% (w/v) aqueous solution of the halogenated xanthene or mixtures thereof, or a physiologically acceptable salt of the halogenated xanthene.
Overall, the independent claims cover a combination approach in which intralesional chemoablation using rose bengal or a halogenated xanthene formulation is administered separately from a systemic immunomodulatory anticancer agent that targets immune system down-regulation or immune system up-regulation.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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