GLA monotherapy for use in cancer treatment
Inventors
Paya Cuenca, Carlos V. • Ter Meulen, Jan Henrik
Assignees
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Publication Number
US-10993956-B2
Publication Date
2021-05-04
Expiration Date
Abstract
The present disclosure relates generally to compositions and methods for treating cancer with a glucopyranosyl lipid A (GLA) in the absence of antigen.
Core Innovation
The invention relates to methods of treating a mammal who suffers from cancer by administering an effective amount of a composition comprising glucopyranosyl lipid A (GLA). The composition is administered by intratumoral injection and comprises GLA of a specified formula together with a pharmaceutically acceptable carrier or excipient. The composition does not comprise antigen and is administered in conjunction with rituximab.
The GLA is defined by alkyl substituent constraints in which R1, R3, R5, and R6 are C11–C20 alkyl, and R2 and R4 are C12–C20 alkyl, including embodiments with undecyl and tridecyl substituents. The disclosure includes multiple composition forms, including aqueous formulations and stable emulsion (SE), as well as oil-in-water emulsion, water-in-oil emulsion, liposome, micelle, and microparticle formulations.
The disclosure includes cancer treatment in mammals including humans and combination treatment with an immune checkpoint inhibitor. The disclosure also describes immune activation through TLR4/innate immunity and immune response readouts such as cytokines and T-cell or CTL responses, including CD8+ effector increase and regulatory T cell suppression.
Claims Coverage
The independent and dependent claims define four main inventive elements: intratumoral administration of an antigen-free GLA composition, a defined GLA structural constraint with specified alkyl ranges, co-administration with rituximab, and optional combination with an immune checkpoint inhibitor.
Intratumoral antigen-free GLA composition treatment in conjunction with rituximab
A method of treating a mammal who suffers from cancer by administering by intratumoral injection an effective amount of a composition comprising GLA and a pharmaceutically acceptable carrier or excipient, wherein the composition does not comprise antigen and wherein the composition is administered in conjunction with rituximab.
GLA with constrained alkyl substituents (C11–C20 and C12–C20 ranges)
The composition comprises GLA of the formula wherein R1, R3, R5, and R6 are C11–C20 alkyl, and wherein R2 and R4 are C12–C20 alkyl.
Specific alkyl substitution embodiment (undecyl and tridecyl)
The composition is limited such that R1, R3, R5, and R6 are undecyl while R2 and R4 are tridecyl.
Cancer indication selected from an enumerated group
The cancer is chosen from a listed group of specific cancer types.
Solid tumor limitation
The cancer is a solid tumor.
Specified formulation type for the GLA composition
The composition is formulated as an oil-in-water emulsion, a water-in-oil emulsion, liposome, micellar formulation, or a microparticle.
Combination with an immune checkpoint inhibitor
The method further includes administering an immune checkpoint inhibitor.
Across the claims, the inventive coverage centers on intratumoral administration of an antigen-free GLA formulation with specified alkyl substituent constraints, combined with rituximab, and further optionally narrowed by cancer type, solid tumor context, GLA substituent selection, formulation form, and addition of an immune checkpoint inhibitor.
Stated Advantages
Immune activation via TLR4/innate immunity and described immune response readouts including cytokines and T-cell/CTL responses.
CD8+ effector increase and regulatory T cell suppression as described immune readouts.
In vivo tumor size reduction and survival increase in B16 melanoma models, and delayed tumor growth in multiple murine tumor models, with enhanced effects reported in combination contexts.
Documented Applications
Preliminary Phase I human observations including intratumoral GLA-SE in Merkel cell carcinoma with complete response in one patient.
Clinical investigation described as combining intratumoral GLA with anti-CTLA-4 and rituximab for follicular low-grade non-Hodgkin's lymphoma (NHL).
Preclinical in vivo treatment reported using GLA-SE in B16 melanoma models showing tumor size reduction and survival increase, and delays in tumor growth in multiple murine tumor models.
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