Immunotherapeutic tumor treatment method
Inventors
Zalevsky, Jonathan • Anand, Neel K. • Cai, Haiying • Deng, Bo-Liang • Ren, Zhongxu • Joshi, Bhalchandra V. • TAGLIAFERRI, Mary • Rubas, Werner • Kivimae, Saul • Pena, Rhoneil L.
Assignees
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Publication Number
US-12030940-B2
Publication Date
2024-07-09
Expiration Date
Abstract
Disclosed herein are methods in the field of cancer immunotherapy that involve the treatment of a subject having cancer by administering to the subject a toll-like receptor 7/8 (TLR7/8) agonist in combination with a long-acting IL-2Rβ-biased agonist and a programmed cell death protein 1 (PD-1)/programmed cell death protein ligand 1 (PD-L1) axis inhibitor, and related compositions, dosage forms, and kits.
Core Innovation
The invention relates to immunotherapy tumor treatment methods that combine a PD-1/PD-L1 axis inhibitor with a long acting IL-2Rβ-biased or IL-2Rβ-preferential agonist together with a toll-like receptor (TLR) agonist covalently attached to a multi-arm, water-soluble, non-peptidic polymer. The disclosed TLR agonist is selected from multi-armed polymer conjugates of R848, imiquimod, or a specified multi-armed polymer conjugate including a (purin-9-yl)methyl)-benzamide structure. The combination is directed to cancer treatment in a subject, and the kit or method includes instructions for administration.
A central concept in the disclosure is to combine immune activation along innate and adaptive pathways, where the IL-2Rβ-activating amount of the long acting IL-2Rβ-preferential agonist is provided together with a PD-1/PD-L1 axis inhibitor and the polymer-conjugated TLR agonist. The disclosure emphasizes synergy between innate and adaptive immune activation and describes treatment regimens that can be concurrent or sequential. It further provides structural and formulation concepts for long-acting multi-arm polymer conjugates for TLR7/8 agonists, including stable vs releasable linkers and polymer arm counts within the multi-arm polymer conjugates.
Claims Coverage
The partial content includes two independent claims. Each independent claim recites three inventive components: a PD-1/PD-L1 axis inhibitor, a polymer-conjugated TLR agonist, and an IL-2Rβ-activating long acting IL-2Rβ-preferential agonist.
Cancer treatment kit with a PD-1/PD-L1 axis inhibitor, polymer-conjugated TLR agonist, and long acting IL-2Rβ-preferential agonist
A kit comprising a PD-1/PD-L1 axis inhibitor; a toll-like receptor agonist covalently attached to a multi-arm, water-soluble, non-peptidic polymer, wherein the TLR agonist is selected from a multi-armed polymer conjugate of R848, a multi-armed polymer conjugate of imiquimod, or a multi-armed polymer conjugate of 4-((6-amino-8-hydroxy-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)-benzamide; and an IL-2Rβ-activating amount of a long acting interleukin-2 receptor beta (IL-2Rβ)-preferential agonist; and instructions for their administration to a subject having a cancer.
Treating cancer by administering a PD-1/PD-L1 axis inhibitor, long acting IL-2Rβ-preferential agonist, and polymer-conjugated TLR agonist
A method of treating a subject having a cancer comprising administering an effective amount of a PD-1/PD-L1 axis inhibitor; administering an effective, IL-2Rβ-activating amount of a long acting IL-2Rβ-preferential agonist selected from multi(2,7-(bis-methoxyPEG-carboxyamide)(9H-fluorene-9-yl)methyl N-carbamate)interleukin-2, (2,7-(bis-methoxyPEG 10 kD-carboxyamide)(9H-fluorene-9-yl)methyl N-carbamate)4-6 interleukin-2, or (2,7-(bis-methoxyPEG-carboxyamide)(9H-fluorene-9-yl)methyl N-carbamate)6 avg interleukin-2; and administering an effective amount of a toll-like receptor (TLR) agonist covalently attached to a multi-arm, water-soluble, non-peptidic polymer, wherein the TLR agonist is selected from a multi-armed polymer conjugate of R848, a multi-armed polymer conjugate of imiquimod, or a multi-armed polymer conjugate of 4-((6-amino-8-hydroxy-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)-benzamide.
Across both independent claims, coverage is centered on combining a PD-1/PD-L1 axis inhibitor with a long acting IL-2Rβ-activating, IL-2Rβ-preferential agonist and a TLR agonist covalently attached to a multi-arm, water-soluble, non-peptidic polymer, for administration to a subject having cancer.
Stated Advantages
enhanced CD8 T-cell priming
local tumor retention
minimal systemic toxicity
Enables treatment outcomes including tumor shrinkage, tumor elimination, and progression-free survival.
Produces immune cell changes including effects on NK cells, CD8 T cells, memory T cells, central memory T cells, and regulatory T cells (CD4+ Tregs, CD25+ Tregs, FoxP3+ Tregs).
Can produce an abscopal effect on the cancer.
Improved survival for the triple combination including a PD-1/PD-L1 axis inhibitor, a long-acting IL-2Rβ-biased agonist, and a multi-arm PEG-linked TLR agonist.
Complete responses reported for the triple combination.
Regression of both primary and contralateral tumors, described as an abscopal-like effect.
Potential for improved efficacy with minimized overlapping toxicity.
Documented Applications
Administration to a subject having a cancer using a kit comprising a PD-1/PD-L1 axis inhibitor, a polymer-conjugated TLR agonist, and a long acting IL-2Rβ-preferential agonist.
Treating a subject having a cancer by administering a PD-1/PD-L1 axis inhibitor, a long acting IL-2Rβ-preferential agonist, and a TLR agonist covalently attached to a multi-arm, water-soluble, non-peptidic polymer.
Combination for an effective to produce an abscopal effect on the cancer.
Use of the described kit components for administration to a subject having a cancer.
In vivo EMT6 tumor study in Balb/c mice assessing aPD-1 alone versus combinations including a long-acting IL-2Rβ-biased agonist RSLAIL-2 and a multi-arm PEG-linked TLR agonist (4-arm-PEG20kD-Gly-CM-N-R848).
Immunotherapy tumor treatment methods for a subject having a cancer, including kit-based administration and a method of treating a subject having cancer.
Abscopal effect on the cancer when the combination includes the PD-1/PD-L1 axis inhibitor, the long acting IL-2Rβ-preferential agonist at an IL-2Rβ-activating amount, and a toll-like receptor agonist.
Survival improvement in an EMT6 tumor model (Example 19).
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