Local delivery of antineoplastic particles in combination with systemic delivery of immunotherapeutic agents for the treatment of cancer
Inventors
diZerega, Gere S. • BALTEZOR, Michael • Campbell, Sam • DECEDUE, Charles J. • MCCLOREY, Matthew • MAULHARDT, Holly
Assignees
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Publication Number
US-11918691-B2
Publication Date
2024-03-05
Expiration Date
Abstract
Disclosed are combination therapy methods useful for the therapeutic treatment of cancer by combining local administration of compositions containing antineoplastic particles, such as taxane particles, with systemic administration of compositions containing immunotherapeutic agents. Local administration methods include topical application, pulmonary administration, intratumoral injection, intraperitoneal injection, arid intracystic injection.
Core Innovation
The invention relates to a method of treating cancer in a subject by administering a first composition comprising taxane particles and a second composition comprising an immunotherapeutic agent. The taxane particles comprise paclitaxel particles, docetaxel particles, cabazitaxel particles, or combinations thereof, comprise at least 95% of the taxane, and have a specific surface area (SSA) of at least 18 m2/g and a mean particle size (number) of from 0.1 microns to 5 microns.
The second composition systemically comprises an immunotherapeutic agent comprising an immune checkpoint inhibitor, and the method treats the cancer by combining locally delivered taxane particle compositions with systemic immunotherapy. Steps (a) and (b) can be conducted in any order or at the same time. The disclosure emphasizes improved efficacy and synergy versus monotherapies.
The disclosure also describes local administration modalities for the taxane particles, including topical application, pulmonary administration, intratumoral injection, intraperitoneal administration, intracystic injection, and body-cavity injection. In the described preclinical and translational context, intratumoral nanoparticle taxane therapies including NanoDoce and NanoPac in tumor xenograft/PDX models show cycle-dependent tumor regression with extensive tumor necrosis and increased immune cell infiltration.
Claims Coverage
The independent claim coverage centers on combining specified taxane particles with systemically administered immune checkpoint inhibitor immunotherapy, with the two administrations being order-independent or simultaneous. The inventive features also include defined taxane composition and particle-parameter constraints, and dependent refinements to routes and formulation.
Taxane particles with purity, SSA, and particle size constraints
Administering a first composition comprising taxane particles to a subject having a tumor, wherein the taxane particles comprise paclitaxel particles, docetaxel particles, cabazitaxel particles, or combinations thereof, wherein the taxane particles comprise at least 95% of the taxane, wherein the taxane particles have a specific surface area (SSA) of at least 18 m2/g, and wherein the taxane particles have a mean particle size (number) of from 0.1 microns to 5 microns.
Systemic immune checkpoint inhibitor immunotherapy
Systemically administering a second composition comprising an immunotherapeutic agent to the subject, wherein the immunotherapeutic agent comprises an immune checkpoint inhibitor.
Concurrent or order-independent administration of the two compositions
Steps (a) and (b) can be conducted in any order or at the same time, thereby treating the cancer.
Specific administration routes for the first composition
The method includes administering the first composition to the subject via topical administration, pulmonary administration, or intraperitoneal injection.
Protein-free first composition
The first composition contains no protein.
Overall, the claim coverage centers on combining specified taxane particles with systemically administered immune checkpoint inhibitor immunotherapy, with order-independent or simultaneous timing and dependent refinements including administration routes and a protein-free formulation constraint.
Stated Advantages
Improved efficacy and synergy versus monotherapies.
Local administration can stimulate an immunological response after systemic dosing.
Documented Applications
Treating cancer in a subject by administering a locally delivered taxane particle first composition together with systemically administered immune checkpoint inhibitor immunotherapy.
Local topical application to skin tumors in the context of a cancer combination therapy with systemic immunotherapy.
Pulmonary or inhalation administration of taxane particles as aerosol formulations using devices such as nebulizers, pMDIs, and DPIs, including NanoPac inhalation work.
Intratumoral injection and other local routes including intraperitoneal, intracystic, and body-cavity administration in the context of the described cancer combination therapy.
Ongoing Phase 1/2 clinical study with cutaneous metastases, with preliminary clinical and photographic results mentioned in the document.
Preclinical tumor models using inhaled paclitaxel particles (NanoPac), including xenograft and orthotopic efficacy and histopathology reporting tumor regression and immune infiltration patterns (TLS/BALT).
Histological and efficacy evaluation of intratumoral nanoparticle taxane therapies, including NanoDoce and NanoPac, in multiple tumor xenograft/PDX models, reporting cycle-dependent tumor regression, extensive tumor necrosis, and increased immune cell infiltration including mononuclear cells and macrophages detected by CD11b/CD68 staining.
Preclinical examples including glioblastoma intratumoral paclitaxel particles with imaging readouts.
Intraperitoneal pharmacokinetics showing unexpectedly high paclitaxel in peritoneal-contact tissues.
Nonclinical and early clinical study outlines for combination strategies involving NanoPac, by inhaled or intratumoral administration, with pembrolizumab.
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