Compositions and methods for inhibiting tumor-induced immune suppression
Inventors
Assignees
Augusta University • Augusta University Research Institute Inc
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Publication Number
US-11446352-B2
Publication Date
2022-09-20
Expiration Date
Abstract
It has been discovered that the cyclic peptide EnnA inactivates the Hsp90 chaperone pathway, but without activating an extensive heat shock response and overexpression of anti-apoptotic proteins. Mechanistically distinct, EnnA inhibits Hsp90 and destabilize PDL-1 and IDO, two major immune checkpoints mediating tumor-induced immune suppression. The provided herein show that EnnA profoundly modulates the cytokine signature of cancer cells and promotes a cytokine profile that favors an immune attack on tumor cells. This translates into highly efficacious anti-tumor activity in vivo, which, when combined with a single dose of chemotherapy, completely reduced the tumor burden in experimental animals and instilled highly efficient immune memory against the primary tumor.
Core Innovation
The invention relates to EnnA (Enniatin A), a cyclic peptide that inhibits a Hsp90 machine without inducing an extensive cellular stress response. Inhibition of the Hsp90 machine is described as affecting immune checkpoint mediators and the tumor immune microenvironment.
The described effects include destabilizing immune checkpoint mediators such as PD-L1 and IDO, with a shift of cancer-cell cytokine profiles toward immunogenicity. The document states that the approach reduces tumor immune suppression, including Tregs and MDSCs, and increases immune memory.
The invention is also described as having strong anti-tumor efficacy in immunocompetent mouse breast tumor models. The document further describes synergy with a single dose of chemotherapy, including cyclophosphamide (CPA), to completely reduce tumor burden and prevent recurrence, linked to functional T-cell immunity and altered PD-1/PD-L1 signaling.
Claims Coverage
The partial content provides one independent method claim (clm-00001). The inventive features are directed to administering EnnA with a single dose of a potentiating agent and/or chemotherapeutic agent to inhibit a Hsp90 machine without inducing an extensive cellular stress response, for reducing cancer cells in specified cancers.
EnnA composition with single dose to inhibit Hsp90 machine without extensive cellular stress response
Administering an effective amount of a composition consisting of Enniatin A (EnnA) and administering a single dose of a potentiating agent and/or chemotherapeutic agent to inhibit a Hsp90 machine without inducing an extensive cellular stress response, thereby reducing cancer cells in a subject having breast cancer, hepatoma, glioma, lymphoma or leukemia.
Across the independent claim and its refinements, the core coverage is a method for reducing cancer cells by administering an EnnA-containing composition together with a single dose of a potentiating agent and/or chemotherapeutic agent that inhibits a Hsp90 machine without inducing an extensive cellular stress response.
Stated Advantages
Inhibits a Hsp90 machine without inducing an extensive cellular stress response.
Reduces cancer cells in a subject having breast cancer, hepatoma, glioma, lymphoma or leukemia.
Reduces immunosuppressive cell populations including Tregs and MDSCs.
Lowers Programmed death-ligand 1 (PD-L1) mRNA and protein levels.
Increases immunogenicity of cancer cells.
Induces or promotes immune memory.
Can synergize with a single dose of chemotherapy, including cyclophosphamide (CPA/CTX), to completely reduce tumor burden and prevent recurrence.
Documented Applications
Immunocompetent mouse breast tumor models (including E0771, AT3, and EM6/EMT6 and 4T1 are mentioned in the partial content) as in vivo contexts where EnnA shows strong anti-tumor efficacy.
Co-therapy contexts with single-dose chemotherapy, including cyclophosphamide (CPA/CTX), in which synergy is described for reducing tumor burden and preventing recurrence.
Immune-mechanism contexts involving functional T-cell immunity, including altered PD-1/PD-L1 signaling and CD8β T-cell infiltration/lessened exhaustion, as described for tumor outcomes.
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