Combination PDL1 and TGF-beta blockade in patients with HPV+ malignancies
Inventors
Strauss, Julius Y. • Gulley, James L. • Hinrichs, Christian S.
Assignees
US Department of Health and Human Services
Publication Number
US-11440963-B2
Publication Date
2022-09-13
Expiration Date
2038-05-08
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Abstract
The invention provides a method of inhibiting a malignancy associated with human papilloma virus (HPV) comprising administering to a subject an agent that blocks PD-L1 and TGF-beta pathways, thereby inhibiting a malignancy associated with HPV in the subject.
Core Innovation
The invention provides a method of inhibiting a malignancy associated with human papilloma virus (HPV) by administering an agent that blocks both PD-L1 and TGF-beta pathways, thereby inhibiting HPV-associated malignancies in a subject. This method is based on the discovery that dual blockade of these pathways yields higher response rates compared to current treatments, including isolated PD-L1 blockade alone.
The background section states that metastatic or refractory/recurrent HPV-associated malignancies such as cervical, anal, oropharyngeal, vulvar, vaginal, penile, and squamous cell rectal cancers are incurable and poorly palliated by standard therapies. Existing second line therapies or single-agent PD-1 inhibitors produce low response rates, generally between 10% and 21%. While PD-1 inhibitory agents have been approved, their efficacy remains limited for HPV-associated cancers.
Although the PD-1/PD-L1 pathway has been targeted therapeutically, the TGF-beta pathway also plays a role in HPV+ malignancies but has not been exploited for treatment. The invention solves the problem by introducing combined blockade of both PD-L1 and TGF-beta pathways, using agents including bifunctional fusion proteins like M7824, which simultaneously inhibit PD-L1 and sequester TGF-beta, thus increasing antitumor immune responses and achieving improved clinical outcomes in patients with HPV+ malignancies.
Claims Coverage
The patent discloses 22 claims with a focus on methods of inhibiting HPV-associated malignancies via agents blocking both PD-L1 and TGF-beta pathways. The independent claims encompass the administration methods, fusion proteins, nucleic acids and vectors encoding the fusion proteins, and compositions comprising these agents.
Method of inhibiting HPV-associated malignancies by dual pathway blockade
Administering to a subject an agent or combination of agents that block both PD-L1 and TGF-beta pathways to inhibit malignancies associated with HPV.
Fusion protein that blocks PD-L1 and TGF-beta
Use of a fusion protein comprising a PD-1 inhibitor (such as a human PD-L1 antibody or IgG1 monoclonal antibody, e.g., avelumab) fused to a TGF-beta inhibitor (such as the extracellular domain of human TGF-beta receptor II), which simultaneously blocks PD-L1 and sequesters TGF-beta.
Nucleic acid and vector encoding the fusion protein
Administration of nucleic acids encoding the fusion protein, including DNA, cDNA, or RNA, in vectors such as plasmids or viral vectors (poxvirus, retrovirus, adenovirus, etc.) enabling expression of the fusion protein in cells.
Pharmaceutical compositions and combination therapies
Formulations comprising the agent with pharmaceutically acceptable carriers and optionally coadministration with additional active agents such as anticancer agents, antibiotics, antivirals, anti-inflammatory agents, and immunotherapy.
The claims cover methods using agents that simultaneously block PD-L1 and TGF-beta pathways, including fusion proteins like M7824, their nucleic acid and vector formulations, and pharmaceutical compositions, providing a comprehensive approach to treating HPV-associated malignancies through dual immune checkpoint inhibition and TGF-beta sequestration.
Stated Advantages
Dual blockade of PD-L1 and TGF-beta pathways achieves significantly higher response rates in patients with HPV+ malignancies compared to existing single-agent PD-1 or PD-L1 therapies.
The combination therapy provides a manageable safety profile with substantial clinical benefit for patients who have progressed or are intolerant to standard first-line therapies.
Use of bifunctional fusion proteins allows simultaneous inhibition of two immunosuppressive pathways, enhancing natural killer and cytotoxic T-lymphocyte activities leading to inhibited tumor proliferation.
Documented Applications
Treatment of metastatic or refractory/recurrent HPV-associated malignancies including cervical cancer, oropharyngeal cancers, squamous cell rectal cancer, anal cancer, vaginal cancer, vulvar cancer, and penile cancer.
Use of M7824 in clinical trials for advanced solid tumors and HPV+ malignancies.
Pharmaceutical compositions including combination therapies with chemotherapeutic agents, anti-inflammatory agents, and immunotherapies.
Use in immunotherapy approaches targeting immune evasion in HPV+ cancers by enhancing antitumor immune responses.
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