System for treating and preventing breast cancer
Inventors
Panicali, Dennis L. • Mazzara, Gail P. • Gritz, Linda R. • Schlom, Jeffrey • Tsang, Kwong-Yok • Hodge, James W.
Assignees
National Institutes of Health NIH • US Department of Health and Human Services
Publication Number
US-8933041-B2
Publication Date
2015-01-13
Expiration Date
2024-11-12
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Abstract
The present invention is directed to a system for treating individuals at risk of or suffering from breast cancer. The system comprises administering to the individual a recombinant poxvirus, where the poxvirus contains in a foreign nucleic acid encoding at least one breast cancer antigen.
Core Innovation
The invention provides a system for treating individuals at risk of or suffering from breast cancer by administering to the individual recombinant poxviruses containing foreign nucleic acids encoding breast cancer associated antigens (BCAAs). These antigens include mucin (such as MUC-1 and variants) and carcinoembryonic antigen (CEA and variants like wCEA(6D)). The method allows tailored immunotherapy by screening individuals to identify specific breast cancer antigens expressed, and by administering sequences encoding those antigens along with immune modulating molecules such as co-stimulatory molecules (e.g., LFA-3, ICAM-1, and B7.1, collectively TRICOM).
The system preferably administers a first recombinant poxvirus followed by regular administrations of at least one second recombinant poxvirus that is preferably from a different genus, for example administering an orthopox (vaccinia such as Wyeth, MVA or NYVAC) as a prime and an avipox (fowlpox or canary pox) as boost vectors. The invention also provides co-administration of granulocyte macrophage colony stimulating factor (GM-CSF) as an adjuvant. Recombinant poxviruses can be engineered to contain multiple breast cancer associated antigens and co-stimulatory molecules either within the same vector or across different vectors administered simultaneously or at intervals.
The problem solved by the invention arises from the lack of effective and specific treatment methods for breast cancer, especially metastatic disease, which are currently non-discriminatory, toxic, and often ineffective. Existing cancer treatments largely target rapidly dividing cells non-specifically. Although diagnosis of breast cancer has improved, treatments generally do not customize to the individual's specific tumor antigen profile. Gene therapy vectors like retroviruses have drawbacks such as integration into host genome and difficulties in infection efficiency. There is a need for an improved, less toxic, effective system capable of utilizing specific antigenic information from genetics and expression analyses to tailor breast cancer treatment.
The invention leverages the advantages of poxviruses as vectors, including their large genome capacity, ability to infect multiple cell types including antigen-presenting cells, high protein expression, capacity to induce both cellular and humoral immune responses, and prior safe use in humans (e.g., smallpox vaccines). By genetically engineering recombinant poxviruses to express breast cancer-associated antigens and immune-modulating co-stimulatory molecules, the system provides a novel adaptable immunotherapy to induce robust targeted immune responses against breast cancer cells.
Claims Coverage
The patent claims disclose multiple inventive features covering methods of inducing immune responses against breast cancer antigens using recombinant poxvirus vectors with specific antigen and co-stimulatory molecule compositions and various vector types and administration protocols.
Administration of recombinant poxvirus vectors encoding mucin and carcinoembryonic antigens
Methods comprising administering to a human diagnosed with breast cancer a first and one or more subsequent poxvirus vectors encoding breast cancer associated antigens of mucin (wMUC-1(6)) and carcinoembryonic antigen (wCEA(6D)), inducing an immunological response against cancer cells expressing these antigens.
Co-administration of co-stimulatory molecules with the poxvirus vectors
Methods involving administration of one or more co-stimulatory molecules, specifically B7.1, LFA-3, and ICAM-1, either encoded within the same poxvirus vectors or in combination with antigen-encoding vectors, to enhance the induced immune response.
Use of diverse poxvirus vector types and heterologous prime-boost regimens
Methods employing first and second poxvirus vectors selected from orthopoxvirus, avipoxvirus, suipoxvirus, capripoxvirus, leporipoxvirus, and iridovirus genera, including combinations where the first vector is an orthopox (e.g., vaccinia Wyeth, MVA, NYVAC) and the second is an avipox, administered at regular intervals such as 20 to 90 days for prime and boosts.
Use of replication impaired or non-replicating poxvirus vectors
The first and/or second poxvirus vectors can be replication impaired or non-replicating to improve safety and specificity.
The claims cover methods of inducing breast cancer-specific immune responses by administering recombinant poxvirus vectors encoding mucin and carcinoembryonic antigens along with co-stimulatory molecules, using selected poxvirus genera in prime-boost regimens, including safety-enhancing replication-deficient vectors.
Stated Advantages
Provides a less toxic and more effective treatment than non-specific regimens for breast cancer.
Enables tailored treatment to the individual patient's antigen expression and disease stage.
Allows expression of multiple therapeutic molecules in a single vector due to large poxvirus genome size.
Induces both cellular and humoral immune responses targeted against breast cancer cells.
Vectors like MVA and fowlpox are safe and well tolerated with established human use history.
Prime-boost strategies using different poxvirus genera improve immune response efficiency.
Adjunct administration of GM-CSF enhances antigen processing and immune activation.
Documented Applications
Treatment of all types and stages of breast cancer, including metastatic and recurrent breast cancer.
Prevention or delay of onset of breast cancer in individuals at increased risk, such as those with hereditary mutations.
Immunotherapy combined with chemotherapy, including specific combination with docetaxel.
Use in personalized therapy protocols adjusted on antigen expression and disease progression via expression profiling.
Use in conjunction with existing treatments like surgery, radiation, hormone therapy, and monoclonal antibody therapy.
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