Custom vectors for treating and preventing pancreatic cancer
Inventors
Panicali, Dennis L. • Mazzara, Gail P. • Gritz, Linda R. • Schlom, Jeffrey • Tsang, Kwong-Yok • Hodge, James W.
Assignees
THERLON BIOLOGICS Corp • National Institutes of Health NIH • US Department of Health and Human Services
Publication Number
US-8901093-B2
Publication Date
2014-12-02
Expiration Date
2024-11-12
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Abstract
The present invention is directed to a system for treating individuals at risk of developing or suffering from pancreatic cancer. The system comprises administering to the individual a recombinant poxvirus, where the poxvirus contains a foreign nucleic acid encoding at least one pancreatic tumor associated antigen (PTAA).
Core Innovation
The invention provides a new method for treating pancreatic cancer in humans by administering recombinant poxviruses that contain pancreatic tumor associated antigens (PTAAs) and immune modulating molecules. The system administers to an individual at risk or suffering from pancreatic cancer a first recombinant poxvirus followed at regular intervals by a second recombinant poxvirus, where these poxviruses comprise at least one gene encoding a PTAA, preferably two, such as CEA and MUC-1 and their variants.
The poxviruses are preferably genetically engineered by inserting the PTAAs into nonessential regions of the viral genome and can deliver immune modulating molecules including co-stimulatory molecules like LFA-3, ICAM-1, and B7.1. The invention emphasizes the use of heterologous prime-boost protocols employing different genera of poxviruses, such as an orthopox vector for priming followed by an avipox vector for boosting to enhance immune response effectiveness.
This approach addresses the clinical problem of pancreatic cancer, which is a leading cause of cancer deaths with poor prognosis and limited efficacy of existing treatments like surgery, radiation, and chemotherapy. Current therapies rarely cure and have significant side effects. The invention leverages advances in immunotherapy, specifically active immunization targeting tumor-associated antigens expressed by pancreatic cancer cells, overcoming issues of reproducibility and specificity found in prior whole tumor-based vaccines or gene therapies using retroviral vectors.
Claims Coverage
The patent includes one independent claim focusing on a method for inducing an immune response against pancreatic cancer by administering recombinant poxvirus vectors encoding specific PTAA sequences and co-stimulatory molecules, in a prime-boost regimen.
Administration of recombinant poxvirus vectors encoding specific pancreatic tumor antigens and co-stimulatory molecules
The method comprises administering to an individual a first and then at regular intervals at least a second poxvirus vector comprising nucleic acid sequences SEQ ID NO: 1 (wMUC-1(6)) and SEQ ID NO: 3 (wCEA(6D)) along with DNA sequences encoding the co-stimulatory molecules ICAM-1, LFA-3, and B7.1.
Use of different genera of poxvirus vectors in prime-boost protocol
The first and the second poxvirus vectors are selected from orthopox, avipox, suipox, capripox, leporipox, and iridovirus vectors, with preferred embodiments including priming with an orthopox virus vector such as attenuated vaccinia (e.g., MVA or NYVAC) and boosting with an avipox vector.
Use of replication-impaired or non-replicating poxvirus vectors
The first and/or second poxvirus vector is a replication-impaired or non-replicating poxvirus vector, preferably an orthopox vector like vaccinia.
Administration schedule with specific intervals
Administration involves one to three administrations of the orthopox vector at set intervals, followed by multiple administrations of the avipox vector at set intervals, with intervals generally ranging from 20 to 90 days.
Induction of cell-mediated immune response targeting malignant pancreatic cells expressing CEA and MUC
The method induces a cell-mediated immune response against malignant pancreatic cells expressing CEA and MUC tumor antigens.
The claims emphasize a method for immunotherapy of pancreatic cancer employing specific recombinant poxvirus vectors encoding pancreatic tumor antigens wMUC-1(6) and wCEA(6D) plus co-stimulatory molecules ICAM-1, LFA-3, and B7.1, using distinct poxvirus genera in a prime-boost regimen to induce a cell-mediated immune response that inhibits tumor growth with defined dosing and vectors.
Stated Advantages
The recombinant poxvirus vectors allow stable insertion and expression of multiple genes, enabling delivery of pancreatic cancer antigens and co-stimulatory molecules simultaneously.
Use of poxviruses provides high protein expression levels, ease of production, and efficient gene delivery to various cell types including antigen presenting cells.
The prime-boost regimen using different genera of poxviruses enhances immune responses by avoiding anti-vector immunity and enabling multiple vaccinations.
The vector system has low replicative efficiency and is non-integrative, reducing the risk of unwanted persistent infections or genome integration problems.
Clinical trials demonstrated the vaccine system to be well tolerated with minimal side effects, including local injection site reactions and minor systemic symptoms.
The system enables tailoring treatment to individual patients based on antigen expression and disease stage, allowing personalized immunotherapy.
The vaccine system can be co-administered with adjuvants such as granulocyte macrophage-stimulating factor (GM-CSF) to enhance antigen presentation and immune response.
Documented Applications
Treatment of pancreatic cancer, including unresectable adenocarcinoma and metastatic (stage IV) pancreatic cancer in humans.
Prevention or delay of pancreatic cancer onset in individuals at increased risk, including those with hereditary predisposition.
Use in patients who have failed prior chemotherapy.
Use in a prime-boost vaccination protocol employing recombinant poxvirus vectors carrying pancreatic cancer associated antigens and co-stimulatory molecules.
Use in combination with standard therapies including surgery, radiation therapy, and chemotherapy.
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