Yeast-Brachyury immunotherapeutic compositions
Inventors
Palena, Claudia • Guo, Zhimin • Apelian, David • Schlom, Jeffrey
Assignees
GlobeImmune Inc • US Department of Health and Human Services
Publication Number
US-9198941-B2
Publication Date
2015-12-01
Expiration Date
2032-03-19
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Abstract
Disclosed are yeast-based immunotherapeutic compositions comprising Brachyury antigens, and methods for the prevention and/or treatment of cancers characterized by the expression or overexpression of Brachyury.
Core Innovation
The invention relates to yeast-based immunotherapeutic compositions comprising a yeast vehicle and cancer antigens that include at least one Brachyury antigen. These compositions evoke an immune response, particularly Brachyury-specific T cell responses, including CD4+ and CD8+ T cell responses, for the prevention and treatment of cancers expressing or overexpressing Brachyury.
The Brachyury protein is a mesodermal transcription factor involved in early development and is implicated in cancer progression by promoting epithelial-mesenchymal transition (EMT), thus contributing to tumor invasiveness, metastatic progression, and chemotherapy or radiation resistance. Tumors expressing Brachyury include those from breast, lung, colon, prostate, and certain lymphomas.
The invention solves the problem of insufficient immunotherapeutic approaches targeting Brachyury-expressing cancers, especially metastatic and late-stage tumors, where conventional therapies often fail. Yeast-Brachyury immunotherapy offers a novel strategy for inducing potent cellular immune responses against Brachyury-positive tumors without requiring exogenous adjuvants, addressing the unmet need for effective therapies to treat or prevent metastatic cancer progression and overcome therapy resistance.
Claims Coverage
The claims define compositions and methods centered on yeast-Brachyury immunotherapeutic compositions, detailing their components, conditions for production, and therapeutic applications. There are multiple inventive features covering composition makeup, antigen expression, production methods, and treatment uses.
Yeast-Brachyury immunotherapeutic composition
A composition comprising a whole, inactivated yeast (preferably Saccharomyces cerevisiae) expressing a Brachyury fusion protein that includes amino acid positions 2-435 of SEQ ID NO:6 or SEQ ID NO:18, which elicits a Brachyury-specific T cell response.
Brachyury fusion protein variants in yeast composition
The Brachyury fusion protein within the composition may specifically comprise the amino acid sequence of positions 2-435 of SEQ ID NO:6, positions 2-435 of SEQ ID NO:18, SEQ ID NO:8, or SEQ ID NO:20, each expressing the antigen under a promoter such as CUP1.
Heat inactivation of yeast
The yeast in the immunotherapeutic composition is whole and heat-inactivated to ensure safety and efficacy.
Method for producing yeast-Brachyury immunotherapeutic
A method involving culturing yeast transformed with a recombinant nucleic acid encoding a Brachyury antigen under CUP1 promoter to mid-log phase without CuSO4, inducing expression by adding CuSO4, culturing for 6-8 hours, then harvesting the yeast.
Use of immunotherapeutic for cancer treatment and metastasis prevention
Methods involving administration of the yeast-Brachyury immunotherapeutic to individuals with cancer to reduce, arrest, reverse, delay, or prevent metastatic progression, including cases with detectable or undetectable Brachyury expression, pre-cancerous lesions, or chemotherapy/radiation resistance.
Combination immunotherapy methods
Methods of treating cancer by administering a first immunotherapeutic composition comprising a yeast vehicle and a non-Brachyury cancer antigen, followed by administration of a yeast-Brachyury immunotherapeutic composition, potentially with additional immunotherapeutic compositions carrying other cancer antigens.
Treatment of Epstein Barr Virus (EBV) associated disease
Use of yeast-Brachyury immunotherapeutic compositions for treating or preventing diseases or conditions associated with EBV infection.
The claims comprehensively cover yeast-Brachyury immunotherapeutic compositions comprising heat-inactivated yeast expressing Brachyury fusion proteins with specified sequences, methods of producing these compositions, and methods of their therapeutic application for cancers characterized by Brachyury expression, including combination therapies and treatment of EBV-related conditions.
Stated Advantages
Yeast-Brachyury immunotherapy effectively targets late-stage and metastatic cancers by preventing or arresting metastatic progression.
The therapy enhances immune responses against Brachyury-expressing tumors without the need for exogenous adjuvants or immunostimulants.
It can reduce chemotherapy and radiation resistance in tumor cells, improving the efficacy of conventional therapies.
It elicits broad and potent cellular immune responses, including CD4+ and CD8+ T cell-mediated immunity and inhibition of regulatory T cells.
The immunotherapy is adaptable for inclusion of multiple tumor antigens, enabling personalized and combinatorial cancer treatment strategies.
Yeast vehicles can be safely heat-inactivated and administered repeatedly without losing efficacy.
Documented Applications
Prevention and treatment of cancers characterized by expression or overexpression of Brachyury, including metastatic and late-stage cancers.
Treatment of cancers from various tissues including breast, small intestine, stomach, kidney, bladder, uterus, ovary, testes, lung, colon, pancreas, prostate, chronic lymphocytic leukemia, and various lymphomas.
Reduction or prevention of chemotherapy-resistance or radiation-resistance in cancer patients undergoing respective therapies.
Treatment or prevention of diseases or conditions associated with Epstein Barr Virus (EBV) infection.
Combination cancer immunotherapy protocols with additional yeast-based immunotherapies targeting other tumor antigens.
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