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Publication Number
US-10751372-B2
Publication Date
2020-08-25
Expiration Date
Abstract
The present invention relates to pharmaceutical vaccine compositions comprising at least one vaccine antigen together with living immune cells. These immune cells include at least a portion of activated T-cells and act as an adjuvant. Methods for using these pharmaceutical compositions to prevent or treat diseases, such as cancer, infectious diseases and autoimmune disease are also included.
Core Innovation
The invention relates to a pharmaceutical composition comprising an adjuvant and a chaperone rich cell lysate (CRCL). The adjuvant comprises living immune cells where at least a portion are activated T-cells in infusion media with cross-linked CD3 and CD28 surface molecules. The CRCL is sourced from a malignant tumor and comprises multiple chaperone complexes enriched by free solution-isoelectric focusing.
The activation of the T-cells is implemented through cross-linking CD3 and CD28 surface molecules. The approach uses living activated T-cells as an adjuvant to drive a Th1/IFN-gamma response, with preference for Th1 deviation from Th2 to address immune evasion. The living activated T-cells are described as preferably Th1 memory CD4+ cells expressing a Th1 phenotype, and the cells are described as producing inflammatory cytokines.
The CRCL component is described as tumor-derived and enriched for multiple immunogenic chaperone complexes, including GRP94/gp96, HSP90, HSP70, and calreticulin. The combined use of cross-linked Th1 cells with tumor-derived CRCL is described as improving tumor-free survival and overall survival compared with monotherapies, including in established leukemia, with significant survival improvement for the combination. The described compositions may also include one or more tumor-associated antigens such as MART-1, gp100, tyrosinase, MUC1, HER2-neu, p53, and ras.
Claims Coverage
The independent claim covers a pharmaceutical composition that combines an adjuvant comprising living immune cells with activated T-cells cross-linked at CD3/CD28 in infusion media and a tumor-derived CRCL enriched for multiple chaperone complexes by free solution-isoelectric focusing, where administration generates a Th-1 response. One independent claim is identified in the provided relevant claims set, with dependent refinements that further define T-cell phenotype/function, cross-linking agents, optional antigen addition, and an allogeneic constraint.
Living immune cell adjuvant with activated T-cells cross-linked CD3/CD28
An adjuvant comprising living immune cells where at least a portion are activated T-cells in infusion media with cross-linked CD3 and CD28 surface molecules.
Malignant tumor-derived CRCL enriched multiple chaperone complexes by free solution-isoelectric focusing
A chaperone rich cell lysate (CRCL) sourced from a malignant tumor, the CRCL comprising multiple chaperone complexes enriched by free solution-isoelectric focusing.
Administration generates a Th-1 response
Administration of the composition to a host generates a Th-1 response.
Activated T-cells expressing CD40L
The composition includes activated T-cells that express CD40L.
Cross-linking CD3 and CD28 using anti-CD3 and anti-CD28 monoclonal antibodies
The cross-linking is performed with anti-CD3 and anti-CD28 monoclonal antibodies.
Memory Th-1 phenotype T-cells
The composition uses memory T-cells of the Th-1 phenotype.
Allogeneic activated T-cells
The activated T-cells are allogeneic to the host.
Optional tumor-associated antigens
The composition further includes one or more tumor-associated antigens.
Overall claim coverage centers on combining an infusion-media adjuvant of living activated T-cells cross-linked at CD3 and CD28 with malignant tumor-derived CRCL enriched for multiple chaperone complexes by free solution-isoelectric focusing, such that administration generates a Th-1 response. Dependent features further specify memory Th-1 phenotype, CD40L expression, anti-CD3/anti-CD28 cross-linking, an allogeneic T-cell constraint, and optional inclusion of tumor-associated antigens.
Stated Advantages
Improves tumor-free survival and overall survival versus monotherapies in the described mouse examples.
Provides significant survival improvement for the combination in established leukemia.
Generates a Th-1 response, including a Th1/IFN-gamma response, by using living activated T-cells as an adjuvant.
Enriches multiple immunogenic chaperone complexes within tumor-derived CRCL using free solution-isoelectric focusing.
Documented Applications
Mouse examples (including a 12B1 leukemia model) where CD3/CD28 cross-linked Th1 cells combined with tumor-derived CRCL improved tumor-free survival and overall survival versus monotherapies.
Therapeutic use in established leukemia, where the combination showed significant survival improvement.
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