Composition for inhibiting tumor cell proliferation
Inventors
Karlsson-Parra, Alex • Andersson, Bengt • Wallgren, AnnaCarin
Assignees
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Publication Number
US-9034317-B2
Publication Date
2015-05-19
Expiration Date
Abstract
This invention pertains to cancer immunotherapy, by providing a proinflammatory dendritic cell (DC), which has been stimulated to maturation ex vivo by specific treatment, a method for such treatment and a composition comprising the proinflammatory DC. The DC may be used as a cell based immunotherapy for inhibiting tumor cell proliferation.
Core Innovation
The invention relates to cancer immunotherapy using ex vivo-generated proinflammatory mature dendritic cells (DC). An immature DC is stimulated ex vivo to become a non-migratory, proinflammatory mature DC by treatment with polyinosinic-polycytidylic acid sodium salt (poly-I:C), resiquimod (R848), and interferon gamma (IFN-γ), but not with prostaglandin E2 (PGE2). The immature DC is obtained from a person other than the subject in need thereof, and the resulting non-migratory, proinflammatory mature DC is injected into a tumor of the subject.
After withdrawal of the stimuli, the non-migratory, proinflammatory mature DC produce sustained chemokines and IL-12p70, supporting recruitment and activation of immune cells. The sustained chemokines include CCL3/MIP-1α and CXCL9/MIG, and optionally CCL5/RANTES, together with IL-12p70. The approach is presented as an allogeneic adjuvant for inducing systemic antitumor effects after intratumoral administration.
The disclosure further describes experimental evidence including sustained cytokine and chemokine production measured by ELISA, induction of maturation in bystander iDCs with upregulation of CD86 and CD83, and an intratumoral study in the MAT B III rat tumor model showing reduced distant tumor volume or weight and increased tumor infiltration by DC/macrophages, NK cells, and CD8+ T cells. Allogeneic manufacturing, storage, and shipping are also described as supported.
Claims Coverage
The provided independent claims define two method variants for treating cancer, each centered on producing non-migratory, proinflammatory mature DC ex vivo with poly-I:C, R848, and IFN-γ, excluding PGE2, and injecting the resulting DC into a tumor. Both independent claims include an allogeneic sourcing limitation for the donor-derived immune cells, with the second independent claim additionally specifying how the immature DC are obtained from monocytes within PBMC.
Ex vivo generation of non-migratory proinflammatory mature DC using poly-I:C, R848, and IFN-γ but not PGE2
Stimulating an immature dendritic cell (DC) to become a non-migratory, proinflammatory mature DC ex vivo by treatment with polyinosinic-polycytidylic acid sodium salt (poly-I:C), resiquimod (R848), and interferon gamma (IFN-γ), but not with prostaglandin E2 (PGE2).
Tumor injection of non-migratory proinflammatory mature DC
Injecting the non-migratory, proinflammatory mature DC into a tumor of the subject.
Allogeneic sourcing of immature DC from a person other than the subject
Wherein the immature DC is obtained from a person other than the subject in need thereof.
Generate immature DC from monocytes isolated from a PBMC population from another person
Generating an immature DC from a monocyte isolated from a population of PBMCs, wherein the population of PBMCs is obtained from a person other than the subject in need thereof.
Across the independent claims, the inventive core is ex vivo stimulation of immature DC into a non-migratory, proinflammatory mature DC using poly-I:C, R848, and IFN-γ but not PGE2, followed by intratumoral injection into the subject. The independent claims further require that the immature DC or the PBMC population used for generating the immature DC is obtained from a person other than the treatment subject.
Stated Advantages
Induces systemic antitumor effects as an allogeneic adjuvant after intratumoral administration.
Supports recruitment and activation of immune cells via sustained chemokines and IL-12p70 after withdrawal of stimuli.
Reduces distant tumor volume or weight and increases tumor infiltration by DC/macrophages, NK cells, and CD8+ T cells in the described rat tumor model.
Supports allogeneic manufacturing, storage, and shipping.
Documented Applications
Treating cancer in a subject in need thereof by intratumoral injection of ex vivo-generated non-migratory, proinflammatory mature dendritic cells.
Using the method to achieve systemic antitumor effects following intratumoral administration of the mature DC.
Target indications are described as including breast cancer, prostate cancer, renal cancer, intestinal cancer, malignant glioma, osteosarcoma, malignant melanoma, pancreatic cancer, malignant lymphoma, and eosophagal cancer.
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