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Pd-1 antibodies in combination with a cytokine-secreting cell and methods of use thereof

Inactive Publication Date: 2009-01-29
MEDAREX INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0012]In yet a further aspect of the invention, administration of the combination results in enhanced therapeutic efficacy relative to administration of the cytokine-expressing cellular immunotherapy or the anti-PD-1 antibody alone.

Problems solved by technology

When cancers progress, it is widely believed that the immune system either fails to respond sufficiently or fails to respond appropriately, allowing cancer cells to grow.
Currently, standard medical treatments for cancer, including chemotherapy, surgery, radiation therapy and cellular therapy, have clear limitations with regard to both efficacy and toxicity.
ever, due to the weak immunogenicity of many cancers, down regulation of MHC molecules, the lack of adequate costimulatory molecule expression and secretion of immunoinhibitory cytokines by cancer cells, the response to such immunotherapies has not resulted in long term efficacy. See
However, direct administration of cytokines for cancer therapy may not be practical, as they are often systemically toxic.

Method used

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  • Pd-1 antibodies in combination with a cytokine-secreting cell and methods of use thereof
  • Pd-1 antibodies in combination with a cytokine-secreting cell and methods of use thereof
  • Pd-1 antibodies in combination with a cytokine-secreting cell and methods of use thereof

Examples

Experimental program
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Effect test

example 1

Immune Response Following Vaccination With a GM-CSF-Secreting Immunotherapy Combined With Administration of Anti-PD-1 Antibody

[0175]Immune responses were measured as increases in tumor antigen-specific T-cells. Such T-cells can be identified by immunological monitoring methods, as described above, including (A) tetramer staining, (B) in vivo CTL activity, and (C) the induction of intracellular IFN-gamma expression following stimulation with a tumor-specific peptide or tumor cells.

[0176]FIG. 1A illustrates the anti-tumor T-cell response induced by administration of GM-CSF-secreting B16F10 cells alone and in combination with an anti-PD-1 antibody, as determined by tetramer staining. On day 0, 1×106 OT-1 transgenic T-cells were adoptively transferred into tumor-bearing C57BL / 6 mice which were challenged on day −1 with 2×105 live B16 cells transduced with the surrogate antigen, ovalbumin (F10.ova). On day 3, mice were immunized with 1×106 irradiated GM-CSF-secreting B16 cells expressing...

example 2

Pro-inflammatory Cytokine Secretion Following GVAX / Anti-PD-1 Combination Immunotherapy

[0180]A further suggestion as to the potential utility of the combination of GM-CSF-secreting immunotherapies and anti-PD-1 antibody in eliciting an anti-tumor immune response is the production of pro-inflammatory cytokines such as TNF-alpha, IFN-gamma, IL-2, IL-5, IL-6, IL-10 and MCP-1 upon restimulation in vitro. Release of such cytokines is often used as a surrogate marker for monitoring tumor-specific immune responses following immunotherapeutic strategies designed to induce anti-tumor immunity.

[0181]FIG. 2 illustrates the secretion of pro-inflammatory cytokines following administration of GM-CSF-secreting B16F10 cells alone and in combination with an anti-PD-1 antibody. On day 0, mice were inoculated subcutaneously with live B16F10 cells. On day 3, mice were immunized with 1×106 irradiated GM-CSF-secreting B16F10 cells (B16.Kd.GM) as immunotherapy alone, or immunotherapy was followed by 200 μg...

example 3

Recruitment of T-cells into Tumors Following GVAX / Anti-PD-1 Combination Immunotherapy

[0183]FIG. 3 illustrates effector CD8 T-cell infiltration into tumors in mice treated with GM-CSF-secreting B16F10 cells alone or in combination with an anti-PD-1 antibody. High numbers of tumor infiltrating lymphocytes (TIL) within tumors have been shown to correlate with overall therapeutic benefit (Dunn et al., Nat. Immunol. 3(11):991-8, 39 (2002); Smyth et al., Nat Immunol. 2(4):293-9 (2001). Thus, the extent of infiltrating lymphocytes in tumors of B16.Kd.GM-treated animals compared to animals treated with the combination therapy was examined. On day 0, mice were inoculated subcutaneously with live B16F10 cells. On day 3, 1×106 irradiated GM-CSF-secreting B16F10 cells (B16.Kd.GM) were injected as immunotherapy alone, or with 200 μg and 100 μg of anti-PD-1 antibody on days 3 and 4, respectively, as combination therapy. At the indicated timepoints, tumors from mice were excised, digested and stai...

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Abstract

The present invention relates to a method of enhancing the anti-tumor response in a mammal. More particularly, the invention is concerned with combinations comprising a cytokine-secreting cell and an anti-PD-1 antibody, and methods of administering the combination for enhanced immune response to tumor cells in a patient with a cancer.

Description

[0001]This application claims benefit of priority of U.S. provisional application No. 60 / 961,743, filed on Jul. 23, 2007, the contents of which are hereby incorporated by reference in their entireties.FIELD OF THE INVENTION[0002]The present invention relates to methods and compositions for enhancing anti-tumor protection in a mammal. More particularly, the invention is concerned with combinations comprising an antibody that specifically binds to human Programmed Death 1 (PD-1) and a cytokine-secreting cell, and methods of administering the combination for enhanced generation of an immune response to tumor cells in a patient.BACKGROUND OF THE INVENTION[0003]The immune system plays a critical role in the pathogenesis of a wide variety of cancers. When cancers progress, it is widely believed that the immune system either fails to respond sufficiently or fails to respond appropriately, allowing cancer cells to grow. Currently, standard medical treatments for cancer, including chemothera...

Claims

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Application Information

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IPC IPC(8): A61K39/395A61K35/12A61P35/00A61K39/00
CPCA61K38/193A61K39/0011A61K39/39558A61K2039/5152A61K2039/5156A61K2039/55516A61K39/3955A61K2039/55522A61K2300/00A61P35/00A61K39/001136A61K39/4611A61K2239/38A61K39/464456A61K2239/57A61K39/46449A61K2039/505
Inventor LI, BETTYJOOSS, KARINKORMAN, ALAN J.
Owner MEDAREX INC
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