Methods and compositions containing mTOR inhibitors for enhancing immune response

A technology of immune response and composition, applied in the field of regulating immune response, can solve problems such as difficulty in achieving successful application

Inactive Publication Date: 2011-12-14
HEALTH RES INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, successful application of cancer vaccines to treat patients is elusive and research into enhancing the efficacy of cancer vaccines is ongoing, an unmet need

Method used

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  • Methods and compositions containing mTOR inhibitors for enhancing immune response
  • Methods and compositions containing mTOR inhibitors for enhancing immune response
  • Methods and compositions containing mTOR inhibitors for enhancing immune response

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] This example provides a description of the materials and methods used to obtain the data as described in Examples 2-9.

[0055] Mice and reagents: Housed, housed and used C57BL / 6, CD4 at RPCI according to IACUC guidelines + TCR transgenic Rag2 -1- (OT-II), CD8 + TCR transgenic Rag2 1 / - (OT-I, wild type), Stat4 -1- OT-I Rag2 -1- , and Tbx21 -1- OT-I Rag2 -1- mice. rmIL-12 (2ng / ml) was provided freely by Wyeth Ltd. (Cambridge, MA). IFN-a was freely provided by T. Tomasi (RPCI). rmlL-7 was purchased from Peprotech (Rocky Mount, NJ). 2-DG, 4-HT and rapamycin were purchased from Sigma-Aldrich (St. Louis, MO). LY290042 was purchased from Calbiochem. Insulin was purchased from Novo Nordisk (Princeton, NJ).

[0056] Stimulation of OT-I cells. According to known techniques, expressing H-2K with b / Ovalbumin antigen and B7.1 latex microspheres to stimulate native OT-I cells. Naive OT-II cells were stimulated with anti-CD3- / anti-CD28-coated latex beads. In some ex...

Embodiment 2

[0061] This example demonstrates that priming native CD8 + Instructions for T cells to undergo type I effector cell differentiation enhance mTOR activity. To study native CD8 + Mechanisms by which T cell instructive (signals 1, 2 and 3 - antigen [Ag], B7.1 [co-stimulatory] and IL-12 [cytokine]) programming into type I effector cell function we set out to confirm IL-12 plays a decisive role in the maturation of OT-I cells to type I effector cells stimulated with an adherent cell line called BOK expressing H-2K b , OVAp and B7.1. Addition of IL-12 resulted in massive production of IFN-γ and cytotoxic T lymphocyte (CTL) activity in OT-I cells at 72 hours ( figure 1 A and 1B, Elementary). In addition, when primary effector OT-I cells (72 hours) were placed in IL-7 for an additional 72 hours (12% IFN-γ measured at 144 hours) and restimulated with Ag and B7.1 (see Example 1) , only IL-12-conditioned OT-I cells re-induced IFN-γ and CTL activity ( figure 1 A and 1B; secondary). ...

Embodiment 3

[0064] This example shows that in CD8 + IL-12 enhances mTOR activity in T cells requires PI3K and STAT4. To determine the control CD8 + Molecular pathways of mTOR activity in T cells, we analyzed the antigen-, B7.1- and IL-12-induced phosphoinositide 3-kinase (PI3K)-Akt kinase pathway for CD8 + Required for mTOR signaling in T cells. Akt phosphorylation (Thr308) in antigen + B7.1 ± IL-12 stimulated OT-I cells was assessed as a functional measure of PI3K activity. While stimulation with antigen+B7.1 for 30 min with or without IL-12 induced similar amounts of Akt phosphorylation, Akt phosphorylation was enhanced up to 48 h in the presence of IL-12, which was controlled by a PI3K inhibitor (LY294002 ) suppressed by ( figure 2 A), thus confirming that IL-12 enhanced antigen+B7.1-induced PI3K activity in OT-I cells. Furthermore, inhibition of PI3K blocked IL-12-enhanced mTOR activity (S6K phosphorylation was observed at 2, 12 and 48 hours) ( figure 2 B), showing that antige...

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Abstract

Provided are compositions and methods for enhancing immune responses to an antigen. The compositions contain an isolated population of CD8+T cells and an inhibitor of mammalian target of rapamycin (mTOR). The method for obtaining an enhanced immune response to an antigen in an individual entails administering to the individual the antigen and an inhibitor of mammalian target of rapamycin (mTOR). CD8+T cells may also be used for adoptive cell transfer (ACT) therapy.

Description

[0001] This application claims priority to US Patent Application No. 61 / 144,537, filed January 14, 2009, and US Patent Application No. 61 / 293,096, filed January 7, 2010, the contents of which are hereby incorporated by reference in their entirety. [0002] This invention was made with government support under Grant No. 5R01CA104645 provided by the National Institutes of Health. The government has certain rights in this invention. field of invention [0003] The present invention relates generally to modulating the immune response, and more particularly to the use of mammalian target of rapamycin (mTOR) inhibitors to enhance cell-mediated immune responses in individuals. Background of the invention [0004] Cancer vaccines are being actively evaluated in clinical and preclinical studies. In theory, recruiting the immune system to attack cancer is attractive. The immune system recognizes tumor-specific antigens and eliminates diseased cells without affecting normal tissues. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A01N43/04A61K35/26A61K39/00
CPCA61K2039/6043A61K31/436A61K39/39A61K39/0011A61K2039/55511A61K2039/55538A61K35/26C12N5/0636A61K2039/5158A61K2039/55516A61K39/00A61K38/208A61P35/00A61P37/04A61K2300/00
Inventor H·金P·施里肯特Y·王李庆生R·拉奥
Owner HEALTH RES INC
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