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Oligonucleotide Compounds that Enhance Immunity to Cancer and Reduce Autoimmunity

Posted Jun 14 2011 8:00pm

Description of Invention:
Suppressive cells, including macrophages and other myeloid-derived suppressor cells, regulatory T cells, and dendritic cells (DCs), have been attributed to tumor growth. DCs in particular are known to be associated with the induction of T cell tolerance in cancer, but molecular mechanisms that control DC dysfunction are complex and a better understanding of DC mechanisms in tumors is needed. Recently FOXO3, originally identified as a tumor suppressor, was associated with DC dysfunction. Additionally, therapeutics targeting FOXO3 are known to be effective at killing many tumors types, synergize with traditional therapies, and show efficacy against tumors that are otherwise resistant to conventional treatments.

The researchers at the NIH have demonstrated for the first time that FOXO3 expression by DC coincides with expression of suppressive genes that negatively regulate T cell function. They have also demonstrated that silencing FOXO3 simultaneously changes DC function, eliminating tolerogenicity and enhancing their immunostimulatory capacity. Specifically, the inventors have developed siRNAs or oligonucleotides that enhance an immune response and neutralize the activity of FOXO3 in DCs by converting suppressive cells into immunostimulatory cells. This novel approach could be applied to cancer vaccines, where dendritic cells could be treated with these small molecules prior to use in clinical therapies. Alternatively, small molecules that stimulate FOXO3 expression could be used for inducing immune suppression for autoimmune diseases like type I diabetes or multiple sclerosis.

Applications:
  • An adjuvant to neutralize FOXO3 and elicit a more potent response to cancer immune-based therapies, either at the time of vaccination or during an on-going anti-tumor immune response.
  • Suppressing an immune response through the induction of FOXO3 expression to prevent tissue-specific autoimmune diseases like type I Diabetes or Multiple sclerosis, where known target antigens have been identified.


Advantages:
  • The ability to treat multiple tumor types linked to FOXO3 expression.
  • siRNAs can be delivered to different organs with minimal cytotoxicity.
  • Through the modulation of FOXO3 gene expression, therapeutics for both cancer and autoimmune diseases can be developed.


Development Status:
Pre-clinical proof of principle

Inventors:
Arthur A Hurwitz (NCI)


Patent Status:
HHS, Reference No. E-086-2010/0
PCT, Application No. PCT/US2011/020315 filed 06 Jan 2011


Relevant Publication:
  1. Watkins SK, Zhu Z, Riboldi E, Shafer-Weaver KA, Stagliano KE, Sklavos MM, Ambs S, Yagita H, Hurwitz AA. FOXO3 programs tumor-associated DCs to become tolerogenic in human and murine prostate cancer. J Clin Invest. 2011 Apr 1;121(4):1361-1372. [ PMID: 21436588 ]


Licensing Status:
Available for licensing.

Collaborative Research Opportunity:
The National Cancer Institute Cancer and Inflammation Program is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize agents that both block FOXO3 function and enforce FOXO3 expression. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.


Portfolios:
Cancer
Cancer - Therapeutics



For Licensing Information Please Contact:
Whitney Hastings
NIH Office of Technology Transfer
6011 Executive Blvd. Suite 325,
Rockville, MD 20852
United States
Email: hastingw@mail.nih.gov
Phone: 301-451-7337
Fax: 301-402-0220


Ref No: 2267

Updated: 06/2011

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