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Increasing the Effectiveness of Cancer Treatment: T Cell Receptors Designed to Release Interleukin-12 Specifically at Cancer Sit

Posted May 01 2011 8:00pm

Description of Invention:
Many conventional chemotherapy drugs currently utilized to treat cancer also yield harsh side effects in patients. In addition, many patients do not respond to generalized chemotherapy and radiation treatments for cancer. There is an urgent need to develop new therapeutic strategies combining fewer side-effects and more specific anti-tumor activity in individual patients. Adoptive immunotherapy is a promising new approach to cancer treatment that engineers an individual's innate and adaptive immune system to fight against specific diseases, including cancer.

T cell receptors (TCRs) are proteins that recognize antigens in the context of infected or transformed cells and activate T cells to mediate an immune response and destroy abnormal cells. TCRs consist of two domains, one variable domain that recognizes the antigen and one constant region that helps the TCR anchor to the membrane and transmit recognition signals by interacting with other proteins. When a TCR is stimulated by an antigen, such as a tumor antigen, some signaling pathways activated in the cell lead to the production of cytokines, which mediate the immune response.

Scientists at the National Institutes of Health (NIH) have developed T cells genetically engineered to express the human interleukin 12 (IL-12) cytokine only in the tumor environment. Specifically, these T cells have been designed to express a human IL-12 gene under the control of the nuclear factor of activated T cells (NFAT) promoter. When the TCR on these T cells recognizes a tumor antigen, IL-12 expression is induced through activation of the NFAT promoter. Thus, IL-12 is only released at the cancer site and only after the activation of the T cell. This technology makes it possible to control the expression of IL-12 to enhance T cell cytolytic activity while also reducing or eliminating the IL-12 toxicity observed with other IL-12 related therapies. Infusing these IL-12 expressing T cells into patients via adoptive immunotherapy could prove to be powerful new tools for attacking tumors.

Applications:
  • Immunotherapeutics to treat and/or prevent the recurrence of a variety of human cancers by adoptively transferring the gene-modified T cells into patients.
  • A drug component of a combination immunotherapy regimen aimed at targeting the specific tumor-associated antigens expressed by cancer cells within individual patients.


Advantages:
The combination of enhanced T cell activity with reduced IL-12 toxicity: IL-12 has shown remarkable properties as an anti-tumor agent, but its clinical development has been hindered by its toxicity. This current technology delivers IL-12 only when and where it is needed — at the tumor site.

Development Status:
Clinical trials utilizing this technology are currently in the planning stage.

Inventors:
Richard A Morgan (NCI)


Patent Status:
HHS, Reference No. E-170-2009/0
PCT, Application No. PCT/US10/31988 filed 22 Apr 2010


Relevant Publication:
  1. L Zhang et al. Improving adoptive T cell therapy using an NFAT driven human single chain IL-12 expression vector. American Society of Gene Therapy 12th Annual Meeting Abstracts. Molecular Therapy (2009) 17, Supplement 1. S1–S396; doi: 10.1038.mt.2009.106.
  2. B Heemskerk et al. Adoptive cell therapy for patients with melanoma, using tumor-infiltrating lymphocytes genetically engineered to secrete interleukin-2. Hum Gene Ther. 2008 May;19(5):496-510. [ PubMed 18444786 ]
  3. RA Morgan et al. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science. 2006 Oct 6;314(5796):126-129. [ PubMed: 16946036 ]


Licensing Status:
Available for licensing.

Collaborative Research Opportunity:
The National Cancer Institute, Surgery Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize adoptive immunotherapies or the development of cancer therapeutics based on the use of T cell receptors. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.


Portfolios:
Cancer
Cancer - Therapeutics



For Licensing Information Please Contact:
Samuel Bish Ph.D.
NIH Office of Technology Transfer
6011 Executive Blvd. Suite 325,
Rockville, MD 20852
United States
Email: bishse@mail.nih.gov
Phone: 301-435-5282
Fax: 301-402-0220


Ref No: 1972

Updated: 05/2011

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