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Synovial Sarcoma X Breakpoint-2 (SSX-2) Specific Human T Cell Receptors for Treating a Wide-Range of Cancers

Posted Nov 25 2010 7:00pm

Description of Invention:
Many current approaches for treating cancer also generate harsh side effects in patients. In addition, a sizable patient population does not respond to generalized chemotherapy and radiation treatments for cancer. There is an urgent need to develop new therapeutic strategies aimed at reducing side-effects and increasing 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. As research and development continues in this area, scientists continue to improve cell transfer therapies by targeting an increasing collection of tumor antigens with more effective immune cell cultures.

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 recognize synovial sarcoma X breakpoint-2 (SSX-2) peptide antigens. SSX proteins, including SSX-2, are expressed primarily by tumor cells from a variety of cancers, including pancreatic cancer where very few treatment options exist. Other than germ cells of the testis, normal cells do not express SSX proteins and, thus, should not be targeted by therapies directed against these proteins. Therefore, SSX proteins represent a promising target for cancer immunotherapy. There are ten (10) known members of the SSX protein family designated SSX-1 through SSX-10. The T cell receptors (TCRs) developed by these NIH scientists have specificity for SSX-2 and deliver a robust immune response when they encounter SSX-2 expressing cells. However, these TCRs also recognize five (5) other SSX family members, including SSX-3, SSX-4, SSX-5, SSX-9, and/or SSX-10, and deliver a productive, intermediate immune response in the context of target cells expressing these antigens. This versatile antigen coverage could allow these SSX-specific TCRs to be utilized in the treatment of multiple types of cancer in a wide array of cancer patients. Infusing cancer patients with SSX-2 specific T cells via adoptive immunotherapy could prove to be a powerful approach for selectively attacking tumors without generating toxicity against noncancerous cells.

Applications:
  • Immunotherapeutics to treat and/or prevent the recurrence of a variety of human cancers, including pancreatic cancer and melanoma, by adoptively transferring the gene-modified T cells into patients whose tumors express a SSX family member protein recognized by this TCR.
  • A drug component of a combination immunotherapy regimen aimed at targeting specific tumor-associated antigens, including SSX-2, SSX-3, SSX-4, SSX-5, SSX-9, and/or SSX-10 expressed by cancer cells within individual patients.
  • A research tool to investigate signaling pathways in SSX-2 expressing cancer cells.
  • An in vitro diagnostic tool to screen for cells expressing an SSX antigen from a recognized member of the SSX protein family.


Advantages:
  • Selective toxicity for tumor cells – SSX-2 and other SSX proteins are only expressed on testis germ cells and tumor cells. Thus, infused cells expressing an anti-SSX-2 TCR should target SSX-expressing tumor cells with little or no toxicity to normal cells. Immunotherapy with these cells is not anticipated to elicit harsh side effects to patients.
  • Ability to recognize multiple SSX antigens – Since these SSX-2 directed TCRs can also recognize five (5) additional SSX family members (SSX-3, 4, 5, 9, and 10), cells expressing these TCRs are expected to be able to fight a larger range of tumor types. If in the course of attacking SSX-2 expressing tumor cells in a patient these cells also encounter tumor cells expressing other recognized SSX antigens, then these cells would still be capable of eliminating the non-SSX-2 expressing cell. The ability of these TCRs to recognize multiple SSX antigens may allow it to be utilized to treat a broader population of patients.
  • Versatile antigen recognition – These TCRs are CD8 and CD4 independent meaning that cells expressing these TCRs are capable of eliciting an immune response in the absence of CD8 or CD4 molecule expression on the T cell. When utilized for immunotherapy, this versatility allows engineered T cells expressing this TCR to recognize and eliminate tumors expressing SSX-2 regardless of how the antigen is presented to the T cell.

    Development Status:
    This technology is in a preclinical stage of development.

    Inventors:
    No Inventor Information Available.

    Patent Status:
    Related Technologies: T cell receptor technologies developed against other CTAs: E-304-2006/0 and E-312-2007/1 (anti-NY-ESO-1) and E-236-2010/0 (anti-MAGE-A3)

    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 the use of T cell receptor gene therapy for the treatment of cancer. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.


    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: 2199

    Updated: 11/2010

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