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Versatile Melanoma Antigen Family A3 (MAGE-A3) Specific Human T Cell Receptors to Treat Cancer that also Recognize Other MAGE-A

Posted Feb 16 2011 7:00pm

Description of Invention:
Current approaches for treating cancer can also generate harsh side effects in patients and many cancer patients do not respond to generalized chemotherapy and radiation. New and improved therapeutic strategies need to be characterized by reduced side-effects and enhancements in 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, such as cancer. Scientists are aiming to improve cell transfer therapies by targeting an increasing collection of tumor antigens with more effective immune cell cultures.

T cell receptors (TCRs) are specialized 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 a variable domain that recognizes the antigen and a constant region that anchors the TCR to the membrane and transmits recognition signals by interacting with other proteins. When a TCR is activated by recognizing its antigen, such as a tumor antigen, signaling pathways are triggered in the cell to produce cytokines that mediate the immune response.

Scientists at the National Institutes of Health (NIH) have developed T cells genetically engineered to recognize melanoma antigen family A3 (MAGE-A3) peptide antigens. MAGE-A superfamily antigens, including MAGE-A3, are expressed primarily by tumor cells from a variety of cancers. Other than germ cells of the testis, normal cells do not express MAGE-A3 and other MAGE-A proteins, which makes these antigens ideal targets for developing cancer immunotherapies. There are twelve (12) known MAGE-A genes designated A1 – A12. The normal function of MAGE-A3 is not completely known, but in cancerous cells it appears to mediate fibronectin-controlled tumor growth and spreading. MAGE-A3 is one of the most widely expressed cancer testis antigens (CTAs) on human tumors and its expression increases as the cancer progresses to more advanced stages. The T cell receptors (TCRs) developed by these NIH scientists have specificity for MAGE-A3 and MAGE-A12 and deliver a robust immune response when they encounter tumor cells expressing these antigens. These TCRs also recognize MAGE-A2 and/or MAGE-A6, but to a lesser extent that MAGE-A3 and MAGE-A12. The ability to recognize antigens from multiple MAGE-A family members could allow these TCRs to be utilized in the treatment of multiple types of cancer in a wide array of cancer patients. Infusing cancer patients with MAGE-A3 specific T cells via adoptive immunotherapy could prove to be a powerful approach for selectively attacking tumors without generating toxicity against noncancerous cells.

  • Immunotherapeutics to treat and/or prevent the recurrence of a variety of human cancers, including melanoma, lung cancers, head and neck cancers, liver cancers, and multiple myeloma, by adoptively transferring the gene-modified T cells into patients whose tumors express a MAGE-A family member protein recognized by this TCR.
  • A drug component of a combination immunotherapy regimen aimed at targeting specific tumor-associated antigens, including MAGE-A3, MAGE-A12, and MAGE-A2 and/or MAGE-A6 expressed by cancer cells within individual patients.
  • A research tool to investigate signaling pathways in MAGE-A antigen expressing cancer cells.
  • An in vitro diagnostic tool to screen for cells expressing a MAGE-A antigens.

  • Selective toxicity for tumor cells — MAGE-A3 and other MAGE-A proteins are only expressed on testis germ cells and tumor cells. Thus, infused cells expressing an anti-MAGE-A3 TCR should target MAGE-A3-expressing tumor cells with little or no toxicity to normal cells. Immunotherapy with these T cells should yield little or no harsh side effects to patients.
  • Ability to recognize multiple MAGE-A antigens — Since these MAGE-A3 directed TCRs can also recognize up to three (3) additional MAGE-A antigens (MAGE-A12, A2, and A6), cells expressing these TCRs are expected to be able to fight a larger range of tumor types. During treatment, if an infused anti-MAGE-A3 T cell culture encounters tumor cells expressing other recognized MAGE-A antigens, these T cells would not only be capable of eliminating the MAGE-A3 expressing tumor cells, but MAGE-A12, MAGE-A2, and MAGE-A6 expressing cells as well. This versatility should allow these TCRs to be utilized to treat a broader range of cancer patients.
  • Expression on a majority of tumors — MAGE-A3 is one of the most highly expressed cancer testis antigens (CTAs) on human tumors. For example, over half of melanoma tumors and non-small cell lung cancer cells express MAGE-A3. A large spectrum of cancer patients should be eligible for treatment with these MAGE-A3 TCRs should they prove successful in clinical studies.

Development Status:
This technology is in an early clinical stage of development.

Richard A Morgan (NCI)

Patent Status:
HHS, Reference No. E-236-2010/0
US, Application No. 61/405,668 filed 22 Oct 2010

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-269-2010/0 (anti-SSX-2)

Relevant Publication:
  1. N Chinnasamy et al. A TCR Targeting the HLA-A*0201-Restricted Epitope of MAGE-A3 Recognizes Multiple Epitopes of the MAGE-A Antigen Superfamily in Several Types of Cancer. J Immunol. 2011 Jan 15;186(2):685-696. [ PubMed: 21149604 ]
  2. V Cesson et al. MAGE-A3 and MAGE-A4 specific CD4(+) T cells in head and neck cancer patients: detection of naturally acquired responses and identification of new epitopes. Cancer Immunol Immunother. 2011 Jan;60(1):23-25. [ PubMed: 20857101 ]

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 anti-MAGE-A T-cell receptors for the adoptive immunotherapy of cancer. Please contact John Hewes, Ph.D. at 301-435-3121 or for more information.

Cancer - Diagnostics
Cancer - Therapeutics
Cancer - Research Materials

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

Ref No: 2223

Updated: 02/2011

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