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

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. CRADA 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 hewesj@mail.nih.gov for more information. Click here to view the NCI collaborative opportunity announcement.

Source: http://www.ott.nih.gov/Technologies/abstractDetails.aspx?RefNo=2223

Jill Wagner Zooey Deschanel Aaliyah Abbie Cornish Adriana Lima