T Cells Attacking Cancer: T Cell Receptors that Recognize the Tyrosinase Tumor Antigen

Description of Invention:
A problem with current chemotherapy-based cancer treatments is the harsh side-effects associated with many cancer drugs. Thus, there is an urgent need to develop new therapeutic strategies combining fewer side-effects and more specific anti-tumor activity. Adoptive cell transfer (ACT) is a promising new immunotherapeutic approach to treat cancer and other diseases by directing an individual's innate and adaptive immune system to recognize specific disease-associated antigens.

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.

Scientists at the National Institutes of Health (NIH) have isolated T cells that recognize the human tyrosinase tumor-associated antigen (TAA) from the tumor infiltrating lymphocytes (TIL) of a melanoma cancer patient. The human tyrosinase antigen is a tumor antigen expressed in a variety of cancers, including skin cancer (melanoma) and brain cancer (glioblastoma). Utilizing the tyrosinase specific T cells, these scientists developed human/mouse hybrid TCRs with enhanced affinity for the tyrosinase TAA. The TCR sequences were modified by making specific amino acid substitutions and replacing certain TCR regions with mouse homologues. These TCRs also showed CD8-independency and, thus, can be expressed in both CD8 and CD4 T cells. T cells expressing these engineered TCRs recognize skin and brain tumor cells in culture. These T cells also exhibit enhanced cytokine induction and better tumor reactivity compared to unmodified TCRs. Previous versions of gene-modified T cells developed by NIH researchers demonstrated objective clinical responses in some cancer patients, which have validated gene-modified T cell immunotherapy as a promising cancer treatment strategy. TCRs directed against the tyrosinase TAA could serve as valuable new immunotherapeutic tools for attacking tumors, especially in patients whose tumors do not express other common TAAs.

Applications:

• Immunotherapeutics to treat and/or prevent the recurrence of a variety of human cancers, including melanomas and glioblastomas, that express tyrosinase by transferring T cells engineered with tyrosinase-specific TCRs into cancer patients.
• A drug component of a combination immunotherapy regimen aimed at targeting the specific tumor-associated antigens expressed by the cancer cells of individual patients.
• Immunotherapeutic to treat and/or prevent tumors that do not express other common tumor-associated antigens, such as MART-1, gp100, and NY-ESO-1.

Advantages:

• The parent tyrosinase-specific TCR was isolated from tumor infiltrating lymphocytes, so the genetically-modified versions should have an elevated affinity for tyrosinase.
• The tyrosinase-specific T cells recognize skin and brain cancer cells in culture. These T cells are predicted to have broad anti-cancer activity once developed to a clinical level.
• CD8 independency: The tyrosinase-specific TCRs can be expressed in both CD8 and CD4 T cells to maximize the cell-mediated immune response to the tumor.
• The tyrosinase-specific T cells should not be rejected by a patient's immune system since the mouse tyrosinase-recognition enhancing TCR sequences are incorporated into a human TCR backbone.

Development Status:
This technology is in the pre-clinical stage of development. The inventors plan to develop the technology into clinical grade reagent for a clinical trial if the pre-clinical data continues to show promising results.

Inventors:
Steven A Rosenberg (NCI)


Patent Status:
HHS, Reference No. E-043-2009/0
PCT, Application No. PCT/US10/21909 filed 25 Jan 2010


Licensing Status:
Available for licensing.

Collaborative Research Opportunity:
The National Cancer Institute, Surgery Branch, Tumor Immunology Section, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize T Cells Attacking Cancer: T Cell Receptors that Recognize the Tyrosinase Tumor Antigen. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.


Portfolios:
Cancer
Cancer - Therapeutics
Infectious Diseases
Infectious Diseases - Therapeutics
Gene Based Therapies
Gene Based Therapies - Therapeutics



For Additional 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: 1958

Updated: 05/2009