The First HLA Class II Restricted T Cell Receptor that Recognizes the Cancer Testis Antigen, MAGE-A3


NIH scientists have developed T cell receptors (TCRs) against the melanoma antigen family A3 (MAGE-A3) tumor antigen in the context of major histocompatibility complex (MHC) class II molecule HLA-DP-beta1*04. They are the first HLA class II restricted MAGE-A3 TCRs developed for use in adoptive immunotherapy. Previously developed MAGE-A3 TCRs are HLA class I restricted and generate CD8+ T cell responses to mediate tumor regression in some patients with MAGE-A3+ tumors. Other patients may not respond due to a lack of CD4+ T cells participation. Cancer immunotherapy with these new HLA class II TCRs could yield a robust and effective CD4+ T cell immune response that selectively targets MAGE-A3 expressing tumors without generating toxicity against healthy cells.

MAGE-A3 is a cancer testis antigen expressed on many types of cancer cells that blocks the functions of tumor suppressor proteins to mediate tumor growth and spreading. MAGE-A3 is not expressed on normal cells other than non-MHC expressing germ cells of the testis, which do not generate an immune response. Thus, MAGE-A3 represents an ideal target for cancer immunotherapies that are predicted to generate fewer toxic side effects than current standard cancer treatments.

Potential Commercial Applications: Competitive Advantages:
  • A personalized immunotherapy to mediate regression of many types of cancers using human T cells expressing a HLA class II TCR.
  • An adoptive immunotherapy combining T cells engineered to express a HLA class I restricted TCR with HLA class II TCR-expressing T cells to enhance the antitumor response by eliciting CD8+ and CD4+ T cell immune responses in patients.
  • A research tool to investigate signaling pathways in MAGE-A3 antigen expressing cancer cells.
  • An in vitro diagnostic tool to screen for cells expressing the MAGE-A3 tumor antigen.
 
  • Class I restricted TCRs can only treat a subset of patients, but since ~80% of patients express the HLA-DP-beta1*04 class II HLA allele, this TCR expands the population pool treatable with MAGE-A3 TCRs to include the majority of patients.
  • MAGE-A3 is a highly expressed tumor target on many cancer cells, so MAGE-A3 TCR therapy should be a viable treatment option for many cancer cases.
  • MAGE-A3 is only expressed on tumor cells and non-MHC expressing cells so these TCRs should target MAGE-A3 expressing tumor cells with little or no side effects/toxicity to normal cells.


Inventors:
Steven Rosenberg (NCI)
Paul Robbins (NCI)
Xin Yao (NCI)


Intellectual Property:
US Application No. 61/701,056
PCT Application No. PCT/US2013/059608


Licensing Contact:
Whitney Hastings ,
NIH Office of Technology Transfer
6011 Executive Blvd. Suite 325
Rockville , MD 20852
Email: hastingw@mail.nih.gov
Phone: 301-451-7337
Fax: 301-402-0220

OTT Reference No: E-230-2012/0

Updated: 09/09/2013