HLA-class II-restricted T Cell Receptors for PIK3CA “Hotspot” Mutations, E545K and N345K

Summary: 

The National Cancer Institute (NCI) seeks co-development partners and/or licensees for a collection of T cell receptors (TCRs) that specifically target PIK3CA mutations to treat patients with tumors expressing these mutations in the context of HLA-DPA1*01:03:01, HLA-DPB1*04:01:01 or HLA-DRB1*04:01.

Description of Technology:

Phosphatidylinositol-4,5-biphosphate 3-kinase catalytic subunit alpha gene, also known as PIK3CA, makes a subunit of the PIK3 enzyme with various cellular functions. Mutations in the PIK3CA can result in the growth of cells through overactivation of the PIK3 enzyme and are associated with the development of several forms of cancers. Indeed, PIK3CA mutation is the third most common mutation in epithelial cancers. Previous studies attempted to inhibit the activity of mutant PIK3CA using both small molecules and monoclonal antibodies. However, these studies showed limited in vivo efficacy in treating tumors with mutant PIK3CA.

The National Cancer Institute (NCI) has developed novel, HLA-class II-restrcited T cell receptors (TCRs) to target two of the most common PIK3CA “hotspot” mutations: E545K and N345K. Two TCRs against N345K are restricted by the common HLA-DPA1*01:03:01 and HLA-DPB1*04:01:01, found in about 85% of the US Caucasian population. The TCR against E545K is rectricted by the common HLA-DRB1*04:01, found in about 17-20% of US Caucasian population. Given the frequency of PIK3CA mutations in various common cancers, these inventions have the potential to benefit a wide range of cancer patients. Targeted therapy against PIK3CA mutations represents therapeutic potential for various types of cancer. Further, as PIK3CA mutations are not present in healthy tissue, this approach could produce fewer off-target effects and a more promising safety profile.

Potential Commercial Applications: 

•    TCR-engineered cell therapy products for cancers expressing PIK3CA mutations – including, but not limited to:
o    breast 
o    endometrial
o    bladder
o    colorectal carcinoma
o    head and neck squamous cell carcinoma
•    Soluble TCR-fusion proteins
•    Combination immunotherapies using ACT alongside other immunotherapies targeting PIK3CA mutations

Competitive Advantages:

•    Targeted therapy
•    Potentially fewer and less severe off-target effects
•    Potentially more promising safety profile
•    Therapeutic potential for various types of cancer