T Cell Receptors Targeting KRAS Mutants for Cancer Immunotherapy/Adoptive Cell Therapy


Mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) gene are among the most common oncogenic drivers in human cancers, affecting nearly a third of all solid tumors. Point mutations in the KRAS gene most frequently affect amino acid position 12, resulting in the substitution of the native glycine (G) residue for other amino acids (e.g., aspartic acid (D), valine (V), cysteine (C) or arginine (R)). The mutations in KRAS occur early in the process of carcinogenesis, and only tumor cells express driver mutations, making them an attractive cancer-specific therapeutic target. However, despite decades of research into the signaling of mutated KRAS and druggability of these mutations with selective inhibitors, no effective therapy has been developed for these common mutated KRAS-driven cancers.

T cell receptors (TCRs) are proteins expressed on the cell surface of T lymphocytes that can recognize peptide antigens from infected and malignant cells in the context of human leukocytes antigen (HLA) molecules with exquisite specificity. Subsequent T cell activation leads to an immune response which aims to eliminate the abnormal cells. T lymphocytes that naturally lack specificity for a tumor antigen can be equipped to express a tumor antigen-specific TCR using genetic engineering. Adoptive transfer of these tumor antigen-specific TCR-engineered T cells into patients with cancer has demonstrated to be a promising cancer treatment strategy. 

Scientists at the NIH have identified a collection of TCRs that specifically recognize mutated KRAS variants (Table 1). These variants cover the most common KRAS driver mutations expressed by a variety of epithelial cancers, including pancreatic, colorectal and lung cancer. The mutated KRAS variants are recognized by the TCRs in the context of specific Class I/Class II HLA alleles. These TCRs are expected to eliminate human cancer cells that express both the appropriate mutated KRAS variant and HLA molecule upon adoptive transfer into patients with cancer. Furthermore, these TCRs can be used for a variety of other experimental therapeutic, diagnostic and research applications.

Table 1: Collection of mutated KRAS TCRs

e-175-2016 Table 1 - Collection of Mutated KRAS TCRs 

 

 

 

 

 

 

 

Table 2: Priority Patent Filings by Invention Reference

e-175-2016 Table 2 - Priority Patent Filings by Invention Reference

 

 

 

 

 

 

 

 



Potential Commercial Applications: Competitive Advantages:
  • A component of a combination immunotherapy aimed at targeting mutated KRAS-driven cancers
  • An in vitro diagnostic tool to screen for cells expressing mutated KRAS in antigen detection assays
  • A research tool to investigate signaling in mutated KRAS antigen expressing cells
  • Use of portions of the TCRs in chimeric proteins for research and therapeutic purposes in mutated KRAS-driven cancers
 
  • Highly expressed target antigens: mutated KRAS variants are frequently expressed by the most common epithelial cancers, including pancreatic, colorectal and lung cancer
  • Cancer-specific driver mutations: mutated KRAS variants are solely expressed by cancer cells, and not by healthy tissues 
  • Variety of HLA-restriction elements: extends the applicability of TCRs as they recognize mutated KRAS variants in the context of multiple HLA molecules

 



Development Stage:
Clinical

Related Invention(s):
E-028-2015
E-180-2015
E-265-2015
E-105-2012
E-495-2013
E-176-2014
E-181-2016
E-239-2017
E-166-2018
E-029-2019
E-031-2020
E-074-2020
E-088-2020


Inventors:

Q. Wang (NCI)  ➽ more inventions...

Z. Yu (NCI)  ➽ more inventions...

K. Hanada (NCI)  ➽ more inventions...

J. Yang (NCI)  ➽ more inventions...

E. Tran (NCI)  ➽ more inventions...

Y.-C. Lu (NCI)  ➽ more inventions...

A. Pasetto (NCI)  ➽ more inventions...

P.F. Robbins (NCI)  ➽ more inventions...

Z. Zheng ()  ➽ more inventions...

S.A. Rosenberg ()  ➽ more inventions...

Noam Levin ()  ➽ more inventions...

Rami Yoseph ()  ➽ more inventions...

Biman Paria ()  ➽ more inventions...

Maria Parkhurtst ()  ➽ more inventions...

Frank Lowery ()  ➽ more inventions...


Intellectual Property:
Application No. PCT/US2015/062269
Application No. PCT/US2016/050875
Application No. PCT/US2017/044615
Application No. PCT/US2018/051641
Application No. PCT/US2018/063581
Application No. 62/749,750
Application No. 62/795,203

Publications:
Wang QJ et al. Cancer Immunol Res 2016.  "Identification of T-cell Receptors Targeting KRAS-mutated Human Tumors" PMID:26701267
Tran et al. N Engl J Med 2016.  "T-Cell Transfer Therapy Targeting Mutant KRAS in Cancer" PMID:27959684
 Tran et al. Science 2015. "Immunogenicity of somatic mutations in human gastrointestinal cancers" PMID: 26516200

Collaboration Opportunity:

Licensing and research collaboration


Licensing Contact:
John Hewes, Ph.D.
Email: John.Hewes@nih.gov
Phone: 240-276-5515

OTT Reference No: E-175-2016
Updated: Jul 21, 2020