About KRAS (Kirsten rat sarcoma viral oncogene homologue)
Under physiological conditions the KRAS gene tightly regulates cell proliferation and survival. However, mutations within KRAS result in uncontrolled proliferation of cells. These mutations lead to the generation of so called neoantigens, which are tumor-specific antigens (TSA) promoting growth and maintenance of tumors. KRAS displays the highest mutation rate in a wide variety of often fatal solid cancer types like pancreatic ductal adenocarcinoma, endometrial, non-small-cell lung cancer, and colorectal cancer. Global incidence of solid tumors expressing KRAS mutations (mKRAS) is estimated to be in excess of 300,000 patients. Most prominent mutations arise from a substitution of only one single amino acid (G= glycine) at position 12 to aspartic acid (D), valine (V) or cysteine (C) (Figure 1, 2).
Figure 1:
TCR-KRAS-HLA modelling complex
Figure 2:
Frequency of KRAS mutations in different cancer types
KRAS and immune escape
Tumors displaying KRAS mutations have been shown to create a tumor microenvironment (TME) affecting immune cells in the TME promoting tumor progression and immune escape. In the presence of KRAS mutations increased levels of inflammatory cytokines have been observed in the TME necessary for tumor initiation and progression.
In additions KRAS mutations have also been associated with elevated expression of Programmed Cell Death 1 Ligand 1 (PD-L1). PD-1 binds to and inactivates T cells, reduces their proliferation and promotes apoptosis of T cells. Moreover, KRAS mutations promote secretion of various chemokine and cytokines facilitating the recruitment of immunosuppressive cells thereby contributing to immune escape. Overall, KRAS mutations enable various paths to actively affect immune regulation.
Targeting KRAS mutations with TCR-T therapies
Engineered T cell therapies, such as CAR-T cells, have shown immense potential in treating various malignant diseases in recent years. However, CAR-T cells require the target antigen to be present on the cell surface, which limits their effectiveness. In addition, the target antigen is often expressed on normal healthy cells, increasing the risk of cytotoxic side effects TCR-T cells, on the other hand, recognize a wider range of targets, including neoantigens that are not present on the cell surface and not accessible to CAR-T therapies. Mutations within the KRAS gene result are unique to cancer cells and absent in healthy normal tissue. Hence, the ability to selectively target these mutations with cell therapies can revolutionize cancer treatment, providing more effective, safer, and personalized therapies for patients with high unmet medical needs.
Our approach
At Medigene we aim to create a broad KRAS library consisting of multiple T cell receptors targeting different KRAS mutations combined with various HLAs covering broad patient populations with high unmet need. All generated TCRs will be further combined with our product enhancement technologies including PD1-41BB and potentially CD40L-CD28 costimulatory switch proteins to enhance the proliferation and persistence of the TCR-T cells and to help mitigate the immunosuppressive effects of the tumor microenvironment.