KRAS G12C-Specific Immunotherapy
Abstract
Lung cancer is a leading cause of cancer-related death among U.S. active-duty Service Members, retired military personnel, and civilians. Tobacco use is a primary cause of lung cancer promoting DNA damage in the normal lung epithelial cells that results in the accumulation of mutations. In the past decade, translational research has revealed that a patient’s immune system (of special interest, is a particular type of white blood cell called T cells) can identify the mutations that are presented on the tumor cell surface. Scientists now refer to these mutated proteins present on the tumor cell surface as neoantigens. Similar to an infectious pathogen (virus or bacteria), the tumor neoantigens can activate the body’s T cells which may serve as a defense mechanism to protect the individual against cancer. In many instances however, the immune response fails to control the tumor resulting in cancer progression and uncontrolled spread throughout the body. In the past decade, immunotherapy has revolutionized cancer treatment resulting in tumor shrinkage and in certain diseases such as melanoma, durable long-term remissions. In lung cancer, addition of anti-PD-1/PD-L1, an immune checkpoint inhibitor, to standard chemotherapy has resulted in improved survival providing definitive evidence for the role of the immune system. The challenge facing scientists is how to build on this success by designing more effective therapies that can harness the patient’s own immune system. In parallel, dramatic progress in the development of new targeted agents that inhibit signaling pathways active in certain subtypes of lung cancer has resulted in improved survival. One recent example is the introduction of new oral inhibitors specific for the KRAS G12C mutation; however, many patients relapse and develop drug resistant disease. Adoptive T cell therapy (ACT) is a novel therapeutic approach that uses the patient’s own T cells to target and kill tumor cells. T cell therapies show great promise for the treatment of several blood cancers; however, progress against non-small cell lung cancer (NSCLC) has been hampered by the paucity of tumor neoantigens. Our current work is focused on developing ACT for the treatment of advanced NSCLC using a strategy that genetically modifies a patient’s T cells to express a receptor (T cell receptor, TCR) that recognizes a genomic alteration in a protein, KRAS, that controls cancer growth and survival. A mutation in KRAS (mKRAS) called G12C is found in 13% of all NSCLC cases in the U.S. Our group recently identified mutated KRAS G12C as a neoantigen in lung cancer. We have isolated a new TCR that is specific for mKRAS G12C neoantigen and fails to react against non-mutated KRAS or other normal proteins. We propose to develop a new T cell therapy which will redirect the patient’s T cells to target mKRAS G12C expressed in lung cancer. In this grant proposal, we seek funding that will allow us to perform key pre-clinical experiments that are required to support the regulatory filing for an Investigational New Drug (IND) application to the United States Food and Drug Administration (FDA). This filling will lead to the initiation of a phase 1 clinical trial of adoptive T cell therapy targeting mKRAS G12C. Our proposal will bring the first T cell therapy targeting mKRAS G12C to the clinic and is responsive to the FY22 LCRP Area of Emphasis, Identify innovative strategies for the treatment of lung cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310366
Entities
People
- Gerald Linette
Organizations
- United States Army
- University of Pennsylvania