T Cell Transfer Therapy Targeting Mutant KRAS in Cancer.
We identified a polyclonal CD8+ T cell response against mutant KRAS G12D in tumor infiltrating lymphocytes obtained from a patient with metastatic colorectal cancer. We observed objective regression of all seven lung metastases after the infusion of approximately 1.11x1011 HLA C*08:02 restricted tumor infiltrating lymphocytes that were composed of four different T cell clonotypes that specifically targeted KRAS G12D. However, one of these lesions had progressed on evaluation 9 months after therapy. The lesion was resected and found to have lost the chromosome 6 haplotype encoding the HLA C*08:02 class I major histocompatibility complex (MHC) molecule. The loss of expression of this molecule provided a direct mechanism of tumor immune evasion. Thus, the infusion of CD8+ cells targeting mutant KRAS mediated effective antitumor immunotherapy against a cancer that expressed mutant KRAS G12D and HLA C*08:02.
The New England journal of medicine