T-Cell Transfer Therapy Targeting Mutant KRAS in Cancer

TLDR

Loss of HLA‑C*08:02 expression on tumor cells directly enabled immune evasion. Infusion of HLA‑C*08:02‑restricted, KRAS G12D‑specific CD8⁺ T cells caused regression of all seven lung metastases, yet one lesion progressed after 9 months due to loss of HLA‑C*08:02, illustrating effective but escape‑prone antitumor activity.

Abstract

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 1.11×1011 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.