T-Cell Transfer Therapy Targeting Mutant KRAS in Cancer

N Engl J Med. 2016 Dec 8;375(23):2255-2262. doi: 10.1056/NEJMoa1609279.

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.

Publication types

  • Case Reports

MeSH terms

  • CD8-Positive T-Lymphocytes*
  • Colorectal Neoplasms / immunology
  • Colorectal Neoplasms / pathology*
  • Colorectal Neoplasms / therapy
  • Female
  • Flow Cytometry
  • Humans
  • Lung / diagnostic imaging
  • Lung Neoplasms / immunology
  • Lung Neoplasms / secondary*
  • Lung Neoplasms / therapy*
  • Lymphocyte Count
  • Middle Aged
  • Proto-Oncogene Proteins p21(ras) / antagonists & inhibitors*
  • Proto-Oncogene Proteins p21(ras) / genetics

Substances

  • KRAS protein, human
  • Proto-Oncogene Proteins p21(ras)