T-Cell Transfer Therapy Targets Mutant KRAS in Metastatic Colorectal Cancer

Key Points

  • CD8-positive cells targeting mutant KRAS provided effective antitumor activity against cancer expressing mutant KRAS G12D and HLA-C*08:02.
  • Loss of heterozygosity of the copy of chromosome 6 encoding HLA-C*08:02 allowed immune evasion in a progressing lesion.

In a case report in The New England Journal of Medicine, Tran et al at the National Cancer Institute describe response to adoptive transfer of ex vivo expanded tumor-infiltrating lymphocytes containing T cells targeting personalized cancer neoepitopes in a patient with lung metastases from colorectal cancer. The patient is part of a phase II study evaluating this approach in metastatic solid cancers.

Identification of Reactive T Cells

The patient had 10 lung lesions as the only source of cancer progression. Three lesions were resected and evaluated for mutations; culturing for reactivity against mutant neoepitopes revealed a polyclonal CD8-positive T-cell response against mutant KRAS G12D in tumor-infiltrating lymphocytes. The culture with the highest frequency of such CD8-positive T cells was expanded for use in treatment.

Prior to cell infusion, the patient underwent a nonmyeloablative lymphodepleting regimen consisting of cyclophosphamide followed by fludarabine. The patient then received a single infusion of approximately 1.11×1011 HLA-C*08:02–restricted tumor-infiltrating lymphocytes composed of four T-cell clonotypes specifically targeting KRAS G12D. Infusion was followed by treatment with five doses of interleukin-2 (aldesleukin [Proleukin]), limited by patient fatigue.

Response to Treatment

All 7 remaining lesions had regressed by first follow-up at 40 days after cell therapy, with the patient having a 9-month partial response until disease progression was observed in 1 lesion. The lesion was resected, and the patient remained clinically disease-free at 4 months afterward.

Pathologic analysis of a responding lesion showed extensive necrosis and no live tumor cells. The progressing lesion was found to have lost the chromosome 6 haplotype encoding the HLA-C*08:02 class I major histocompatibility complex molecule, with this loss of expression indicating a direct mechanism of tumor immune evasion.

As stated by the authors: “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…. [W]e found direct evidence of tumor immune evasion … through loss of heterozygosity of the copy of chromosome 6 that encoded HLA-C*08:02.”

The study was supported by the Center for Cancer Research Intramural Research Program of the National Cancer Institute.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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