CAR-T CELL THERAPY FOR KRAS MUTANT COLORECTAL CANCER

n 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.