Immunotherapy that targets immune checkpoints such as PD-1 and PD-L1 has revolutionized treatment for several solid tumors, but has shown limited success in gastrointestinal cancers. To overcome this resistance, new approaches are being explored. One such strategy involves genetically modifying tumor-infiltrating lymphocytes (TILs) to enhance their antitumor efficacy. Two related studies published in The Lancet Oncology and Nature Medicine now explore the clinical potential of genetically engineered TILs in metastatic GI cancers.

In a first-in-human, single-center, phase 1 trial reported in The Lancet Oncology, Lou et al. tested the safety and efficacy of knockout of CISH, which encodes cytokine-inducible SH2-containing protein, in TILs from 12 patients with metastatic gastrointestinal epithelial cancers. Immune cells were edited using CRISPR–Cas9 technology to remove the CISH gene, which normally limits T cell activity. The modified TILs were given to patients after chemotherapy followed by high-dose IL-2 administration. The treatment was generally well tolerated, with expected side effects mostly related to the initial chemotherapy treatment used to reduce lymphocytes or to the IL-2 administration, with no severe immune-related toxicities. One patient with microsatellite instability-high colorectal cancer had a complete response lasting more than 21 months, and half of the patients showed stable disease after 28 days.