In a first-in-human, single-institution phase I trial reported in The Lancet Oncology, Lou et al found that autologous tumor-infiltrating lymphocytes (TILs) genetically edited with CRISPR-Cas9 to target the intracellular immune checkpoint CISH were tolerable and showed evidence of activity in patients with metastatic colorectal cancer.
The TILs are edited to enable knockout of CISH, which encodes cytokine-inducible SH2-containing protein, a novel intracellular immune checkpoint target.
Study Details
The study included patients enrolled at University of Minnesota Medical School between May 2020 and September 2022. Patients had a diagnosis of metastatic gastrointestinal epithelial cancer with progressive disease following at least one first-line standard therapy, measurable disease with at least one lesion identified as resectable for TIL generation, and at least one other measurable lesion for evaluating treatment response.
TILs were obtained from tumor biopsies and expanded on the basis of neoantigen reactivity, subjected to CRISPR-Cas9-mediated CISH knockout, and infused into patients after nonmyeloablative lymphocyte-depleting chemotherapy (cyclophosphamide at 60 mg/kg per dose on study days –6 and –5, and fludarabine at 25 mg/m² per dose on days –7 to –3); TIL infusion was followed by up to six doses of high-dose interleukin-2 (IL2; 720,000 IU/kg per dose) every 8 hours.
Key Findings
CISH-knockout TIL products were successfully manufactured for 19 (86%) of 22 enrolled patients; 12 (63%) of the 19 received a single CISH-knockout TIL infusion. Median follow-up among the 12 patients was 129 days (interquartile range = 15–283).
Treatment-related severe adverse events occurred in all patients; the most common grade 3/4 events were hematologic events (12 patients, attributable to the lymphodepleting regimen or IL-2), fatigue (4 patients, 33%), and anorexia (3 patients, 25%). No serious adverse events or treatment-related deaths were associated with TIL treatment. No grade ≥ 3 cytokine-release syndrome or neurotoxicity events were observed.
Stable disease at day 28 was observed in six patients (50%) and at 56 days in four (33%). One patient with microsatellite instability–high colorectal cancer refractory to anti–PD-1/CTLA-4 therapies had a complete response ongoing at > 21 months.
The investigators concluded: “These results support the safety and potential antitumor activity of inhibiting the immune checkpoint CISH through the administration of neoantigen-reactive CISH-knockout TILs, with implications for patients with advanced metastatic cancers refractory to checkpoint inhibitor immunotherapies, and provide the first evidence that a novel intracellular checkpoint can be targeted with therapeutic effect.”
Emil Lou, MD, Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by Intima Bioscience. For full disclosures of all study authors, visit The Lancet Oncology.
