A phase I trial of PD-1 deficient engineered T cells with CRISPR/Cas9 in patients with advanced non-small cell lung cancer.

Abstract

3050 Background: We performed the first phase I clinical trial (NCT02793856) to assess safety of CRISPR/Cas9-mediated knockout of PD-1 gene in autologous T lymphocytes (PD-1-/- T) therapy in patients with metastatic non-small cell lung cancer (NSCLC). Methods: We assigned patients with advanced NSCLC with positive PD-L1 expression who had progressed after 3rd line standard therapeutic regimens. Two patients were enrolled in Pre-A cohort who received PD-1-/- T therapy with 2 x 107 cells/kg for one cycle and were observed for another cycle. Then 3 cohorts (A, B, C) enrolled 3 patients in each group receiving PD-1-/- T cells therapy with 1×107/kg, 2×107/kg, 4×107/kg in each cycle, respectively. Patients received PD-1-/- T therapy until disease progression or study withdrawal. Primary outcome was safety. Secondary end points were 8 weeks disease control rate (DCR) and progression-free survival (PFS). In exploratory analyses, next-generation sequencing was performed on PD-1 editing region of T cells and CDR3 region of T-cell receptor. Results: Nine patients were enrolled and eight patients received totally 17 cycles of PD-1-/- T therapy. Twenty-three adverse events (AEs) related to PD-1-/- T cell infusion occurred (Table 1). No 3-5 AEs were observed. Of note, one patient in Pre-A group suffered grade 1 arrhythmia (premature beat) that lasted for 42.4 weeks. Seven patients were response evaluable. Two patients experienced stable disease (SD) with 17.6 and 22.0 weeks, respectively. Other 5 patients had progression disease (PD). Eight-week DCR was 28.6% and median PFS was 7.6 weeks. In exploratory data, two patients with SD showed higher diversity of T cell repertoire in PBMC than other 5 patients with PD. Conclusions: Patients receiving PD-1-/- T therapy seemed safe. Further larger size studies are warranted to explore effective dose and related immune response. Clinical trial information: NCT02793856. Total Cohort ( N = 8) Pre-A (N = 2) A (N = 3) B (N = 3) Events Grade 1 2 ≥3 1 2 ≥3 1 2 ≥3 1 2 ≥3 Fever 2 2 Hyperhidrosis 3 3 Rash 1 1 Arthralgia 1 1 Fatigue 2 1 1 Infusion related reaction 1 1 Arrhythmia 1 1 Hypertension 1 1 Aminotransferase increased 2 1 1 White blood cell decreased 7 7 Thrombocytopenia 2 2 Total 22 1 0 5 0 0 10 1 0 7 0 0 All level events 23 5 11 7