First-in-man Phase 1 Clinical Trial of Gene Therapy for Advanced Pancreatic Cancer: Safety, Biodistribution, and Preliminary Clinical Findings

Abstract

This phase 1 trial was aimed to determine the safety, pharmacokinetics, and preliminary clinical activity of CYL-02, a nonviral gene therapy product that sensitizes pancreatic cancer cells to chemotherapy. CYL-02 was administrated using endoscopic ultrasound in 22 patients with pancreatic cancer that concomitantly received chemotherapy (gemcitabine). The maximum-tolerated dose (MTD) exceeded the maximal feasible dose of CYL-02 and was not identified. Treatment-related toxicities were mild, without serious adverse events. Pharmacokinetic analysis revealed a dose-dependent increase in CYL-02 DNA exposure in blood and tumors, while therapeutic RNAs were detected in tumors. No objective response was observed, but nine patients showed stable disease up to 6 months following treatment and two of these patients experienced long-term survival. Panels of plasmatic microRNAs and proteins were identified as predictive of gene therapy efficacy. We demonstrate that CYL-02 nonviral gene therapy has a favorable safety profile and is well tolerated in patients. We characterize CYL-02 biodistribution and demonstrate therapeutic gene expression in tumors. Treated patients experienced stability of disease and predictive biomarkers of response to treatment were identified. These promising results warrant further evaluation in phase 2 clinical trial.

Initial Characterization of Integrase-Defective Lentiviral Vectors for Pancreatic Cancer Gene Therapy

“…These vectors encode for DCK, a protein (1) we previously demonstrated to sensitize PDAC-derived cells to chemotherapy and to elicit a strong antitumoral bystander effect, 26 and (2) that was recently transferred in patients using nonviral gene therapy during a phase I clinical trial for PDAC. 4 We found that both IDLV and parental vectors drive detectable expression of DCK in PDAC-derived cell lines. When combined with gemcitabine, both vectors inhibited cancer cell proliferation to a similar extent.…”

“…During the Thergap clinical trial, we demonstrated that the intratumoral injection of gene therapy is well tolerated, safe, and feasible, and that patients may benefit from the therapy, as 7 out of 9 patients survived more than 1 year after treatment, with 2 long survivors (>2 years). 4 While this clinical trial is important, our next goal is to improve the delivery vehicles used in patients, that is, PEI nonviral vector, to elevate the therapeutic index of gene therapy, to serve in future early phase clinical trials. Our group extensively demonstrated the efficacy of lentiviral-based vectors to transduce and kill PDAC cells both in vitro and in vivo.…”

“…We performed the first-in-human clinical trial, based on the use of nonviral vectors to transfer anticancer genes that sensitize PDAC cells to gemcitabine chemotherapy. 4 This early phase clinical trial demonstrated that intratumoral gene delivery is safe and feasible in patients with PDAC who cannot undergo surgery. In addition, a population of patients with locally advanced tumors benefited from this treatment, with two patients surviving for two years after gene therapy.…”

“…In addition, a population of patients with locally advanced tumors benefited from this treatment, with two patients surviving for two years after gene therapy. 4 From our experience, the success of gene therapy protocols strongly relies on the identification of gene delivery vectors with significant delivery efficacy, as we have found that PDAC-derived cells are very resistant to gene transfer. Indeed, we have experimented synthetic (polyethylenimine, PEI) and viral-based (adenovirus, SV40) vectors, which demonstrated gene delivery to PDAC cells and evidence of therapeutic efficacy, both in vitro and in vivo.…”

Circulating miR-155, miR-145 and let-7c as diagnostic biomarkers of the coronary artery disease

“…The different miRNA profiles of 754 miRNA between CAD patients and control subjects were determined using the Life Technologies TaqMan Open Array Human MicroRNA panel 34 . Reverse transcription (RT) and preamplification were performed on all samples using Megaplex Primer Pools miRNA validation.…”