Treatment of advanced gastrointestinal cancer with genetically modified autologous mesenchymal stem cells - TREAT-ME-1 - a phase I, first in human, first in class trial

Abstract

PurposeThis phase I, first in human, first in class clinical study aimed at evaluating the safety, tolerability and efficacy of treatment with genetically modified mesenchymal stromal cells (MSC) in combination with ganciclovir (GCV). MSC_apceth_101 are genetically modified autologous MSCs used as vehicles for a cell-based gene therapy in patients with advanced gastrointestinal adenocarcinoma.Experimental designThe study design consisted of a dose-escalation 3 + 3 design. All patients (n = 6) were treated with up to three applications of MSC_apceth_101, followed by GCV infusions given on three consecutive days starting 48 hours after injection of MSC_apceth_101. Three of six patients received a total dose of 1.5 × 106 cells/kg. Two patients received three doses of 1 × 106 cells/kg, while one patient received only two doses of 1 × 106 cells/kg due to a SADR.ResultsSix patients received MSC_apceth_101. No IMP-related serious adverse events occurred. Adverse-events related to IMP-injection were increased creatinine, cough, fever, and night sweat. TNF, IL-6, IL-8, IL-10 and sE-Selectin, showed that repeated application is immunologically safe, but induces a switch of the functional properties of monocytes to an inflammatory phenotype. Treatment induced stable disease in 4/6 patients, and progressive disease in 2/6 patients.ConclusionTreatment with MSC_apceth_101 in combination with GCV demonstrated acceptable safety and tolerability in patients with advanced gastrointestinal adenocarcinoma.

Treatment of advanced gastrointestinal cancer with genetically modified autologous mesenchymal stem cells: Results from the phase 1/2 TREAT‐ME‐1 trial

“…We previously reported from the Phase 1 part of this Phase 1/2 study, in which MSC_apceth_101 was given to 6 patients with advanced gastrointestinal adenocarcinoma at low (total dose of 1.5 × 10 6 cells/kg in three patients) or high (total dose of 3.0 x 10 6 cells/kg in three patients) doses. In this analysis, more patients were treated with MSC than in our earlier Phase 1 study, allowing us to confirm our earlier findings of acceptable safety and tolerability of MSC in patients with advanced gastrointestinal adenocarcinoma. Furthermore, there were no new clinically relevant safety signals in this larger cohort of patients.…”

“…In the Phase 1 part of the Phase 1/2 TREAT‐ME‐1 (Treatment of advanced tumors with mesenchymal cells 1) trial, MSC_apceth_101 was given to six patients with advanced gastrointestinal adenocarcinoma at low (total dose of 1.5 × 10 6 cells/kg) or high doses (total dose of 3.0 × 10 6 cells/kg) followed by ganciclovir infusions. The results demonstrated good safety and tolerability, and induced stable disease in four patients . In the current analysis, we report further Phase 1/2 results from the TREAT‐ME‐1 trial in 10 patients with advanced gastrointestinal carcinoma in which we further investigated the safety, tolerability and efficacy of high dose MSC_apceth_101 followed by ganciclovir infusions in 3 patients from the Phase 1 part of the study and 7 patients from the Phase 2 part of the study.…”

“…This was a Phase 1/2, open‐label, single‐center trial (EudraCT number: 2012‐003741‐15). The treatment plan for the Phase 1 part of this study has been previously reported . The Phase 2 part of the study involved the observation of two patient groups: Group 1 consisted of patients with adenocarcinoma that had relapse or progression.…”

Concise Review: Mesenchymal Stem Cell-Based Drug Delivery: The Good, the Bad, the Ugly, and the Promise

“…Preclinical development of TK‐expressing MSCs by Bruns and Nelson et al led to the landmark TREAT‐ME1 study in gastrointestinal adenocarcinomas [NCT02008539], the first clinical trial to use genetically engineered autologous MSCs. Due to the small study size (n = 6), conclusions are limited, but it should be noted the treatment was safe and tolerable with no significant adverse events attributed to the MSC infusion product .…”

Prodrug suicide gene therapy for cancer targeted intracellular by mesenchymal stem cell exosomes

“…Immortalized neural stem engineered to express bacterial cytosine deaminase with 5‐fluorocytosine (5‐FC) as a prodrug was employed . First clinical studies employing autologous MSC engineered to express thymidine kinase of Herpes simplex virus with ganciclovir prodrug for advanced gastrointestinal tumors were initiated recently . MSC tumor tropism inspired us to develop suicide gene transduced MSCs with retrovirus vector allowing to select homogenous cell population of transduced MSCs .…”