First-in-Human, First-in-Child Trial of Autologous MSCs Carrying the Oncolytic Virus Icovir-5 in Patients with Advanced Tumors

Abstract

We present here the results of a first-in-human, first-in-child trial for patients with relapsed/refractory solid tumors using Celyvir, an advanced therapy medicine that combines autologous mesenchymal stem cells (MSCs) carrying an oncolytic adenovirus. Celyvir was manufactured from a bone marrow aspirate and then given intravenously. Patients received weekly infusions for 6 weeks at a dose of 2 × 106 cells/kg (children) or 0.5-1 × 106 cells/kg (adults), 2 × 104 viral particles per cell. Fifteen pediatric and 19 adult patients were recruited, but 18 were screen failures, mainly because rapid disease progression before Celyvir was available. No grade 2-5 toxicities were reported. Adenoviral replication detected by PCR was found in all but 2 pediatric patient and in none of the adult ones. Absolute numbers of circulating leukocytes suffered minor changes along therapy, but some subsets showed differences comparing the pediatric versus the adult cohorts. Two patients with neuroblastoma showed disease stabilization, and one of them continued on treatment for up to 6 additional weeks. Celyvir, the combination of MSCs and oncolytic adenovirus, is safe and warrants further evaluation in a phase 2 setting. The use of MSCs may be a strategy to increase the amount of oncolytic virus administered to patients, minimizing toxicities and avoiding direct tumor injections.

Trial registration: ClinicalTrials.gov NCT01844661.

Keywords: clinical trial; mesenchymal stem cells; oncolytic virotherapy; pediatric tumor.

Copyright © 2020 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1

Patients Recruited and Procedures during the Trial IC, informed consent signed; BMA, bone marrow aspirate; vp, viral particles; W, withdrawn; PD, progressive disease; SD, stable disease.

Figure 2

Changes in Circulating Leukocyte Subpopulation Counts in Patients Treated with Celyvir Absolute peripheral blood cell counts of different leukocyte subpopulations from pediatric (white) and adult (black) patients. Figures represent the mean ± standard mean error. Dose 1 corresponds to baseline, since blood samples were always drawn immediately before the administration of Celyvir. *p 

Figure 3

Changes in Circulating Leukocyte Subpopulation Counts in Pediatric Patients Treated with Celyvir Absolute peripheral blood cell counts of different leukocyte subpopulations from nonresponder (filled) and responder (empty) pediatric patients. Figures represent the mean ± standard mean error. Dose 1 corresponds to baseline, since blood samples were always drawn immediately before the administration of Celyvir.

Figure 4

Changes in Circulating Lymphocyte Counts in Pediatric Patients Treated with Celyvir Changes in circulating T (left) and B (right) lymphocyte subpopulation counts in pediatric patients treated with Celyvir. Individual patients are shown. Dose 1 corresponds to baseline, since blood samples were always drawn immediately before the administration of Celyvir.