In a report published online in the Lancet, investigators describe the results of the phase 1, first-in-man study of human neural stem cells in patients with chronic ischaemic stroke (PISCES study). In their study, Dheeraj Kalladka and others found that stem cell treatment was associated with improved neurological function and induced no cell-related adverse events.
CTX0E03 is an immortalised human neural stem-cell line from which a drug product (CTX-DP) was developed for allogeneic therapy. Previous research in rats implanted with CTX-DP resulted in dose-dependent improvement in sensorimotor function four weeks after middle cerebral artery occlusion stroke. Those data prompted investigation of the safety and tolerability of this treatment in stroke patients.
“We did an open-label, single-site, dose-escalation study. Men aged 60 years or older with stable disability (National Institutes of Health Stroke Scale [NIHSS] score ≥6 and modified Rankin Scale score 2–4) 6–60 months after ischaemic stroke were implanted with single doses of two million, five million, 10 million, or 20 million cells by stereotactic ipsilateral putamen injection. Clinical and brain imaging data were collected over two years. The primary endpoint was safety (adverse events and neurological change),” Kalladka et al explain.
Between September 2010 and January 2013, 13 men were recruited into the study, of whom 11 (mean age 69 years, range 60–82) received CTX-DP. Median NIHSS score before implantation was 7 (IQR 6–8) and the mean time from stroke was 29 (SD 14) months. Three men had subcortical infarcts only and seven had right-hemisphere infarcts. No immunological or cell-related adverse events were seen. Other adverse events were related to the procedure or comorbidities. Hyperintensity around the injection tracts on T2-weighted fluid-attenuation inversion recovery MRI was seen in five patients. At two years, improvement in NIHSS score ranged from 0 to 5 (median 2) points.
The authors conclude that the PISCES study provides evidence that single intracerebral doses of CTX-DP up to 20 million cells induced no cell-related adverse events and were associated with improved neurological function.
NeuroNews spoke to PISCES principal investigator, Keith Muir (SINAPSE professor of Clinical Imaging & consultant neurologist, University of Glasgow, Queen Elizabeth University Hospital, Glasgow, UK) to find out about the future of stem cell research for patients with chronic ischaemic stroke.
What is the next step in your research?
A phase 2 trial, PISCES-2, is underway at several hospital sites in the UK, and will involve around 20 patients at earlier stages of recovery after stroke than in PISCES-1. The endpoint for PISCES-2 is change in upper limb neurological function, rather than the safety focus of PISCES-1.
Did the study leave any unanswered questions?
Many! We need to establish long-term safety, and in due course, to investigate efficacy in a randomised, controlled trial. We have further data to explore including brain imaging studies, and the long-term follow-up of patients will continue for some years.
Now that stem cell treatment has been proven to help to improve neurological function of stroke patients, do you think there will be a greater uptake of the treatment?
While our data are interesting, PISCES-1 does not prove improvements of neurological function: that will require a much larger, controlled trial. It is not possible to draw conclusions about the efficacy of stem cell implantation from our data. There should be no use of cell therapies outside properly regulated clinical trials, since the totality of human data from clinical trials to date is extremely limited from all cell types.
What kinds of neurological improvements did patients experience?
As noted in the paper, some patients noted improved standing balance and better ability to transfer; others noted some improvements in hand movement.
Is there any reason why all of the patients treated in the study were male?
It was a precautionary measure for this very early stage research and relates to the way in which the cells have been genetically modified. Expression of the growth factor gene that allows long-term viability of the cells in culture is controlled by a modified oestrogen receptor that is activated by a minor metabolite of tamoxifen. Cells are removed from culture before implantation, and in the absence of the growth factor gene being switched on, differentiate into brain cells of various kinds. Although there was no foreseeable way that use of the drug tamoxifen could expose anyone to enough of the metabolite to reactivate the growth factor gene, women were excluded from this study as the group likely to have potential exposure to tamoxifen. Subsequently, long-term safety data from animal studies have become available, and there was no sex restriction for PISCES-2, which has recruited both men and women.