Australian MS patients who took part in a pioneering trial of autologous Epstein Barr virus-specific T cell therapy have shown clinical improvements that have been maintained for up to three years.
In 2015, 10 patients with progressive MS took part in a phase 1 clinical trial of autologous EBV-specific T cell therapy in Queensland. The trial was based on the hypothesis that defective elimination of EBV-infected B cells by cytotoxic CD8+ T cells might predispose to the development of MS by enabling the accumulation of EBV-infected autoreactive B cells in CNS.
In the initial trial, patients received four escalating doses of T cells at fortnightly intervals and were monitored for 26 weeks from the first infusions.
There were no treatment-related serious adverse effects and seven of the ten patients who received T cell therapy experienced clinical improvement. Improvement was related to the level of EBV-specific CD8+ T cell reactivity in the T cell product.
Now the researchers from Queensland University and the Department of Neurology, Royal Brisbane and Women’s Hospital, have followed up the patients for up to three years.
They found that four of the seven patients who showed clinical improvement at six months after T cell therapy still had at least some degree of sustained clinical improvement at year two, including reduced fatigue in three participants, and reduced Expanded Disability Status Scale score in two participants.
At year three, three of the patients still showed some evidence of sustained clinical improvement.
As in the initial study, there were no serious treatment-related adverse events and clinical improvement was associated with higher EBV-specific CD8+ T cell reactivity in the administered T cell product.
Writing in Frontiers in Neurology, the researchers, led by neurologist Dr Zara Ioannides, said the sustained clinical improvements seen after EBV-specific T cell therapy were contrary to the expected decline of patients with progressive forms of MS.
They postulated that these improvements were due to the killing of EBV-infected B cells in the CNS by the adoptively transferred CD8+ T cells and that this prevents further autoimmune attack on the CNS and allows neurological recovery through remyelination, dendritic and axonal sprouting, and synaptic remodelling.
“An important goal of future studies should be to determine whether EBV-specific T cell therapy decreases the number of EBV-infected B cells in the CNS and whether this correlates with clinical improvement in MS,” they wrote.
The waning responses might be due to the progressive decrease in the frequency of EBV-specific T cells in the CD8+ population, seem with increasing duration of disease, they added.
CD8+ T cell exhaustion induced by a persistently high EBV latent antigen load in MS might gradually decrease the cytotoxic effect of the adoptively transferred CD8+ T cells on EBV-infected B cells in the CNS and thereby allow further autoimmune attack on the CNS, they said.
“Repeated administration of EBV-specific T cell therapy every 12 months should help sustain clinical improvement in MS,” they suggested.
Meanwhile, further trials are underway with an off-the-shelf, allogeneic EBV T-cell therapy, ATA188, in patients with progressive MS.