Treatment with donor T-cells primed against infection are a promising new strategy to address the poor outcomes for haematology patients with invasive fungal disease, Sydney-based experts have concluded.
Writing in Clinical and Translational Immunology, Dr Shivashni Deo and Professor David Gottlieb from Westmead Hospital said the benefits of cell therapy for fungal prophylaxis and treatment could parallel those for treatments of viral infections such as cytomegalovirus, Epstein-Barr virus and adenovirus.
But given that only one small study of ‘adoptive’ T-cell therapy for aspergillosis had been published, larger-scale clinical trials are still needed.
“The prolonged immune deficiency resulting from haematopoietic stem cell transplant and chemotherapy predisposes to a high risk of invasive fungal infections,” they said.
“Despite the recent advances in molecular diagnostic testing, early initiation of pre-emptive antifungal therapy and the use of combination pharmacotherapy, mortality from invasive mould infections remain high among recipients of allogeneic stem cell transplant.
“The increasing incidences of previously rare and drug-resistant strains of fungi present a further clinical challenge.”
Rates of invasive fungal disease ranged from about 1% in autologous stem-cell transplant recipients to 8% in mis-matched or unrelated donor recipients. One-year mortality was about 75% in patients with Aspergillus infection, the most common cause, and more than 90% in patients with invasive fusariosis.
‘Adoptive’ T-cell therapy used in vitro-expanded fungus-specific CD4 cells of the TH-1 type, obtained from donors.
The technique was proven in murine models, but only one small study in humans had been reported.
Nine of ten patients with aspergillosis treated with the cells cleared the infection within about 8 weeks, while 6 of 13 untreated controlled patients died within 5 weeks.
Since that trial, published in 2005. techniques for generating fungus-specific T-cells had advanced considerably.
“Selection of the patient and timing of T-cell infusion will undoubtedly be paramount for success,” Dr Deo and Professor Gottlieb said.
Toxicity concerns included the risk of over-stimulating antigen-specific T-calls and provoking a cytokine release syndrome. This could theoretically be countered by genetically modifying T-cells to include an inducible suicide gene that could be activated if needed.
“Whether the use of fungus-directed T-cell therapy will improve patient outcomes and reduce the need for fungal pharmacotherapy will not be known until larger-scale clinical trials are conducted,” they concluded.
“Specific T-cell therapy may be a novel therapeutic option for a group of patients for whom current treatment options are at best suboptimal.”