Compassionate access to virus-specific T cells for adoptive immunotherapy over 15 years

Abstract

Adoptive T-cell immunotherapy holds great promise for the treatment of viral complications in immunocompromised patients resistant to standard anti-viral strategies. We present a retrospective analysis of 78 patients from 19 hospitals across Australia and New Zealand, treated over the last 15 years with "off-the-shelf" allogeneic T cells directed to a combination of Epstein-Barr virus (EBV), cytomegalovirus (CMV), BK polyomavirus (BKV), John Cunningham virus (JCV) and/or adenovirus (AdV) under the Australian Therapeutic Goods Administration's Special Access Scheme. Most patients had severe post-transplant viral complications, including drug-resistant end-organ CMV disease, BKV-associated haemorrhagic cystitis and EBV-driven post-transplant lymphoproliferative disorder. Adoptive immunotherapy is well tolerated with few adverse effects. Importantly, 46/71 (65%) patients show definitive clinical improvement including reduction in viral load, clinical symptoms and complete resolution of end-organ disease. In addition, seven high-risk patients remain disease free. Based on this long-term encouraging clinical experience, we propose that a dedicated nationally funded centre for anti-viral cellular therapies should be considered to provide T cell therapies for critically ill patients for compassionate use.

Fig. 1

Flow diagram showing participant allocation, follow-up, and analysis.

Fig. 2. Characteristics of SAS patients.

A The number of SAS requests we received between 2008 and 2023. B The proportions of adult and paediatric patients in this cohort. C The geographic location of origin of the patients. D Underlying diseases in the patients. E The types of organ transplants within the patient cohort.

Fig. 3. Viral disease characteristics.

A The viral causes of disease in the patient cohort. B The types of viral disease detected in patients.

Fig. 4. Schematic of the process used for the manufacture and administration of T cell therapy.

Peripheral blood mononuclear cells (PBMC) isolated from the peripheral blood of healthy volunteers were stimulated with selected viral peptide epitopes and then cultured for 14 to 17 days in the presence of  IL-2. Subsequently, virus-specific T cells were assessed for antigen-specific reactivity and stored as a cryogenic bank. Virus-specific T cells were matched with appropriate patients based on HLA class I and class II alleles as outlined in the material and methods section. (created with BioRender.com under a paid subscription).

Fig. 5. Multi-virus-specific T cell immunotherapy.

A Representative flow cytometry analysis showing multiple virus T cell specificities in a single T cell product. B Virus specificities of batches of T cell product within the multi-virus-specific T cell bank.

Fig. 6. Clinical outcome following adoptive T cell therapy.

A The proportion of patients who were treated with the supplied T cell therapy. B The proportion of patients who displayed clinical improvement. C Representative analysis of viraemia relative to the administration of T cells for a patient with CMV complications. D Representative analysis of viraemia relative to the administration of T cells for a patient with AdV complications.