The increase in the number of solid organ and bone marrow transplants over the last three decades has had a significant impact on the lives of many people worldwide, who otherwise would have succumbed to their disease. Despite the remarkable success of transplanting tissue between genetically distinct individuals, the need to suppress or deplete the recipient’s immune system to prevent graft rejection leaves them highly susceptible to a variety of opportunistic infections1,3. While the development of anti-viral drugs, particularly against CMV, has had a dramatic impact on mortality associated with viral disease following transplantation, many patients still succumb to these opportunistic infections or develop toxicities from anti-viral drugs. There remains a lack of effective treatments for EBV, AdV and BKV/JCV. Virus-specific adoptive T cell immunotherapy has provided a last line of treatment for many patients without any remaining viable options. Although generally unproven in terms of effectiveness in randomised clinical studies, evidence over the last three decades has demonstrated real-world effectiveness of this approach18. Our own observations over the last 15 years provides additional support for the use of virus-specific T cell therapy to reduce the morbidity and mortality associated with viral infections in immunocompromised patients19.
The first evidence of virus-specific adoptive T cell therapy in transplant patients was provided in 1992 by Riddell and colleagues, who demonstrated that CMV-specific T cells could be generated from HSCT donors and administered to transplant recipients20. This was closely followed by work from Rooney and colleagues, who demonstrated the use of EBV-specific T cell therapy in HSCT recipients21. Due to the presence of genetic modification that allows long-term tracking, these EBV-specific T cells have since been shown to survive for more than two decades in the recipients22,23. Since these early observations, multiple studies have reported the use of donor-derived virus-specific T cell therapy in more than 150 HSCT recipients 12,24–26.
One limitation of the donor-derived approach is the need for the HSCT donor to have immunological memory to the virus in question. This approach is also not applicable to SOT patients when donor T cells are not available. We and others have shown that autologous T cell therapy can be generated from both SOT and HSCT recipients, demonstrating a good safety profile and clinical efficacy18. We used this autologous approach in several patients treated compassionately in the current report. However, this approach is not feasible for all patients, predominantly due to difficulties in manufacturing cells from heavily immunocompromised patients. To overcome this limitation, Dorothy Crawford’s group pioneered the use of healthy donor blood to generate a bank of allogeneic EBV-specific T cells27,28. In this setting, donors were selected to provide broad HLA coverage, allowing matching between the T cell donor and the patient with viral disease. Based on this approach, the allogeneic EBV-specific T cell therapy tabelecleucel (Ebvallo) was recently approved to treat EBV-associated PTLD in Europe29,30. It is unclear if and when this will be available for patients in other regions of the world. This allogeneic approach has been extended to CMV and other virus-associated diseases in adult and paediatric settings, although most have not moved beyond early phase clinical studies31–33. We have also treated a number of patients included in the current report using allogeneic T cell therapy specific for a single virus.
Despite emerging data showing potential for allogeneic virus-specific T cell banks, it is challenging to generate a bank with broad HLA coverage that can target all known transplant-associated infectious complications, particularly those that are rare. To overcome this, Leen et al. pioneered the development of T cell therapy products containing multiple virus specificities34. This has now been extended by other groups to products including up to eight pathogens, including fungi35–38. Most patients in the current report were treated using T cells generated using a multi-virus-targeted approach. While EBV and/or CMV-specific T cells were typically dominant in these products, the majority also contained BKV/JCV- and AdV-specific CD4+ T cells. Importantly, we didn’t see any obvious evidence of reduced efficacy against these viruses, indicating that the use of a multi-virus-targeted approach does not impact the potency of virus-specific T cell therapy. It is important to emphasise that this is only an observational retrospective analysis and not a formal clinical trial.
Based on this retrospective analysis, we can draw two key conclusions. First, adoptive T cell therapy (either autologous or allogeneic) was generally safe, with no reported serious adverse reactions. Importantly, there was no evidence of precipitation of graft rejection or graft-versus-host disease. Second, virus-specific T cell therapy seems to be more effective in patients who had less disease burden and were treated early rather than at a late stage of clinical symptoms, evidenced by 24 patients who had late-stage disease and did not respond to adoptive T cell therapy. Overall, the compassionate use of virus-specific T cell therapies provides an opportunity to deliver therapies to severely immunocompromised patients who otherwise have limited options.