Adoptive T-Cell Therapy of a Lung Transplanted Patient with Severe CMV Disease and Resistance to Antiviral Therapy

Abstract

Infections with cytomegalovirus (CMV) can induce severe complications after transplantation, particularly in patients resistant to virostatic therapy. Adoptive transfer of CMV-specific T-cell lines has demonstrated promising results in patients after hematopoietic stem cell transplantation. However, the generation of specific T-cell lines ex vivo and their function in vivo is complicated in solid organ transplant (SOT) recipients. Here, we present the successful adoptive transfer of autologous CMV-specific T cells to a lung transplant recipient with ganciclovir-resistant CMV-pneumonia requiring mechanical ventilation. Infused T cells rapidly expanded in vivo and efficiently inhibited viral replication as confirmed by extensive longitudinal immunological monitoring. After full recovery, the patient was released from the clinic. After 4 weeks, the infection reappeared and persisted at a low level even after a second T-cell infusion. Our experimental data indicate that this could be the consequence of the late differentiated phenotype of the infused T cells and therefore their insufficient longevity in vivo. In summary, our report signifies the high therapeutic potential of adoptive immunotherapy in the treatment of SOT recipients when all other measures show no effect. Further studies have to elucidate the most potent strategies to generate antigen-specific T cells with high functional capacity and robust long-term persistence.

CMV: Prevention, Diagnosis and Therapy

“…While still experimental, adoptive infusions of CMV-specific T cells may prove helpful in certain situations (100,101).…”

Peripheral Blood–Derived Virus-Specific Memory Stem T Cells Mature to Functional Effector Memory Subsets with Self-Renewal Potency

“…A doptive T cell therapy has emerged as an effective treatment option in viral diseases after solid organ and stem cell transplantation (1)(2)(3)(4). However, T cell engraftment and longevity of the efficacy is incidentally limited in chronically immunocompromised patients due to insufficient persistence of T cells after infusion and reduced proliferation (3,5,6).…”

“…However, T cell engraftment and longevity of the efficacy is incidentally limited in chronically immunocompromised patients due to insufficient persistence of T cells after infusion and reduced proliferation (3,5,6). The ultimate objective is to adoptively transfer in those patients a long-lived memory T cell population with stem cell-like behavior, as a capacity to self-renew and the ability to differentiate to facilitate potent antigenic cytotoxicity.…”

Conference Scene: Autoimmunity and Transplantation: Basic Science and Clinic Translation Meet in Geneva

“…T-cell adoptive transfer in SOT patients with severe human CMV disease was performed after isolation and expansion of CMV-specific effector T cells according to the same molecular protocol established by the group. Such an approach has a drama tic impact on human CMV viremia and clinical outcome, but relapse of viral load and drop of IFN-g-producing T cells occurred within 6 weeks after T-cell infusion [15]. This effect appears to be related to a higher frequency of Foxp3 + Tregs as well as CMV-specific Tr1 cells in the peripheral blood of patients compared with healthy controls, as well as lower percentages of multifunctional central memory T cells.…”