Transfer of Hexon‐ and Penton‐selected adenovirus‐specific T cells for refractory adenovirus infection after haploidentical stem cell transplantation

Abstract

Adenovirus (HAdV) infections confer a high risk of morbidity and mortality for immunocompromised patients after stem cell transplantation (SCT). Treatment with standard antiviral drugs is of limited efficacy and associated with a high rate of adverse effects. HAdV‐specific T cells are crucial for sustained viral elimination and the efficacy of adoptive T‐cell therapy with donor‐derived HAdV‐specific T cells has been reported by several investigators. Here, we report our experience with the transfer of HAdV‐specific T cells specific for penton, which was recently identified as an immunodominant target of T cells, and hexon in a 14‐year‐old boy after T‐cell‐depleted haploidentical SCT for myelodysplastic syndrome (MDS). He developed severe HAdV‐associated enteritis complicated by acute graft‐versus‐host disease (GvHD). The patient received ten infusions of allogeneic HAdV‐specific T cells manufactured from the haploidentical stem cell donor using the CliniMacs Interferon‐γ (IFN‐γ) cytokine capture and immunomagnetic selection. Initially, T cells were generated against the immunodominant target hexon and in subsequent transfers dual antigen‐specific T cells against hexon and penton were applied. T‐cell transfers were scheduled individually tailored to current immunosuppressive treatment. Each transfer was followed by reduction of HAdV load in peripheral blood and clinical improvement. Importantly, T‐cell responses to both penton and hexon pools emerged in patient blood after repetitive transfers. Unfortunately, the patient experienced bacterial sepsis, and in this context, severe GvHD requiring intensive immunosuppression followed by secondary progression of HAdV infection. The patient succumbed to multiorgan failure 283 days after SCT. This case demonstrates the feasibility of HAdV‐specific T‐cell transfer even in the presence of immunosuppressive treatment. Targeting of multiple immunodominant viral proteins may prove valuable in patients with complicated HAdV infections.

Minor Histocompatibility Antigen-Specific T Cells

“…The transferred memory T cells expanded after BMT and augmented GVL. This approach could be translated to humans by vaccinating donors months before HCT or intended post-HCT infusion and then specifically selecting the minor H antigen T cells using a immunomagnetic bead-based technique, such as Streptamer selection (137)(138)(139)(140) or the Miltenyi Biotec CliniMACs Cytokine Capture System (142,143). Alternatively, after donor vaccination with hematopoietic-restricted minor H antigens, donor T cells could be collected and depleted of naïve T cells to avoid GVHD (104), and the minor H antigen-specific T cell enriched memory T cells could be delivered with or following the stem cell graft.…”

Other Respiratory Viruses as a Cause of Community-Acquired Pneumonia

“…150,156 The adoptive transfer of adenovirus-specific T cells has been described, but more data are needed to inform the safety and efficacy of this approach. 157…”

High-intensity interval training in allogeneic adoptive T-cell immunotherapy – a big HIT?

“…It is established that the delay in the reconstitution of virusspecific CD8 + and/or CD4 + T-cell responses is a critical factor in viral recrudescence and viral disease and that the permanent control and elimination of a virus depends on the presence of functional virus-specific T cells (VSTs) [18,19]. The adoptive transfer of donor-derived memory VSTs with defined specificity has developed into a prophylactic and/or curative approach for common post-HSCT and post-SOT viral infections without a significant risk of toxicity or GvHD [2,3,[20][21][22][23][24][25][26]. Recently, we demonstrated the successful use of EBV-specific T cells as a consolidating treatment for a patient suffering from EBVassociated PTLD of the central nervous system [27].…”

“…Clinical-grade VSTs can be rapidly isolated directly from blood leukapheresis donations by the cytokine capture system (CliniMACS CCS) [26,28,29].…”

“…AdV-specific T cells). However, clinical studies showed that the adoptive transfer of even relatively low numbers of VSTs (0.4 × 10 3 to 8 × 10 4 /kg CMV-VSTs, 0.2 × 10 3 to 6 × 10 4 /kg EBV-VSTs, 0.3 × 10 3 to 3 × 10 4 /kg AdV-VSTs) resulted in the decrease in viral load without acute toxicities or GvHD induction [2,5,24,26]. Studies over the last 30 years successfully demonstrated the feasibility of the adoptive T-cell transfer with a treatment response in 74% of 246 evaluable published patients including 85% of CMV-responders, 62% of EBVresponders and 74% of AdV-responders [5,18,[30][31][32][33][34][35].…”