Management of Adenovirus in Children after Allogeneic Hematopoietic Stem Cell Transplantation

Table 2

Clinical trials using virus-specific cytotoxic T cells in the HSCT setting.

Reference number (centre)	Virus specificity	Expansion protocol	Antigen used	Infused number and type of cells	Patients treated	Clinical results
[62] (Texas)	EBV, CMV, ADV	Donor PBMCs infected with vector and restimulated, repetitively, with irradiated EBV-LCLs transduced with same vector over 10–12 weeks	Clinical-grade; Ad5f35pp65 vector	Median 5×10^7 polyclonal cells/m^2infused at 35–150 d after HSCT (median 62 d)	11 infused (children and adults; 10 prophylactically,; 1 treated for ADV infection)	3/3 cleared CMV and 3/3 cleared EBV infection/PTLD without antivirals; 3 patients with infection and 1 with disease cleared ADV after-CTL. No GVHD
[67] (Tuebingen)	ADV	IFN-𝛾 selection after 16 h stimulation; Cytokine-secreting cells magnetically enriched	Adenoviral antigen type; C (nonclinical grade)	1.2--50×10^3/kg ADV-reactive polyclonal T cells infused	9 children with ADV infection	5 out of 6 with ADV responded; 1 died at 30 days from ADV infection; 5 deaths (3 due to ADV infection)
[64] (Texas)	EBV + ADV	PBMCs infected with vector Responder cells restimulated weekly with irradiated autologous LCL transduced with the same vector IL-2 being added twice weekly from day 14. CTLs cryopreserved after 3 or 4 simulations	Ad5f35^null vector MOI 200 vp/cell	20 CTL lines with EBV and ADV specificity produced, 13 lines infused; Dose of 5×10^6 to 1.35×10^8 cells/m^2 at 40 to 150 days after HSCT (median 77 days)	13 children [(M)MUD or haplo]; 2 with active ADV disease; 11 prophylactic	No toxicities or GVHD, monitored for 3 months.; Only detected increases in ADV-sp T cells in peripheral blood in those with active ADV infection (2 out of 13)
[60] (London)	ADV	PBMCs stimulated for 16 hrs with ADV-hexon antigen Cytokine-secreting cells selected using anti-IFN-𝛾microbeads and Miltenyi Mini-MACS column within 24 h	Commercially available purified ADV-hexon antigen (Binding Site, UK)	3 received 𝛾-captured cells from original stem cell donor; Cells (10^4--10^5/kg) received on average 80 d after original graft (range 34–122)	5 patients treated (3 with original donor; 2 third-party haploidentical donor)	Blood viraemia resolved in 3; IFN-𝛾 secreting ADV-specific T cells present in 4 patients; 3 died—1 of bystander GVHD after clearing virus
[65] (Texas)	ADV, CMV, EBV	Banked 3rd party PMBCs transduced with vector and stimulated with EBV-LCL transduced with same vector	Ad5f35pp65 vector	32 virus-specific lines from individuals with common HLA polymorphisms immune to EBV, CMV, or ADV; Each patient received up to 2×10^7 cells/m^2	18 lines administered to 50 patients with severe viral illness with one of the viruses	Cumulative rates of complete or partial responses at 6 weeks were 74% for the whole group; 2 de novo GVHD (grade 1).
[68] (Texas)	ADV, CMV, EBV	Donor PBMCs stimulated with nucleofacted DCs and cultured over 2-3 weeks with IL4 and IL7.	DCs nucleofacted with range of EBV, CMV, and ADV viral antigens	22 trivirus and 14 bivirus CTL lines. Each patient received 0.5--2×10^7 cells/m^2	10 patients with viral reactivation treated between day 27 and month 52 after HSCT	Viral clearance and increased frequency of VSTs in 80%; 1 stage 2 skin GVHD