The Safety and Efficacy of Targeted Virus Specific Cytotoxic T-Lymphocytes (VST) Manufactured By the IFN-g Cytokine Capture System (CCS) for the Treatment of Refractory Adenovirus (ADV), Cytomegalovirus (CMV), Epstein Barr Virus (EBV) and BK Virus (BKV) in Children, Adolescents and Young Adults (CAYA) after Allogenic Hematopoietic Stem Cell Transplantation (Allo-HSCT), Solid Organ Transplantation (SOT), or with Primary Immunodeficiency (PID) (IND# 17449)

Viral infection remains a major cause of morbidity and mortality after allo-HSCT (Bollard/Heslop Blood 2016). Antibiotics for treatment of viral infection in immunocompromised patients are limited in efficacy and associated with toxicity (Gerdemann BBMT 2004; Sili Cytother 2012). Increasing evidence suggests that use of VST for immunocompromised patients with viral infections can provide therapeutic benefit and improve OS (Bollard/Heslop Blood 2016; Sutrave Cytother 2017). Methods of VST production include ex-vivo expansion and direct selection (Gottlieb Cytother 2017). Ex-vivo expansion requires prolonged manufacturing time, is associated with exhaustion, and provides a limited donor pool. Direct selection results in rapid production and allows for expanded HLA matching. A multicenter consortium (VIRCTLC) was created to investigate the safety and efficacy of VST (Figure 1) manufactured by the IFN- CCS process automated on the CliniMACS® Prodigy device (Miltenyi Biotec) for immunocompromised patients with viral infection. To determine the safety and efficacy of VST therapy for immunocompromised CAYA patients with viral infection. CAYA patients after allo-HSCT, SOT or with PID with refractory ADV, CMV, EBV or BKV infections despite 2 weeks of appropriate anti-viral therapy, and/or resistance to antibiotics and/or intolerance to antibiotics were eligible. Donors were screened with viral specific antigen (PepTivator®) to predict successful VST manufacturing. Eligible donor PBMC were collected with non-mobilized apheresis. VST were isolated using the CliniMACS® Prodigy following specific stimulation of PBMC with specific viral MACS PepTivator® pools, generously provided by Miltenyi Biotec. Production of CD4+ and CD8+ VST was performed as previously described (Feucthinger Blood 2010). Target cell dose was 0.5 × 104 CD3+/kg for HLA mismatched related donors and 2.5 × 104 CD3+/kg for matched related donors. Based on response and safety, additional doses of VST were given every 2 weeks, for a maximum of 5 infusions. Thirteen patients were treated under IND 17449 and other single INDs. Median number of VST infusions was 2 (1-5). Mean±SEM CD3+ cell dose infused was 0.48±0.03 × 104. There were 10 CR (PCR negative), 2 PR (PCR≥1 log decrease), and 1 too early to assess (ORR 100%, CRR 83%). Median time to maximal response was 24 days (range 3-111). No patient developed aGVHD, extensive cGVHD, infusion reaction or CRS associated with VST infusions. One patient experienced recurrence of aGVHD, possibly related to VST. (Table 1) Preliminary results of this pilot study demonstrate that VST are safe and efficacious in CAYA with refractory viral infections after alloHSCT, SOT or with PID. VST manufacturing utilizing the CliniMACS® Prodigy device is rapid (24 hours), reproducible and effective. Accrual is ongoing.