Phase 3 Randomized Trial for Refractory ADV or CMV Infection With Family Matched CTLs and Standard of Care (SOC) vs SOC Alone

An Open-Label Prospective Randomized Trial of Family Donor-Derived ADV or CMV CTLs Plus Standard of Care (SOC) vs SOC Alone in Children, Adolescents and Young Adults Following Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) With Refractory ADV or CMV Infection/Viremia

Patients with refractory ADV or CMV infection post allogeneic stem cell transplant will be randomized to either Family donor-derived viral specific cytotoxic T lymphocytes (CTLs) plus standard of care (SOC) vs SOC alone.

We hypothesize that Family donor-derived viral specific cytotoxic T lymphocytes (CTLs) manufactured by direct selection utilizing the CliniMACS Prodigy® and Cytokine Capture System® plus standard of care (SOC) vs SOC alone in children, adolescents and young adults (CAYA) following allogeneic hematopoietic stem cell transplantation (HSCT) with medically refractory viral infection/viremia and/or intolerant or resistant to anti-viral antibiotic therapy will be associated with a significantly improved probability of Day +100 (time of onset on study) viral progression free survival (VPFS).

Patient Eligibility Cohort 1 (ADV) -Patients with ADV infections (Cohort 1) (pneumonitis, hepatitis, cystitis, and/or colitis) post AlloHSCT with one or more of the following: Increasing or persistent ADV RT-PCR DNA (> 1000 ADV PCR copies) after 7 days of appropriate anti-viral therapy AND/OR Medical intolerance to anti-viral therapies including one or more of the following: > grade 2 renal insufficiency secondary to cidofovir and/or other > grade 2 toxicities secondary to cidofovir AND/OR Known resistance to cidofovir

Patient Eligibility (Cohort 2) (CMV)

-Patients with CMV infections (pneumonitis, hepatitis, colitis) with one or more of the following: Increasing or persistent CMV RT-PCR DNA (>1000 copies) after 7 days of appropriate anti-viral therapy AND/OR Medical intolerance to anti-CMV antibiotic therapies: ANC > 500/mm3 secondary to ganciclovir AND/OR > grade 2 renal toxicity secondary to either foscarnet or cidofovir AND/OR Known resistance to ganciclovir and/or foscarnet

• Consent: written informed consent given (by patient or legal representative) prior to any study related procedures
• Performance Status >30% (Lansky < 16 yrs and Karnofsky > 16 years (BOTH COHORTS)
• Age: 0.01 to 30.00 years (BOTH COHORTS)
• Females of childbearing potential with a negative urine pregnancy test at study entry only (BOTH COHORTS)

Donor Eligibility

• Related donor available with a T-cell response to the ADV MACS PepTivators (Cohort 1) or CMV MACS PepTivator (Cohort 2). As defined in Appendix II, B, 8.2, the donor is considered suitable if the percentage of IFN+ T-cells is >0.01% after stimulation with ADV PepTivators (Cohort 1) or CMV PepTivators (Cohort 2).
• Third-party related allogeneic donor: If original donor is not available or does not have a T-cell response to ADV MCAS PepTivator (Cohort 1) or CMV PepTivator (Cohort 2), third party allogeneic donor (family donor > 3 HLA A, B, DR match to recipient) with a T-cell response at least to the ADV MCAS PepTivator (Cohort 1) or CMV PepTivator (Cohort 2) AND
• Allogeneic donor disease screening is complete similar to hematopoietic stem cell donors (Appendix 1) AND
• Obtained informed consents by donor or donor legally authorized representative prior to donor collection

Patient Exclusion Criteria (Both Cohorts)

• Patient with acute GVHD > grade 2 or moderate or extensive chronic GVHD at the time of CTL infusion.
• Patient receiving steroids (>0.5 mg/kg prednisone equivalent) at the time of CTL infusion.
• Patient treated with donor lymphocyte infusion (DLI) within 4 weeks prior to CTL infusion.
• Patient with poor performance status determined by Karnofksy (patients > 16 yrs) or Lansky (patients < 16 years) score < 30%.
• Concomitant enrollment in another experimental clinical trial investigating the treatment of refractory ADV or CMV infections.
• Any known medical condition which cold compromise participation in the study according to investigators assessment.
• Known AIDS or uncontrolled HIV infection
• Known hypersensitivity to iron dextran
• Encephalitis and/or retinitis