This study measures the tolerability of viral-specific T cells against Cytomegalovirus (CMV) in adult solid organ transplant (SOT) recipients. Participants are expected to be on study for 52 +/- 3 weeks.
Viral infections, or their reactivation in the immunocompromised host, remain serious complications that adversely affect outcomes of transplantation. These infections may be refractory to pharmacologic treatment and result in increased morbidity and mortality after transplantation. Furthermore, the available pharmacologic therapies can result in severe toxicities. Once an infection occurs, adequate immune reconstitution is decisive for recovery from viral disease after solid organ transplantation. The present trial will consist of the treatment of solid organ transplant recipients diagnosed with severe CMV infection when standard antiviral therapy is ineffective (disease progression on therapy, decline in viral load less than 10-fold in 2 weeks, known drug resistance), or toxic (end-organ damage), with virus-specific T cells using the CliniMACS® Prodigy System. These are the patients with the greatest unmet need and greatest risk or morbidity and allograft loss due to CMV infection. CMV-specific T cells will be isolated from donor leukapheresis products using the CliniMACS® Prodigy. Prior studies on transfer of CMV-specific T cells have been shown to be safe and efficacious in the treatment of CMV infections. The primary objective of this Phase I trial is to evaluate the safety and tolerability of CMV-specific T-cell transfer in adult patients suffering from CMV infections following solid organ transplantation using a dose escalation design. The incubation with viral antigens (MACS GMP PepTivator) allows the enrichment of CMV-specific CD4+(Cluster of Differentiation 4) and CD8+(Cluster of Differentiation 8) T cells. Increasing evidence of the safety and efficacy of CMV-specific T-cell is available. Furthermore, the safety and efficacy of the specific manufacturing approach using the fully automated protocol of the ClinMACS® Prodigy for the isolation of CMV-specific T cells against CMV has been described and demonstrated that these cells retain their biological properties.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
2
Naturally occurring, allogeneic donor lymphocytes derived from a leukapheresis or a whole blood product, enriched for CMV-specific CD4+ and CD8+ T cells Suspension of CMV-specific T cells in 10 mL of 0.9% NaCl with 2% Human Serum Albumin(HSA) via IV bolus injection * Low Dose Tier - Viral-Specific T cell infusion 5 x10\^3 cells/kg body weight(BW) * Mid Dose Tier - Viral-Specific T cell infusion 1.25 x10\^4 cells/kg BW * High Dose Tier - Viral-Specific T cell infusion 2.5 x10\^4 cells/kg BW Product will be administered fresh intravenously to recipient within four hours of collection.
University of Wisconsin School of Medicine and Public Health
Madison, Wisconsin, United States
Safety and Tolerability:Time of Occurence of Acute GVHD
Time to occurrence of acute GVHD of any grade will be evaluated using the Kaplan-Meier method to assess incidence and severity of acute GVHD from day of T-cell transfer. The first day of GVHD onset at a certain grade will be used to calculate a cumulative incidence curve for that GVHD grade. Overall, cumulative incidence curves will be computed along with the 95% confidence intervals until Week 12 after T-cell transfer with death considered as a competing risk.
Time frame: up to 15 weeks
Safety and Tolerability: Number of infusion-related adverse events
Incidence of grades 3-5 infusion-related adverse events, grades 4-5 non-hematological adverse events within four weeks of the CMV-VST dose that are not due to the pre-existing infection or original malignancy or pre-existing co-morbidities
Time frame: up to 7 weeks
Incidence of acute infusion-related toxicity
Incidence of acute infusion-related toxicity as assessed by maximum toxicity on the day of T-cell transfer, evaluated by measuring vital signs prior to and at different times after the T-cell transfer and monitoring of specific adverse events (chills, nausea, vomiting, diarrhea, abdominal pain, allergic reactions, respiratory dysfunction or headache from T-cell transfer to 4 hours post injection)
Time frame: from T-cell transfer to 4 hours post injection, upto 3 weeks
Severity of acute infusion-related toxicity as measured by Cytokine release syndrome (CRS) Grading criteria
Severity of acute infusion-related toxicity will be assessed by CRS grading criteria. Grade 1 Symptoms are not life threatening and require symptomatic treatment only, (e.g., fever, nausea, fatigue, headache, myalgias, malaise) Grade 2 Symptoms require and respond to moderate intervention Grade 3 Symptoms require and respond to aggressive intervention Grade 4 Life-threatening symptoms Grade 5 Death Any grade 3 or greater occurrence of CRS will be considered a serious adverse event for this study.
Time frame: from T-cell transfer to 4 hours post injection, upto 3 weeks
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
Number of Participants of Newly Occurring Acute Rejection after T-cell Transfer
Incidence and severity of acute rejection of the organ allograft will in part be measured by number of participants of newly occurring acute rejection after T-cell transfer
Time frame: up to 15 weeks
Incidence of de novo Antibodies against Organ Allograft Donor (dnDSA) after T-cell Transfer
Incidence and severity of acute rejection of the organ allograft will in part be measured by presence of de novo antibodies against organ allograft donor (dnDSA) after T-cell transfer
Time frame: up to 55 weeks
Incidence of GVHD Grade ≥1
Incidence and severity of Graft-versus-host disease (GVHD) will be measured by occurrence of acute GVHD grade ≥1 or aggravation of pre-existing acute GVHD after T-cell transfer
Time frame: up to 15 weeks
Feasibility: Was production of CMV Virus specific T lymphocyte (VST) from donors accomplished?
There is no minimum cell count required for the study as it can vary. Successful production of CMV Virus specific T lymphocyte (VST) from donors will be tracked by a Yes/No question. Production of cell accomplished: yes/no
Time frame: up to 3 weeks
Feasibility: Participant Drop-out rate
Evaluation of feasibility of CMV specific T cell transfer in adult patients suffering from severe CMV infection following solid organ transplantation in part will be measured by participant drop out rate
Time frame: up to 3 weeks
Feasibility: Time from patient inclusion to administration of CMV-VST
Evaluation of feasibility of CMV specific T cell transfer in adult patients suffering from severe CMV infection following solid organ transplantation in part will be measured by the amount of time from patient inclusion to administration of CMV-VST
Time frame: up to 21 days
Efficacy: Percentage of patients with ≥1 log decrease in CMV viral load
Evaluation of efficacy of CMV-specific T-cell transfer in adult patients suffering from severe CMV infection following solid organ transplantation in part will be measured in terms of percentage of patients with ≥1 log decrease in CMV viral load at Week 12
Time frame: up to 15 weeks
Efficacy:Time to 1 log change in CMV viral load
Evaluation of efficacy of CMV-specific T-cell transfer in adult patients suffering from severe CMV infection following solid organ transplantation in part will be measured in terms of time to 1 log change in CMV viral load
Time frame: up to 15 weeks
Efficacy:Number of Participants with CMV clearance
Efficacy evaluation in part will be measured by number of participants with CMV clearance. Either negative polymerase chain reaction (PCR) or \<250 copies/mL will be considered as CMV clearance.
Time frame: up to 15 weeks
Efficacy: Time of clearance of CMV
Efficacy evaluation in part will be measured by number of days to achieve CMV clearance. Either negative polymerase chain reaction \[PCR\] or \<250 copies/mL)will be considered as CMV clearance.
Time frame: up to 55 weeks
Efficacy: Number of participants having CMV reactivation
Efficacy in part will be measured by number of participants with CMV reactivations following initial viral clearance
Time frame: up to 55 weeks
Efficacy: Overall Survival of Participant
Overall survival rate of participants will be measured by time from T-cell transfer to death, graft loss, or last follow-up throughout the study
Time frame: up to 55 weeks
Efficacy:Number of Participants with Clinical response/resolution of symptoms of underlying viral infection
Efficacy in part will be measured by number of patients with resolution of clinical symptoms of underlying CMV infection from Day 7 (Week 1) to Week 12 after T-cell transfer as compared to Day 0
Time frame: up to 15 weeks