BK With VST for Kidney Transplant Patients
Study Details
Study Description
Brief Summary
This study measures the safety, feasibility, and efficacy of viral-specific T cells (VST) against BK Virus (BKV) in adult kidney transplant recipients. Participants are expected to be on study for 52 weeks.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
Detailed Description
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 kidney transplantation. The present trial will consist of the treatment of kidney transplant recipients diagnosed with severe BK infection as defined by a viral load ≥ 250 copies/mL and BKN, with virus-specific, antigen-selected T cells using the CliniMACS® Prodigy System. BK-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 Cytomegalovirus (CMV) infections, so the same methods will be used to transfer BK-specific T cells.
The main trial objective is to evaluate the safety and feasibility of BK-specific T-cell transfer in adult patients suffering from BK infections following kidney transplantation. The incubation with viral antigens (MACS Good Manufacturing Practice (GMP) PepTivator) allows the enrichment of BK-specific CD4+ and CD8+ 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 CliniMACS® Prodigy for the isolation of CMV-specific T cells against CMV has been described and has demonstrated that these cells retain their biological properties. Based on the CMV data, the investigators believe BK-specific T cells will follow the same pattern.
Study Overview
This phase I, open label, non-randomized, non-placebo controlled, single group assignment study will assess the safety and tolerability of transfer of BK-specific T cells isolated from a leukapheresis product. Secondary objectives will focus on the feasibility and efficacy of the BK-specific T-cell transfer. The Investigational Medicinal Product (IMP) will be generated automatically by the CliniMACS® Prodigy using the CliniMACS Cytokine Capture System (IFNγ) after incubation with MACS GMP PepTivator® BKV LT & VP1 for enrichment of virus-specific T-cells in adult patients suffering from BK infections following kidney transplantation.
Safety and tolerability will be assessed by determining the incidence and severity of acute infusion-related toxicities, incidence and severity of acute rejection of the kidney allograft, occurrence and time to newly occurring acute GVHD grade ≥1 until Week 12 after T-cell transfer, and aggravation of pre-existing acute GVHD grade ≥1 until Week 12.
Feasibility of BK virus specific T-cells will be assessed by determining the successful production of BK-VST from donors on an intent-to-treat basis, measuring dropout rate and reasons for drop out as well as time from patient inclusion to administration of the IMP.
Efficacy will be assessed by determining the number of patients and time to reaching ≥1 log decrease in BK viral load, number of patients with BK clearance, time to BK clearance, and number of patients with resolution of clinical BK organ disease by Week 12. Number of BK reactivations following BK viral clearance and overall survival (OS) will be determined at Week 52.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: BK with VST Adult patients with BKV infection and nephropathy (BKN) following kidney transplantation. Consented patients who lack a donor or have a cell manufacturing failure will be entered into an observational group and will be replaced, if they do not become eligible during the study period |
Drug: BK-specific T cells from Donor Lymphocytes
Naturally occurring, allogeneic donor lymphocytes derived from a leukapheresis, enriched for BK-specific CD4+ and CD8+ T cells
Suspension of BK-specific T cells in approximately 7 mL (5-10 mL range for volume of IMP) of 0.9% NaCl with 2.5% HSA at a cell dose of: ≥ 300 and ≤ 5,000 BK virus-specific CD3+ T cells/kg body weight (BW).
IV bolus injection; IV push of IMP over approximately 2-4 minutes, resulting in an infusion rate of approximately 3 mL/min.
|
Outcome Measures
Primary Outcome Measures
- Incidence of Adverse Events up to 4 hours post Cell Infusion [cell infusion is on study day 0, safety data collected up to 4 hours post injection]
Safety of the intervention against BKV (BKV-VST) in adult kidney transplant recipients is in part measured by incidence of acute infusion-related toxicity on the day of T-cell transfer evaluated by measuring vital signs prior to and at different time points 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).
- Incidence of Adverse Events up to 4 weeks of T-cell Transfer [up to 4 weeks]
Safety of the intervention against BKV (BKV-VST) in adult kidney transplant recipients is in part measured by incidence of grade 3-5 infusion-related adverse events, grades 4-5 non-hematological adverse events within 4 weeks of T-cell transfer that are not due to the pre-existing infection or original malignancy or pre-existing co-morbidities.
- Incidence of newly occurring acute rejection of kidney allograft until Week 12 after T-cell transfer [up to 12 weeks]
Incidence and severity of acute rejection of the kidney allograft is in part measured by incidence of newly occurring acute rejection of kidney allograft until Week 12 after T-cell transfer.
- Incidence of de novo antibodies against kidney allograft donor (dnDSA) until Week 52 after T-cell transfer [up to 52 weeks]
Incidence and severity of acute rejection of the kidney allograft is in part measured by incidence of de novo antibodies against kidney allograft donor (dnDSA) until Week 52 after T-cell transfer.
- Incidence of newly occurring acute GVHD grade ≥1 or aggravation of pre-existing acute GVHD until Week 12 after T-cell transfer [up to 12 weeks]
Incidence and severity of Graft-versus-host disease (GVHD) is in part measured by the incidence of newly occurring acute GVHD grade ≥1 or aggravation of pre-existing acute GVHD until Week 12 after T-cell transfer.
- Incidence of newly occurring acute GVHD grade ≥1 from Day 0 to Week 12 [up to 12 weeks]
Incidence and severity of GVHD is in part measured by the incidence of newly occurring acute GVHD grade ≥1 from Day 0 to Week 12.
Secondary Outcome Measures
- Incidence of successful production of BK Virus specific T lymphocyte (VST) from donors on intent-to-treat basis [up to 1 week]
Evaluation of feasibility of BK specific T cell transfer in adult participants suffering from severe BKV infection following kidney transplantation is in part measured by the successful production of BK Virus specific T lymphocyte (VST) from donors on intent-to-treat basis
- Number of Participants who Drop-out of the Study [up to 52 weeks]
Evaluation of feasibility of BK specific T cell transfer in adult participants suffering from severe BKV infection following kidney transplantation is in part measured by the participant drop out rate.
- Summary of Reasons why Participants Drop-out of the Study [up to 52 weeks]
Evaluation of feasibility of BK specific T cell transfer in adult participants suffering from severe BKV infection following kidney transplantation is in part evaluated by the reasons that participants drop out of the study.
- Time from Participant inclusion to administration of BK-VST [up to 1 week]
Evaluation of feasibility of BK specific T cell transfer in adult participants suffering from severe BKV infection following kidney transplantation is in part measured by the amount of time from participant inclusion to administration of BK-VST.
- Percentage of Participants with ≥1 log decrease in BK viral load at Week 12 [up to week 12]
Evaluation of efficacy of BK-specific T-cell transfer in adult participants suffering from severe BK infection following kidney transplantation is in part measured by the percentage of participants with ≥1 log decrease in BK viral load at Week 12.
- Amount of Time to 1 log change in BK viral load [up to week 12]
Evaluation of efficacy of BK-specific T-cell transfer in adult participants suffering from severe BK infection following kidney transplantation is in part measured by the amount of time to 1 log change in BK viral load.
- Number of Participants with BKV clearance from Day 7 to Week 12 after T-cell transfer [up to week 12]
Evaluation of efficacy of BK-specific T-cell transfer in adult participants suffering from severe BK infection following kidney transplantation is in part measured by the number of participants with BKV clearance (defined as either negative polymerase chain reaction (PCR) or <250 copies/mL) from Day 7 to Week 12 after T-cell transfer.
- Amount of Time to BKV clearance from Day 0 of T-cell transfer to first day of 2 subsequent negative BKV PCR studies [up to week 12]
Evaluation of efficacy of BK-specific T-cell transfer in adult participants suffering from severe BK infection following kidney transplantation is in part measured by the amount of time to BKV clearance (defined as either negative PCR or <250 copies/mL) from Day 0 of T-cell transfer to first day of 2 subsequent negative BKV PCR studies.
- Number of Participants with resolution of underlying BKV infection from Day 7 (Week 1) to Week 12 after T-cell transfer as compared to Day 0 [up to 12 weeks]
Clinical response/resolution of underlying viral infection is measured by the number of participants with resolution of underlying BKV infection from Day 7 (Week 1) to Week 12 after T-cell transfer as compared to Day 0.
- Number of BKV reactivations following initial viral clearance until Week 52 [up to week 52]
Effect on BKV reactivation is measured by the number of BKV reactivations following initial viral clearance until Week 52 .
- Overall Survival (OS) Rate [up to week 52]
OS rate: time from T-cell transfer (Day 0) to death, graft loss, or last follow-up throughout the study from Day 1 to Week 52.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Adult (age ≥ 18 and ≤75) patients suffering from BKV infection/viremia following kidney transplantation
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BKV viremia defined as positive (≥ 250 copies/mL) BK qPCR AND
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Presence of evidence of invasive BKV infection (BK Nephropathy)
AND ONE OF THE FOLLOWING CRITERIA:
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New, persistent and/or worsening BKV-related symptoms, signs and/or markers of end organ compromise despite being on lower immunosuppressive medication, OR
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Experiencing adverse effects of lower immunosuppressive medications (e.g., dnDSA, biopsy proven rejection)
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Original donor ≥ 18 years if available, BKV IgG positive, eligible and capable of undergoing a single standard 2 blood volume leukapheresis or donation of one unit of whole blood OR If original donor is not available, BKV IgG negative OR ineligible, then a BKV IgG positive fully or partially matched (at least 2/6 HLA-A, -B, -DRB1) family donor will be used
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Written informed consent given by patient
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Written informed consent given by donor
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Eligible Donor
Exclusion Criteria:
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Non-kidney organ transplant recipient
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Patient with acute rejection of the kidney allograft at time of T-cell transfer
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Patient receiving steroids (>0.5 mg/kg body weight (BW) prednisone equivalent) at the time of T-cell transfer
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Patient treated with Thymoglobulin (ATG), Alemtuzumab or T-cell immunosuppressive monoclonal antibodies within 28 days
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Patients with extra renal tissue invasive BKV infection ( biopsy proven)
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Concomitant enrollment in another clinical trial interfering with endpoints of this study
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Any medical condition which could compromise participation in the study according to the investigator's assessment
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Known HIV infection
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Female patient who is pregnant or breast-feeding, or adult of reproductive potential not willing to use an effective method of birth control during study treatment Note: Women of childbearing potential must have a negative urine pregnancy test at study entry.
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Patients unwilling or unable to comply with the protocol or unable to give informed consent
Donor selection priority: The original donor will be the first choice as source of T cells. If the original donor is not available for donation of peripheral mononuclear cells or does not meet all donor eligibility criteria, alternative related donors will be selected, with preference for fully matched related donors over those with partial HLA matching (≥ 2/6 HLA loci).
- All donors must be ≥ 18 years old, available, BK IgG positive, eligible and capable of undergoing a single standard 2 blood volume leukapheresis.
If original kidney transplant donor is not available, BK IgG negative or ineligible, a BK IgG positive fully or partially matched (≥ 2/6 HLA loci) family donor will be used.
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Related donors must be at least partially HLA compatible, matching with recipient in at least 2/6 HLA loci (HLA-A, HLA-B and HLA-DRB1 will be considered for this).
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Donors must be BK IgG seropositive.
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Donor must meet the criteria for donor selection defined in the Standard Operating Policies and Procedures (SOP B2.001) of the UWHC Hematopoietic Stem Cell Transplant Program.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Wisconsin School of Medicine and Public Health | Madison | Wisconsin | United States | 53705 |
Sponsors and Collaborators
- University of Wisconsin, Madison
Investigators
- Principal Investigator: Sandesh Parajuli, MD, University of Wisconsin, Madison
- Study Director: Jacques Galipeau, MD, University of Wisconsin, Madison
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 2021-1058
- A534280
- Protocol Version 8/2/2021
- Galipeau SMPH-PACT Support