Clinical trial NCT05042076: BK With VST for Kidney Transplant Patients
Official title: A Phase I Study Evaluating Safety and Tolerability of Viral-Specific T (VST) Cells Against BK Virus (BKV) in Adult Kidney Transplant Recipients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Kidney Transplant Infection
BK Virus Infection
Keywords: virus specific T lymphocyte
VST
Lead sponsor: University of Wisconsin, Madison
Sponsor class: OTHER
First posted: 2021-09-13
Enrollment: 3
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Single-center, Phase I, open label, non-randomized, non-placebo controlled
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: Inclusion Criteria:

* Age18 ≤ 75 years
* Have BKV infection/viremia following kidney transplantation, where BKV viremia is defined as positive BKV qPCR (≥ 250 copies)
* Have evidence of invasive BKV infection (BK Nephropathy)
* Experience one of the following:

  * New, persistent and/or worsening BKV-related symptoms, signs and/or markers of end organ compromise despite being on lower immunosuppressive medication
  * Adverse effects of lower immunosuppressive medications (e.g., dnDSA, biopsy proven rejection)
* Eligible Donor
* Provide Written informed consent

Exclusion Criteria:

* Non-kidney organ transplant recipient
* Patient with acute rejection of the kidney allograft at time of T-cell transfer
* Patient receiving steroids (\>0.5 mg/kg body weight (BW) prednisone equivalent) at the time of T-cell transfer
* Patient treated with Thymoglobulin (ATG), Alemtuzumab or T-cell immunosuppressive monoclonal antibodies within 28 days prior to T-cell transfer
* Extra renal tissue invasive BK infection
* Concomitant enrollment in another clinical trial interfering with endpoints of this study
* Any medical condition which could compromise participation in the study according to the investigator's assessment
* Known HIV infection
* 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.
* Patients unwilling or unable to comply with the protocol or unable to give informed consent

Donor Eligibility

* ≥ 18 years old
* Available and capable of undergoing a single standard 2 blood volume leukapheresis
* HLA Compatible (see Donor selection priority below):

  * Original kidney transplant donor
  * Fully HLA matched family member (6/6 HLA match considering HLA-A, HLA-B and HLA-DRB1 genes)
  * Partially matched family member (≥ 2/6 HLA match, considering HLA-A, HLA-B and HLA-DRB1 genes)
* BK IgG seropositive
* Meets the criteria for donor eligibility defined in the UW Program for Advanced Cell Therapy Standard Operating Policies and Procedures for Donor Evaluation and Eligibility Determination for the Donation of Viral Specific T Cells, which is in compliance with FACT standards for Immune Effector Cells, and 21 CFR 1271, subpart C.
* Provide written informed consent

Donor selection priority: The original kidney donor will be the first choice of donor peripheral mononuclear cells. If the original donor is not available or does not meet all donor eligibility criteria, alternative related donors will be selected, with preference for fully matched related donors (6/6 HLA match, considering HLA-A, -B, and -DRB1 genes) over related donors with partial HLA match (≥ 2/6 HLA match, considering HLA-A, -B, and -DRB1 genes).

Note that if the selected donor is related, but not a biological parent or child of the recipient (i.e., at least haploidentical), then high resolution testing of HLA-A and HLA-B will be performed on donor and recipient (if high resolution HLA genotyping not already available in the medical record). If the degree of matching at high resolution reveals a less favorable match than an alternative donor, then prioritization of the alternative donor will occur.

Primary outcomes:
measure: Incidence of Adverse Events up to 4 hours post Cell Infusion
timeFrame: cell infusion is on study day 0, safety data collected up to 4 hours post injection
measure: Incidence of Adverse Events up to 4 weeks of T-cell Transfer
timeFrame: up to 4 weeks
measure: Incidence of newly occurring acute rejection of kidney allograft until Week 12 after T-cell transfer
timeFrame: up to 12 weeks
measure: Incidence of de novo antibodies against kidney allograft donor (dnDSA) until Week 52 after T-cell transfer
timeFrame: up to 52 weeks
measure: Incidence of newly occurring acute GVHD grade ≥1 or aggravation of pre-existing acute GVHD until Week 12 after T-cell transfer
timeFrame: up to 12 weeks
measure: Incidence of newly occurring acute GVHD grade ≥1 from Day 0 to Week 12
timeFrame: up to 12 weeks
Secondary outcomes:
measure: Incidence of successful production of BK Virus specific T lymphocyte (VST) from donors on intent-to-treat basis
timeFrame: up to 1 week
measure: Number of Participants who Drop-out of the Study
timeFrame: up to 52 weeks
measure: Summary of Reasons why Participants Drop-out of the Study
timeFrame: up to 52 weeks
measure: Time from Participant inclusion to administration of BK-VST
timeFrame: up to 1 week
measure: Percentage of Participants with ≥1 log decrease in BK viral load at Week 12
timeFrame: up to week 12
measure: Amount of Time to 1 log change in BK viral load
timeFrame: up to week 12
measure: Number of Participants with BKV clearance from Day 7 to Week 12 after T-cell transfer
timeFrame: up to week 12
measure: Amount of Time to BKV clearance from Day 0 of T-cell transfer to first day of 2 subsequent negative BKV PCR studies
timeFrame: up to week 12
measure: 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
timeFrame: up to 12 weeks
measure: Number of BKV reactivations following initial viral clearance until Week 52
timeFrame: up to week 52
measure: Overall Survival (OS) Rate
timeFrame: up to week 52
Other outcomes:
Locations:
city: Madison
country: United States
facility: University of Wisconsin School of Medicine and Public Health
state: Wisconsin
Study officials:
affiliation: University of Wisconsin, Madison
name: Sandesh Parajuli, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Wisconsin, Madison
name: Jacques Galipeau, MD
role: STUDY_DIRECTOR
References: