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Allogeneic Virus-specific T Cell Lines (VSTs)

Primary Purpose

Viral Infections After HSCT

Status
Active
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
VSTs
Sponsored by
Catherine Bollard
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Viral Infections After HSCT

Eligibility Criteria

4 Weeks - 45 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Received prior myeloablative or non-myeloablative allogeneic hematopoietic stem cell transplant using either bone marrow, single/double cord blood or PBSC
  2. Cells administered as;

    1. Treatment of persistent or relapsed reactivation or infection
    2. Early treatment for single or multiple infections with EBV, CMV and/or adenovirus
  3. Steroids less or equal to 0.5 mg/kg/day prednisone

5)Bilirubin <3x, AST <3x, Serum creatinine <2x upper limit of normal, Hgb >8.0, plts >20 6) Pulse oximetry of > 90% on room air 7) Available VSTs 8) Negative pregnancy test (if female of childbearing potential after reduced intensity conditioning) 9) Patient or parent/guardian capable of providing informed consent.

Exclusion Criteria:

  1. Received ATG, Campath or other T cell immunosuppressive monoclonal antibodies in the last 28 days.
  2. Patients with other uncontrolled infections
  3. Received donor lymphocyte infusion in last 28 days
  4. Evidence of GVHD > or equal to grade 2
  5. Active and uncontrolled relapse of malignancy

Sites / Locations

  • Childrens National Medical Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

VSTs against three viruses

Arm Description

Patients will receive 2 x 107 partially HLA-matched VSTs/m2 as a single infusion. In the rare case where insufficient banked cell product is available, a lower number of cells may be infused after discussion with the principal investigator, patient and/or guardian and the treatment team. If participants have a partial response (as defined by a 50% fall in viral load) they are eligible to receive up to 4 additional doses from day 28 after the initial infusion and at 2 weekly intervals thereafter.

Outcomes

Primary Outcome Measures

Assessments of patients with adverse events after VSTs infusion.
Safety of administration of VSTs is 45 days for GVHD. The safety endpoint will be defined as acute GvHD grades III-IV related to the T cell product within 45 days of the last VST dose and that are not due to the pre-existing infection or the original malignancy or pre-existing co-morbidities as defined by the NCI Common Terminology Criteria for Adverse Events (CTCAE)

Secondary Outcome Measures

Assessments of viral load response to the CTL infusion
Increase in viral load of at least 50% from baseline or dissemination to other sites of disease.
Assessments of Antiviral Immunity
Patient serum and peripheral blood mononuclear cells will be monitored for virus-specific activity by phenotypic and functional studies including ELIspot with appropriate viral specific peptide mixtures and available HLA-restricted epitope peptides, intracellular cytokine staining, serum cytokine profiling and/or other assays as they become available for immune profiling purposes.

Full Information

First Posted
July 13, 2015
Last Updated
September 19, 2023
Sponsor
Catherine Bollard
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1. Study Identification

Unique Protocol Identification Number
NCT02510417
Brief Title
Allogeneic Virus-specific T Cell Lines (VSTs)
Official Title
Administration of Most Closely HLA-matched Multivirus-specific Cytotoxic T-Lymphocytes for the Treatment of EBV, CMV, Adenovirus Infections Post Allogeneic Stem Cell Transplant
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
October 28, 2014 (Actual)
Primary Completion Date
September 2024 (Anticipated)
Study Completion Date
April 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Catherine Bollard

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The primary purpose of the study is to evaluate whether most closely HLA-matched multivirus-specific T cell lines obtained from a bank of allogeneic virus-specific T cell lines (VSTs) have antiviral activity against three viruses: EBV, CMV and adenovirus. Reconstitution of anti-viral immunity by donor-derived VSTs has shown promise in preventing and treating infections associated with CMV, EBV and adenovirus post-transplant. However, the time taken to prepare patient-specific products and lack of virus-specific memory T cells in cord blood and seronegative donors, limits their value. An alternative is to use banked partially HLA-matched allogeneic VSTs. A prior phase II study at our institution using trivirus-specific VSTs generated using monocytes and EBV-transformed B cells gene-modified with a clinical grade adenoviral vector expressing CMV-pp65 to activate and expand specific T cells showed the feasibility, safety and activity of this approach for the treatment of refractory CMV, EBV and Adenovirus infections. However, the production process was lengthy, requiring 8-12 weeks, with exposure to biohazards (B95.8 EBV viral strain and adenovector), while antigenic competition between different viral components precluded increasing the spectrum of specificity beyond these three viruses. Investigator have overcome these limitations and in the current trial, they will evaluate whether rapidly generated, allogeneic most closely HLA-matched multivirus-specific VSTs, activated using overlapping peptide libraries spanning immunogenic antigens from CMV, adenovirus and EBV will be safe and produce anti-viral effects in allogeneic HSCT recipients infected with one of more of the targeted viruses that are persistent despite conventional anti-viral therapy. The study agent will be assessed for safety (stopping rules defined) and antiviral activity.
Detailed Description
Investigators evaluated the clinical utility of Multivirus VSTs in recipients of matched related, matched unrelated, or haploidentical donor transplants. To date, 10 clinical-grade multivirus-directed VSTs have been generated from donor PBMCs. These lines were polyclonal, comprising both CD4+ (57±5%) and CD8+ (35±5%) cells and retained expression of the memory markers CD45RO+CD62L+ (58±8%). Their specificity was dependent on the prior viral exposure of the cell donor; 7/8 tested lines had activity against Adv,8/8 against CMV, 6/8 against EBV. None of the lines reacted against recipient PHA blasts - indicating lack of alloreactive potential in these rapidly generated lines. Investigators administered these multivirus-specific donor-derived VSTs to 3 allogeneic HSCT recipients in a dose escalation study all on DL1 (5x106/m2). There were no immediate infusion toxicities, and no de novo acute GvHD, demonstrating the in vivo safety of these mVST. Further, antiviral efficacy has been observed in 1 patient with refractory CMV. In addition, in a recently published paper from Baylor College of Medicien (Anapoulous et al, STM 2014) they have treated VSTs manufactured with a similar methodology, but targeting 5 viruses instead of 3 with specificity to BK virus and HHV6. In that study 10 patients were treated with 4 on DL1 (5x10e6/m2), 4 on DL2 (1x10e7/m2) and 2 on DL3 (2x10e7/m2) and again saw no immediate infusion toxicities, and no de novo acute GvHD, demonstrating the in vivo safety of these mVST. Three patients received the cells as viral prophylaxis (days 38-43 post-HSCT) and none developed viral infections at up to 3 months post-treatment. The other 7 patients received the cells as treatment for one or more active infections between days 59-139 post-HSCT. Based on viral load measurements by day 42 post-infusion, the VSTs were successful in controlling active infections with CMV (1 complete (CR) and 1 partial response (PR)), EBV (2 CRs, including a case of frank PTLD); Adv (1 CR); HHV6 (1 CR); and BK (3 CR, 1 PR, 1NR). Of note, 3 BK virus responders had tissue disease with severe hemorrhagic cystitis and all had marked improvement or disappearance of hematuria following infusion. One patient subsequently had an episode of transient but severe bladder pain in association with inflammation seen on cytoscopy coincident with a 6 log fall in urine BK viral load. Only non-responder was a patient with BK infection whose line lacked activity for this virus, likely reflecting the serostatus of the donor. In addition, 3 patients subsequently reactivated other viruses than those for which they were initially treated, but all cleared these infections by week 12, without the requirement for additional cell infusions (CMV: 1CR; EBV: 1CR; BK: 1CR; HHV6: 1CR). Finally, 1 patient received multivirus specific VSTs under a single patient protocol as an emergency treatment for widespread and bulky rituximab-resistant EBV-PTLD. Post VST treatment there was an immediate decline in the patient's EBV viral load with complete and sustained resolution of PTLD, coincident with an increase in circulating EBV-specific T cells. However, the profound anti-tumor activity mediated by the rapidly-expanding EBV-directed T cells also produced a transient systemic inflammatory response syndrome, which was controlled with steroids and anti-TNFR antibody, with no long term adverse effects. Thus, infusion of donor-derived, multivirus specific VSTs generated with clinical grade pepmixes and infused either prophylactically or as treatment for one or more viral infections has been safe and is associated with the appearance of virus-reactive T cells in peripheral blood that have been able to control infection with above mentioned viruses.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Viral Infections After HSCT

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
31 (Actual)

8. Arms, Groups, and Interventions

Arm Title
VSTs against three viruses
Arm Type
Experimental
Arm Description
Patients will receive 2 x 107 partially HLA-matched VSTs/m2 as a single infusion. In the rare case where insufficient banked cell product is available, a lower number of cells may be infused after discussion with the principal investigator, patient and/or guardian and the treatment team. If participants have a partial response (as defined by a 50% fall in viral load) they are eligible to receive up to 4 additional doses from day 28 after the initial infusion and at 2 weekly intervals thereafter.
Intervention Type
Biological
Intervention Name(s)
VSTs
Intervention Description
most closely HLA-matched multivirus-specific T cell lines obtained from a bank of allogeneic virus-specific T cell lines (VSTs) have antiviral activity against three viruses: EBV, CMV and adenovirus
Primary Outcome Measure Information:
Title
Assessments of patients with adverse events after VSTs infusion.
Description
Safety of administration of VSTs is 45 days for GVHD. The safety endpoint will be defined as acute GvHD grades III-IV related to the T cell product within 45 days of the last VST dose and that are not due to the pre-existing infection or the original malignancy or pre-existing co-morbidities as defined by the NCI Common Terminology Criteria for Adverse Events (CTCAE)
Time Frame
45 days
Secondary Outcome Measure Information:
Title
Assessments of viral load response to the CTL infusion
Description
Increase in viral load of at least 50% from baseline or dissemination to other sites of disease.
Time Frame
12 months
Title
Assessments of Antiviral Immunity
Description
Patient serum and peripheral blood mononuclear cells will be monitored for virus-specific activity by phenotypic and functional studies including ELIspot with appropriate viral specific peptide mixtures and available HLA-restricted epitope peptides, intracellular cytokine staining, serum cytokine profiling and/or other assays as they become available for immune profiling purposes.
Time Frame
12 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
4 Weeks
Maximum Age & Unit of Time
45 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Received prior myeloablative or non-myeloablative allogeneic hematopoietic stem cell transplant using either bone marrow, single/double cord blood or PBSC Cells administered as; Treatment of persistent or relapsed reactivation or infection Early treatment for single or multiple infections with EBV, CMV and/or adenovirus Steroids less or equal to 0.5 mg/kg/day prednisone 5)Bilirubin <3x, AST <3x, Serum creatinine <2x upper limit of normal, Hgb >8.0, plts >20 6) Pulse oximetry of > 90% on room air 7) Available VSTs 8) Negative pregnancy test (if female of childbearing potential after reduced intensity conditioning) 9) Patient or parent/guardian capable of providing informed consent. Exclusion Criteria: Received ATG, Campath or other T cell immunosuppressive monoclonal antibodies in the last 28 days. Patients with other uncontrolled infections Received donor lymphocyte infusion in last 28 days Evidence of GVHD > or equal to grade 2 Active and uncontrolled relapse of malignancy
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Catherine Bollard, MD
Organizational Affiliation
Children's National Research Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
Childrens National Medical Center
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20010
Country
United States

12. IPD Sharing Statement

Learn more about this trial

Allogeneic Virus-specific T Cell Lines (VSTs)

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