Phase I/II Trial of Early Infusion of Rapidly-generated Multivirus Specific T Cells (MVST) to Prevent Post Transplant Viral Infections

December 14, 2019 updated by: National Heart, Lung, and Blood Institute (NHLBI)

Allogeneic hematopoetic stem cell transplantation (SCT) is frequently complicated by life threatening viral reactivation. Conventional antiviral therapy is suboptimal for cytomegalovirus (CMV), adenovirus (AdV) and Epstein-Barr virus (EBV) and nonexistent for BK virus (BKV). An alternative approach to prevent viral reactivation is to infuse virus-specific cytotoxic T cells (CTL) prepared from the donor early after SCT. Such multivirus-specific CTL cells (MVST) have been successfully used in a number of centers to prevent or treat CMV, Ad and EBV. Activity of BKV-reactive cells has not been studied. Multi virus-specific T cells (MVST) are donor lymphocytes that are highly enriched for viral antigens and expanded in vitro before infusion into the transplant recipient. Viral reactivation is a particular problem inT cell depleted SCT. Median time to CMV reactivation is estimated as 28 days post T-depleted transplant, but infusion of MVST within the immediate post-SCT period has not been previously studied. This protocol will be the first of a planned series of cellular therapies to be layered on our existing T lymphocyte depleted transplant platform protocol 13-H-0144.

The aim of this study is to determine the safety and efficacy of very early infusion of MVST directed against the four most common viruses causing complications after T-depleted SCT. GMP-grade allogeneic MVST from the stem cell donor will be generated using monocyte-derived donor dendritic cells (DCs) pulsed with overlapping peptide libraries of immunodominant antigens from CMV, EBV, Ad, and BKV and expanded in IL-7 and IL-15 followed by IL-2 for 10-14 days. A fraction of the routine donor leukapheresis for lymphocytes obtained prior to stem cell mobilization will be used to generate the MVST cells. MVST passing release criteria will be cryopreserved ready for infusion post SCT.

Eligible subjects on NHLBI protocol 13-H-0144 will receive a single early infusion of MVST within 30 days (target day +14, range 0-30 days) post SCT. Phase I safety monitoring will continue for 6 weeks. Viral reactivation (CMV, EBV, Ad, BK) will be monitored by PCR by serial blood sampling. The only antiviral prophylaxis given will be acyclovir to prevent herpes simplex and varicella zoster reactivation. Subjects with rising PCR exceeding threshold for treatment, or those with clinically overt viral disease will receive conventional antiviral treatment. Patients developing acute GVHD will receive standard treatment with systemic steroids. These patients are eligible for reinfusion of MVST when steroids are tapered.

The clinical trial is designed as a single institution, open label, non-randomized Phase I/II trial of MVST in transplant recipients, designed as 3-cohort dose escalation Phase I followed by a 20 subject extension Phase II at the maximum tolerated dose of cells. Safety will be monitored continuously for a period of 6 weeks post T cell transfer. The primary safety endpoint will be the occurrence of dose limiting toxicity, defined as the occurrence of Grade IV GVHD or any other SAE that is deemed to be at least probably or definitely related to the investigational product. The primary efficacy endpoint for the phase II will be the proportion of CMV reactivation requiring treatment at day 100 post transplant. Secondary endpoints are technical feasibility of MSVT manufacture, patterns of virus reactivation by PCR, and clinical disease from EBV, Ad, BK, day 100 non-relapse mortality.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

Allogeneic hematopoetic stem cell transplantation (SCT) is frequently complicated by life threatening viral reactivation. Conventional antiviral therapy is suboptimal for cytomegalovirus (CMV), adenovirus (AdV) and Epstein-Barr virus (EBV) and nonexistent for BK virus (BKV). An alternative approach to prevent viral reactivation is to infuse virus-specific cytotoxic T cells (CTL) prepared from the donor early after SCT. Such multivirus-specific CTL cells (MVST) have been successfully used in a number of centers to prevent or treat CMV, Ad and EBV. Activity of BKV-reactive cells has not been studied. Multi virus-specific T cells (MVST) are donor lymphocytes that are highly enriched for viral antigens and expanded in vitro before infusion into the transplant recipient. Viral reactivation is a particular problem inT cell depleted SCT. Median time to CMV reactivation is estimated as 28 days post T-depleted transplant, but infusion of MVST within the immediate post-SCT period has not been previously studied. This protocol will be the first of a planned series of cellular therapies to be layered on our existing T lymphocyte depleted transplant platform protocol 13-H-0144.

The aim of this study is to determine the safety and efficacy of very early infusion of MVSTr cells directed against the four most common viruses causing complications after T-depleted SCT. GMP-grade allogeneic MVSTr from the stem cell donor will be generated using or peripheral blood mononuclear cells (PBMCs) pulsed with overlapping peptide libraries of immunodominant antigens from CMV, EBV, Ad, and BKV and expanded in IL-7 and IL-15 followed by IL-2 for 14 days. A fraction of the routine donor leukapheresis for lymphocytes obtained prior to stem cell mobilization will be used to generate the MVST cells. MVST passing release criteria will be cryopreserved ready for infusion post SCT.

Eligible subjects on NHLBI protocol 13-H-0144 will receive a single early infusion of MVSTr on day +7 post transplant range 0-14 days) post SCT. Phase I safety monitoring will continue for 6 weeks after infusion. Viral reactivation (CMV, EBV, Ad, BK) will be monitored by PCR by serial blood sampling. The only antiviral prophylaxis given will be acyclovir to prevent herpes simplex and varicella zoster reactivation. Subjects with rising PCR exceeding threshold for treatment, or those with clinically overt viral disease will receive conventional antiviral treatment. Patients developing acute GVHD will receive standard treatment with systemic steroids. These patients are eligible for reinfusion of MVST when steroids are tapered.

The clinical trial is designed as a single institution, open label, non-randomized Phase I trial of MVSTr in transplant recipients, designed as a single cohort Phase I study. Safety will be monitored continuously for a period of 6 weeks post MVSTr transfer. The primary safety endpoint will be the occurrence of dose limiting toxicity (DLT), defined as the occurrence of Grade IV GVHD, Grade III cytokine release syndrome (CRS), Grade III autoimmunity or any other SAE that is deemed to be at least probably or definitely related to the investigational product.

Study Type

Interventional

Enrollment (Actual)

12

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Maryland
      • Bethesda, Maryland, United States, 20892
        • National Institutes of Health Clinical Center, 9000 Rockville Pike

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 75 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

  • INCLUSION CRITERIA: Recipient
  • Ages 18-75 years inclusive
  • Patients with hematologic malignancies who have signed consent for NHLBI transplant protocol 13-H-0144.
  • Susceptible to CMV reactivation post transplant (either donor or recipient need to be seropositive for CMV at any time prior to transplant).
  • Ability to comprehend the investigational nature of the study and provide informed consent.

EXCLUSION CRITERIA: Recipient

  • Positive pregnancy test for women of childbearing age.
  • DLCO adjusted for Hb and ventilation < 50% predicted prior to SCT
  • Left ventricular ejection fraction < 40% (evaluated by ECHO) or < 30% (evaluated by MUGA) prior to SCT
  • AST/SGOT > 10 times ULN (>grade 3, CTCAE)
  • Bilirubin > 5 times ULN (>grade 3, CTCAE)
  • Estimated GFR < 15 mL/min
  • Receiving Ganciclovir, Foscarnet or Cidofovir
  • Receiving corticosteroids at the dose equivalent to 0.5 mg/kg/day of methylprednisolone
  • Evidence of active autoimmune process

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Non-Randomized
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: -1
1x10e4 MVST/kg infusion
Biological: MVST
MVST Infusion
Experimental: 1
1x10e5 MVST/kg infusion
Biological: MVST
MVST Infusion
Experimental: 2
5x10e5 MVST/kg infusion
Biological: MVST
MVST Infusion
Experimental: 3
1x10e6 MVST/kg infusion
Biological: MVST
MVST Infusion
Experimental: 3B
1x10e6 MVSTr/kg infusion
Biological: MVSTr

PBMCs will be collected by apheresis prior to mobilization for Hematopoietic stem cells collection, donor apheresis will be used partially to prepare DLIs per PI specification and remaining will be further processed by elutriation.

Monocytes and Lymphocytes are cryopreserved for further manufacture of MVSTr.
Experimental: 4
5x10e6 MVSTr/kg infusion
Biological: MVSTr

PBMCs will be collected by apheresis prior to mobilization for Hematopoietic stem cells collection, donor apheresis will be used partially to prepare DLIs per PI specification and remaining will be further processed by elutriation.

Monocytes and Lymphocytes are cryopreserved for further manufacture of MVSTr.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Occurrence of dose limiting toxicity
Time Frame: 6 weeks
6 weeks

Secondary Outcome Measures

Outcome Measure
Time Frame
EBV, Ad, BK, day 100 non-relapse mort.
Time Frame: 100 days
100 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

  • Principal Investigator: Minocher M Battiwalla, M.D., National Heart, Lung, and Blood Institute (NHLBI)

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

September 3, 2014

Primary Completion (Actual)

November 17, 2017

Study Completion (Actual)

December 29, 2017

Study Registration Dates

First Submitted

September 3, 2014

First Submitted That Met QC Criteria

September 3, 2014

First Posted (Estimate)

September 4, 2014

Study Record Updates

Last Update Posted (Actual)

December 17, 2019

Last Update Submitted That Met QC Criteria

December 14, 2019

Last Verified

December 29, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 140182
  • 14-H-0182

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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