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Adoptive Cellular Immunotherapy for Progressive Multifocal Leukoencephalopathy With Ex Vivo Generated Polyomavirus-Specific T-Cells

Primary Purpose

Progressive Multifocal Leukoencephalopathy

Status

Completed

Phase

Early Phase 1

Locations

United States

Study Type

Interventional

Intervention

PyVST

About this trial

This is an interventional treatment trial for Progressive Multifocal Leukoencephalopathy focused on measuring HLA Matched, JCV, Donor, PyVST, PML

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

INCLUSION CRITERIA - PATIENT:
Clinically definite PML, defined as clinical signs and MRI compatible with active PML and the presence of JCV by PCR in CSF
Modified Rankin Scale 1-4, inclusive
Age 18 or older
Patient medically stable and able to tolerate travel to NIH
Available PyVST
Subjects of childbearing or child-fathering potential must be willing to use a medically acceptable form of birth control, which includes abstinence, while they are being treated on this study
Willing and able to participate in all aspects of trial design and follow-up
Able to provide informed consent at the time of study enrollment (not required for reinfusions).

EXCLUSION CRITERIA - PATIENT:

Patients with human immunodeficiency virus (HIV infection)
Patients who have been treated with natalizumab
Patients with readily reversible immunosuppressive state
Patients receiving immunosuppressive or immunomodulatory therapies within 28 days of screening for enrollment that could interfere with PyVST function
Patients with other uncontrolled infections. For bacterial infections, patients must be receiving definitive therapy and have no signs of progressing infection for 72 hours prior to enrollment. For fungal infections, patients must be receiving definitive systemic anti-fungal therapy and have no signs of progressing infection for 1 week prior to enrollment.
Patients who have received donor lymphocyte infusion (DLI) within 28 days
Uncontrolled relapse of malignancy
Patients with any other associated CNS disease that might confound outcomes
Patients with contraindication to MRI (including cardiac pacemakers and some infusion pumps, other metallic implants, metallic foreign objects)
MRI findings consistent with immune system reconstitution inflammatory syndrome (IRIS) and determined to be mounting an adequate immune response to the infection
Patients with medical contraindication to LP
For subjects who have previously received PyVST infusions, any treatment-limiting toxicity (defined in Section 8.3) to previous infusions
Subjects with a positive pregnancy test or who are nursing.

INCLUSION CRITERIA - DONOR:

Ability to provide informed consent at the time of enrollment
First degree relative of patient (sibling, parent/child)
Age 18 or older

EXCLUSION CRITERIA - DONOR:

Sickling hemoglobinopathies including HbSS and HbSC by history and peripheral blood smear; donors with HbAS are acceptable
HbsAg, anti-HBc, anti-HCV, anti-HIV, anti-HTLV, and RPR
Cardiovascular instability, severe anemia, inadequate venous access, severe coagulation disorder or any other medical condition that the Principal Investigator or Apheresis Unit staff considers a contraindication to the apheresis procedure or research blood draw.
Positive pregnancy test

Sites / Locations

National Institutes of Health Clinical Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment Arm

Arm Description

ex vivo generated polyomavirus-specific T cells from HLA-matched donor

Outcomes

Primary Outcome Measures

Characterization of the safety and feasibility of PyVST infusion for the treatment of PML based on development of Treatment Limiting Toxicity

Secondary Outcome Measures

PML lesion volume

Change from baseline to day 28 in PML lesion volume, as seen on brain MRI

Gadolinium enhancement

Change in pattern of gadolinium enhancement from baseline to day 3, day 7, day 14, and day 28 MRI scans of participants' brains

Modified Rankin Score

Change from baseline to day 28 in the modified Rankin Score (mRS).

JC viral load in CSF

Change from baseline to day 28 in JC viral load in CSF

Full Information

NCT ID

NCT02694783

First Posted

February 27, 2016

Last Updated

October 20, 2023

Sponsor

National Institute of Neurological Disorders and Stroke (NINDS)

1. Study Identification

Unique Protocol Identification Number

NCT02694783

Brief Title

Adoptive Cellular Immunotherapy for Progressive Multifocal Leukoencephalopathy With Ex Vivo Generated Polyomavirus-Specific T-Cells

Official Title

A Pilot Study of Adoptive Cellular Immunotherapy for Progressive Multifocal Leukoencephalopathy With Ex Vivo Generated Polyomavirus-Specific T-cells

Study Type

Interventional

2. Study Status

Record Verification Date

October 19, 2023

Overall Recruitment Status

Completed

Study Start Date

March 28, 2016 (Actual)

Primary Completion Date

December 13, 2019 (Actual)

Study Completion Date

March 6, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

National Institute of Neurological Disorders and Stroke (NINDS)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

5. Study Description

Brief Summary

Background: Progressive Multifocal Leukoencephalopathy (PML) is a brain infection in people with a weakened immune system. Researchers think polyoma virus specific T cells (PyVST) therapy can treat PML. The PyVST cells are made from blood cells of a healthy relative. They are grown in a lab to expand the virus-killing cells, then given to the person with PML. Objective: To test whether PyVST safely treats PML. Eligibility: Adults ages 18 and older with PML Healthy adults ages 18 and older who have: Been screened under protocol 97-H-0041 A sibling, parent, or child with PML and matching cells Design: Participants will be screened with: Medical history Physical exam Blood and urine tests PML participants will also be screened with: Cerebrospinal fluid removed by needle in the back. MRI: A dye is injected in a vein. They lie on a table that slides into a cylinder. Questionnaires Healthy participants will have apheresis: Blood flows through a needle in one arm into machine that separates blood cells needed for donation. The rest of the blood is returned by needle to the other arm. Some participants may have a central line placed in a vein instead. They can have apheresis up to 3 times, at least 28 days apart. Participants with PML will receive the PyVST cells by needle in the arm. They will stay in the hospital 1 week. They can do this up to 3 times, at least 28 days apart. After each infusion, they will have weekly visits for 1 month. Then they will have 4 visits over 1 year. Visits include repeats of screening tests.

Detailed Description

Objective This pilot clinical trial will aim to determine the feasibility and potential toxicities associated with treating patients with progressive multifocal leukoencephalopathy (PML) with polyomavirus (PyV)-specific partially matched polyclonal allogeneic T cells. It will further provide initial efficacy data for this indication. Study Population Up to 18 subjects with definite PML, defined as clinical signs and MRI compatible with active PML and the presence of JCV by PCR in CSF. Subjects must be 18 years of age or older and must have a first degree, partially HLA- matched relative able and willing to act as a donor of lymphocytes. Subjects with underlying reversible immunosuppression (i.e.- HIV or MS status post treatment with natalizumab), or subjects with uncontrolled malignancy will be excluded. Subjects with evidence of active CNS inflammation as determined by presence of significant contrast enhancement within the PML lesions by MRI will also be excluded because it is assumed such patients are already mounting an adequate immune response against the infection. Design This will be a first-in-human pilot study assessing the feasibility and toxicity profile of NIH PyVST cellular product in subjects with PML. Subjects will be screened under the existing NIH Natural History study of PML (13-N-0017). Sequential enrollment will be spaced at least 28 days apart. An initial fixed dose PyVST infusion (target dose of 1 x 10(6) PyVST/kg (+/- 10%)) will be administered by intravenous (IV) infusion, followed by 2x 10(6) PyVST/kg (+/-10%) up to 2 times to each subject if needed. Outcome Measures Safety will be monitored to 28 days continuously with stopping rules based on the treatment-related serious adverse event rate. Secondary outcomes include survival, assessed at day 28 and at 1 year following the last infusion. CSF viral titers, MR imaging, and clinical disability scales will also be collected.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Progressive Multifocal Leukoencephalopathy

Keywords

HLA Matched, JCV, Donor, PyVST, PML

7. Study Design

Primary Purpose

Treatment

Study Phase

Early Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

60 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Treatment Arm

Arm Type

Experimental

Arm Description

ex vivo generated polyomavirus-specific T cells from HLA-matched donor

Intervention Type

Biological

Intervention Name(s)

PyVST

Intervention Description

ex vivo generated polyomavirus-specific T cells from HLA-matched donor

Primary Outcome Measure Information:

Title

Characterization of the safety and feasibility of PyVST infusion for the treatment of PML based on development of Treatment Limiting Toxicity

Description

Characterization of the safety and feasibility of PyVST infusion for the treatment of PML based on development of Treatment Limiting Toxicity

Time Frame

ongoing

Secondary Outcome Measure Information:

Title

PML lesion volume

Description

Change from baseline to day 28 in PML lesion volume, as seen on brain MRI

Time Frame

change from baseline to day 28

Title

Gadolinium enhancement

Description

Change in pattern of gadolinium enhancement from baseline to day 3, day 7, day 14, and day 28 MRI scans of participants' brains

Time Frame

Change in pattern of gadolinium enhancement from baseline to day 3, day 7, day 14, and day 28

Title

Modified Rankin Score

Description

Change from baseline to day 28 in the modified Rankin Score (mRS).

Time Frame

Change from baseline to day 28

Title

JC viral load in CSF

Description

Change from baseline to day 28 in JC viral load in CSF

Time Frame

Change from baseline to day 28

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

INCLUSION CRITERIA - PATIENT: Clinically definite PML, defined as clinical signs and MRI compatible with active PML and the presence of JCV by PCR in CSF Modified Rankin Scale 1-4, inclusive Age 18 or older Patient medically stable and able to tolerate travel to NIH Available PyVST Subjects of childbearing or child-fathering potential must be willing to use a medically acceptable form of birth control, which includes abstinence, while they are being treated on this study Willing and able to participate in all aspects of trial design and follow-up Able to provide informed consent at the time of study enrollment (not required for reinfusions). EXCLUSION CRITERIA - PATIENT: Patients with human immunodeficiency virus (HIV infection) Patients who have been treated with natalizumab Patients with readily reversible immunosuppressive state Patients receiving immunosuppressive or immunomodulatory therapies within 28 days of screening for enrollment that could interfere with PyVST function Patients with other uncontrolled infections. For bacterial infections, patients must be receiving definitive therapy and have no signs of progressing infection for 72 hours prior to enrollment. For fungal infections, patients must be receiving definitive systemic anti-fungal therapy and have no signs of progressing infection for 1 week prior to enrollment. Patients who have received donor lymphocyte infusion (DLI) within 28 days Uncontrolled relapse of malignancy Patients with any other associated CNS disease that might confound outcomes Patients with contraindication to MRI (including cardiac pacemakers and some infusion pumps, other metallic implants, metallic foreign objects) MRI findings consistent with immune system reconstitution inflammatory syndrome (IRIS) and determined to be mounting an adequate immune response to the infection Patients with medical contraindication to LP For subjects who have previously received PyVST infusions, any treatment-limiting toxicity (defined in Section 8.3) to previous infusions Subjects with a positive pregnancy test or who are nursing. INCLUSION CRITERIA - DONOR: Ability to provide informed consent at the time of enrollment First degree relative of patient (sibling, parent/child) Age 18 or older EXCLUSION CRITERIA - DONOR: Sickling hemoglobinopathies including HbSS and HbSC by history and peripheral blood smear; donors with HbAS are acceptable HbsAg, anti-HBc, anti-HCV, anti-HIV, anti-HTLV, and RPR Cardiovascular instability, severe anemia, inadequate venous access, severe coagulation disorder or any other medical condition that the Principal Investigator or Apheresis Unit staff considers a contraindication to the apheresis procedure or research blood draw. Positive pregnancy test

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Irene CM Cortese, M.D.

Organizational Affiliation

National Institute of Neurological Disorders and Stroke (NINDS)

Official's Role

Principal Investigator

Facility Information:

Facility Name

National Institutes of Health Clinical Center

City

Bethesda

State/Province

Maryland

ZIP/Postal Code

20892

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

34302788

Citation

Cortese I, Beck ES, Al-Louzi O, Ohayon J, Andrada F, Osuorah I, Dwyer J, Billioux BJ, Dargah-Zada N, Schindler MK, Binder K, Reoma L, Norato G, Enose-Akahata Y, Smith BR, Monaco MC, Major EO, Jacobson S, Stroncek D, Highfill S, Panch S, Reich DS, Barrett J, Nath A, Muranski P. BK virus-specific T cells for immunotherapy of progressive multifocal leukoencephalopathy: an open-label, single-cohort pilot study. Lancet Neurol. 2021 Aug;20(8):639-652. doi: 10.1016/S1474-4422(21)00174-5.

Results Reference

derived

Links:

URL

https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2016-N-0072.html

Description

NIH Clinical Center Detailed Web Page

Learn more about this trial

Adoptive Cellular Immunotherapy for Progressive Multifocal Leukoencephalopathy With Ex Vivo Generated Polyomavirus-Specific T-Cells

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