Multivirus-specific Cytotoxic T Lymphocytes (mCTL)

NCT02510404 | Completed Phase 1 DMC

• 1 other identifier: TREPID
• Study Type: interventional
• Target: 1
• Locations: 1 country
• Sites: 1

Brief Summary

PIDD represent an expanding group of genetic disorders that compromise immunity against bacteria, viruses, and fungi. The most severe forms of PIDD cause profound susceptibility to opportunistic infections due to impaired or absent T-cell immunity. These diseases can be rapidly fatal unless treated via hematopoietic stem cell transplantation (HSCT). Chronic viral illnesses are a common presenting feature of many of these disorders, and studies have shown that survival of HSCT is profoundly impacted by the patient's pre-transplant disease status. Primary infections with viruses such as cytomegalovirus (CMV) and Epstein-Barr virus (EBV) are common, and respiratory viruses such as adenovirus also frequently cause infection. In patients with severe combined immunodeficiency (SCID), a prior study identified these viruses as the most common causes of mortality in the immediate period following HSCT. Though some forms of PIDD are amenable to HSCT without requiring conditioning chemotherapy, many forms require a variable degree of pre-conditioning to ensure that stable engraftment of the donor cells is achieved. The administration of cytotoxic chemotherapy used in the conditioning regimens can however increase the risk for regimen related toxicity and for some patients (especially those with active viral infections) this risk is particularly high, leading to high treatment related mortality rates. For these reasons, many such patients are not even considered candidates for HSCT or are delayed getting to HSCT and ultimately succumb to infection before they can receive the transplant. The primary objective of this study is to determine the safety of administering third-party multivirus-specific cytotoxic T lymphocytes (mCTL) from adult CMV seropositive donors to treat refractory viral infections in patients with primary immunodeficiency disorders (PIDD) prior to hematopoietic stem cell transplantation (HSCT).

Conditions

Refractory Viral Infections

Outcome Measures

Primary Outcomes (1)

• Assessments of patients with adverse events after mCTLs infusion

  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)

  45 days

Secondary Outcomes (2)

• Assessments of viral load response to the mCTLs infusion

  12 months

• Assessments of Antiviral Immunity

  12 months

Study Arms (1)

mCTLs against three viruss

EXPERIMENTAL

The investigator will use 3 different dose levels starting with 5 x 106 (a T cell number more than an order of magnitude lower than that administered at the time of an unmanipulated marrow infusion), followed by 1 x 107 and a final dose 2 x 107 mCTLs/m2. They will give the option of administering 2 additional doses (at the same level) of the same or different cell lines, 28 days after the first dose, in subjects that have limited or no improvement in viral count after one dose in the absence of any toxicities attributable to the infusion,or who receive other therapy that may affect the persistence or function of the infused mCTLs.

Biological: mCTLs

Interventions

mCTLs BIOLOGICAL

The investigators have elected to limit this phase I study to PIDD patients with active viral infections unable to be controlled with standard pharmacotherapy, who are therefore likely to benefit from mCTLs treatment. This trial will be performed as dose-escalation study. Patients will be evaluated for matched lines from a bank of third-party mCTLs, derived from CMV seropositive donors. These lines will have been used clinically in prior clinical trials, with safety demonstrated in the post-HSCT setting.

mCTLs against three viruss

Eligibility Criteria

• Age: 4 Weeks - 45 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Diagnosis of primary immunodeficiency with established plan to undergo myeloablative or non-myeloablative allogeneic hematopoietic stem cell transplant for treatment thereof or diagnosis of a form of primary immunodeficiency for which hematopoietic stem cell transplantation is not indicated.
• Active infection with EBV, CMV, and/or Adenovirus, unable to be successfully controlled with standard therapy.
• Steroids less than 0.5 mg/kg/day prednisone
• Karnofsky/Lansky score of ≥ 50
• ANC greater than 500/µL.
• Bilirubin \<2x, AST \<3x, Serum creatinine \<2x upper limit of normal, Hgb \>8.0
• Pulse oximetry of \> 90% on room air
• Negative pregnancy test (if female of childbearing potential)
• Patient or parent/guardian capable of providing informed consent.

You may not qualify if:

• Patients with other uncontrolled infections (see 2.3.2 for definitions)
• Patients who received ATG, Campath, or other T cell immunosuppressive monoclonal antibodies in the last 28 days
• Received donor lymphocyte infusion in last 28 days
• Diagnosis of Omenn's syndrome or MHC class I deficiency
• Active and uncontrolled malignancy
• Pregnant or lactating
• Unable to wean steroids to ≤0.5 mg/kg/day prednisone.
• Patients with Grade 3 hyperbilirubinemia

Sponsors & Collaborators

• Catherine Bollard: lead
• Children's National Research Institute: collaborator

Study Sites (1)

Childrens National Medical Center

Washington D.C., District of Columbia, 20010, United States

Location

MeSH Terms

Conditions

Virus Diseases

Condition Hierarchy (Ancestors)

Infections

Study Officials

• Catherine Bollard, MD

  Children's National Research Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Director- Program for Cell Enhancement and Technologies for Immunotherapy (CETI)

Study Record Dates

• First Submitted: July 13, 2015
• First Posted: July 29, 2015
• Study Start: April 1, 2014
• Primary Completion: May 8, 2019
• Study Completion: June 8, 2019
• Last Updated: January 18, 2020

Record last verified: 2020-01

Locations

US (1)