Antiviral Cellular Therapy for Enhancing T-cell Reconstitution Before or After Hematopoietic Stem Cell Transplantation
- Conditions
- Cytomegalovirus InfectionsAdenovirus InfectionEBV Infection
- Interventions
- Biological: Virus Specific T-cell (VST) infusion
- Registration Number
- NCT03475212
- Lead Sponsor
- Pediatric Transplantation & Cellular Therapy Consortium
- Brief Summary
The purpose of this study is to evaluate whether virus-specific T cell lines (VSTs) are safe and can effectively control three viruses (EBV, CMV, and adenovirus) in patients who have had a stem cell transplant and also in patients that have a primary immunodeficiency disorder with no prior stem cell transplant.
- Detailed Description
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 required 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 Baylor College of Medicine 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. More recent protocols utilizing synthetic viral peptide pools allow ex vivo expansion of T-cells targeting multiple viral antigens in 10-12 days without use of viral transduction.
The study will evaluate whether partially-HLA matched allogeneic 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 immunodeficient recipients infected with one of more of the targeted viruses that are persistent despite conventional anti-viral therapy.
This study will evaluate safety and efficacy of partially-matched VST therapy in A) patients who have persistent viral infections in the post-HSCT period, and B) patients with primary immunodeficiency conditions who have persistent viral infections and have not undergone HSCT.
The study agent will be assessed for safety and antiviral activity.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 52
- Patients with simultaneous infections with CMV, EBV and/or Adenovirus infections are eligible if one or more infection(s) is persistent or relapsed despite standard therapy as defined above. Patients with multiple infections with one or more reactivation and one or more controlled infection are eligible to enroll.
- Clinical status at enrollment that allows tapering of steroids to equal or less than 0.5 mg/kg/day prednisone (or equivalent) prior to infusion of the VST doses.
- Negative pregnancy test in female patients if applicable (childbearing potential who have received a reduced intensity conditioning regimen).
- Written informed consent and/or signed assent line from patient, parent or guardian.
Exclusion Criteria
- Patients receiving ATG, Campath, Basiliximab or other immunosuppressive monoclonal antibodies targeting T-cells within 28 days of screening for enrollment.
- Patients who have received donor lymphocyte infusion (DLI) or other experimental cellular therapies within 28 days.
- Current therapy with ruxolitinib or other JAK inhibitors within the previous 3 days.
- Patients with other uncontrolled infections, defined as bacterial or fungal infections with clinical signs of worsening despite standard therapy. 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.
- Progressing infection is defined as hemodynamic instability, worsening physical signs, or radiographic findings attributable to infection. Persisting fever without other signs or symptoms will not be interpreted as progressing infection.
- Patients with active and uncontrolled relapse of malignancy (if applicable).
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Virus specific T cell lines (VSTs) against three viruses Virus Specific T-cell (VST) infusion The study will evaluate whether partially-HLA matched allogeneic 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 immunodeficient recipients infected with one of more of the targeted viruses that are persistent despite conventional anti-viral therapy.
- Primary Outcome Measures
Name Time Method Incidence of Treatment-Emergent Adverse Events 30 days The safety endpoint, dose-limiting toxicity (DLT), will be defined as acute GvHD grades III-IV or grades 3-5 infusion-related adverse events or grades 4-5 non-hematological adverse events related to the T cell product within 30 days of each 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), Version 4.03.
Efficacy of VST at 30 days as measured by viral load 30 days Peripheral blood and, where relevant, stool and urine will be monitored for CMV, EBV, and/or adenovirus viral load. For patients with multiple viral infections, the response against the primary viral target will determine the classification. For the infection under treatment response in viral load will be assessed at 30 days after the first VST infusion
Feasibility to identify suitable HLA matched VST products 30 days Feasibility will be defined as the ability of the investigators to identify suitable partially HLA- matched VST products from the VST bank at Children's National Medical Center for referred study subjects. The percentage of referred patients with potential partially-matched VST products identified will be recorded, as will timing between patient referral and treatment.
- Secondary Outcome Measures
Name Time Method Reconstitution of Antiviral Immunity following VST infusions 3 months Patient serum and peripheral blood mononuclear cells will be monitored for virus-specific activity during the 3 months following VST infusion by the following measures:
1. T cell phenotyping by flow cytometry (including % CD3, CD4, CD8, TCRalpha/beta and CD45RA-/CCR7+, among other markers)
2. Antiviral T cell responses to CMV, EBV, and/or Adenovirus antigens by IGN-g ELIspot (spot forming units) and Intracellular cytokine staining ( %IFN-gamma and TFNa+ of CD4 and CD8 cells)
3. T cell repertoire and antiviral specificity by TCR sequencing (%clonotype frequencies)Persistence of infused VSTs 1 month and 3 months Persistence of infused T cells will be monitored at 1 month and 3 months following VST infusion using deep sequencing and additional tests as indicated to track the TCR v-beta repertoire in the patient peripheral blood prior to and post-infusion.
Survival 6 months and 12 months Overall survival at 6 and 12 months post VST infusion will be computed.
Effects on Clinical Signs of Viral Infection 3 months If a patient has organ involvement, clinical response will be monitored. For patients with EBV lymphoma and measurable disease, response will be assessed by RECIST criteria.
Trial Locations
- Locations (30)
Riley Hospital for Children - Indiana University
🇺🇸Indianapolis, Indiana, United States
Phoenix Children's Hospital
🇺🇸Phoenix, Arizona, United States
City of Hope
🇺🇸Duarte, California, United States
University of California, Los Angeles
🇺🇸Los Angeles, California, United States
Children's Hospital Los Angeles
🇺🇸Los Angeles, California, United States
Stanford Lucile Packard Children's Hospital
🇺🇸Palo Alto, California, United States
UCSF Medical Center
🇺🇸San Francisco, California, United States
Children's Hospital Colorado
🇺🇸Aurora, Colorado, United States
Yale
🇺🇸New Haven, Connecticut, United States
Children's National Medical Center
🇺🇸Washington, DC, District of Columbia, United States
Emory University/Children's Healthcare of Atlanta
🇺🇸Atlanta, Georgia, United States
Ann & Robert H. Lurie Children's Hospital of Chicago
🇺🇸Chicago, Illinois, United States
Tufts Medical Center
🇺🇸Boston, Massachusetts, United States
Dana-Farber Cancer Institute/ Boston Children's Hospital
🇺🇸Boston, Massachusetts, United States
University of Michigan
🇺🇸Ann Arbor, Michigan, United States
Spectrum Health - Helen DeVos Children's Hospital
🇺🇸Grand Rapids, Michigan, United States
University of Minnesota
🇺🇸Minneapolis, Minnesota, United States
Washington University
🇺🇸Saint Louis, Missouri, United States
Roswell Park Comprehensive Cancer Center
🇺🇸Buffalo, New York, United States
Columbia University Medical Center
🇺🇸New York, New York, United States
Duke University Medical Center
🇺🇸Durham, North Carolina, United States
Oregon Health & Science University
🇺🇸Portland, Oregon, United States
The Children's Hospital
🇺🇸Philadelphia, Pennsylvania, United States
Medical University of South Carolina
🇺🇸Charleston, South Carolina, United States
St. Jude
🇺🇸Memphis, Tennessee, United States
UT Southwestern Medical Center
🇺🇸Dallas, Texas, United States
Children's Mercy
🇺🇸San Antonio, Texas, United States
Methodist Healthcare System of San Antonio
🇺🇸San Antonio, Texas, United States
Virginia Commonwealth University
🇺🇸Richmond, Virginia, United States
Fred Hutchinson Cancer Research Center/Seattle Chlindren's/University of Washington School of Medicine
🇺🇸Seattle, Washington, United States