NST Therapy for Chronic Norovirus in Immunocompromised Patients
(ATLANTIC Trial)
Recruiting in Palo Alto (17 mi)
+1 other location
Overseen byMichael Keller, MD
Age: Any Age
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Children's National Research Institute
Must not be taking: Monoclonal antibodies, JAK inhibitors
Disqualifiers: Uncontrolled infections, Active malignancy, others
No Placebo Group
Trial Summary
What is the purpose of this trial?
This is a Phase I dose-escalation study to evaluate the safety of norovirus -specific T-cell (NST) therapy for chronic norovirus infection in participants following hematopoietic stem cell transplantation (HSCT) or with primary immunodeficiency disorders (PID) who have not undergone HSCT.
Do I need to stop my current medications for the trial?
The trial requires that you stop taking certain medications, like biological or immunosuppressive monoclonal antibodies, at least 28 days before the infusion. If you're on steroids, the dose must be reduced to less than 0.5 mg/kg/day of prednisone (or equivalent) at least 7 days before the infusion.
What data supports the effectiveness of the treatment Norovirus-specific T-cell (NST) therapy for chronic norovirus in immunocompromised patients?
How is NST therapy different from other treatments for chronic Norovirus in immunocompromised patients?
NST therapy is unique because it uses Norovirus-specific T-cells (a type of immune cell) to target and fight the virus directly, which is different from other treatments like fecal microbiota transplantation (FMT) that focus on restoring gut bacteria balance. This approach is particularly novel as there are no standard treatments specifically for chronic Norovirus in immunocompromised patients.678910
Eligibility Criteria
This trial is for people aged 3 months to 80 years with chronic norovirus infection after a bone marrow transplant or those with primary immunodeficiency. They must have stable health indicators like specific blood counts and organ function tests, not be pregnant, and able to consent. Those who've had certain recent treatments or uncontrolled infections can't join.Inclusion Criteria
Documentation of chronic norovirus infection:
- HB Core antibody
I have had norovirus symptoms and positive tests for it over the last three months or more.
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Exclusion Criteria
I am on a final treatment for a bacterial infection and have not worsened or had ongoing stomach issues in the last 7 days.
I am on anti-fungal treatment and my fungal infection hasn't worsened in the last 7 days.
My cancer is not currently under control.
See 16 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive norovirus-specific T-cell (NST) therapy with dose escalation to evaluate safety
45 days
Multiple visits for NST infusion and monitoring
Safety Monitoring
Participants are monitored for infusion-related reactions and GVHD for 1 year following first infusion
12 months
Regular visits for safety assessments and symptom scoring
Follow-up
Participants are monitored for antiviral activity and changes in viral loads
12 months
Stool viral loads evaluated periodically
Treatment Details
Interventions
- Norovirus-specific T-cell (NST) therapy (CAR T-cell Therapy)
Trial OverviewThe study is testing the safety of Norovirus-specific T-cell therapy in patients who either received a stem cell transplant or have an immune deficiency but haven't had a transplant. It's a Phase I trial where they gradually increase the dose to find out what's safe.
Participant Groups
1Treatment groups
Experimental Treatment
Group I: Norovirus -specific T-cell (NST) therapy for chronic norovirus infectionExperimental Treatment1 Intervention
This is a Phase I dose-escalation study to evaluate the safety of norovirus -specific T-cell (NST) therapy for chronic norovirus infection in participants following hematopoietic stem cell transplantation (HSCT) or with primary immunodeficiency disorders (PID) who have not undergone HSCT. There are two arms in this study:
1. Arm A: Participants who receive donor-derived NST therapy after HSCT
2. Arm B: Participants who receive partially HLA matched NSTs. The following participants apply:
* Participants with PID who have not undergone HSCT
* Participants who undergo HSCT but do not have available donor derived NSTs
* Participants who have donors from whom NSTs cannot be generated due to norovirus seronegativity
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
National Institutes of Health (NIH)Bethesda, MD
Children's National HospitalWashington, United States
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Who Is Running the Clinical Trial?
Children's National Research InstituteLead Sponsor
References
[Immunotherapy for refractory viral infections]. [2019]Various antiviral agents have been developed, which are sometimes associated with toxicity, development of virus-resistant strain, and high cost. Virus-specific T-cell (VST) therapy provides an alternative curative therapy that can be effective for a prolonged time without eliciting drug resistance. VSTs can be directly separated using several types of capture devices and can be obtained by stimulating peripheral blood mononuclear cells with viral antigens (virus, protein, or peptide) loaded on antigen-presenting cells (APC). APC can be transduced with virus-antigen coding plasmid or pulsed with overlapping peptides. VST therapy has been studied in drug non-responsive viral infections after hematopoietic cell transplantation (HCT). Several previous studies have demonstrated the efficacy of VST therapy without significant severe GVHD. In addition, VSTs from a third-party donor have been prepared and administered for post-HCT viral infection. Although target viruses of VSTs include herpes virus species and polyomavirus species, a wide variety of pathogens, such as papillomavirus, intracellular bacteria, and fungi, can be treated by pathogen-specific T-cells. Perhaps, these specific T-cells could be used for opportunistic infections in other immunocompromised hosts in the near future.
Generation of Norovirus-Specific T Cells From Human Donors With Extensive Cross-Reactivity to Variant Sequences: Implications for Immunotherapy. [2021]Chronic norovirus infection in immunocompromised patients can be severe, and presently there is no effective treatment. Adoptive transfer of virus-specific T cells has proven to be safe and effective for the treatment of many viral infections, and this could represent a novel treatment approach for chronic norovirus infection. Hence, we sought to generate human norovirus-specific T cells (NSTs) that can recognize different viral sequences.
Virus-specific T cells for adenovirus infection after stem cell transplantation are highly effective and class II HLA restricted. [2022]Infection with adenoviruses is a common and significant complication in pediatric patients after allogeneic hematopoietic stem cell transplantation. Treatment options with traditional antivirals are limited by poor efficacy and significant toxicities. T-cell reconstitution is critical for the management of adenoviral infections, but it generally takes place months after transplantation. Ex vivo-generated virus-specific T cells (VSTs) are an alternative approach for viral control and can be rapidly generated from either a stem cell donor or a healthy third-party donor. In the context of a single-center phase 1/2 clinical trial, we treated 30 patients with a total of 43 infusions of VSTs for adenoviremia and/or adenoviral disease. Seven patients received donor-derived VSTs, 21 patients received third-party VSTs, and 2 received VSTs from both donor sources. Clinical responses were observed in 81% of patients, with a complete response in 58%. Epitope prediction and potential epitope identification for common HLA molecules helped elucidate HLA restriction in a subset of patients receiving third-party products. Intracellular interferon-γ expression in T cells in response to single peptides and response to cell lines stably transfected with a single HLA molecule demonstrated HLA-restricted CD4+ T-cell response, and these results correlated with clinical outcomes. Taken together, these data suggest that VSTs are a highly safe and effective therapy for the management of adenoviral infection in immunocompromised hosts. The trials were registered at www.clinicaltrials.gov as #NCT02048332 and #NCT02532452.
Reprint of: Virus-Specific T Cells: Broadening Applicability. [2020]Virus infection remains an appreciable cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). Although pharmacotherapy and/or antibody therapy may help prevent or treat viral disease, these drugs are expensive, toxic, and often ineffective due to primary or secondary resistance. Further, effective treatments are limited for many infections (eg, adenovirus, BK virus), which are increasingly detected after alternative donor transplants. These deficiencies in conventional therapeutics have increased interest in an immunotherapeutic approach to viral disorders, leading to adoptive transfer of virus-specific cytotoxic T lymphocytes (VSTs), which can rapidly reconstitute antiviral immunity post-transplantation without causing graft-versus-host disease. This review will explore how the VST field has improved outcomes for many patients with life-threatening viral infections after HSCT, and how to broaden applicability beyond the "patient-specific" products, as well as extending to other viral diseases even outside the context of HSCT.
Virus-Specific T Cells: Broadening Applicability. [2021]Virus infection remains an appreciable cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). Although pharmacotherapy and/or antibody therapy may help prevent or treat viral disease, these drugs are expensive, toxic, and often ineffective due to primary or secondary resistance. Further, effective treatments are limited for many infections (eg, adenovirus, BK virus), which are increasingly detected after alternative donor transplants. These deficiencies in conventional therapeutics have increased interest in an immunotherapeutic approach to viral disorders, leading to adoptive transfer of virus-specific cytotoxic T lymphocytes (VSTs), which can rapidly reconstitute antiviral immunity post-transplantation without causing graft-versus-host disease. This review will explore how the VST field has improved outcomes for many patients with life-threatening viral infections after HSCT, and how to broaden applicability beyond the "patient-specific" products, as well as extending to other viral diseases even outside the context of HSCT.
Clinical Review on the Utility of Fecal Microbiota Transplantation in Immunocompromised Patients. [2020]Fecal microbiota transplantation (FMT) represents a promising management modality for Clostridium difficile infection (CDI). In immunocompromised patients, FMT is utilized for CDI as well as emerging non-CDI indications such as inflammatory bowel disease and graft versus host disease. PURPOSE OF REVIEW: This review aims to shed light on the safety and efficacy of FMT in immunocompromised patients, including patients suffering for human immunodeficiency virus infection, solid organ and hematopoietic stem cell transplant recipients, cancer patients, and patients on immunosuppressive therapies. RECENT FINDINGS: Though the body of evidence concerning the use of FMT in immunocompromised is growing, no clinical trials exist to date. Present literature weighs in favor of FMT in immunocompromised patients, with an acceptable adverse effect profile and minimal risk of infectious adverse events. Further large scale studies and randomized controlled trials to validate the utility of FMT in immunocompromised individuals will be a welcomed endeavor.
Eosinophilic gastroenteritis and graft-versus-host disease induced by transmission of Norovirus with fecal microbiota transplant. [2021]Fecal microbiota transplantation (FMT) was performed to decolonize gastrointestinal tract from antibiotic-resistant bacteria before allogeneic hematopoietic cells transplantation (alloHCT). AlloHCT was complicated by norovirus gastroenteritis, acute graft-versus-host disease, and eosinophilic pancolitis. Norovirus was identified in samples from FMT material. Symptoms resolved after steroids course and second norovirus-free FMT from another donor.
Fecal Microbiota Transplantation: Beyond Clostridium difficile. [2022]Fecal microbiota transplantation (FMT) has been established as standard of care in the treatment of antibiotic refractory Clostridium difficile infection (RCDI). This review examines the current evidence that exists to support the use of FMT in the treatment of human disease beyond C. difficile infection.
A systematic review of economic evaluation in fecal microbiota transplantation. [2021]Fecal microbiota transplantation (FMT) is an effective therapy in recurrent Clostridium difficile infection (rCDI). It is only recommended for this indication by European and American guidelines. Other indications of FMT are being studied, such as inflammatory bowel disease (IBD), and they have shown promising results.
Fecal microbiota transplantation for refractory diarrhea in immunocompromised diseases: a pediatric case report. [2020]Immunocompromised (IC) patients have an increased risk of refractory diarrhea. Fecal microbiota transplantation (FMT) is a safe and effective therapy for infection-related diarrhea which are mainly mediated by the loss of the microbial colonization, although there is concern that IC patients may be at higher risk of infectious complications related to FMT. And reports of FMT in IC children are limited.