NST Therapy for Chronic Norovirus in Immunocompromised Patients

(ATLANTIC Trial)

Recruiting at 3 trial locations

Overseen By Michael Keller, MD

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: Children's National Research Institute

Must not be taking: Monoclonal antibodies, JAK inhibitors

Disqualifiers: Uncontrolled infections, Active malignancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 45 days

48 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test a new treatment called norovirus-specific T-cell (NST) therapy, which could help people with long-lasting norovirus infections. The focus is on individuals with weakened immune systems due to past stem cell or organ transplants or primary immunodeficiency disorders. The study will assess the treatment's safety for those with chronic norovirus, particularly those who have tested positive for the virus multiple times over three months. Ideal participants are those who have had stem cell or organ transplants and continue to experience norovirus symptoms. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new therapy.

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.

Is there any evidence suggesting that norovirus-specific T-cell (NST) therapy is likely to be safe for humans?

Research has shown that norovirus-specific T-cell (NST) therapy is considered safe for treating viral infections. Previous studies have found that transferring virus-specific T cells is generally well-tolerated. For instance, a study with 30 children using similar virus-specific T cells showed a high success rate of 81%, indicating promising safety results.

However, this current study is in its early stages, focusing primarily on assessing the safety of NST therapy. While similar treatments have provided good safety data, the safety of this specific therapy is still under careful study. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for chronic norovirus?

Unlike standard treatments for chronic norovirus in immunocompromised patients, which mainly focus on managing symptoms and preventing dehydration, Norovirus-specific T-cell (NST) therapy targets the virus itself. Researchers are excited about this treatment because it uses specially designed T-cells that can directly attack and eliminate the norovirus, offering a more targeted and potentially effective approach. This therapy is especially promising for patients who have undergone hematopoietic stem cell transplantation (HSCT) or have primary immunodeficiency disorders, as it provides a tailored immune boost to fight off the virus, something current treatments lack.

What evidence suggests that norovirus-specific T-cell therapy might be an effective treatment for chronic norovirus infection?

Research has shown that a new treatment called norovirus-specific T-cell (NST) therapy could benefit people with weakened immune systems who suffer from chronic norovirus infections. Participants in this trial will receive NST therapy, which uses T cells, a type of immune cell, to target norovirus. Studies have found that these T cells can increase in number when targeting norovirus, suggesting they might help combat the virus. This therapy has also proven effective against other viruses, such as adenovirus, in similar patients. In some cases, restoring NST responses was linked to clearing chronic norovirus infections. While more research is needed, these early results offer hope for those with ongoing infections. ^{1 2 3 4 5}

Who Is on the Research Team?

Michael Keller, MD

Principal Investigator

CNH

Are You a Good Fit for This Trial?

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.

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Norovirus-specific T-cell (NST) therapy

Trial Overview The 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.

How Is the Trial Designed?

Group I: Norovirus -specific T-cell (NST) therapy for chronic norovirus infection Experimental Treatment 1 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 have undergone HSCT but do not have available donor derived NSTs, or those for whom NSTs cannot be generated due to norovirus seronegativity. * Participants who have undergone SOT.

Who Is Running the Clinical Trial?

Children's National Research Institute

Lead Sponsor

Trials

227

Recruited

258,000+

Published Research Related to This Trial

Fecal microbiota transplantation (FMT) was used to help eliminate antibiotic-resistant bacteria in patients before undergoing allogeneic hematopoietic cell transplantation (alloHCT), highlighting its potential role in improving gut health prior to major medical procedures.

In this case, complications arose during alloHCT, including norovirus gastroenteritis, but symptoms improved after administering steroids and a second FMT from a different donor that was free of norovirus, suggesting the importance of donor selection in FMT efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Eosinophilic gastroenteritis and graft-versus-host disease induced by transmission of Norovirus with fecal microbiota transplant. Bilinski, J., Lis, K., Tomaszewska, A., et al.[2021]

Fecal microbiota transplantation (FMT) is already a standard treatment for antibiotic refractory Clostridium difficile infection and shows potential benefits for a variety of other conditions, including inflammatory bowel disease and neuropsychiatric disorders, based on small studies.

The effectiveness of FMT in these conditions is linked to its ability to restore a healthy gut microbiota, but more large-scale research is needed to fully understand its limitations and optimal use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fecal Microbiota Transplantation: Beyond Clostridium difficile. Millan, B., Laffin, M., Madsen, K.[2022]

In a phase 1/2 clinical trial involving 30 pediatric patients, ex vivo-generated virus-specific T cells (VSTs) demonstrated a high clinical response rate of 81% for treating adenoviral infections after hematopoietic stem cell transplantation, with 58% achieving complete response.

The study indicates that VSTs, whether derived from the stem cell donor or healthy third-party donors, are a safe and effective alternative to traditional antiviral treatments, which often have limited efficacy and significant side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Virus-specific T cells for adenovirus infection after stem cell transplantation are highly effective and class II HLA restricted. Rubinstein, JD., Zhu, X., Leemhuis, T., et al.[2022]

Researchers successfully generated norovirus-specific T cells (NSTs) from healthy donors, which showed a significant expansion and targeted multiple viral antigens, indicating a potential for effective treatment in immunocompromised patients with chronic norovirus infection.

The NSTs demonstrated strong cross-reactivity to various viral variants and identified key immunodominant epitopes, suggesting that these T cells could be a promising approach for antiviral immunotherapy against norovirus.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Generation of Norovirus-Specific T Cells From Human Donors With Extensive Cross-Reactivity to Variant Sequences: Implications for Immunotherapy. Hanajiri, R., Sani, GM., Saunders, D., et al.[2021]

Fecal microbiota transplantation (FMT) is a cost-effective treatment for recurrent Clostridium difficile infection (rCDI), with all economic evaluations showing it to be more cost-effective than other standard treatments at a threshold of ≤$50,000 per quality-adjusted life year (QALY).

The systematic review included 9 high-quality economic evaluations, primarily focusing on rCDI and inflammatory bowel disease (IBD), indicating that while FMT is effective for rCDI, further studies are needed to explore its economic impact for other conditions like IBD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A systematic review of economic evaluation in fecal microbiota transplantation. Stalder, T., Kapel, N., Diaz, S., et al.[2021]

Fecal microbiota transplantation (FMT) shows promise as a safe and effective treatment for Clostridium difficile infection (CDI) in immunocompromised patients, with a low risk of adverse effects and infections.

Current evidence supports the use of FMT for non-CDI conditions like inflammatory bowel disease and graft versus host disease, but more large-scale clinical trials are needed to confirm its efficacy in these populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Review on the Utility of Fecal Microbiota Transplantation in Immunocompromised Patients. Abu-Sbeih, H., Ali, FS., Wang, Y.[2020]

Fecal microbiota transplantation (FMT) was successfully performed in two immunocompromised children with refractory diarrhea, leading to symptom remission without any infectious complications.

The procedure resulted in the reconstruction of a diverse microbiota, indicating that FMT is a safe and effective treatment option for managing diarrhea in immunocompromised patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fecal microbiota transplantation for refractory diarrhea in immunocompromised diseases: a pediatric case report. Zhong, S., Zeng, J., Deng, Z., et al.[2020]

Adoptive transfer of virus-specific cytotoxic T lymphocytes (VSTs) has emerged as a promising immunotherapeutic approach to effectively combat viral infections after hematopoietic stem cell transplantation (HSCT), addressing the limitations of conventional antiviral drugs.

This method not only helps reconstitute antiviral immunity without causing graft-versus-host disease but also shows potential for broader application beyond individual patients and for treating other viral infections outside of HSCT contexts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reprint of: Virus-Specific T Cells: Broadening Applicability. Barrett, AJ., Prockop, S., Bollard, CM.[2020]

Adoptive transfer of virus-specific cytotoxic T lymphocytes (VSTs) has emerged as a promising immunotherapeutic approach to effectively combat viral infections after hematopoietic stem cell transplantation (HSCT), offering a way to restore antiviral immunity without causing graft-versus-host disease.

This review highlights the potential of VSTs to improve outcomes for patients suffering from life-threatening viral infections post-transplant and discusses strategies to expand their use beyond individual patient products and into other viral diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Virus-Specific T Cells: Broadening Applicability. Barrett, AJ., Prockop, S., Bollard, CM.[2021]

Virus-specific T-cell (VST) therapy offers a promising alternative to traditional antiviral agents, as it can effectively treat viral infections without causing drug resistance or significant toxicity, particularly in patients who are unresponsive to other treatments after hematopoietic cell transplantation (HCT).

Studies have shown that VST therapy is effective against various viruses, including herpes and polyomaviruses, and can be safely administered without causing severe graft-versus-host disease (GVHD), suggesting its potential for broader use in treating opportunistic infections in immunocompromised patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Immunotherapy for refractory viral infections]. Morio, T., Fujita, Y., Takahashi, S.[2019]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04691622

Study Details | NCT04691622 | Adoptive T Lymphocyte ... 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 ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7325618/

Generation of Norovirus-Specific T Cells From Human Donors ... We successfully generated T cells targeting multiple norovirus antigens with a mean 4.2 ± 0.5-fold expansion after 10 days.

3. academic.oup.com academic.oup.com/jid/article/231/3/773/7733396

Reconstitution of Norovirus-Specific T-Cell Responses ... Chronic norovirus infection (CNI) causes significant morbidity in immunocompromised patients. No effective prevention or treatment currently exists. Methods.

4. withpower.com withpower.com/trial/phase-1-primary-immunodeficiency-diseases-9-2021-9607c

NST Therapy for Chronic Norovirus in ... Research shows that virus-specific T-cell therapy has been effective in treating other viral infections, like adenovirus, in patients with weakened immune ...

5. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39140311/

Reconstitution of Norovirus-Specific T-Cell Responses ... This report is the first to demonstrate reconstitution of NST immunity after HSCT closely temporally aligned with clearance of CNI.