NST Therapy for Chronic Norovirus in Immunocompromised Patients

(ATLANTIC Trial)

Recruiting at 1 trial location

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

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?

Research shows that virus-specific T-cell therapy has been effective in treating other viral infections, like adenovirus, in patients with weakened immune systems. This suggests that similar T-cell therapies could potentially help manage chronic norovirus infections. ^{1 2 3 4 5}

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. ^{6 7 8 9 10}

Research Team

Michael Keller, MD

Principal Investigator

CNH

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.

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

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

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.

Participant Groups

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 undergo HSCT but do not have available donor derived NSTs * Participants who have donors from whom NSTs cannot be generated due to norovirus seronegativity

Who Is Running the Clinical Trial?

Children's National Research Institute

Lead Sponsor

Trials

227

Recruited

258,000+

Findings from Research

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]

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]

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]

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]

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 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]

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) 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]

References

1. Japan pubmed.ncbi.nlm.nih.gov

[Immunotherapy for refractory viral infections]. [2019]

2. United States pubmed.ncbi.nlm.nih.gov

Generation of Norovirus-Specific T Cells From Human Donors With Extensive Cross-Reactivity to Variant Sequences: Implications for Immunotherapy. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

Virus-specific T cells for adenovirus infection after stem cell transplantation are highly effective and class II HLA restricted. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Reprint of: Virus-Specific T Cells: Broadening Applicability. [2020]

5. United States pubmed.ncbi.nlm.nih.gov

Virus-Specific T Cells: Broadening Applicability. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

Clinical Review on the Utility of Fecal Microbiota Transplantation in Immunocompromised Patients. [2020]

7. Denmark pubmed.ncbi.nlm.nih.gov

Eosinophilic gastroenteritis and graft-versus-host disease induced by transmission of Norovirus with fecal microbiota transplant. [2021]

8. United States pubmed.ncbi.nlm.nih.gov

Fecal Microbiota Transplantation: Beyond Clostridium difficile. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

A systematic review of economic evaluation in fecal microbiota transplantation. [2021]

10. England pubmed.ncbi.nlm.nih.gov

Fecal microbiota transplantation for refractory diarrhea in immunocompromised diseases: a pediatric case report. [2020]