EBV-specific CTLs for EBV Infection

Recruiting at 8 trial locations

Overseen By Mitchell S Cairo, MD

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: New York Medical College

Must not be taking: Steroids

Disqualifiers: Acute GVHD, HIV, pregnancy, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new method for treating difficult Epstein-Barr Virus (EBV) infections using special immune cells called cytotoxic T-lymphocytes (CTLs). It targets patients who have undergone an organ or stem cell transplant and continue to struggle with EBV infections unresponsive to regular antiviral treatments. Potential participants are those with persistent EBV symptoms, such as ongoing fever and swollen organs, even after two weeks of standard treatment. The trial aims to determine if these CTLs can reduce the virus and improve symptoms when other treatments have failed. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does exclude patients who are on certain treatments like steroids above a specific dose or those who have had a donor lymphocyte infusion recently. It's best to discuss your current medications with the trial team.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that a type of immune cell treatment, called EBV-specific cytotoxic T lymphocytes (CTLs), is generally safe and well-tolerated in patients. Studies have demonstrated that these cells can be safely administered to people with Epstein-Barr Virus (EBV) infections. Specifically, patients with EBV-related conditions have experienced positive outcomes without serious side effects.

Other research has found that EBV-specific CTLs can be safely and effectively transfused. While minor side effects might occur, serious problems are rare. In summary, strong evidence supports EBV-specific CTLs as a safe treatment option for those dealing with difficult EBV infections. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for Epstein-Barr virus (EBV) infections, which mainly involve antiviral medications and supportive care, the investigational cytotoxic T-lymphocytes (CTLs) work by harnessing the body's immune system. These CTLs are specially designed to target and destroy EBV-infected cells, offering a more direct and potentially effective approach. Researchers are excited about this treatment because it could provide a more precise and durable response by specifically training the immune system to recognize and attack the virus, potentially reducing reliance on broad-spectrum antivirals and their associated side effects.

What evidence suggests that Cytotoxic T-lymphocytes might be an effective treatment for refractory EBV infection?

Research has shown that special immune cells, called EBV-specific cytotoxic T-lymphocytes (CTLs), can help treat stubborn Epstein-Barr Virus (EBV) infections, especially after transplants. In this trial, participants with refractory EBV will receive EBV-specific CTLs. Studies have demonstrated that these CTLs can safely and effectively manage diseases related to EBV. Specifically, one study found that 68% of patients survived for at least one year, and this rate remained steady for up to five years. These CTLs work by finding and destroying cells infected with EBV, aiding the immune system in fighting the infection. Overall, EBV-specific CTLs have shown promising results for people dealing with EBV infections after transplants. ^{1 2 6 7 8}

Who Is on the Research Team?

Mitchell S Cairo, MD

Principal Investigator

New York Medical College

Are You a Good Fit for This Trial?

This trial is for children and young adults aged 0.1 to 30 years with stubborn EBV infections after a stem cell or organ transplant, or those with primary immunodeficiencies. They must have tried antiviral treatments without success and not be on other experimental EBV studies, high-dose steroids, or have severe graft-versus-host disease.

Inclusion Criteria

Consent: Written informed consent given (by patient or legal representative) prior to any study-related procedures

Obtained informed consents by donor or donor legally authorized representative prior to donor collection

I have an Epstein-Barr virus infection after a transplant and my current treatment isn’t working.

Exclusion Criteria

Known hypersensitivity to iron dextran

Any medical condition which could compromise participation in the study according to the investigator's assessment

I am taking steroids equivalent to more than 0.5 mg/kg of prednisone at the time of my cell therapy infusion.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive up to 5 doses of EBV-specific CTLs, with response monitored by EBV PCR

12 weeks

Weekly monitoring visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 weeks

Weekly monitoring visits

What Are the Treatments Tested in This Trial?

Interventions

• Cytotoxic T-lymphocytes

Trial Overview The study tests if special immune cells called cytotoxic T-lymphocytes from related donors can fight off tough Epstein-Barr Virus (EBV) infections in patients who haven't responded well to standard treatments after receiving transplants.

How Is the Trial Designed?

Group I: Refractory EBV Experimental Treatment 1 Intervention

Patients with refractory EBV will get one dose of EBV specific CTLs. If they don't show a response based on EBV PCRs, patients may get up to another 4 doses of EBV-CTLs (5 doses maximum)

Cytotoxic T-lymphocytes is already approved in United States, European Union for the following indications:

Approved in United States as EBV-specific CTLs for:

• Refractory EBV infection post Allogeneic Hematopoietic Stem Cell Transplantation (AlloHSCT)
• Primary immunodeficiencies (PID)
• Post solid organ transplant

Approved in European Union as EBV-specific CTLs for:

• EBV-associated lymphoproliferative disease (LPD)
• Refractory EBV infection

Who Is Running the Clinical Trial?

New York Medical College

Lead Sponsor

Trials

73

Recruited

8,700+

University of California, Los Angeles

Collaborator

Trials

1,594

Recruited

10,430,000+

Children's Hospital of Philadelphia

Collaborator

Trials

749

Recruited

11,400,000+

Indiana University

Collaborator

Trials

1,063

Recruited

1,182,000+

University of California, San Francisco

Collaborator

Trials

2,636

Recruited

19,080,000+

Washington University School of Medicine

Collaborator

Trials

2,027

Recruited

2,353,000+

Nationwide Children's Hospital

Collaborator

Trials

354

Recruited

5,228,000+

Medical College of Wisconsin

Collaborator

Trials

645

Recruited

1,180,000+

Published Research Related to This Trial

EBV-specific cytotoxic T lymphocytes (CTLs) can be successfully generated from patients with Hodgkin's disease, showing potential as a treatment option for EBV-positive cases, with successful generation in 9 out of 13 patients studied.

Infused CTLs persisted in the body for over 13 weeks and maintained their ability to combat EBV, suggesting that this adoptive transfer approach could enhance the immune response in patients with relapsed Hodgkin's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes for the treatment of patients with EBV-positive relapsed Hodgkin's disease. Roskrow, MA., Suzuki, N., Gan, Yj., et al.[2021]

In a study of seven patients with Chronic Active Epstein-Barr Virus Infection (CAEBV), four showed the presence of EBV-specific cytotoxic T lymphocytes (CTLs) in their blood, indicating a potential immune response, while three did not have detectable CTLs.

The presence of EBV-specific CTLs was more common in patients with active disease, and in two patients who initially lacked these CTLs, they reappeared after treatment with allogeneic bone marrow transplantation, suggesting that CTL failure may contribute to the development of CAEBV.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Virus-specific cytotoxic T cells in chronic active Epstein-Barr virus infection. Shibayama, H., Imadome, KI., Onozawa, E., et al.[2017]

In a study involving nine donors (seven EBV-seropositive and two EBV-seronegative), it was found that EBV-seropositive individuals had a significantly higher frequency of cytotoxic T lymphocyte precursors (CTLp), indicating a robust immune response to the virus.

The CTLp were exclusively derived from the CD4-CD8+ T cell population, and the study identified that certain HLA-A and HLA-B antigens can preferentially restrict these CTLp, suggesting a complex interaction between the virus and the host's immune system.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Limiting-dilution analysis of the HLA restriction of anti-Epstein-Barr virus-specific cytolytic T lymphocytes. Bourgault, I., Gomez, A., Gomard, E., et al.[2018]

Polyclonal Epstein-Barr virus (EBV)-specific cytotoxic T cells (CTL) have shown promise in treating EBV-associated malignancies, indicating their potential effectiveness in targeting specific cancers.

The chapter discusses strategies to enhance the antitumor activity of these EBV-specific CTLs, which could lead to improved T cell therapies for various tumors with known antigens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T cell therapies. Gottschalk, S., Bollard, CM., Straathof, KC., et al.[2019]

CAR T cell therapy has shown high response rates and potential cures for patients with relapsed or refractory B lymphoid malignancies, but it can also lead to serious immune-mediated side effects, particularly cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS).

Management of these side effects is critical and typically involves close monitoring and treatments like anti-interleukin-6 antibodies and corticosteroids, as these complications can lead to severe immune suppression and increase the risk of infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicity of Chimeric Antigen Receptor T Cells and its Management. Wudhikarn, K., Soh, SY., Huang, H., et al.[2023]

In a study of 42 patients receiving prophylactic treatment with gene-marked virus-specific cytotoxic T lymphocytes (CTLs), none developed Epstein-Barr virus-associated lymphoproliferative disease (EBV-LPD), while 15% of those who did not receive CTLs developed the disease, indicating the efficacy of CTL prophylaxis.

The infused CTLs not only persisted for up to 3 years but also effectively targeted tumor sites, leading to complete regression in two patients, showcasing their potential as a treatment for EBV-LPD and possibly for other conditions like relapsed EBV-positive Hodgkin's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunotherapy for Epstein-Barr virus-associated cancers. Rooney, CM., Roskrow, MA., Smith, CA., et al.[2019]

In a study involving 5 HIV-infected patients, most showed detectable T cell responses to Epstein-Barr virus (EBV), particularly targeting the EBNA-3 antigen, indicating a potential for immunotherapy in this population.

The researchers successfully created EBV-specific cytotoxic T lymphocytes (EBV-CTL) that were highly effective against the virus and produced interferon-gamma, paving the way for future clinical applications in adoptive immunotherapy for EBV-associated lymphomas in HIV patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Establishment of cytotoxic T lymphocytes specific for autologous Epstein-Barr virus in HIV-infected patients: the feasibility study of EBV-specific immunotherapy for patients with EBV-associated lymphoma. Hansasuta, P., Incomserb, P., Buranapraditkun, S., et al.[2006]

Anti-CD19 CAR T cell therapy is the standard treatment for patients with multiple relapsed or refractory primary mediastinal B-cell lymphoma, and checkpoint inhibitors like pembrolizumab are safe and effective for those who cannot undergo stem cell transplantation.

A case study highlighted a severe skin reaction in a patient after CAR T cell infusion, suggesting potential immune-mediated adverse effects when combining CAR T therapy with checkpoint inhibitors, indicating a need for further research into these interactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Case Report: Severe cutaneous adverse event associated with checkpoint inhibition in the setting of CAR T-cell therapy: beyond CRS. Masucci, C., Pepe, S., La Rocca, U., et al.[2023]

T-cell-engaging immunotherapies, like blinatumomab and CAR T-cell therapy, have shown remarkable remission rates in patients with relapsed or refractory acute lymphoblastic leukemia (ALL), highlighting their efficacy in treating this challenging condition.

Cytokine release syndrome (CRS) is a significant side effect of these therapies, characterized by symptoms like fever and malaise, and can lead to severe complications. Management strategies include using tocilizumab for severe CRS and preventive measures like corticosteroid premedication during blinatumomab treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cytokine release syndrome with novel therapeutics for acute lymphoblastic leukemia. Frey, NV., Porter, DL.[2022]

Adoptive immunotherapy using allogeneic EBV-specific cytotoxic T-lymphocytes (CTL) was found to be safe and effective in treating patients with therapy-refractory EBV-positive Hodgkin disease, with one patient remaining disease-free for 22 months after treatment.

In a pilot trial involving 6 patients, 5 showed decreases in measurable disease after receiving EBV CTL infusions, indicating potential antitumor effects, although the exact contribution of the chemotherapy fludarabine in one cohort remains unclear.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adoptive immunotherapy with allogeneic Epstein-Barr virus (EBV)-specific cytotoxic T-lymphocytes for recurrent, EBV-positive Hodgkin disease. Lucas, KG., Salzman, D., Garcia, A., et al.[2020]

Blinatumomab is a promising new treatment for adults with relapsed or refractory B-cell acute lymphoblastic leukemia, showing effectiveness in targeting and destroying tumor cells by engaging both T-cells and B-cells.

While there are potential side effects like immunological toxicities and cytokine release syndrome, most patients tolerate blinatumomab well, indicating a favorable safety profile compared to traditional therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical use of blinatumomab for B-cell acute lymphoblastic leukemia in adults. Lee, KJ., Chow, V., Weissman, A., et al.[2022]

Adoptive immune transfer of Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes (CTL) shows promise as a treatment for EBV-associated lymphoproliferative disorders, particularly in patients who have undergone bone marrow transplantation.

This immunotherapy approach has also been applied successfully in a patient with severe chronic active EBV infection, highlighting its potential for broader clinical use in managing EBV-related diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Adoptive immune therapy using EBV-specific CTL]. Kuzushima, K., Morishima, T.[2011]

In a study of 75 patients with large B-cell lymphoma receiving CAR T-cell therapy, high pretreatment levels of the cytokine IL6 were linked to severe immune-mediated toxicities like cytokine release syndrome (CRS) and neurotoxicity (NT).

The research also found that certain gene expressions in tumor biopsies indicated a proinflammatory tumor microenvironment, which may increase the risk of toxicity, suggesting that personalized management strategies could help mitigate these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tumor Microenvironment Composition and Severe Cytokine Release Syndrome (CRS) Influence Toxicity in Patients with Large B-Cell Lymphoma Treated with Axicabtagene Ciloleucel. Faramand, R., Jain, M., Staedtke, V., et al.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03266653

EBV-specific Cytotoxic T-lymphocytes (CTLs) for Refractory ... A Pilot Study in the Treatment of Refractory Epstein-Barr Virus (EBV) Infection With Related Donor EBV Cytotoxic T-Lymphocytes in Children, Adolescents and ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2817637/

Long-term outcome of EBV-specific T-cell infusions to prevent ... We conclude that the CTL lines described here provide safe and effective prophylaxis or treatment for lymphoproliferative disease in transplantation recipients.

3. astctjournal.org astctjournal.org/article/S2666-6367(25)01383-1/fulltext

Long-Term Efficacy of Epstein-Barr Virus-Specific T Cells ... Donor-derived EBV-CTLs are a safe and effective treatment for EBV-PTLD following haploidentical HSCT. Our findings support the long-term ...

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S2666636725013831

Long-Term Efficacy of Epstein-Barr Virus-Specific T Cells ... The 1-year overall survival rate was 68.0% (95% CI, 51.3% to 80.0%), and survival remained stable without significant decline up to 5 years.

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC1988944/

Epstein Barr virus–specific cytotoxic T lymphocytes expressing ... Adoptive transfer of Epstein Barr virus (EBV)–specific cytotoxic T-lymphocytes (EBV-CTLs) has shown that these cells persist in patients with EBV+ Hodgkin ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT00058591

Treating Severe Chronic Epstein-Barr Virus (EBV) Infection ... Treating Severe Chronic Epstein-Barr Virus (EBV) Infection With EBV Specific Cytotoxic T Lymphocytes (CTLs) (SCAEBV). ClinicalTrials.gov ID NCT00058591.

7. sciencedirect.com sciencedirect.com/science/article/pii/S1465324923000993

Epstein‒Barr virus–associated cellular immunotherapy Currently, many clinical studies have demonstrated that EBV-specific cytotoxic T lymphocytes and other cell therapies can be safely and effectively transfused ...

8. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/34510581/

EBV-specific cytotoxic T lymphocytes for refractory ... We conclude that adoptive therapy with EBV-specific CTLs is safe, well-tolerated, and effective in PTLD.