EBV-specific CTLs for EBV Infection

Recruiting at 7 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

Trial Summary

What is the purpose of this trial?

Related donor Epstein-Barr Virus (EBV) specific cytotoxic T cells (CTLs) manufactured with the Miltenyi CliniMACS Prodigy Cytokine Capture System will be administered in children, adolescents and young adults with refractory EBV infection post Allogeneic Hematopoietic Stem Cell Transplantation (AlloHSCT), with primary immunodeficiencies (PID) or post solid organ transplant. Funding Source: FDA OOPD

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.

What data supports the effectiveness of the treatment EBV-specific CTLs for EBV infection?

Research shows that EBV-specific cytotoxic T-lymphocytes (CTLs) are effective in preventing and treating EBV-related diseases, such as lymphoproliferative disease, especially in patients with weakened immune systems. In some studies, patients treated with these CTLs showed tumor regression and improved immune responses against the virus. ^{1 2 3 4 5}

Is EBV-specific CTL therapy safe for humans?

There is no specific safety data available for EBV-specific CTL therapy in the provided research articles. ^{6 7 8 9 10}

How is the treatment EBV-specific CTLs different from other treatments for EBV infection?

EBV-specific CTLs (Cytotoxic T-lymphocytes) are unique because they are tailored to target and destroy cells infected with the Epstein-Barr virus, unlike general antiviral drugs. This treatment involves using the patient's own immune cells, which are modified to specifically recognize and attack EBV-infected cells, offering a personalized and potentially more effective approach for conditions like EBV-associated lymphomas. ^{3 5 11 12 13}

Research Team

Mitchell S Cairo, MD

Principal Investigator

New York Medical College

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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 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]

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]

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]

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]

References

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

Adoptive immunotherapy with allogeneic Epstein-Barr virus (EBV)-specific cytotoxic T-lymphocytes for recurrent, EBV-positive Hodgkin disease. [2020]

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

Immunotherapy for Epstein-Barr virus-associated cancers. [2019]

3. Germany pubmed.ncbi.nlm.nih.gov

T cell therapies. [2019]

4. United States 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. [2021]

5. Japan pubmed.ncbi.nlm.nih.gov

[Adoptive immune therapy using EBV-specific CTL]. [2011]

6. New Zealand pubmed.ncbi.nlm.nih.gov

Clinical use of blinatumomab for B-cell acute lymphoblastic leukemia in adults. [2022]

7. Japan pubmed.ncbi.nlm.nih.gov

Toxicity of Chimeric Antigen Receptor T Cells and its Management. [2023]

8. United States 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. [2021]

9. Switzerland 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. [2023]

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

Cytokine release syndrome with novel therapeutics for acute lymphoblastic leukemia. [2022]

11. Thailand 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. [2006]

12. Japan pubmed.ncbi.nlm.nih.gov

Virus-specific cytotoxic T cells in chronic active Epstein-Barr virus infection. [2017]

13. England pubmed.ncbi.nlm.nih.gov

Limiting-dilution analysis of the HLA restriction of anti-Epstein-Barr virus-specific cytolytic T lymphocytes. [2018]