EBV-Specific Cytotoxic T-Lymphocytes for Lymphoma

(GRALE Trial)

Recruiting at 2 trial locations

Overseen By Helen Heslop, MD

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: Baylor College of Medicine

Must not be taking: Systemic corticosteroids

Disqualifiers: HIV, HTLV, HBV, HCV, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: 4 weeks

136 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new method to combat lymphomas and related diseases using specially trained white blood cells called GRALE T cells (EBV-specific cytotoxic T lymphocytes). These cells target and destroy cancer cells linked to the Epstein Barr Virus (EBV), often present in these cancers. The trial aims to identify the safest effective dose while monitoring for side effects. Suitable participants include those with Hodgkin or non-Hodgkin Lymphoma, or similar conditions, that have recurred or not fully responded to standard treatments, and have an EBV-positive diagnosis. As a Phase 1 trial, this research seeks to understand how the treatment works in people, offering participants the chance to be among the first to receive this innovative therapy.

Do I need to stop my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications, but you must be off other investigational therapies for 4 weeks before joining the study. PD1/PDL inhibitors are allowed if medically necessary.

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

Research has shown that earlier studies tested GRALE T cells, a type of special white blood cell, on patients with certain lymphomas linked to the Epstein-Barr virus (EBV). These studies found that about 60% of patients who received these cells experienced some positive response. Some even had a complete response, meaning their cancer disappeared after treatment.

Regarding safety, these studies suggest that the treatment is generally well-tolerated. Current research aims to find the safest dose of GRALE T cells, so researchers closely monitor any side effects. Since GRALE T cells are still under study, they have not yet received FDA approval for this use. However, the side effects observed so far have been manageable, which reassures those considering joining the trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about GRALE T cells for treating lymphoma because they offer a targeted approach by harnessing the body's immune system to fight the disease. Unlike standard treatments like chemotherapy or radiation, which can affect healthy cells as well as cancerous ones, GRALE T cells are engineered to specifically target and kill Epstein-Barr Virus (EBV)-infected cancer cells. This precision reduces collateral damage to healthy tissues, potentially leading to fewer side effects and improved outcomes. Additionally, these T cells can be given with or without lymphodepletion, offering flexibility based on patient needs.

What evidence suggests that GRALE T cells might be an effective treatment for lymphoma?

Research has shown that GRALE T cells, a type of immune cell therapy, may help treat patients with lymphoma related to the Epstein-Barr virus (EBV). In earlier studies, about 60% of these patients responded well to the treatment, with some experiencing complete tumor shrinkage. In this trial, participants will receive EBV-specific T cells in one of two groups: Group A, for patients in second or subsequent relapse or with active disease, and Group B, for patients in remission or with minimal residual disease after stem cell transplant. These T cells are specially trained to find and destroy cancer cells infected with EBV. While the early results are promising, researchers continue to study the therapy to ensure its effectiveness and safety. ^{1 2 3 4 5}

Who Is on the Research Team?

Helen E Heslop, MD

Principal Investigator

Baylor College of Medicine

Are You a Good Fit for This Trial?

This trial is for individuals of any age or sex with EBV-positive Hodgkin's or non-Hodgkin's Lymphoma, T/NK-lymphoproliferative disease, or severe chronic active Epstein Barr Virus (CAEBV). They must have a life expectancy of at least 6 weeks, stable organ function, and be willing to use effective birth control. It excludes those with HIV/HTLV/HBV/HCV infections, pregnant/lactating women, high-dose steroid users, and patients with severe infections.

Inclusion Criteria

Any patient, regardless of age or sex, with EBV-positive Hodgkin's or non-Hodgkin's Lymphoma (regardless of histologic subtype), or EBV (associated)-T/NK-lymphoproliferative disease or Severe Chronic Active EBV (CAEBV)* and In second or subsequent relapse (or first relapse or with active disease if immunosuppressive chemotherapy contraindicated or multiply relapsed patients in remission who have a high risk of relapse)** OR any patient with primary disease or in first remission if immunosuppressive chemotherapy is contraindicated, e.g. patients who develop Hodgkin disease after solid organ transplantation or if the Lymphoma is a second malignancy e.g. a Richter's transformation of CLL. (Group A) OR In remission or with minimal residual disease status after autologous or syngeneic SCT. (Group B)

My tests show high levels of the EBV virus in my blood or tissues.

My kidney function, measured by creatinine, is within twice the normal limit for my age.

Exclusion Criteria

I am taking more than 0.5 mg/kg/day of corticosteroids.

You are pregnant or breastfeeding.

I do not have a severe ongoing infection.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive two doses of GRALE T cells, 14 days apart, to assess safety and initial response

4 weeks

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, with follow-up testing similar to post-infusion assessments

5 years

Annual visits or contact by research nurse

Optional Extension

Participants may receive additional doses of GRALE T cells if there is a reduction in lymphoma size, followed by extended monitoring

Up to 5 years after last dose

What Are the Treatments Tested in This Trial?

Interventions

• GRALE T cells

Trial Overview The study tests GRALE T cells designed to fight EBV-infected cells in lymphoma patients. The goal is to determine the highest safe dose of these lab-made T cells using a new technique and assess their side effects and potential benefits against HD/NHL/EBV-related diseases.

How Is the Trial Designed?

Group I: EBV-specific T cells: B Experimental Treatment 1 Intervention

Group B: Patients in remission or with minimal residual disease (MRD) status after autologous or syngeneic SCT. Patients may receive cells with or without lymphodepletion. Patients will be treated at Dose Level 3. Each patient will receive 2 injections, 14 days apart, according to the following dosing schedule: Day 0: 1 x 10\^8 cells/m2 Day 14: 2 x 10\^8 cells/m2

Group II: EBV-specific T cells: A Experimental Treatment 1 Intervention

Group A: Patients in second or subsequent relapse (or first relapse or with active disease if immunosuppressive chemotherapy contraindicated or multiple relapsed patients in remission who are at a high risk of relapse)\*\* or any patient with primary disease or in first or subsequent remission if immunosuppressive chemotherapy is contraindicated. Patients may receive cells with or without lymphodepletion. Patients will be treated at Dose Level 3. Each patient will receive 2 injections, 14 days apart, according to the following dosing schedule: Day 0: 1 x 10\^8 cells/m2 Day 14: 2 x 10\^8 cells/m2 \*\* Patients with relapsed or refractory lymphoma that are eligible for a stem cell transplant will not be treated on this study as an alternative to transplant.

GRALE T cells is already approved in United States for the following indications:

Approved in United States as GRALE T cells for:

• Investigational use for Hodgkin lymphoma, non-Hodgkin lymphoma, T/NK-lymphoproliferative disease, and severe chronic active Epstein Barr Virus (CAEBV)

Who Is Running the Clinical Trial?

Baylor College of Medicine

Lead Sponsor

Trials

1,044

Recruited

6,031,000+

Harris County Hospital District

Collaborator

Trials

7

Recruited

410+

The Methodist Hospital Research Institute

Collaborator

Trials

299

Recruited

82,500+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Center for Cell and Gene Therapy, Baylor College of Medicine

Collaborator

Trials

114

Recruited

2,900+

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

Published Research Related to This Trial

In males with X-linked lymphoproliferative syndrome (XLP), B lymphocytes can express Epstein-Barr virus (EBV) proteins and present them to T cells, indicating that these B cells are capable of triggering an immune response despite the disease's associated deficiencies.

The inability of the immune system to eliminate EBV-infected B cells in XLP is not due to a defect in the B cells themselves, as they can effectively present viral antigens and induce cytotoxic T cell responses, suggesting that other factors contribute to the disease's pathology.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Epstein-Barr virus-infected B cells of males with the X-linked lymphoproliferative syndrome stimulate and are susceptible to T-cell-mediated lysis. Jäger, M., Benninger-Döring, G., Prang, N., et al.[2019]

Antigen-specific cytotoxic T lymphocytes (CTLs) generated from induced pluripotent stem cells show rejuvenated function and strong antitumor effects against Epstein-Barr virus (EBV)-associated lymphomas, which are common in Asia and have a poor prognosis.

The study developed allogeneic EBV-specific CTLs for potential 'off-the-shelf' therapy, making it feasible for clinical use in treating these lymphomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Induced pluripotent stem cell-derived rejuvenated cytotoxic T lymphocyte therapy for Epstein-Barr virus-associated lymphomas: application to clinical practice]. Ando, M.[2022]

Cytotoxic T cells specific to Epstein-Barr virus (EBV) were successfully generated from lymphocyte cultures of EBV-seropositive donors, indicating a strong immune response in individuals previously exposed to the virus.

The study demonstrated that the cytotoxicity of these T cells is restricted to HLA antigens, suggesting that the effectiveness of T cell responses against EBV is dependent on the compatibility of HLA molecules between the T cells and the target cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

HLA antigen-related restriction of T lymphocyte cytotoxicity to Epstein-Barr virus. Misko, IS., Moss, DJ., Pope, JH.[2019]

The study demonstrated that EBV-specific cytotoxic T cells can be effectively generated in vitro, showing that both OKT4+ and OKT8+ T cell colonies can exhibit specific cytotoxicity against EBV-infected cells, highlighting their potential role in targeted immune responses.

The research revealed complex patterns of cytotoxicity based on HLA haplotypes, indicating that T cell responses are influenced by specific HLA-A,B,C and HLA-DR antigens, which could have implications for understanding individual variations in immune responses to EBV.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

HLA-DR-antigen-associated restriction of EBV-specific cytotoxic T-cell colonies. Misko, IS., Pope, JH., Hütter, R., et al.[2020]

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 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 involving 14 patients with relapsed Epstein Barr virus (EBV)+ Hodgkin's disease, infused EBV-specific cytotoxic T lymphocytes (CTLs) were well tolerated and showed significant antitumor activity, with five patients achieving complete remission for up to 40 months.

The infused CTLs not only expanded and persisted in the body but also effectively targeted tumor sites, leading to a decrease in viral load and improvement in symptoms like fever and night sweats, indicating their potential as a viable treatment option for EBV+ Hodgkin lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cytotoxic T lymphocyte therapy for Epstein-Barr virus+ Hodgkin's disease. Bollard, CM., Aguilar, L., Straathof, KC., et al.[2020]

A new strategy for creating EBV-specific cytotoxic T cell therapy lines shows strong effectiveness in targeting EBV-associated lymphomas, particularly after bone marrow or solid organ transplants.

This method involves stimulating peripheral blood mononuclear cells with irradiated EBV-transformed cells, resulting in T cell lines that specifically kill EBV-positive targets while sparing non-EBV targets, highlighting a targeted approach to treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Feasibility of cellular adoptive immunotherapy for Epstein-Barr virus-associated lymphomas using haploidentical donors. Orentas, RJ., Lemas, MV., Mullin, MJ., et al.[2007]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT01555892

NCT01555892 | Cytotoxic T-Lymphocytes for EBV-positive ... The purpose of this study is to find the largest safe dose of LMP-specific cytotoxic GRALE T cells created using this new manufacturing technique.

2. clinicaltrial.be clinicaltrial.be/en/details/75496?per_page=100&recruiting=1&enrolling_by_invitation=0&active_not_recruiting=0&not_yet_recruiting=0&completed=0&only_recruiting=1&only_eligible=0

Cytotoxic T-Lymphocytes for EBV-positive Lymphoma, ... Administration of Rapidly Generated EBV-Specific Cytotoxic T-Lymphocytes To Patients With EBV-Positive Lymphoma ... EBV-specific (GRALE) T cells ...

3. withpower.com withpower.com/trial/phase-1-lymphoproliferative-disorders-2013-4960b

EBV-Specific Cytotoxic T-Lymphocytes for Lymphoma What data supports the effectiveness of the treatment GRALE T cells, EBV-specific cytotoxic T lymphocytes, and LMP-specific cytotoxic T cells for lymphoma?

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39908567/

Differential antibody response to EBV proteome ... - PubMed These trials were registered at www.clinicaltrials.gov as #NCT01555892 (Cytotoxic T-Lymphocytes for EBV-positive Lymphoma [GRALE]), #NCT02973113 ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S247395292500076X

Differential antibody response to EBV proteome following ... These trials were registered at www.clinicaltrials.gov as #NCT01555892 (Cytotoxic T-Lymphocytes for EBV-positive Lymphoma [GRALE]), #NCT02973113 ...