EBV-Specific Cytotoxic T-Lymphocytes for Lymphoma

(GRALE Trial)

Recruiting at 1 trial location

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

Trial Summary

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.

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

Research shows that EBV-specific cytotoxic T lymphocytes (CTLs) can expand in the body, reach tumor sites, and reduce viral load in patients with EBV-positive Hodgkin's disease. Some patients experienced complete remission or stable disease after treatment, suggesting potential effectiveness for EBV-associated lymphomas. ^{1 2 3 4 5}

Is EBV-specific cytotoxic T-lymphocyte therapy safe for humans?

Research shows that EBV-specific cytotoxic T-lymphocyte therapy is generally well tolerated in humans, with studies indicating it can persist in the body and enhance immune response without significant safety concerns. ^{1 2 3 5 6}

How is the treatment GRALE T cells different from other treatments for lymphoma?

GRALE T cells are unique because they are specifically designed to target and kill cells infected with the Epstein-Barr virus (EBV), which is associated with certain types of lymphoma. This treatment involves using the patient's own immune cells, which are modified to recognize and attack EBV-infected cells, offering a targeted approach compared to traditional therapies. ^{1 3 7 8 9}

What is the purpose of this trial?

Subjects have a type of lymph gland disease called Hodgkin or non-Hodgkin Lymphoma or T/NK-lymphoproliferative disease or severe chronic active Epstein Barr Virus (CAEBV) which has come back, is at risk of coming back, or has not gone away after treatment, including the best treatment we know for these diseases. Some of these patients show signs of virus that is called Epstein Barr virus (EBV) that causes mononucleosis or glandular fever ("mono" or the "kissing disease") before or at the time of their diagnosis. EBV is found in the cancer cells of up to half the patients with HD and NHL, suggesting that it may play a role in causing Lymphoma. The cancer cells and some immune system cells infected by EBV are able to hide from the body's immune system and escape destruction. We want to see if special white blood cells, called GRALE T cells, that have been trained to kill EBV infected cells can survive in the blood and affect the tumor. We have used this sort of therapy to treat a different type of cancer called post transplant lymphoma. In this type of cancer the tumor cells have 9 proteins made by EBV on their surface. We grew T cells in the lab that recognized all 9 proteins and were able to successfully prevent and treat post transplant lymphoma. However, in HD and NHL, T/NK-lymphoproliferative disease, and CAEBV, the tumor cells and B cells only express 4 EBV proteins. In a previous study, we made T cells that recognized all 9 proteins and gave them to patients with HD. Some patients had a partial response to this therapy but no patients had a complete response. We then did follow up studies where we made T cells that recognized the 2 EBV proteins seen in patients with lymphoma, T/NK-lymphoproliferative disease and CAEBV. We have treated over 50 people on those studies. About 60% of those patients who had disease at the time they got the cells had responses including some patients with complete responses. This study will expand on those results and we will try and make the T cells in the lab in a simpler faster way. These cells are called GRALE T cells. These GRALE T cells are an investigational product not approved by the FDA. 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. We will learn what the side effects are and to see whether this therapy might help patients with HD or NHL or EBV associated T/NK-lymphoproliferative disease or CAEBV.

Research Team

Helen E Heslop, MD

Principal Investigator

Baylor College of Medicine

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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 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 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+

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

References

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

Cytotoxic T lymphocyte therapy for Epstein-Barr virus+ Hodgkin's disease. [2020]

2. Germany pubmed.ncbi.nlm.nih.gov

T cell therapies. [2019]

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

Feasibility of cellular adoptive immunotherapy for Epstein-Barr virus-associated lymphomas using haploidentical donors. [2007]

4. 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]

5. 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]

6. Japan 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]. [2022]

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

HLA antigen-related restriction of T lymphocyte cytotoxicity to Epstein-Barr virus. [2019]

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

HLA-DR-antigen-associated restriction of EBV-specific cytotoxic T-cell colonies. [2020]

9. United States 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. [2019]