T-cell Therapy for Lymphoma

(ATECRAB Trial)

Recruiting at 1 trial location

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: Baylor College of Medicine

Disqualifiers: Pregnancy, HIV, HBV, HCV, others

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

Compensation: Varies

Number of Visits: 1

Duration: 6 weeks

3 Participants Needed

Trial Summary

What is the purpose of this trial?

Patients on this study have a type of lymph gland cancer called non-Hodgkin Lymphoma or chronic Lymphocytic Leukemia. Their lymphoma or CLL has come back or has not gone away after treatment. Because there is no standard treatment for the cancer at this time or because the currently used treatments do not work fully in all cases, patients are being asked to volunteer to take part in a gene transfer research study using special immune cells. The body has different ways of fighting infection and disease. No single way seems perfect for fighting cancers. This research study combines two different ways of fighting disease: antibodies and T cells. Antibodies are types of proteins that protect the body from infectious diseases and possibly cancer. T cells, also called T lymphocytes, are special infection-fighting blood cells that can kill other cells, including cells infected with viruses and tumor cells. Both antibodies and T cells have been used to treat patients with cancers. They have shown promise, but have not been strong enough to cure most patients. The antibody used in this study is called anti-CD19. This antibody sticks to lymphoma cells because of a substance on the outside of these cells called CD19. CD19 antibodies have been used to treat people with lymphoma and CLL. For this study, the anti-CD19 antibody has been changed so that instead of floating free in the blood it is now attached to T cells. When an antibody is joined to a T cell in this way it is called a chimeric receptor. These chimeric receptor-T cells seem to be able to kill tumors, but they don't last very long and so their chances of fighting the cancer are limited. Investigators found that T cells work better if they also attach a protein called CD28 to the T cells. This protein makes the T cells more active and survive longer. Also they found that T cells that are also trained to recognize the virus that causes infectious mononucleosis (called Epstein Barr Virus or EBV) can stay in the blood stream for many years. These CD19-CD28 chimeric receptor T cells and CD19 chimeric-EBV specific T cells are investigational products not approved by the FDA. The purpose of this study is to find the biggest dose of chimeric T cells that is safe to administer, to see how long each of the T cell populations (CD19-CD28 and CD19-EBV-specific) last, to assess what the side effects are, and to evaluate whether this therapy might help people with lymphoma or CLL.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you must not be on any investigational agents or have received tumor vaccines in the past six weeks, and you cannot have been treated with rituximab in the past eight weeks.

What data supports the effectiveness of the treatment T-cell Therapy for Lymphoma?

Research shows that using Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes (CTLs) can be effective in treating EBV-related lymphomas, with some patients achieving complete remission. This suggests that similar T-cell therapies might be beneficial for lymphoma patients. ^{1 2 3 4 5}

Is T-cell therapy for lymphoma safe for humans?

Research shows that T-cell therapy, specifically using EBV-specific cytotoxic T lymphocytes (CTLs), is generally safe for humans. Studies involving patients with various EBV-related conditions reported minimal side effects, such as localized swelling and fever, with no serious complications observed. ^{2 4 5 6 7}

How does the T-cell therapy for lymphoma differ from other treatments?

This T-cell therapy is unique because it uses the patient's own T-cells (a type of immune cell) that are specifically trained to target and kill cells infected with the Epstein-Barr virus (EBV), which is associated with certain types of lymphoma. Unlike traditional treatments like chemotherapy, this approach aims to harness the body's immune system to fight the disease more precisely. ^{1 5 8 9 10}

Research Team

Carlos Ramos, MD

Principal Investigator

Baylor College of Medicine

Eligibility Criteria

This trial is for people with certain types of blood cancers like non-Hodgkin Lymphoma or chronic Lymphocytic Leukemia that have returned or persisted despite treatment. Participants must be over the worst side effects of past treatments, not on other experimental drugs, and without severe liver, heart, or kidney issues. They should also not be pregnant, free from serious infections like HIV/HBV/HCV/CMV, and willing to use effective birth control.

Inclusion Criteria

I have recurring low or intermediate grade B-cell lymphoma or B-CLL, or I can't complete standard therapy.

I haven't received rituximab in the last 8 weeks.

I am not currently on experimental drugs or had cancer vaccines in the last 6 weeks.

Exclusion Criteria

History of hypersensitivity reactions to murine protein-containing products

I do not have an active infection with HIV, hepatitis B, hepatitis C, or CMV.

My tumor is located where it could block my airway if it grows.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive an infusion of CD19-CD28 chimeric receptor T cells and CD19 chimeric receptor-EBV specific T cells, with possible cyclophosphamide pre-treatment

6 weeks

1 visit (in-person) for infusion, followed by clinic visits for monitoring

Evaluation

Evaluation period to assess benefit from treatment, with potential for additional doses if beneficial

4-6 weeks

Regular monitoring visits

Follow-up

Participants are monitored for safety and effectiveness after treatment, including long-term follow-up for gene transfer side effects

15 years

Treatment Details

Interventions

• Autologous or Syngeneic PBTLs and EBV-CTLs

Trial Overview The study tests T cells modified with an anti-CD19 antibody (chimeric receptor-T cells) and a protein CD28 to make them more active against cancer. It also uses T cells trained to fight Epstein-Barr Virus (EBV). The goal is to find the highest safe dose of these chimeric T cells, understand their longevity in the body and side effects, and see if they help treat lymphoma or CLL.

Participant Groups

Group I: autologous or syngeneic PBTLs and EBV-CTLs Experimental Treatment 1 Intervention

The subject will be assigned a dose of CD19-CD28 chimeric receptor T cells at study entry.

Who Is Running the Clinical Trial?

Baylor College of Medicine

Lead Sponsor

Trials

1,044

Recruited

6,031,000+

Center for Cell and Gene Therapy, Baylor College of Medicine

Collaborator

Trials

114

Recruited

2,900+

The Methodist Hospital Research Institute

Collaborator

Trials

299

Recruited

82,500+

Findings from Research

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]

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]

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]

In a study of 114 patients receiving EBV-specific cytotoxic T lymphocyte (CTL) infusions, the treatment showed minimal toxicity and effectively prevented EBV-related lymphoproliferative disease (LPD), with no cases in the 101 patients who received prophylaxis.

Among the 13 patients treated for existing LPD, 11 achieved sustained complete remissions, demonstrating the efficacy of CTLs in treating this condition, with functional CTLs persisting for up to 9 years.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term outcome of EBV-specific T-cell infusions to prevent or treat EBV-related lymphoproliferative disease in transplant recipients. Heslop, HE., Slobod, KS., Pule, MA., et al.[2023]

In a study involving 9 patients with refractory or recurrent angioimmunoblastic T-cell lymphoma (AITL), EBV-specific CTL therapy demonstrated a 66.7% response rate, with 55.6% achieving objective remission after treatment.

The therapy was found to be safe, with only mild side effects like fever and rash reported, and no cases of graft-versus-host disease, indicating a favorable safety profile for this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy and safety of Epstein-Barr virus-specific antigen peptide-activated cytotoxic T-cells treatment for refractory or recurrent angioimmunoblastic T-cell lymphoma: A prospective clinical observational study. Bingjie, W., Lihong, W., Yongjin, S., et al.[2020]

A patient with relapsed EBV-positive Hodgkin's Disease achieved disease stabilization for 6 months after receiving gene-marked autologous EBV-specific cytotoxic T lymphocytes (CTLs), demonstrating the potential efficacy of this immunotherapy approach.

The donor-derived CTL infusion led to a complete remission 5 years post-transplant, highlighting the importance of targeting multiple EBV antigens (LMP1 and LMP2) for a stronger immune response against the cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vivo expansion of LMP 1- and 2-specific T-cells in a patient who received donor-derived EBV-specific T-cells after allogeneic stem cell transplantation. Bollard, CM., Gottschalk, S., Huls, MH., et al.[2019]

References

1. Germany pubmed.ncbi.nlm.nih.gov

T cell therapies. [2019]

2. England pubmed.ncbi.nlm.nih.gov

Safety of allogeneic Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes for patients with refractory EBV-related lymphoma. [2020]

3. Japan pubmed.ncbi.nlm.nih.gov

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

4. 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]

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

Establishment and characterization of a bank of cytotoxic T lymphocytes for immunotherapy of epstein-barr virus-associated diseases. [2023]

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

Long-term outcome of EBV-specific T-cell infusions to prevent or treat EBV-related lymphoproliferative disease in transplant recipients. [2023]

7. England pubmed.ncbi.nlm.nih.gov

The efficacy and safety of Epstein-Barr virus-specific antigen peptide-activated cytotoxic T-cells treatment for refractory or recurrent angioimmunoblastic T-cell lymphoma: A prospective clinical observational study. [2020]

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

Treatment of solid organ transplant recipients with autologous Epstein Barr virus-specific cytotoxic T lymphocytes (CTLs). [2021]

9. England pubmed.ncbi.nlm.nih.gov

Treatment of relapsed Hodgkin's disease using EBV-specific cytotoxic T cells. [2019]

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

In vivo expansion of LMP 1- and 2-specific T-cells in a patient who received donor-derived EBV-specific T-cells after allogeneic stem cell transplantation. [2019]