TGFbeta-resistant Immune Cells for Lymphoma

(TGF-beta Trial)

Recruiting at 1 trial location

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: Baylor College of Medicine

Disqualifiers: Severe infection, GVHD, HIV, pregnancy, others

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

Compensation: Varies

Number of Visits: 2

Duration: 6 weeks for initial treatment, with potential extension

8 Participants Needed

Trial Summary

What is the purpose of this trial?

Patients have a type of lymph gland cancer called HD, NHL or lymphoepithelioma (these 3 diseases will be referred to as "Lymphoma"). The lymphoma has come back or has not gone away after treatment. This is a research study using special immune system cells called TGFb-resistant LMP-specific cytotoxic T lymphocytes (DNR-CTL), a new experimental therapy. Some patients with Lymphoma show signs of infection with the Epstein Barr virus (EBV) before or at the time of their Lymphoma diagnosis. EBV is found in the cancer cells of up to 1/2 the patients with Lymphoma, suggesting it may play a role in causing Lymphoma. The cancer cells infected by EBV are able to hide from the body's immune system and escape being killed by releasing a substance called Transforming Growth Factor-beta (TGFb). The investigators want to see if special white blood cells (called T cells) that have been given a gene that they hope will let them survive against TGFb and that have been trained to kill EBV infected cells can also survive in the blood and kill the tumor. Investigators have used this sort of therapy with specially trained T cells to treat a different type of cancer that occurs after bone marrow and solid organ transplant called post transplant lymphoma. In this type of cancer they were able to successfully prevent and treat post transplant lymphoma. However when they used a similar approach in HD some patients had a partial response to this therapy, but no patients had a complete response. In a follow-up study they tried to find out if they could improve this treatment by growing T cells that recognize 2 of the proteins expressed on Lymphoma cells called LMP-1 and LMP2a. These special T cells were called LMP-specific cytotoxic T-lymphocytes (CTLs). Although some patients had tumor responses, CTL therapy alone did not cure those who had a lot of disease. Investigators think that a reason for this is that the tumor cells are releasing TGFb. For this reason, they want to find out if they can make the CTL resistant to TGFb by putting in a new gene called TGFb resistance gene. Investigators hope that this will improve this treatment for relapsed lymphoma. These TGFb-resistant LMP-specific CTLs are an investigational product not approved by FDA. The purpose of this study is to find the largest safe dose of TGFb resistant LMP-specific CTLs, to learn what the side effects are and to see whether this therapy might help patients with Lymphoma.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, you must have been off other investigational therapies for one month before joining the study.

What data supports the effectiveness of the treatment TGFbeta resistant LMP-specific CTLs for lymphoma?

Research shows that TGFbeta-resistant immune cells, like the ones used in this treatment, have been engineered to resist the suppressive effects of TGFbeta, a substance that tumors use to weaken the immune system. These modified cells have shown enhanced ability to fight tumors in laboratory and animal studies, suggesting they could be effective in treating lymphoma. ^{1 2 3 4 5}

Is the TGFbeta-resistant immune cell treatment safe for humans?

The TGFbeta-resistant immune cell treatment has been tested in humans with Hodgkin lymphoma, showing that it can safely expand and persist without causing acute or long-term toxicity. This suggests it is generally safe for human use. ^{1 6 7 8 9}

How is the treatment TGFbeta-resistant LMP-specific CTLs different from other treatments for lymphoma?

This treatment is unique because it uses immune cells (CTLs) that are engineered to resist the suppressive effects of TGF-beta, a substance produced by tumors that usually weakens the immune response. This allows the immune cells to better attack the lymphoma cells, potentially improving the effectiveness of the treatment compared to standard therapies that do not address TGF-beta's inhibitory effects. ^{1 2 4 7 10}

Research Team

Helen E Heslop, MD

Principal Investigator

Baylor College of Medicine

Eligibility Criteria

This trial is for individuals with EBV-positive lymphoma or lymphoepithelioma, regardless of age or sex. They should have a life expectancy of at least 6 weeks post-CTL infusion, be able to perform daily activities (Karnofsky score ≥50), and have certain levels of blood and liver function. It's not for those with severe infections, significant GVHD after transplant, HIV positive status, or pregnant women.

Inclusion Criteria

Patients with bilirubin 3x normal or less, AST 5x normal or less, and Hgb greater than 8.0

Patients with life expectancy 6 weeks or greater from the time of CTL infusion.

Patients should have been off other investigational therapy for one month prior to entry in this study.

Exclusion Criteria

I am not pregnant and understand the need for contraception during the study.

HIV positive at time of procurement cells for CTL generation

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 TGFb-resistant LMP-specific CTLs with initial two doses given two weeks apart, followed by up to six additional doses if beneficial

6 weeks for initial treatment, with potential extension

2 visits for initial doses, up to 6 additional visits for extended treatment

Follow-up

Participants are monitored for safety, effectiveness, and long-term outcomes after treatment

15 years

Treatment Details

Interventions

• TGFbeta resistant LMP-specific CTLs

Trial Overview The study tests TGFbeta-resistant LMP-specific CTLs in patients whose lymphoma has returned or persisted despite treatment. The goal is to find the highest safe dose, understand side effects, and see if this gene-modified therapy can fight cancer by targeting EBV-infected cells that evade the immune system.

Participant Groups

Group I: TGFbeta resistant LMP-specific CTLs Experimental Treatment 1 Intervention

CTLs be given by intravenous injection over 1-10 minutes through either a peripheral or a central line. If patients with active disease have stable disease or a partial response at their 6 week or subsequent evaluations they will be eligible to receive up to 6 additional doses of CTLs at 1-2 monthly intervals-each of which will consist of the same cell number as their second injection.

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

In a study involving 9 patients with refractory/relapsed B cell lymphoma, a novel anti-CD19 CAR T cell therapy showed a high overall response rate of 77.8%, with 55.6% achieving complete remission.

The treatment demonstrated a favorable safety profile, with only 11.1% of patients experiencing severe cytokine release syndrome and neurotoxicity, while some patients maintained complete remission for over 20 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel dominant-negative PD-1 armored anti-CD19 CAR T cell is safe and effective against refractory/relapsed B cell lymphoma. Liu, X., Zhang, Y., Li, K., et al.[2021]

References

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

Antitumor activity of EBV-specific T lymphocytes transduced with a dominant negative TGF-beta receptor. [2021]

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

Soluble and membrane-bound TGF-β-mediated regulation of intratumoral T cell differentiation and function in B-cell non-Hodgkin lymphoma. [2021]

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

Loss of functional cell surface transforming growth factor beta (TGF-beta) type 1 receptor correlates with insensitivity to TGF-beta in chronic lymphocytic leukemia. [2021]

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

Adapting a transforming growth factor beta-related tumor protection strategy to enhance antitumor immunity. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Clonal restriction of the expansion of antigen-specific CD8+ memory T cells by transforming growth factor-{beta}. [2020]

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

Tumor-Specific T-Cells Engineered to Overcome Tumor Immune Evasion Induce Clinical Responses in Patients With Relapsed Hodgkin Lymphoma. [2022]

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

Adoptive transfer of tumor-reactive transforming growth factor-beta-insensitive CD8+ T cells: eradication of autologous mouse prostate cancer. [2021]

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

A novel dominant-negative PD-1 armored anti-CD19 CAR T cell is safe and effective against refractory/relapsed B cell lymphoma. [2021]

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

Ablation of Cbl-b provides protection against transplanted and spontaneous tumors. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Transforming growth factor-beta 1 enhances the generation of allospecific cytotoxic T lymphocytes. [2018]