TGF-beta Resistant Cytotoxic T-lymphocytes for Nasopharyngeal Cancer

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: Baylor College of Medicine

Must be taking: Chemotherapy agents

Disqualifiers: HIV, Pregnancy, Severe infection

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

Compensation: Varies

Number of Visits: 7

14 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. However, you must be off any investigational therapy for 4 weeks before joining the study.

What data supports the effectiveness of the treatment TGF-beta Resistant Cytotoxic T-lymphocytes for Nasopharyngeal Cancer?

Research shows that using Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes (CTLs) in patients with nasopharyngeal carcinoma (NPC) can lead to significant antitumor activity, with some patients experiencing complete or partial remission. This suggests that targeting EBV-related antigens with CTLs can be an effective treatment strategy for NPC. ^{1 2 3 4 5}

Is the treatment with TGF-beta Resistant Cytotoxic T-lymphocytes for Nasopharyngeal Cancer safe?

Research shows that using Epstein-Barr virus-specific cytotoxic T-cells in nasopharyngeal cancer patients appears to be safe, with patients generally tolerating the treatment well. However, one patient experienced increased swelling at the site of pre-existing disease. ^{2 3 5 6 7}

How is the treatment DNR.NPC-specific T cells unique for nasopharyngeal cancer?

This treatment is unique because it uses TGF-beta resistant cytotoxic T-lymphocytes, which are designed to overcome the immunosuppressive environment created by the tumor and the Epstein-Barr virus, potentially enhancing the immune system's ability to target and destroy cancer cells. ^{3 8 9 10 11}

What is the purpose of this trial?

Patients have nasopharyngeal carcinoma (NPC). This study is a gene transfer research study using special immune cells. Most patients with NPC show evidence of infection with the virus that causes infectious mononucleosis Epstein Barr virus (EBV) before or at the time of their diagnosis. EBV is found in the cancer cells of almost all patients with advanced stage NPC, suggesting that it may play a role in causing the disease. The cancer 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 T cells, that have been trained to recognize and kill special parts of EBV infected cells can survive in patient's blood and affect the tumor. We already have given EBV-specific cytotoxic T cells to 30 patients with active NPC and have seen anti-tumor activity in 14 of 30 patients. We are now trying to find out if we can improve this treatment. First, we want to give T cells where more of the cells recognize at least two of the four EBV proteins expressed on NPC cells. We call these cells NPC-specific cytotoxic T cells. Second, we found that T cells work better if we add a receptor to the T cells called DNR (Dominant Negative Receptor). DNR makes T cells resistant to TGFbeta, a factor secreted by cancer cells that helps them escape being killed by the immune system. In this study we will therefore place the DNR gene into NPC-specific T cells (DNR.NPC-specific T cells). In other clinical studies using T cells, some investigators found that giving chemotherapy before the T cell infusion can improve the amount of time the T cells stay in the body and therefore the effect the T cells can have. Giving chemotherapy before a T cell infusion is called lymphodepletion since the chemotherapy is specifically chosen to decrease the number of lymphocytes in the body. Decreasing the number of patient's lymphocytes first should allow the T cells we infuse to expand and stay longer in their body, and potentially kill cancer cells more effectively. The chemotherapy we will use for lymphodepletion is a combination of cyclophosphamide and fludarabine. Cyclophosphamide and fludarabine are the chemotherapy agents most commonly used for lymphodepletion in immunotherapy clinical trials.

Research Team

Helen Heslop, MD

Principal Investigator

Baylor College of Medicine/Texas Children's Hospital /Houston Methodist Hospital

Eligibility Criteria

This trial is for people with nasopharyngeal carcinoma, a type of cancer linked to the Epstein-Barr virus. Participants must have a certain level of white blood cells, kidney function within specific limits, and not be pregnant or HIV positive. They should expect to live at least six weeks and agree to use effective birth control during and after the study.

Inclusion Criteria

The patient must meet the following eligibility criteria to be included for TREATMENT: Nasopharyngeal Carcinoma in first or subsequent relapse or with primary refractory disease, EBV positive tumor, Patients with life expectancy greater than or equal to 6 weeks, Bilirubin less than or equal to 3x upper limit of normal, AST less than or equal to 5x upper limit of normal, ANC>750/microliter, Platelets > 50,000/microliter, Hgb ≥ 7.0g/dl (can be transfused), Creatinine less than or equal to 2x upper limit of normal for age, Creatinine clearance (as estimated by Cockcroft Gault or Schwartz) greater than or equal to 60 ml/min, Pulse oximetry of > 90% on room air, Off investigational therapy for 4 weeks prior to study entry, Karnofsky or Lansky score of greater than or equal to 50%, Sexually active patients must be willing to utilize one of the more effective birth control methods during the study and for 6 months after the study is concluded. The male partner should use a condom, Informed consent explained to, understood by and signed by patient/guardian. Patient/guardian given copy of informed consent.

I have nasopharyngeal carcinoma that has returned or didn't respond to treatment, and it's EBV positive. I've signed the informed consent.

Exclusion Criteria

I am not pregnant, breastfeeding, or have a severe infection.

At time of Procurement: Known HIV positivity

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Lymphodepletion

Participants receive chemotherapy with cyclophosphamide and fludarabine for lymphodepletion before T-cell infusion

3 days

1 visit (in-person)

T-cell Infusion

Participants receive DNR.NPC-specific T cells infusion, with a second dose given 2 weeks after the first

2 weeks

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, with regular blood tests and imaging studies

15 years

Regular visits every 3 months for 1 year, every 6 months for 4 years, then yearly

Treatment Details

Interventions

• Cyclophosphamide and Fludarabine
• DNR.NPC-specific T cells
• NPC-specific cytotoxic T cells

Trial Overview The trial tests genetically modified T cells designed to fight cancer by targeting EBV-infected cells in patients with nasopharyngeal carcinoma. Some participants will receive these T cells alone, while others will also get chemotherapy drugs cyclophosphamide and fludarabine beforehand to potentially enhance results.

Participant Groups

Group I: DNR.NPC-specific T cells or DNR.NPC-specific T cells + c/f Experimental Treatment 2 Interventions

DNR.NPC-specific T cells or DNR.NPC-specific T cells + c/f

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+

Center for Cell and Gene Therapy, Baylor College of Medicine

Collaborator

Trials

114

Recruited

2,900+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a study of 26 nasopharyngeal carcinoma (NPC) cases, PD-L1 was expressed in 46.2% of cases, and its expression was significantly associated with advanced tumor stages, indicating it may serve as a prognostic marker.

CTLA-4 was found in 88.4% of NPC cases and its high expression correlated with worse overall survival and disease progression, suggesting that targeting both PD-L1 and CTLA-4 could be a promising immunotherapy approach for NPC, particularly in EBV-associated cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Expression of Immune Checkpoint Regulators, Cytotoxic T-Lymphocyte Antigen-4, and Programmed Death-Ligand 1 in Epstein-Barr Virus-associated Nasopharyngeal Carcinoma. Ahmed, MM., Gebriel, MG., Morad, EA., et al.[2022]

References

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

Cell therapy of stage IV nasopharyngeal carcinoma with autologous Epstein-Barr virus-targeted cytotoxic T lymphocytes. [2022]

2. China pubmed.ncbi.nlm.nih.gov

[The ex vivo expansion of gamma delta T cells from the peripheral blood of patients with nasopharyngeal carcinoma and their cytotoxicity to nasopharyngeal carcinoma lines in vitro]. [2014]

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

Functional inactivation of EBV-specific T-lymphocytes in nasopharyngeal carcinoma: implications for tumor immunotherapy. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Adoptive transfer of allogeneic Epstein-Barr virus (EBV)-specific cytotoxic T cells with in vitro antitumor activity boosts LMP2-specific immune response in a patient with EBV-related nasopharyngeal carcinoma. [2020]

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

Treatment of nasopharyngeal carcinoma with Epstein-Barr virus--specific T lymphocytes. [2022]

6. England pubmed.ncbi.nlm.nih.gov

A phase II randomised controlled trial of adjuvant tumour-infiltrating lymphocytes for pretreatment Epstein-Barr virus DNA-selected high-risk nasopharyngeal carcinoma patients. [2023]

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

Expression of Immune Checkpoint Regulators, Cytotoxic T-Lymphocyte Antigen-4, and Programmed Death-Ligand 1 in Epstein-Barr Virus-associated Nasopharyngeal Carcinoma. [2022]

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

Elevated serum levels of transforming growth factor beta1 in Epstein-Barr virus-associated nasopharyngeal carcinoma patients. [2019]

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

Cytotoxic potential despite impaired activation pathways in T lymphocytes infiltrating nasopharyngeal carcinoma. [2022]

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

Tumour heterogeneity and intercellular networks of nasopharyngeal carcinoma at single cell resolution. [2023]

11. France pubmed.ncbi.nlm.nih.gov

[The biology of nasopharyngeal carcinoma in 2001: update and perspective]. [2018]