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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment for nasopharyngeal carcinoma (NPC), a cancer often linked to the Epstein Barr virus (EBV). Researchers are testing engineered T cells designed to recognize and attack EBV-infected cancer cells. The goal is to determine if these T cells, especially when modified to resist certain cancer defenses, can survive longer in the body and effectively combat the tumor. Individuals with NPC who have an EBV-positive tumor and have experienced a relapse or have not responded to initial treatment might be suitable candidates for this trial. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity 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. However, you must be off any investigational therapy for 4 weeks before joining the study.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that EBV-specific cytotoxic T cells, which target virus-infected cells, are generally safe for patients. In previous studies, patients who received these T cells did not experience major safety issues. The new treatment, DNR.NPC-specific T cells, includes a feature that helps them resist a protein called TGF-beta, which usually helps cancer evade the immune system.

The safety of similar T cell treatments, including those with the DNR receptor, has been studied and is often well-tolerated, meaning patients usually do not experience severe side effects. However, this study is in its early stages, so researchers are still learning about the safety of this specific treatment.

Patients will also receive chemotherapy with drugs like cyclophosphamide and fludarabine before the T cell treatment. This is common in these studies to enhance the effectiveness of the T cells. While chemotherapy can have side effects, it is a standard part of this approach. Overall, existing evidence suggests that the treatment is likely to be safe, but ongoing research will provide more information. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for nasopharyngeal cancer, which often include chemotherapy and radiation, the investigational approach using DNR.NPC-specific T cells is unique because it harnesses the body's immune system to specifically target cancer cells. These T cells are engineered to resist TGF-beta, a protein often exploited by cancer cells to evade immune detection. By overcoming this resistance, the treatment aims to enhance the body's natural ability to fight the cancer more effectively. Researchers are excited about this treatment because it represents a shift towards personalized immunotherapy, potentially offering a more targeted and less toxic alternative to traditional therapies.

What evidence suggests that this trial's treatments could be effective for nasopharyngeal cancer?

Research has shown that T cells, a type of immune cell, can be trained to attack cancer cells linked to the Epstein-Barr virus (EBV), often found in nasopharyngeal carcinoma (NPC). In earlier studies, these EBV-specific T cells helped shrink tumors in 14 out of 30 patients with NPC. In this trial, participants will receive either DNR.NPC-specific T cells alone or in combination with Cyclophosphamide and Fludarabine. The DNR.NPC-specific T cells are enhanced with a special receptor called DNR, which makes them resistant to TGFbeta, a substance that helps cancer cells evade the immune system. By resisting TGFbeta, T cells can live longer and fight cancer cells more effectively. These findings suggest that this approach could improve treatment outcomes for patients with NPC. ^{1 3 6 7 8}

Who Is on the Research Team?

Helen Heslop, MD

Principal Investigator

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

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT02065362

TGF-beta Resistant Cytotoxic T-lymphocytes in Treatment ... DNR makes T cells resistant to TGFbeta, a factor secreted by cancer cells that helps them escape being killed by the immune system.

2. withpower.com withpower.com/trial/phase-1-carcinoma-1-2015-a4360

TGF-beta Resistant Cytotoxic T-lymphocytes for ... 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 ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12147895/

Tumor-infiltrated double-negative regulatory T cells predict ... Tumor-infiltrated double-negative regulatory T cells predict outcome of T cell-based immunotherapy in nasopharyngeal carcinoma.

4. nature.com nature.com/articles/s41698-024-00601-1

Immunotherapy for recurrent or metastatic nasopharyngeal ... In this review, we will focus on clinically approved immunotherapy regimens for R/M-NPC therapy and discuss novel immunotherapy strategies, challenges, and ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S0305737224001683

Advances and challenges in immunotherapy for locally ... This review provides an overview of immunotherapy principles in NPC, discusses recent advances and challenges associated with ICIs in the primary treatment for ...

6. reporter.nih.gov reporter.nih.gov/search/_h5SkPTHv0KNhC8zoqZAdA/project-details/9005819

RePORT RePORTER - National Institutes of Health (NIH) | Investigators in Project 4 (S. Gottschalk and H. Heslop) and elsewhere have shown that administration of EBV-specific cytotoxic T cells (EBV-CTLs) is safe and ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11499120/

Revolutionizing the treatment for nasopharyngeal cancer Knockdown of B7-H3 in tumor cells, combined with anti-PD-L1 treatment, restored NK cell function and enhanced cytotoxicity against NPC cells.

8. journals.sagepub.com journals.sagepub.com/doi/10.1177/17588359221096214

Current status and advances of immunotherapy in ... ... DNR.NPC-specific T-cells ... specific T cells results in sustained clinical responses in patients with locoregional nasopharyngeal carcinoma.