Gene-Modified T Cells for Advanced Cancers

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Roswell Park Cancer Institute

Must not be taking: Corticosteroids, Immunosuppressive drugs

Disqualifiers: Severe autoimmune, Active infection, Brain metastases, others

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

Compensation: Varies

Number of Visits: 1

Duration: 1 week

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the best dose and evaluate the side effects of gene-modified T cells, with or without the chemotherapy drug decitabine, in treating advanced cancers. The focus is on cancers that express the NY-ESO-1 gene and have spread to other parts of the body. By modifying T cells (a type of immune cell) to recognize the NY-ESO-1 gene, the trial investigates whether this can help the immune system fight cancer more effectively. Good candidates for this trial include those with advanced melanoma, ovarian cancer, synovial sarcoma, or other solid tumors that have not responded to standard treatments and test positive for the NY-ESO-1 gene. 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 have to stop taking my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you must not be on any other investigational agents and should not have used systemic steroids in the last 4 weeks before enrollment, except for certain allowed uses like inhaled or topical steroids.

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

Research has shown that gene-modified T cells, like those in this trial, have been used safely in past studies. These studies found that the treatment is generally well-tolerated, with most side effects being temporary. For instance, trials with similar treatments for other cancers reported manageable side effects like tiredness or fever.

When combined with decitabine, research indicates that gene-modified T cells can also be safe. Decitabine, a chemotherapy drug, may cause some common side effects related to chemotherapy, but these are usually not severe. The combination aims to enhance treatment effectiveness without introducing major safety concerns.

As this trial is in an early phase, it focuses on safety and determining the right dose. The treatment has passed initial safety tests but is still under careful study to ensure it remains safe while effectively fighting cancer. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for advanced cancers, which often include chemotherapy and radiation, gene-modified T cells offer a cutting-edge approach by harnessing the body's own immune system to fight cancer. This treatment involves modifying a patient's T cells to better recognize and attack cancer cells. Researchers are particularly excited because this method targets tumors more precisely and could potentially lead to fewer side effects compared to traditional therapies. Additionally, the use of TGFbDNRII-transduced tumor-infiltrating lymphocytes represents a novel mechanism of action that could improve patient outcomes by overcoming the suppressive tumor environment, enhancing the immune response.

What evidence suggests that this trial's treatments could be effective for advanced cancers?

Research has shown that specially modified T cells can effectively target and fight tumors. These T cells are designed to attack specific cancer cells, such as those with the NY-ESO-1 gene. In this trial, participants in Cohort I will receive TGFbDNRII-transduced autologous tumor-infiltrating lymphocytes (TILs) following cyclophosphamide treatment. Studies have found that using TILs can lead to significant improvements in patients with advanced cancers.

Participants in Cohort II will receive a combination of decitabine, cyclophosphamide, and TGFbDNRII-transduced TILs. Decitabine makes certain cancer cells more noticeable to the immune system. This combination aims to strengthen the immune system's attack on cancer cells, offering hope for people with advanced cancers. ^{1 2 3 5 6}

Who Is on the Research Team?

Philip McCarthy

Principal Investigator

Roswell Park Cancer Institute

Are You a Good Fit for This Trial?

This trial is for patients with advanced cancers like melanoma, ovarian, peritoneal or fallopian tube carcinoma, and synovial sarcoma that express the NY-ESO-1 gene. Participants need available tissue for testing or agree to a biopsy, have a caregiver nearby, meet medical criteria, use birth control, understand the study's nature and consent to it. They must not have brain metastases or severe autoimmune diseases.

Inclusion Criteria

Patients must understand the investigational nature of the study and provide informed consent

Patients must arrange for a caregiver available 24/7 and lodging within 45 minutes drive to the treatment center

Patients must meet specific medical and laboratory criteria

Exclusion Criteria

You have had a serious autoimmune disease or inflammatory bowel disease in the past.

Pregnancy or breast-feeding

I am currently taking steroids or drugs that affect my immune system.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients undergo leukapheresis and receive cyclophosphamide and/or decitabine followed by TGFbDNRII-transduced autologous tumor infiltrating lymphocytes infusion

1 week

Multiple visits for leukapheresis and infusions

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 15 years

Visits at weeks 1-4, 6, 8, 12, at 6 and 9 months, every 6 months for 5 years, then yearly for 10 years

What Are the Treatments Tested in This Trial?

Interventions

• Decitabine
• Gene-Modified T Cells

Trial Overview The trial tests gene-modified T cells with/without decitabine in treating advanced malignancies expressing NY-ESO-1. It aims to find out how well these treatments work and their best doses by modifying patients' T cells to target tumor cells better.

How Is the Trial Designed?

Group I: Cohort II (decitabine, cyclophosphamide, TCR/dnTGFbetaRII) Experimental Treatment 5 Interventions

Patients undergo leukapheresis on day -6 and receive decitabine IV over 1 hour on days -6 to -4 and cyclophosphamide IV over 2 hours on days -3 and -2. Patients then receive TGFbDNRII-transduced autologous tumor infiltrating lymphocytes IV over 15 minutes on day 0. Eligible patients who showed initial response/disease control, may receive a second TGFbDNRII-transduced autologous tumor infiltrating lymphocytes infusion at any time after progression is confirmed.

Group II: Cohort I (cyclophosphamide, TCR/dnTGFbetaRII) Experimental Treatment 4 Interventions

Patients undergo leukapheresis on day -6 and receive cyclophosphamide IV over 2 hours on days -5 and -4. Patients then receive TGFbDNRII-transduced autologous tumor infiltrating lymphocytes IV over 15 minutes on day 0. Eligible patients who showed initial response/disease control, may receive a second TGFbDNRII-transduced autologous tumor infiltrating lymphocytes infusion at any time after progression is confirmed.

Who Is Running the Clinical Trial?

Roswell Park Cancer Institute

Lead Sponsor

Trials

427

Recruited

40,500+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

CAR-T cell therapies have shown significant clinical success in treating cancer by effectively targeting tumor-associated antigens, leading to complete and durable responses in many patients during early trials.

Despite their effectiveness, there are safety concerns regarding potential toxicities from engineered cells, prompting the exploration of strategies like integrating failsafe switches to enhance safety in cancer immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Engineering Hematopoietic Cells for Cancer Immunotherapy: Strategies to Address Safety and Toxicity Concerns. Resetca, D., Neschadim, A., Medin, JA.[2018]

Genetic modification of T cells to express receptors specific for tumor-associated antigens can redirect their function, enhancing their ability to target and eliminate tumor cells, which is crucial for treating common cancers.

Recent advances in gene design and cell production techniques have improved the clinical application of this adoptive immunotherapy, potentially leading to more effective treatments for patients with various types of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genetic redirection of T cells for cancer therapy. Westwood, JA., Kershaw, MH.[2010]

Genetic modification of T lymphocytes enhances their ability to recognize and attack tumor cells, which is crucial for improving cancer immunotherapy.

These modifications not only boost antitumor activity but also improve safety and allow for tracking of T cells using non-invasive imaging techniques, making them valuable for both research and treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting tumours with genetically enhanced T lymphocytes. Sadelain, M., Rivière, I., Brentjens, R.[2021]

Engineered T cell therapies, like CAR T cells and TCR T cell therapies, have shown remarkable efficacy in treating certain blood cancers, highlighting their potential as a powerful tool in cancer immunotherapy.

However, these therapies also pose unique safety challenges, such as cytokine release syndrome and neurotoxicity, which require careful nonclinical safety assessments to ensure patient safety during development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nonclinical safety assessment of engineered T cell therapies. Lebrec, H., Maier, CC., Maki, K., et al.[2022]

T cells play a crucial role in fighting cancer, and recent advances in immunotherapy are focusing on enhancing their effectiveness through genetic engineering.

The introduction of tumor-specific receptors, such as Chimeric Antigen Receptors (CAR) and T cell receptors (TcR), shows promise in ongoing clinical trials, indicating a potential for strong anti-tumor responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Muscle CARs and TcRs: turbo-charged technologies for the (T cell) masses. Kalos, M.[2012]

Adoptive transfer of antigen-specific T cells shows promise for treating viral infections in immunosuppressed patients, but achieving effective T-cell therapy for cancer is more challenging due to issues like T-cell tolerance and impaired survival in the body.

Genetic modification of T cells before transfer may help overcome obstacles such as tumor evasion tactics and improve the effectiveness of T-cell therapies for both cancer and infectious diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genetic modification of T cells for immunotherapy. Berger, C., Berger, M., Feng, J., et al.[2019]

T cells are highly effective in targeting cancer due to their sensitivity and specificity to antigens, but challenges like the rarity of tumor-reactive T cells and their unpredictable persistence limit their use in therapies.

Advancements in genetic modification technologies are being explored to enhance T cell responses to tumor antigens, with ongoing research focused on leveraging the diverse characteristics of T cells to improve the efficacy and safety of cancer immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genetically retargeting CD8+ lymphocyte subsets for cancer immunotherapy. Turtle, CJ., Riddell, SR.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9713507/

Decitabine increases neoantigen and cancer testis antigen ... We demonstrate that DAC increases neoantigen and CTA mRNA expression through DNA hypomethylation. This results in increased neoantigen presentation by MHC class ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12436572/

Tumor-Infiltrating Lymphocyte Therapy for the Treatment of ... Tumor-infiltrating lymphocyte (TIL) therapy is a type of personalized immunotherapy that harnesses the antitumor activity of endogenous immune ...

3. go.drugbank.com go.drugbank.com/conditions/DBCOND0030058

Metastatic Melanoma (DBCOND0030058) NCT01740557. Genetically Modified Therapeutic Autologous Lymphocytes Followed by Aldesleukin in Treating Patients With Stage III or Metastatic Melanoma.

4. sciencedirect.com sciencedirect.com/science/article/pii/S1465324924009708

Entering a new era of tumor-infiltrating lymphocyte cell ... All in all, outcomes achieved with TIL cell therapy compare favorably with current best available therapy in the second-line advanced melanoma and beyond, where ...

5. nature.com nature.com/articles/s41392-025-02269-w

CAR-T cell therapy for cancer: current challenges and ... This genetic modification reduces the risk of T-cell exhaustion, graft-versus-host effect, and enhances the overall efficacy of CAR-T therapies, ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT03019003

Oral Decitabine (ASTX727) and Durvalumab in Recurrent ... This is a non-randomized, open-label, Phase Ib study to assess the safety and efficacy of a DNA methyltransferase inhibitor and immune checkpoint ...