Engineered T-Cell Therapy for Advanced Cancer

(IGNYTE-ESO Trial)

Not currently recruiting at 77 trial locations

Overseen By EU GSK Clinical Trials Call Center

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: Adaptimmune

Must not be taking: Steroids, Immunosuppressants

Disqualifiers: CNS metastases, Prior malignancy, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: Until disease progression (up to 5 years)

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called letetresgene autoleucel (lete-cel) for individuals with advanced synovial sarcoma or myxoid/round cell liposarcoma, both types of cancer. The goal is to determine if this engineered T-cell therapy is safe and effective. The study consists of two parts: one for those who haven't received other treatments and another for those who have already undergone chemotherapy. It suits individuals with one of these cancers, whose cancer hasn't spread to the brain, and whose tumor shows a specific marker known as NY-ESO-1. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications, but it does mention that washout periods (time without taking certain medications) for prior radiotherapy and systemic chemotherapy must be followed. It's best to discuss your specific medications with the trial team.

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

Research has shown that letetresgene autoleucel, or lete-cel, is generally safe for patients. Studies found no treatment-related deaths, indicating it did not cause any fatal side effects. Most patients tolerated the treatment well. Although some side effects can occur, previous research found them to be non-life-threatening. This suggests that lete-cel is relatively safe for humans. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike standard treatments for advanced cancers like synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCLS), which often involve chemotherapy, letetresgene autoleucel (lete-cel) offers a personalized approach by engineering a patient's own T cells to target cancer. This treatment works by genetically modifying these T cells to better recognize and attack cancer cells, offering a novel mechanism of action compared to traditional chemotherapy. Researchers are excited about lete-cel because it has the potential to improve outcomes by harnessing the body's immune system more effectively, potentially leading to more durable responses with fewer side effects.

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

Research shows that letetresgene autoleucel, or lete-cel, may help treat advanced cancers like synovial sarcoma and myxoid/round cell liposarcoma. In this trial, participants will receive lete-cel as part of the study's substudy arms. Studies have found that 42% of patients with these cancers experienced tumor shrinkage, meaning nearly half saw positive results. This treatment uses specially engineered T-cells to boost the immune system's ability to fight cancer. Previous patients experienced manageable side effects similar to those from other T-cell treatments. This offers hope that lete-cel could be a helpful option for people facing these tough conditions. ^{3 5 6 7 8}

Who Is on the Research Team?

Adaptimmune

Principal Investigator

Adaptimmune

Are You a Good Fit for This Trial?

This trial is for people with advanced tumors that test positive for NY-ESO-1. Participants must be at least 10 years old, have a specific performance status, and match certain HLA types. They should have good organ function and measurable disease but no history of severe autoimmune diseases, previous similar treatments, or recent major surgery.

Inclusion Criteria

Consultation for prior history per protocol specifications

My tumor is positive for NY-ESO-1.

I am mostly active and can carry out daily activities without significant help.

Exclusion Criteria

I have had a stem cell transplant from a donor.

I have a severe autoimmune disease that needed strong medication in the last year.

I have had gene therapy with an integrating vector before.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Leukapheresis

Eligible participants will be leukapheresed to manufacture engineered T cells

1 week

Treatment

Participants receive letetresgene autoleucel, a genetically engineered T-cell therapy

Until disease progression (up to 5 years)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

What Are the Treatments Tested in This Trial?

Interventions

• Cyclophosphamide
• Fludarabine
• Letetresgene autoleucel (lete-cel, GSK3377794)

Trial Overview The trial tests the safety and effectiveness of genetically engineered T-cell therapy (lete-cel) combined with Fludarabine and Cyclophosphamide in treating solid tumors expressing NY-ESO-1 or LAGE-1a. It's designed to see how well these therapies work against advanced cancers.

How Is the Trial Designed?

Group I: Substudy 2: lete-cel in advanced (metastatic or unresectable) SS or MRCLS post anthracycline chemo Experimental Treatment 3 Interventions

Eligible participants will be leukapheresed to manufacture engineered T cells. Participants will then receive letetresgene autoleucel.

Group II: Substudy 1: lete-cel in previously untreated advanced (metastatic or unresectable) SS or MRCLS Experimental Treatment 3 Interventions

Eligible participants will be leukapheresed to manufacture engineered T cells. Participants will then receive letetresgene autoleucel.

Who Is Running the Clinical Trial?

Adaptimmune

Lead Sponsor

Trials

25

Recruited

10,000+

GlaxoSmithKline

Lead Sponsor

Trials

4,834

Recruited

8,389,000+

Headquarters

London, UK

Known For

Vaccines & Medicines

Top Products

**Advair (salmeterol, fluticasone propionate)**, **Shingrix (shingles vaccine)**, **Augmentin (amoxicillin/clavulanate potassium)**, **Ventolin (salbutamol sulfate)

Dame Emma Walmsley

GlaxoSmithKline

Chief Executive Officer since 2017

MA in Classics and Modern Languages from Oxford University

Dr. Hal Barron

GlaxoSmithKline

Chief Medical Officer since 2018

MD from Harvard Medical School

Published Research Related to This Trial

Adoptive transfer of tumor-reactive lymphocytes has shown success in treating metastatic melanoma, leading to the development of T cell receptor (TCR) gene engineering to enhance normal T cells' ability to target tumors.

Initial clinical studies indicate that TCR gene-engineered T cells can effectively mediate tumor regression in patients, showcasing the potential of this approach for treating melanoma and other cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genetic engineering with T cell receptors. Zhang, L., Morgan, RA.[2023]

Adoptive T-cell therapy (ACT) has shown the ability to induce complete and lasting tumor regression in certain cancers, particularly metastatic melanoma, with some patients potentially being cured.

Recent advancements in identifying mutated gene products as targets for TILs and the use of engineered T cells (like those expressing chimeric antigen receptors) suggest that ACT could be expanded to treat a wider range of malignancies beyond melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exploiting the curative potential of adoptive T-cell therapy for cancer. Hinrichs, CS., Rosenberg, SA.[2023]

In a study of 91 patients with relapsed/refractory large B-cell lymphoma (LBCL), treatment with the CAR T-cell therapy tisagenlecleucel (tisa-cel) resulted in a best overall response rate of 60% and a complete response rate of 32%, indicating its efficacy in a real-world setting.

The safety profile of tisa-cel was manageable, with only 5% of patients experiencing severe cytokine release syndrome and 1% experiencing neurotoxicity, suggesting that it can be safely administered in standard-of-care settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world evidence of tisagenlecleucel for the treatment of relapsed or refractory large B-cell lymphoma. Iacoboni, G., Villacampa, G., Martinez-Cibrian, N., et al.[2021]

The manufacturing process for lisocabtagene maraleucel (liso-cel), an autologous CAR T-cell therapy, has been optimized to ensure high product quality and consistency, even with diverse starting materials from patients with various hematologic malignancies.

Improvements in the manufacturing process led to over 95% T-cell purity and enhanced viability of the CAR T-cell product, demonstrating that liso-cel can effectively maintain its therapeutic potential despite variability in patient-derived materials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Developing lisocabtagene maraleucel chimeric antigen receptor T-cell manufacturing for improved process, product quality and consistency across CD19+ hematologic indications. Teoh, J., Brown, LF.[2022]

In a retrospective analysis of 7 patients with prior allogeneic stem cell transplants (alloSCT) who received cilta-cel, an overall response rate of 85.7% was observed, indicating that cilta-cel is effective even in this heavily pretreated group.

The safety profile of cilta-cel in patients with prior alloSCT was similar to that of patients without alloSCT, with manageable side effects like cytokine release syndrome and no reported cases of graft-versus-host disease, suggesting that cilta-cel may be a viable treatment option for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ciltacabtagene Autoleucel in Patients With Prior Allogeneic Stem Cell Transplant in the CARTITUDE-1 Study. Htut, M., Dhakal, B., Cohen, AD., et al.[2023]

The novel TCR 'single editing' (SE) approach allows for the disruption of only the endogenous TCR α chain, enabling the introduction of tumor-specific TCRs, which is safer and more efficient than traditional methods that require extensive cell manipulation.

In preclinical models, SE T cells demonstrated effective tumor rejection with a favorable safety profile, significantly improving survival rates compared to TCR transferred (TR) cells, which showed high alloreactivity and risk of graft-versus-host disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NY-ESO-1 TCR single edited stem and central memory T cells to treat multiple myeloma without graft-versus-host disease. Mastaglio, S., Genovese, P., Magnani, Z., et al.[2021]

T cell receptor (TCR) gene therapy shows promise in treating malignant tumors by enabling T cells to specifically target and respond to tumor cells.

To improve the effectiveness of TCR-engineered T cell therapy, it is crucial to select the right TCRs and develop strategies that enhance T cell movement and accumulation in tumor tissues, potentially leading to better treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TCR-engineered T cells to treat tumors: Seeing but not touching? Debets, R., Donnadieu, E., Chouaib, S., et al.[2021]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO-24-01466

Letetresgene Autoleucel in Advanced/Metastatic Myxoid ... This study is the first demonstrating the clinical promise of lete-cel in HLA-/NY-ESO-1-positive patients with advanced MRCLS.

2. asco.org asco.org/abstracts-presentations/ABSTRACT340279

Safety and efficacy of letetresgene autoleucel (lete-cel; ... A single lete-cel infusion after high LD showed antitumor activity in advanced MRCLS and a manageable safety profile consistent with other lete-cel studies.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT05993299

Study to Evaluate Safety and Antitumor Activity of Lete-Cel ... This trial will evaluate safety and efficacy of human engineered T-cell therapies, in participants with advanced tumors. This trial is a sub study of the Master ...

4. onclive.com onclive.com/view/lete-cel-generates-durable-responses-in-synovial-sarcoma-and-myoxid-round-cell-liposarcoma

Lete-Cel Generates Durable Responses in Synovial ... Patients with metastatic myxoid/round cell liposarcoma or synovial sarcoma expressing NY-ESO-1 and HLA achieved an ORR of 42% with lete-cel.

5. targetedonc.com targetedonc.com/view/fda-grants-lete-cel-btd-in-myxoid-round-cell-liposarcoma

FDA Grants Lete-cel BTD in Myxoid/Round Cell Liposarcoma The phase 2 trial showed a 42% response rate with lete-cel in synovial sarcoma and MRCLS, with manageable adverse events.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11788651/

Safety and Tolerability of Letetresgene Autoleucel ... The study aims to evaluate the safety, tolerability, and antitumor response of letetresgene autoleucel (lete-cel), genetically modified autologous T cells.

7. aacrjournals.org aacrjournals.org/clincancerres/article/doi/10.1158/1078-0432.CCR-24-1591/750315/am/Safety-and-Tolerability-of-Letetresgene-Autoleucel

Safety and Tolerability of Letetresgene Autoleucel (Lete-cel ... Limited anti-tumor activity was observed; one of 18 patients had a durable response persisting for 18 months. Pharmacokinetic data showed similar T-cell ...

8. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39576208/

Pilot Studies in Patients with Advanced Non-Small Cell Lung ... Lete-cel demonstrated a manageable safety profile. No fatal treatment-related serious adverse events (AE) were reported in either study.