Engineered T-Cell Therapy for Advanced Cancer

(IGNYTE-ESO Trial)

Recruiting at 72 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)

103 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial will evaluate safety and efficacy of human engineered T-cell therapies, in participants with advanced tumors.

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.

What data supports the effectiveness of the treatment Letetresgene autoleucel (lete-cel, GSK3377794) for advanced cancer?

Research shows that Letetresgene autoleucel (lete-cel) demonstrated clear but temporary antitumor activity in patients with relapsed/refractory multiple myeloma, with a 50% overall response rate in a small pilot study. Additionally, similar T-cell therapies have shown promise in treating other cancers, such as melanoma, by targeting specific tumor antigens. ^{1 2 3 4 5}

Is engineered T-cell therapy, specifically letetresgene autoleucel, safe for humans?

Letetresgene autoleucel (lete-cel) has been studied in patients with relapsed/refractory multiple myeloma and synovial sarcoma, showing a manageable safety profile. Common side effects included grade 3/4 cytopenias (low blood cell counts) and cytokine release syndrome (CRS), which were generally resolved or improved. The treatment demonstrated clear but temporary antitumor activity. ^{1 6 7 8 9}

How is the treatment Letetresgene autoleucel (lete-cel) unique for advanced cancer?

Letetresgene autoleucel (lete-cel) is a unique treatment because it involves genetically modifying a patient's own T-cells to specifically target cancer cells expressing certain proteins, like NY-ESO-1, which is different from standard chemotherapy or radiation that targets all rapidly dividing cells. This personalized approach aims to enhance the body's immune response against cancer. ^{1 10 11 12 13}

Research Team

Adaptimmune

Principal Investigator

Adaptimmune

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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]

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]

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]

References

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

Safety and efficacy of letetresgene autoleucel alone or with pembrolizumab for relapsed/refractory multiple myeloma. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Exploiting the curative potential of adoptive T-cell therapy for cancer. [2023]

3. England pubmed.ncbi.nlm.nih.gov

TCR-engineered T cells to treat tumors: Seeing but not touching? [2021]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Genetic engineering with T cell receptors. [2023]

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

Treating cancer with genetically engineered T cells. [2023]

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

Biomarker correlates with response to NY-ESO-1 TCR T cells in patients with synovial sarcoma. [2022]

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

Real-world evidence of tisagenlecleucel for the treatment of relapsed or refractory large B-cell lymphoma. [2021]

8. England 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. [2022]

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

Ciltacabtagene Autoleucel in Patients With Prior Allogeneic Stem Cell Transplant in the CARTITUDE-1 Study. [2023]

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

Engineering strategies for broad application of TCR-T- and CAR-T-cell therapies. [2022]

11. United States 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. [2021]

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

Multiplex Genome-Edited T-cell Manufacturing Platform for "Off-the-Shelf" Adoptive T-cell Immunotherapies. [2017]

13. Switzerland pubmed.ncbi.nlm.nih.gov

Signaling via a CD28/CD40 chimeric costimulatory antigen receptor (CoStAR™), targeting folate receptor alpha, enhances T cell activity and augments tumor reactivity of tumor infiltrating lymphocytes. [2023]