letetresgene autoleucel (GSK3377794)

P2, N=103, Active, not recruiting, Adaptimmune | Trial primary completion date: Nov 2022 --> Aug 2024

P1/2, N=34, Terminated, GlaxoSmithKline | Phase classification: P1b/2a --> P1/2

Key eligibility criteria were: age ≥10 years; HLA-A*02:01, A*02:05, or A*02:06; NY-ESO-1+ (≥30% of cells 2+/3+); optional bridging therapy consisting of 2 cycles of doxorubicin (dox) between apheresis and lymphodepletion (LD); and measurable disease. Pts received fludarabine (range: 60–120 mg/m^2) and cyclophosphamide (range: 1800–3600 mg/m^2) for LD, and a transduced T-cell dose between 1 to 15x10^9... This study highlights the challenge to enroll advanced/metastatic treatment-naïve rare sarcoma pts in a cell therapy trial, with 7 pts enrolled over ~2.5 years. Encouraging efficacy was seen in a small population of treatment-naïve pts in the advanced/metastatic setting with 80% ORR, with all responses ongoing at the time of this analysis. The TEAEs for SS1 are consistent with the known safety profile of lete-cel.

P2, N=7, Active, not recruiting, GlaxoSmithKline

Two responders, but none of the non-responders, exhibited elevated cytokine levels post lete-cel infusion. Lete-cel had a manageable safety profile consistent with other lete-cel studies and demonstrated clear but transient antitumor activity in patients with RRMM.

P1b/2a, N=34, Terminated, GlaxoSmithKline | N=54 --> 34 | Trial completion date: May 2025 --> Nov 2022 | Active, not recruiting --> Terminated | Trial primary completion date: May 2025 --> Jun 2022; The study was terminated for reasons pertaining to feasibility

Background: Letetresgene autoleucel (lete-cel; GSK3377794) is an autologous T-cell therapy expressing an affinity-enhanced T-cell recep- tor (TCR) to improve recognition of cancer cells expressing NY-ESO-1 and/or LAGE-1a. This master protocol will evaluate the safety and efficacy of next generation NY-ESO-1 specific TCR-T cells in SS/MRCLS or NSCLC.

Background: Letetresgene autoleucel (lete-cel; GSK3377794) is an autologous T cell therapy expressing an affinity-enhanced T cell receptors (TCR) to improve recognition of cancer cells expressing NY-ESO-1 and/or LAGE-1a. This study is recruiting. This substudy will evaluate the safety and efficacy of GSK3901961 in NSCLC.

P2, N=103, Active, not recruiting, GlaxoSmithKline | Recruiting --> Active, not recruiting

Background Letetresgene autoleucel (lete-cel; GSK3377794) is a first-generation (1st gen) NY-ESO-1-specific T-cell receptor (TCR) therapy with demonstrated clinical activity in solid tumors. Conclusions In addition to supporting the hypothesis that genetic reprogramming with Gen-R technology can delay the onset of exhaustion and improve the long-term durable functions of LYL331, these data show that c-Jun overexpression can provide immediate benefits to the NY-ESO-1-specific TCR therapy during primary stimulation in vitro . Based on these promising pre-clinical data, LYL331 may have the potential to improve clinical responses in patients with solid tumor malignancies.

Autologous T cells transduced to express a high affinity T-cell receptor specific to NY-ESO-1 (letetresgene autoleucel, lete-cel) show promise in the treatment of metastatic synovial sarcoma, with 50% overall response rate. Analysis of tumor samples post-treatment illustrates lete-cel infiltration and a decrease in expression of macrophage genes, suggesting remodeling of the tumor microenvironment. Here we report potential predictive and pharmacodynamic markers of lete-cel response that may inform LDR, cell dose, and strategies to enhance anticancer efficacy.

Letetresgene autoleucel (lete-cel), an adoptive T-cell receptor therapy, is currently being investigated in clinical trials in previously treated metastatic SS (mSS) patients (pts) with NY-ESO-1 positive tumors who express at least one of the human leukocyte antigen (HLA) HLA-A*02-01/05/06 (HLA*A) alleles, with encouraging preliminary results... This is the first study to examine the prognostic impact of both NY-ESO-1 and HLA*A type in mSS patients, and the first prognostic study in this population using real-world data and archival tissue. Assessing efficacy of adoptive T-cell therapies in highly selected patients, versus standard treatment through randomized trials, is difficult. In this context, it is essential to ensure that expression of NY-ESO-1 and HLA*A type does not modify the natural history of the disease.Unadjusted results report a longer OS in patients whose tumors express NY-ESO-1, even if the prognostic impact of this antigen disappears in the multivariate analysis.

Background Letetresgene autoleucel is a genetically engineered NY-ESO-1–specific TCR T-cell therapy being investigated in mSS patients whose tumours express the NY-ESO-1 antigen and who are HLA-A*02:01, HLA-A*02:05, or HLA-A*02:06 allele positive (NY+/HLA+)...Conclusions Nationally representative prevalence and clinical profile of mSS patients with NY+/HLA+ tumours were previously unknown and have been documented by this study. Among primary tumour samples, no relationship was observed between NY-ESO expression and age of samples, HLA sub-type, or line of treatment.

Background: Letetresgene autoleucel (lete-cel; GSK3377794) is an autologous T-cell therapy expressing an affinity-enhanced T-cell receptor (TCR) to improve recognition of cancer cells expressing NY-ESO-1 and/or LAGE-1a. Analyses will be descriptive. The master protocol is open for recruitment.

P2, N=23, Completed, GlaxoSmithKline | Active, not recruiting --> Completed | Trial completion date: Aug 2022 --> Mar 2022

P1b/2a, N=54, Active, not recruiting, GlaxoSmithKline | Recruiting --> Active, not recruiting

We previously generated specific peptide enhanced affinity receptor TCRs recognizing the HLA-A*02-restricted peptides New York esophageal squamous cell carcinoma 1 (NY-ESO-1)/l-Ag family member-1A (TCR: GSK3377794, formerly NY-ESO-1) and melanoma Ag gene A10 (TCR: ADP-A2M10, formerly melanoma Ag gene A10). In this article, we show that exogenous TGF-β inhibited in vitro proliferation and effector functions of human T cells expressing these first-generation high-affinity TCRs, whereas inhibition was reduced or abolished in the case of second-generation TCRs coexpressed with dnTGFβRII (e.g., GSK3845097)...As an example, immunohistochemistry/RNAscope identified TGF-β-positive cells close to T cells in tumor nests and stroma, which had low frequencies of cells expressing IFN-γ in a non-small cell lung cancer setting. Coexpression of dnTGFβRII may therefore improve the efficacy of TCR-transduced T cells.

NY-ESO-1 expression across SS and MRCLS indications express highly similar IHC intensity levels inclusive of 1+, 2+ and 3+ and demonstrated a high prevalence of 71% and 97%, respectively at TPS 1%. As such, NY-ESO-1 strong staining in both SS and MRCLS indications, in a high percentage of patients evaluated supports the tests utility as an aid in the identification of patients who may be eligible for NY-ESO-1 specific T cells (lete-cel) TCR targeted therapy. NY-ESO-1 expression levels and positive prevalence using a clinical trial IHC assay is consistent with what has been reported in the literature (1,2) and demonstrated consistent nuclear and cytoplasmic staining localization in tumor cells in SS and MRCLS sub-types, which are morphologically distinct forms of cancers arising from soft tissues.

Objective: Letetresgene autoleucel (lete-cel; GSK3377794) is an autologous T-cell therapy using a genetically modified T-cell receptor (TCR) to improve recognition of cancer cells expressing NY-ESO-1/LAGE-1a...Exploratory endpoints include laboratory parameters, overall survival, and anti-GSK3901961 or -GSK3845097 titers as applicable... This study was funded by GSK (209012; NCT04526509). Editorial support was provided by Eithne Maguire, PhD and Katie Crossland, PhD of Fishawack Indicia, part of Fishawack Health, UK; funded by GSK. This abstract was previously presented at the American Association for Cancer Research (April 10–15 and May 17–21, 2021) and the American Society of Clinical Oncology Annual Meeting (June 4–8, 2021).

This study was funded by GSK (208467; NCT03967223). Editorial support was provided by Eithne Maguire, PhD, and Katie Crossland, PhD, of Fishawack Indicia, part of Fishawack Health, UK, and funded by GSK. This abstract was first presented at American Society of Clinical Oncology Annual Meeting on June 4 8, 2021.

This open label, pilot study evaluates lete-cel efficacy and safety in advanced MRCLS following low-dose (Cohort 1 [C1]; 30 mg/m2 fludarabine [flu] x 3d + 600 mg/m2 cyclophosphamide [cy] x 3d) or high-dose (Cohort 2 [C2]; 30 mg/ m2 flu x 4d + 900 mg/m2 cy x 3d; initiated based on C1 data) LD. 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. The trial is active but no longer recruiting (NCT02992743). MRCLS is included in a separate, ongoing lete-cel study (NCT03967223).

A single lete-cel infusion was associated with antitumor activity in 6/6 heavily pretreated RRMM patients, including 1 CR, 1 VGPR, 1PR. Both responses in Arm 2 occurred prior to pembro initiation. The associated safety profile was manageable and consistent with that seen in other lete-cel studies.

P2, N=23, Active, not recruiting, GlaxoSmithKline | Trial completion date: Oct 2021 --> Aug 2022

Higher AUC0–28d was correlated with Cmax and maximum tumor volume reduction. Trial Registration NCT02992743

P2, N=23, Active, not recruiting, GlaxoSmithKline | Phase classification: P1/2 --> P2

Background: Letetresgene autoleucel (lete-cel; GSK3377794) are autologous T cells engineered to express a high affinity TCR capable of recognizing the HLA-A*02:01, *02:05, *02:06 and SLLMWITQC antigen complex... NY-ESO-1 & LAGE-1a were expressed in all indications investigated. NGS was highly correlated to IHC and Sanger sequencing and may be an alternative method for identifying a higher number of tumors that express biomarkers of interest. Our data show a unique platform for comprehensive assessment of disease which may improve patient stratification and management strategies.

P1/2, N=20, Active, not recruiting, GlaxoSmithKline | Recruiting --> Active, not recruiting | Phase classification: P2 --> P1/2

Clinical Trial Registry Number: NCT04526509 Funding: GlaxoSmithKline (209012) Background: Letetresgene autoleucel (lete-cel; GSK3377794) is an autologous T-cell therapy using a genetically modified T-cell receptor (TCR) to improve recognition of cancer cells expressing NY-ESO-1/LAGE-1a . Exploratory endpoints include laboratory parameters, overall survival, and anti-GSK3901961 or -GSK3845097 titers as applicable . Analyses will be descriptive.

Funding: GSK (209012; NCT04526509) Background: Letetresgene autoleucel (lete-cel; GSK3377794) is an autologous T-cell therapy expressing a genetically modified T-cell receptor (TCR) to improve recognition of cancer cells expressing NY-ESO-1 and/or LAGE-1a. Exploratory endpoints include laboratory parameters, overall survival, and anti-GSK3901961 and anti-GSK3845097 titers for the respective substudies. The substudies are open and recruiting.

P1, N=6, Terminated, GlaxoSmithKline | Phase classification: P2 --> P1 | N=20 --> 6 | Trial completion date: Jan 2023 --> Nov 2020 | Recruiting --> Terminated | Trial primary completion date: Apr 2021 --> Jul 2020; The study was terminated following an internal review of the company's research and development portfolio

Background: Letetresgene autoleucel (lete-cel; GSK3377794) is an autologous T cell therapy engineered to express a modified T cell receptor (TCR) to improve recognition of NY-ESO-1 and/or LAGE-1a expressing cancer cells. Exploratory endpoints include laboratory parameters, overall survival, progression-free survival, disease control rate, time to response, and anti-GSK3901961 titers. The study is currently open and recruiting.

Background: Letetresgene autoleucel (lete-cel; GSK3377794) is an autologous T cell therapy engineered to express a modified T cell receptor (TCR) to improve recognition of NY-ESO-1 and/or LAGE-1a expressing cancer cells. Exploratory endpoints include laboratory parameters, overall survival, progression-free survival, disease control rate, time to response, and anti-GSK3901961 titers. The study is currently open and recruiting.

Background: Letetresgene autoleucel (lete-cel; GSK3377794) is an autologous T cell therapy engineered to express a modified T cell receptor (TCR) to improve recognition of NY-ESO-1 and/or LAGE-1a expressing cancer cells. Exploratory endpoints include laboratory parameters, overall survival, progression-free survival, disease control rate, time to response, and anti-GSK3901961 titers. The study is currently open and recruiting.

Background: Letetresgene autoleucel (lete-cel; GSK3377794) is an autologous T cell therapy engineered to express a modified T cell receptor (TCR) to improve recognition of NY-ESO-1 and/or LAGE-1a expressing cancer cells. Exploratory endpoints include laboratory parameters, overall survival, progression-free survival, disease control rate, time to response, and anti-GSK3901961 titers. The study is currently open and recruiting.

P1, N=10, Completed, GlaxoSmithKline | Active, not recruiting --> Completed | Trial completion date: Dec 2021 --> Aug 2020

P1, N=10, Active, not recruiting, GlaxoSmithKline | Trial completion date: Aug 2020 --> Dec 2021

P1b/2a, N=54, Recruiting, GlaxoSmithKline | Trial completion date: Jul 2021 --> May 2025 | Trial primary completion date: Jul 2021 --> May 2025

Patients in both arms will provide cells via leukapheresis to manufacture autologous NY-ESO-1–specific T cells, undergo lymphodepletion (fludarabine + cyclophosphamide), and then receive GSK3377794 infusion (1−8x109 transduced T cells)...Results - Conclusion As of January 2020, 3 patients have been treated. Funding: GlaxoSmithKline (208470).

Patients in both arms will provide cells via leukapheresis to manufacture autologous NY-ESO-1–specific T cells, undergo lymphodepletion (fludarabine + cyclophosphamide), and then receive GSK3377794 infusion (1−8x109 transduced T cells)...As of January 2020, 3 patients have been treated. Funding: GlaxoSmithKline (208470) Research Funding: GlaxoSmithKline

P1, N=10, Active, not recruiting, GlaxoSmithKline | Trial completion date: Dec 2021 --> Aug 2020

Each patient will undergo leukapheresis to obtain cells for autologous NY-ESO-1-specific T-cell manufacturing, followed by lymphodepleting chemotherapy with fludarabine + cyclophosphamide, then GSK3377794 infusion of 1−8x109 transduced T cells...A similar presentation will be presented at the ASH Annual Meeting, Orlando, FL, USA, Dec 7-10, 2019. This study (NCT03168438) is funded by GSK.

P1, N=10, Active, not recruiting, GlaxoSmithKline | Trial completion date: Sep 2020 --> Dec 2021 | Trial primary completion date: Feb 2020 --> Jun 2020