Delving into the Latest Updates on Letetresgene autoleucel with Synapse

Overview

Basic Info

Drug Type

TCR-T Cell therapy

Synonyms

Lete-cel, NY-ESO-1c259-modified T cells, NYESO SPEAR Tcell therapy GlaxoSmithKline

+ [4]

Target

NY-ESO-1

Action

modulators

Mechanism

NY-ESO-1 modulators(Cancer/testis antigen 1 modulators)

Therapeutic Areas

NeoplasmsSkin and Musculoskeletal DiseasesOther Diseases

Active Indication

LAGE-1a Positive Solid TumorsMyxoid LiposarcomaNY-ESO-1 Positive Solid Tumors+ [1]

Inactive Indication

Advanced Lung Non-Small Cell CarcinomaAdvanced Lung Non-Small Cell Squamous CarcinomaGastrointestinal Neoplasms+ [8]

Originator Organization

Adaptimmune Ltd.

Active Organization

Adaptimmune Ltd.

Inactive Organization

GSK PlcMerck GmbH

Drug Highest PhasePhase 2

First Approval Date-

RegulationBreakthrough Therapy (United States)

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Structure/Sequence

Sequence Code 1277315156

Source: *****

A Phase 1b/2a Pilot Randomized Study to Evaluate the Safety and Tolerability of Autologous T-Cells Expressing Enhanced TCRs (T-Cell Receptors) Specific for NY-ESO-1/LAGE-1a (GSK3377794) Alone, or in Combination with Pembrolizumab in HLA-A2+ Participants with NY-ESO-1- or LAGE-1a-Positive Advanced or Recurrent Non-Small Cell Lung Cancer - Pilot immunotherapy study with GSK3377794 (NY-ESO T-cells) in NSCLC patients.

Start Date28 Feb 2020

Sponsor / Collaborator

GSK Plc

NCT03967223

/ Active, not recruitingPhase 2

Master Protocol to Assess the Safety and Antitumor Activity of Genetically Engineered NY-ESO-1-Specific (c259) T Cells, Alone or in Combination With Other Agents, in HLA-A2+ Participants With NY-ESO-1 and/or LAGE-1a Positive Solid Tumors (IGNYTE-ESO)

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

Start Date31 Dec 2019

Sponsor / Collaborator

Adaptimmune Ltd.

NCT05993299

/ Active, not recruitingPhase 2

Evaluation of Safety and Antitumor Activity of Lete-Cel (GSK3377794) in HLA-A2+ Participants With NY-ESO-1 Positive Previously Untreated Advanced (Metastatic or Unresectable) Synovial Sarcoma and Myxoid/Round Cell Liposarcoma

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 study NCT03967223.

Start Date31 Dec 2019

Sponsor / Collaborator

Adaptimmune Ltd.

100 Clinical Results associated with Letetresgene autoleucel

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100 Translational Medicine associated with Letetresgene autoleucel

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100 Patents (Medical) associated with Letetresgene autoleucel

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5

Literatures (Medical) associated with Letetresgene autoleucel

03 Feb 2025·Clinical Cancer Research

Safety and Tolerability of Letetresgene Autoleucel (GSK3377794): Pilot Studies in Patients with Advanced Non–Small Cell Lung Cancer

Article

Author: Zajic, Stefan ; Lopes, Gilberto ; Calvo, Emiliano ; Govindan, Ramaswamy ; Suchindran, Sunil ; Goodison, Sophia ; Neal, Joel ; Felip, Enriqueta ; Eleftheriadou, Ioanna ; Tarek, Nidale ; Jenkins, Ben ; O’Cearbhaill, Róisín Eilish ; Chisamore, Michael ; Carlisle, Jennifer W. ; Schoenfeld, Adam J. ; Hiltermann, T. Jeroen N. ; Edelman, Martin J. ; Corigliano, Ellie ; Altan, Mehmet ; Heymach, John V. ; Furqan, Muhammad ; Zauderer, Marjorie ; Villaruz, Liza C. ; Ramos-Hernandez, Natalia

AbstractPurpose:The study aims to evaluate the safety, tolerability, and antitumor response of letetresgene autoleucel (lete-cel), genetically modified autologous T cells expressing a T-cell receptor specific for New York esophageal squamous cell carcinoma 1 (NY-ESO-1)/LAGE-1a shared epitope, alone or in combination with pembrolizumab, in HLA-A*02–positive (HLA-A*02:01, HLA-A*02:05, and/or HLA-A*02:06) patients with NY-ESO-1– and/or LAGE-1a–positive non–small cell lung cancer.Patients and Methods:Study 208749 was a single-arm study of lete-cel alone. Study 208471 was a multiarm study of lete-cel alone or in combination with pembrolizumab in patients with advanced or recurrent non–small cell lung cancer.Results:More than 2,500 patients were screened for target expression. In the multiarm study, 738 (45%) of 1,638 tested patients were HLA-A*02–positive. NY-ESO-1 and LAGE-1a testing was positive in 12% (62/525) and 4% (15/348) of tested patients, respectively. Forty-one patients positive for HLA-A*02 and antigen expression were screened in the single-arm study. Overall, 43 patients underwent leukapheresis and 18 received lete-cel across studies. Lete-cel demonstrated a manageable safety profile. No fatal treatment-related serious adverse events (AE) were reported in either study. Cytopenias and cytokine release syndrome were the most common treatment-emergent AEs. Combining pembrolizumab with lete-cel did not seem to increase toxicity over lete-cel alone. Limited antitumor activity was observed; one of 18 patients had a durable response persisting for 18 months. Pharmacokinetic data showed similar T-cell expansion in all patients.Conclusions:Extensive HLA-A*02 and antigen expression testing was performed to identify potential participants. Lete-cel was generally well tolerated and had no unexpected AEs. Antitumor activity was observed in a limited number of patients.

11 Apr 2023·Blood Advances

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

Article

Author: Zajic, Stefan ; Rapoport, Aaron P. ; Urbano, Alisa ; Eleftheriadou, Ioanna ; Chisamore, Michael ; Suchindran, Sunil ; Huff, Anne ; Hoffman, James E. ; D’Souza, Jimson W. ; Kapoor, Gurpreet S. ; Faitg, Thomas ; Nishihori, Taiga

AbstractThis pilot study assessed the safety and efficacy of letetresgene autoleucel (lete-cel; GSK3377794), a genetically modified autologous T-cell therapy targeting New York esophageal squamous cell carcinoma-1 (NY-ESO-1)/L antigen family member 1 isoform A (LAGE-1a)–positive myeloma cells, alone or in combination with pembrolizumab in patients with relapsed/refractory multiple myeloma. Eligible patients expressed NY-ESO-1 and/or LAGE-1a and either HLA-A∗02:01, ∗02:05, or ∗02:06. Patients received lete-cel single infusion alone (arm 1) or with pembrolizumab (arm 2). 127 patients were screened, and 6 patients (3 per arm) were enrolled; patients in arm 1 and 2 received lete-cel alone, or with pembrolizumab, respectively. All patients exhibited grade 3/4 cytopenias, which resolved or improved to grade 1. One patient (arm 1) had grade 3/4 lete-cel–related adverse events (AEs); 2 patients (arm 2) had grade 3/4 AEs related to lete-cel and lymphodepletion. Three patients with grade 1/2 cytokine release syndrome (CRS) exhibited elevated post–lete-cel interleukin-6 levels versus those without CRS. Pooled overall response rate was 50% including 1 patient each with confirmed clinical response, very good clinical response, and partial response, and progression-free survival ranged from 1.3 to 5.2 months. Responders (arm 1: n = 1; arm 2: n = 2) had a time-to-response of 3 weeks, duration of response of 2.1 months. Two responders, but no nonresponders, exhibited elevated cytokine levels after lete-cel infusion. Lete-cel had a manageable safety profile and demonstrated clear but transient antitumor activity in patients with relapsed/refractory multiple myeloma. This trial was registered at www.clinicaltrials.gov as #NCT03168438.

01 Dec 2019·Journal for ImmunoTherapy of CancerQ2 · MEDICINE

Systemic and local immunity following adoptive transfer of NY-ESO-1 SPEAR T cells in synovial sarcoma

Q2 · MEDICINE

ArticleOA

Author: Mackall, Crystal L ; Chagin, Karen ; Trivedi, Trupti ; Dryer-Minnerly, Rebecca ; Van Tine, Brian A ; Winkle, Erin Van ; Wang, Ruoxi ; Fayngerts, Svetlana ; Nunez, Daniel ; Araujo, Dejka M ; Iyengar, Malini ; Amado, Rafael ; Abdul Razak, Albiruni R ; Tipping, Alex J ; Melchiori, Luca ; Druta, Mihaela ; Betts, Gareth ; Bath, Natalie ; Wilky, Breelyn ; D'Angelo, Sandra P ; Binder, Gwendolyn K ; Basu, Samik ; Demetri, George D ; Ramachandran, Indu ; Navenot, Jean-Marc ; Lowther, Daniel E ; Chow, Warren A ; Grupp, Stephan A ; Glod, John

BACKGROUNDGene-modified autologous T cells expressing NY-ESO-1^c259, an affinity-enhanced T-cell receptor (TCR) reactive against the NY-ESO-1-specific HLA-A*02-restricted peptide SLLMWITQC (NY-ESO-1 SPEAR T-cells; GSK 794), have demonstrated clinical activity in patients with advanced synovial sarcoma (SS). The factors contributing to gene-modified T-cell expansion and the changes within the tumor microenvironment (TME) following T-cell infusion remain unclear. These studies address the immunological mechanisms of response and resistance in patients with SS treated with NY-ESO-1 SPEAR T-cells.METHODSFour cohorts were included to evaluate antigen expression and preconditioning on efficacy. Clinical responses were assessed by RECIST v1.1. Engineered T-cell persistence was determined by qPCR. Serum cytokines were evaluated by immunoassay. Transcriptomic analyses and immunohistochemistry were performed on tumor biopsies from patients before and after T-cell infusion. Gene-modified T-cells were detected within the TME via an RNAish assay.RESULTSResponses across cohorts were affected by preconditioning and intra-tumoral NY-ESO-1 expression. Of the 42 patients reported (data cut-off 4June2018), 1 patient had a complete response, 14 patients had partial responses, 24 patients had stable disease, and 3 patients had progressive disease. The magnitude of gene-modified T-cell expansion shortly after infusion was associated with response in patients with high intra-tumoral NY-ESO-1 expression. Patients receiving a fludarabine-containing conditioning regimen experienced increases in serum IL-7 and IL-15. Prior to infusion, the TME exhibited minimal leukocyte infiltration; CD163⁺ tumor-associated macrophages (TAMs) were the dominant population. Modest increases in intra-tumoral leukocytes (≤5%) were observed in a subset of subjects at approximately 8 weeks. Beyond 8 weeks post infusion, the TME was minimally infiltrated with a TAM-dominant leukocyte infiltrate. Tumor-associated antigens and antigen presentation did not significantly change within the tumor post-T-cell infusion. Finally, NY-ESO-1 SPEAR T cells trafficked to the TME and maintained cytotoxicity in a subset of patients.CONCLUSIONSOur studies elucidate some factors that underpin response and resistance to NY-ESO-1 SPEAR T-cell therapy. From these data, we conclude that a lymphodepletion regimen containing high doses of fludarabine and cyclophosphamide is necessary for SPEAR T-cell persistence and efficacy. Furthermore, these data demonstrate that non-T-cell inflamed tumors, which are resistant to PD-1/PD-L1 inhibitors, can be treated with adoptive T-cell based immunotherapy.TRIAL REGISTRATIONClinicalTrials.gov, NCT01343043 , Registered 27 April 2011.

28

News (Medical) associated with Letetresgene autoleucel

15 Nov 2024

·endpts.com

Adaptimmune to 'redefine' itself as a sarcoma biotech, cuts a third of staffers

Adaptimmune is slashing its headcount as part of a broader company restructuring aimed at saving $300 million over the next few years through 2028. The company said it will axe 33% of its employees in the first quarter of next year, according to its third-quarter earnings release Wednesday. Adaptimmune had 449 employees at the end of 2023. It also said it will stop enrollment in a Phase 2 trial of its T cell therapy, uza-cel, in platinum-resistant ovarian cancer. “We will reduce our UK footprint and research functions and suspend clinical trial activities with uza-cel for ovarian cancer, which will remove the associated CMC and development costs in the coming years,” CEO Adrian Rawcliffe said on an earnings call. But Rawcliffe added that its work with uza-cel is not yet done as its collaboration with Galapagos in head and neck cancer will not be affected, with plans for a clinical proof-of-concept trial still in place. Nonetheless, these moves reflect Adaptimmune’s mission to “redefine itself as a sarcoma-focused business,” by shifting its resources towards its T cell immunotherapy Teclera and another late-stage sarcoma candidate, lete-cel, the company said. Teclera won an FDA accelerated approval in August for synovial sarcoma. The company plans to start a rolling BLA for lete-cel in advanced or metastatic myxoid/round cell liposarcoma and synovial sarcoma by the end of 2025. The biotech, which has headquarters in Philadelphia and Oxford, UK, believes Teclera and lete-cell could together hit $400 million in peak US sales. As for the rollout of Teclera, the drugmaker is working with so-called “sarcoma centres of excellence” to establish them as authorized treatment centers (ACTs), a process that can take “several months to complete,” according to TD Cowen analysts. So far, nine ACTs have been established, which is at the upper end of Adaptimmune’s guidance of six to ten centers in the first 90 days of launch, Rawcliffe said during the earnings call. “We have an additional four sites that have signed contracts and a further 15 sites that are in active contract negotiations,” he added. Earlier in its pipeline, Adaptimmune is advancing two preclinical candidates: ADP-600 for solid tumors and ADP-520 for hematological malignancies, among other indications. The company said it is currently in “active discussions” with an eye to partnering with these programs.

ImmunotherapyCell TherapyAccelerated ApprovalPhase 2

14 Nov 2024

·www.pharmaceutical-technology.com

Adaptimmune nears second sarcoma approval as Phase II trial hits endpoints

The primary analysis of the IGNYTE-ESO trial comprises data from 64 patients with either synovial sarcoma or myxoid/round cell liposarcoma (MRCLS). Credit: Nadiia Lapshynska via Shutterstock. Adaptimmune ’s pivotal Phase II trial of its investigational T cell therapy lete-cel has met its primary endpoint, with the company now eyeing up its second sarcoma approval. UK-based Adaptimmune will submit a rolling Biologics License Application (BLA) to the US Food and Drug Administration (FDA) for lete-cel for the treatment of advanced or metastatic synovial sarcoma and myxoid/round cell liposarcoma (MRCLS) by the end of 2025. Data from the Phase II IGNYTE-ESO trial (NCT03967223) showed that 42% of patients treated with lete-cel achieved a response. In synovial sarcoma, the median response lasted for 18.3 months, while in MRCLS, the median response was 12.2 months. All patients experienced treatment-emergent adverse events (TEAEs), including cytopenia, cytokine release syndrome and rash. Adaptimmune said that safety findings were consistent with previous data, showing no unexpected adverse events. The primary analysis of the IGNYTE-ESO trial comprises data from 64 patients with either synovial sarcoma or MRCLS. Investigators will share detailed results from the trial on 16 November at the Connective Tissue Oncology Society (CTOS) 2024 annual meeting in San Diego, US. Synovial sarcoma and MRCLS are rare and often aggressive cancers with limited treatment options. Synovial sarcoma is a soft tissue cancer that arises in the limbs, primarily affecting young adults. MRCLS is a subtype of liposarcoma that can spread quickly and prove challenging to treat with conventional methods like surgery, chemotherapy, and radiotherapy. Adaptimmune is on its way to building a portfolio of sarcoma treatments. The company achieved its first FDA approval in August 2024 for Tecelra (afami-cel), a T cell receptor (TCR) therapy for adults with metastatic synovial sarcoma. This approval marked several firsts, including the first engineered cell therapy for solid tumours, and the first new therapy for synovial sarcoma in over a decade. According to a GlobalData analyst , the approval of lete-cel would multiply the US addressable market by 2.5 times, from 400 patients annually with Tecelra to 1,000. The treatments could be combined or administered sequentially, as lete-cel targets another antigen. GlobalData is the parent company of Pharmaceutical Technology. Adaptimmune has actively engaged in several partnerships to bolster its position in the cell therapy space. In 2021, the company teamed up with Roche’s subsidiary Genentech on T cell therapy development – a five-year agreement with a potential value exceeding $3bn. However, Genentech walked away from the partnership in April 2024 for reasons that were not disclosed. The cell therapy company quickly pivoted, securing a $665m deal with Galapagos just seven weeks later. This deal, including a $100m upfront payment, granted Adaptimmune rights to uza-cel, a MAGE-A4 T cell therapy. The company has further partnered with Agilent Technologies to develop the MAGE-A4 ICH 1F9 pharmDx companion diagnostic, which won FDA approval in August, as well as with Thermo Fisher Scientific to include Tecelra in the labelling for their SeCore CDx HLA-A Locus Sequencing System.

Cell TherapyPhase 2Clinical ResultImmunotherapyDrug Approval

13 Nov 2024

·endpts.com

Adaptimmune's second T cell receptor cell therapy for rare sarcomas passes pivotal test

Adaptimmune announced Wednesday that its experimental cell therapy based on T cell receptors shrank tumors by at least 30% in nearly half of the patients in a pivotal clinical trial. In 64 patients with previously treated synovial sarcoma or myxoid/round cell liposarcoma, six saw signs of cancer disappear completely. Another 21 had a partial response to the cell therapy, which is called lete-cel. Adaptimmune now plans to start an FDA submission for the therapy in both cancers by the end of 2025. Detailed data from the study are set to be presented on Saturday at the Connective Tissue Oncology Society’s annual meeting in San Diego. The median duration of response was 12.2 months, according to the press release , and median progression-free survival was 5.3 months. Adaptimmune noted that all patients experienced adverse events, which included cytopenias, cytokine release syndrome and rash. Lete-cel targets NY-ESO-1, an antigen found on solid tumors. It’s a cell therapy that GSK once worked on with Lyell Immunopharma before the UK pharma walked away from the program. In August, Adaptimmune won the first FDA approval for a cell therapy based on T cell receptors. That approval, also in synovial sarcoma, was granted to its MAGE-A4-targeted treatment, which is called Tecelra.

Cell TherapyImmunotherapyDrug ApprovalClinical ResultClinical Study

100 Deals associated with Letetresgene autoleucel

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Recurrent Non-Small Cell Lung Cancer	Phase 2	United Kingdom	GSK Plc	31 Dec 2018
Recurrent Non-Small Cell Lung Cancer	Phase 2	Canada	GSK Plc	31 Dec 2018
Recurrent Non-Small Cell Lung Cancer	Phase 2	Spain	GSK Plc	31 Dec 2018
Recurrent Non-Small Cell Lung Cancer	Phase 2	United States	GSK Plc	31 Dec 2018
Multiple Myeloma	Phase 2	United States	GSK Plc	13 May 2011
Myxoid Liposarcoma	Preclinical	United States	GSK Plc	06 Dec 2016
Melanoma	Preclinical	United States	Merck GmbH	14 Jul 2015
Gastrointestinal Neoplasms	Preclinical	United Kingdom	-	27 Sep 2014
Recurrent ovarian cancer	Preclinical	United States	Adaptimmune Ltd.	09 Jul 2013
Multiple Myeloma	Preclinical	United States	GSK Plc	13 May 2011

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02992743 (NCT02992743, Pubmed \| J Clin Oncol)	Phase 2	Myxoid Liposarcoma NY-ESO-1-positive \| HLA-A02:05 \| HLA-A02:06-positive	23	Letetresgene Autoleucel (Cohort 1 (Reduced-dose lymphodepletion regimen))	(khohtodvhm) = jphwvldqbd toittocifc (ctzafsrefb, 2.5 - 55.6) View more	Positive	21 Jan 2025
				Letetresgene Autoleucel (Cohort 2 (Standard-dose lymphodepletion regimen))	(khohtodvhm) = vroicdydxc toittocifc (ctzafsrefb, 12.2 - 73.8) View more
NCT03967223 (IGNYTE-ESO, Company_Website) Manual	Phase 2	Synovial Sarcoma \| Myxoid Liposarcoma	64	lete-cel	(qlpqnglrgn) = cjqmmpznhh czvfqpemrl (zctupjymzv ) View more	Positive	13 Nov 2024
				lete-cel (synovial sarcoma)	(qlpqnglrgn) = sjejrudzhl czvfqpemrl (zctupjymzv ) View more
NCT03967223 (IGNYTE-ESO, ASCO2024)	Phase 2	Synovial Sarcoma \| Myxoid Liposarcoma NY-ESO-1	98	Lete-cel	(honkygoarh) = sjncomrhbo ycqasaecdb (iubtlwiumi, 20.3% - 62.3%) View more	Positive	24 May 2024
SITC2023	Not Applicable	Synovial Sarcoma NY-ESO-1 positive	-	lete-cel 10% dose on day 1, 30% on day 2, 60% on day 3	wrpszrtvxc(mbylcbrroo) = puahxdgsfl kxdnialrnc (jvpvyukrww, 33% - 57%)	-	02 Nov 2023
				lete-cel single dose	wrpszrtvxc(mbylcbrroo) = otsfmzrppm kxdnialrnc (jvpvyukrww, 33% - 57%)
NCT03967223 (IGNYTE-ESO , Corporate Publications) Manual	Phase 2	Synovial Sarcoma \| Myxoid Liposarcoma Third line	45	lete-cel	(esclpvtxly) = aufijzwhoo wrikcdkokf (wyfanykpdh ) View more	Positive	31 Oct 2023
NCT05993299 (CTgov)	Phase 2	Synovial Sarcoma \| Myxoid Liposarcoma	7	fludarabine+cyclophosphamide+lete-cel	(gsbccwlfux) = gubvvbebnu nzsjtqxztm (utvlcyrtjj, yhbidhxtdr - wbzimvaqvs) View more	-	16 Oct 2023
NCT02992743 (MRCLS \| NCT02992743, CTgov)	Phase 2	Myxoid Liposarcoma	23	GSK3377794 (Reduced Lymphodepletion Dose Plus GSK3377794)	eyrzzztxhj(klckhobtrw) = gkwjuypexi ojttoouyni (rvjhoyensd, zbuqpcbjxg - wwpobxtpng) View more	-	28 Nov 2022
				GSK3377794 (Standard Lymphodepletion Dose Plus GSK3377794)	eyrzzztxhj(klckhobtrw) = wbvfrpbzoc ojttoouyni (rvjhoyensd, wqfgnuxkhz - nnlddjtdwk) View more
NCT02992743 (MRCLS, ASCO2022) Manual	Phase 2	Myxoid Liposarcoma	20	fludarabine+cyclophosphamide+GSK3377794 (Cohort 1 [C1])	(lwgkbtfate) = irjacurfki dbipjqsoyb (vkkuazqphe ) View more	Positive	02 Jun 2022
				fludarabine+cyclophosphamide+GSK3377794 (Cohort 2 [C2])	(lwgkbtfate) = trbzrtgekn dbipjqsoyb (vkkuazqphe ) View more
NCT03168438 (CTgov)	Phase 1	Relapse multiple myeloma \| Multiple Myeloma	6	fludarabine+cyclophosphamide+GSK3377794 (GSK3377794)	junvemraka(bowperggkn) = zurljzkyps kjfofnovho (hzptfxtiyw, kyvxtdwpgb - dytuqkcigz) View more	-	11 Jan 2022
				Pembrolizumab+GSK3377794 (GSK3377794+Pembrolizumab)	junvemraka(bowperggkn) = eereofpnup kjfofnovho (hzptfxtiyw, rqjougnpuy - yirlnjdhyo) View more
ESMO2021	Not Applicable	Ovarian Cancer \| Squamous Cell Carcinoma of Head and Neck \| Bladder Cancer \| Stomach Cancer	-	Letetresgene autoleucel (lete-cel; GSK3377794)	edgiutndri(uzuzxoymyz) = mmtzsgrlda qiseymiyjo (sqnzwzlwya ) View more	-	16 Sep 2021