{"entity":{"id":"paper-spearhead-1-lancet-2024","kind":"paper","name":"SPEARHEAD-1: afamitresgene autoleucel, the first engineered T-cell receptor therapy approved for a solid tumour, in synovial sarcoma","aka":[],"tldr":"T cells taken from patients and engineered to recognise the MAGE-A4 protein shrank tumours in about four in ten patients with advanced synovial sarcoma, leading to the first approval of a TCR T-cell therapy for any solid cancer.","summary":"Single-arm phase 2 trial of 52 patients (44 with synovial sarcoma, 8 with myxoid/round cell liposarcoma) who were HLA-A*02 positive with MAGE-A4-expressing tumours, previously treated with anthracycline or ifosfamide, treated with a single infusion of afamitresgene autoleucel (afami-cel), autologous T cells expressing an affinity-enhanced MAGE-A4-specific T-cell receptor, after lymphodepleting chemotherapy. Primary endpoint was objective response rate.\n\nThe response rate was 37% overall and 39% in synovial sarcoma, with a median duration of response of about 12 months. Cytokine release syndrome occurred in about 70% but was mostly low grade. It led to FDA accelerated approval in 2024 (Tecelra), the first TCR-T and the first engineered cell therapy approved for a solid tumour.","asOf":"2026-09-08","links":[{"label":"PubMed search: SPEARHEAD-1 afamitresgene autoleucel Lancet","url":"https://pubmed.ncbi.nlm.nih.gov/?term=SPEARHEAD-1+afamitresgene+autoleucel+synovial+sarcoma+Lancet"},{"label":"ClinicalTrials.gov NCT04044768","url":"https://clinicaltrials.gov/study/NCT04044768"},{"label":"PubMed search","url":"https://pubmed.ncbi.nlm.nih.gov/?term=SPEARHEAD-1%20afamitresgene%20autoleucel%20synovial%20sarcoma%20D'Angelo%20Lancet%202024"}],"tags":[],"related":["paper-c-144-01-lifileucel-melanoma-jco-2021"],"cancers":["sarcoma"],"sections":[],"technologies":["tcr-t"],"targets":["mage-a4"],"drugs":["afamitresgene-autoleucel","letetresgene-autoleucel"],"companies":["adaptimmune"],"institutions":[],"pathways":[],"terms":["orr","crs","accelerated-approval"],"trials":[],"people":["jean-yves-blay"],"bottlenecks":["b-rare-cancers","b-manufacturing-cell-therapy","b-trial-diversity"],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2024,"doi":"10.1016/S0140-6736(24)00319-2","pmid":"38554725","authors":"D'Angelo SP, Araujo DM, Abdul Razak AR, et al.","paperType":"rct","findings":["Objective response 37% overall (19 of 52); 39% in synovial sarcoma and 25% in myxoid/round cell liposarcoma.","Median duration of response about 12 months; median PFS about 3.8 months and median OS about 15 months in a heavily pretreated population.","Cytokine release syndrome in about 70% of patients, grade 3 in around 2%; cytopenias were common after lymphodepletion.","Eligibility required both HLA-A*02 genotype and MAGE-A4 expression, satisfied by roughly a third of screened synovial sarcoma patients.","Manufacturing success was high but the process took several weeks per patient."],"whatItMeans":"Patients with advanced synovial sarcoma, a rare cancer of young adults with few effective drugs, now have an approved cell therapy that produces responses lasting about a year in a substantial minority, if their tissue type and tumour antigen match. It proves that engineered T cells can work against a solid tumour when a good target is present, which had been elusive. It is not a cure for most, requires specialised centres, and only a minority of patients are eligible.","caveats":["Single-arm trial with a response-rate endpoint; no randomised comparison and OS benefit is unproven.","Restricted to HLA-A*02-positive patients, which excludes many people of non-European ancestry.","Responses are usually not durable beyond a year; mechanisms of relapse (antigen loss, T-cell exhaustion) are being studied.","Very high cost and complex logistics for a rare indication."],"changedPractice":true,"participants":52},"route":"/key-papers/paper-spearhead-1-lancet-2024/","neighbours":{"paper":[{"id":"paper-c-144-01-lifileucel-melanoma-jco-2021","kind":"paper","name":"C-144-01: lifileucel, tumour-infiltrating lymphocytes grown from a patient's own tumour, in melanoma after checkpoint inhibitors have failed","route":"/key-papers/paper-c-144-01-lifileucel-melanoma-jco-2021/"}],"cancer":[{"id":"sarcoma","kind":"cancer","name":"Sarcomas (soft tissue, bone, GIST)","route":"/cancers/sarcoma/"},{"id":"synovial-sarcoma","kind":"cancer","name":"Synovial sarcoma","route":"/cancers/synovial-sarcoma/"}],"technology":[{"id":"tcr-t","kind":"technology","name":"TCR-T cell therapy","route":"/technologies/tcr-t/"}],"target":[{"id":"mage-a4","kind":"target","name":"MAGE-A4","route":"/targets/mage-a4/"}],"drug":[{"id":"afamitresgene-autoleucel","kind":"drug","name":"Afamitresgene autoleucel","route":"/drugs/afamitresgene-autoleucel/"},{"id":"letetresgene-autoleucel","kind":"drug","name":"Letetresgene autoleucel","route":"/drugs/letetresgene-autoleucel/"}],"company":[{"id":"adaptimmune","kind":"company","name":"Adaptimmune","route":"/companies/adaptimmune/"}],"term":[{"id":"accelerated-approval","kind":"term","name":"Accelerated approval","route":"/terms/accelerated-approval/"},{"id":"crs","kind":"term","name":"Cytokine release syndrome (CRS)","route":"/terms/crs/"},{"id":"orr","kind":"term","name":"Objective response rate (ORR)","route":"/terms/orr/"}],"person":[{"id":"jean-yves-blay","kind":"person","name":"Jean-Yves Blay","route":"/people/jean-yves-blay/"},{"id":"sandra-dangelo","kind":"person","name":"Sandra P. D'Angelo","route":"/people/sandra-dangelo/"}],"bottleneck":[{"id":"b-manufacturing-cell-therapy","kind":"bottleneck","name":"Manufacturing cost and time for living and radioactive medicines","route":"/bottlenecks/b-manufacturing-cell-therapy/"},{"id":"b-rare-cancers","kind":"bottleneck","name":"Rare and paediatric cancers without markets","route":"/bottlenecks/b-rare-cancers/"},{"id":"b-trial-diversity","kind":"bottleneck","name":"Trials do not represent the people who get cancer","route":"/bottlenecks/b-trial-diversity/"}],"journal":[{"id":"lancet","kind":"journal","name":"The Lancet","route":"/journals/lancet/"}],"idea":[{"id":"idea-tcr-t-beyond-hla-a2","kind":"idea","name":"Extending sarcoma TCR-T beyond HLA-A*02","route":"/ideas/idea-tcr-t-beyond-hla-a2/"}]}}