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    An open-label, multicenter phase I/IIa study evaluating the safety and clinical activity of clonal neoantigen reactive T cells in patients with advanced non-small cell lung cancer (CHIRON)

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    Authors
    Jamal-Hanjani, M.
    Greystoke, A.
    Thistlethwaite, Fiona C
    Summers, Yvonne J
    Allison, Jennifer
    Cave, J.
    Orchard, K.
    Ottensmeier, C.
    Middleton, G.
    Khoja, L.
    Grant, M.
    Patel, S.
    Robertson, J.
    Peggs, K.
    Forster, M.
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    Affiliation
    University College London, London, United Kingdom
    Issue Date
    2021
    
    Metadata
    Show full item record
    Abstract
    Background: Lung cancer is the most common cause of cancer-related death worldwide with over 1.6 million deaths per year. Non-small cell lung cancer (NSCLC) accounts for 80% of cases, the majority of which are adenocarcinomas. 75% of patients present with inoperable tumours and/or with distant metastatic spread, with 5-year survival for stage IV disease as low as 5%. Treatment options include chemotherapy, targeted therapies for specific mutations, and - increasingly - immune checkpoint inhibitors (CPI). Adoptive cell therapies (ACT) can produce durable responses in pre-treated NSCLC. Evidence also suggests potential benefit of combining ACT with CPIs, even after acquired resistance. Efforts to improve efficacy include the expansion of T cells able to recognise patient-specific clonal tumour neoantigens. Clonal tumour neoantigens arise early in cancer evolution and represent a subset of patient-specific mutations present in all cancer cells. Developing ACTs that target clonal neoantigens represents a personalised approach to treating all cancer cells concurrently, minimising the risk of tumour escape and reducing potential for off-target toxicities. Insights gained from applying the PELEUS bioinformatic platform (developed using UK TRACERx study data) to matched tumour and blood samples from NSCLC patients – as part of a tissue acquisition study (NCT03517917) – has enabled the manufacture of a personalized clonal neoantigen-reactive T cell (cNeT) product (ATL001), which is now in clinical development. Methods: The CHIRON Study (NCT04032847), is a first-in-human, open-label, multi-centre, phase I/IIa study to characterise the safety and clinical activity of ATL001 administered intravenously in up to 40 adults with advanced unresectable or metastatic NSCLC. Following consent and screening, patients enter the study for procurement of tumor tissue and blood to manufacture ATL001. Tissue may be procured during treatment with standard systemic therapies. Patients in Cohort A receive cyclophosphamide/fludarabine on days -6 to -4, followed by a single dose of ATL001 and 10 daily doses of subcutaneous IL-2; Patients in Cohort B will additionally receive one dose of pembrolizumab between days -13 and -6 before receiving ATL001, then restart pembrolizumab 2 weeks after receiving ATL001 and continue for up to 12 months. Key eligibility criteria include treatment with at least one prior systemic therapy (including a PD-1 inhibitor). Primary endpoints are the safety and tolerability of ATL001 as a monotherapy and in combination with pembrolizumab. Secondary endpoints include change in tumor size and response rate by RECIST 1.1 and imRECIST. Correlative studies will investigate the effects of cNeT dose and engraftment kinetics on clinical activity. The study began enrolling patients in Cohort A in August 2019.
    Citation
    Jamal-Hanjani M, Greystoke A, Thistlethwaite F, Summers YJ, Allison J, Cave J, et al. An open-label, multicenter phase I/IIa study evaluating the safety and clinical activity of clonal neoantigen reactive T cells in patients with advanced non-small cell lung cancer (CHIRON). Vol. 39, Journal of Clinical Oncology. American Society of Clinical Oncology (ASCO); 2021. p. TPS9138–TPS9138.
    Journal
    Journal of Clinical Oncology
    URI
    http://hdl.handle.net/10541/624886
    DOI
    10.1200/JCO.2021.39.15_suppl.TPS9138
    Additional Links
    https://dx.doi.org/10.1200/JCO.2021.39.15_suppl.TPS9138
    Type
    Meetings and Proceedings
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1200/JCO.2021.39.15_suppl.TPS9138
    Scopus Count
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