437 Optimised achilles VELOSTM process 2b manufacturing platform generates a significant dose boost of reactive CD8 and CD4 clonal neoantigen-reactive T cells for the treatment of solid cancer

• Published in: Journal for immunotherapy of cancer Vol. 11; no. Suppl 1; p. A486
• Main Authors: Sassi, Monica, Gomez, Sandro, Rologi, Evi, Madigan, Meghan, Tang, Joanne, Thirkell, Sarah, Banwo, Samuel Jide, Ogunleye, Temi, McKeeman, Sophie, Law, Claire, Meyyappan, Unnaamalai, Kotsiou, Eleni, Newton, Katy, Oakes, Theres, Kosmac, Miha, Goodsell, Luke, Carolan, Connor, Ahern, Justin, Hillyer, Tim, Ndlovu, Bongi, Fraser, Henrieta, Quezada, Sergio A, Samuel, Edward
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd 01.11.2023; BMJ Publishing Group LTD; BMJ Publishing Group
• Subjects: Cancer; Immunotherapy; Lymphocytes; Manufacturing; Melanoma; Peptides; Regular and Young Investigator Award Abstracts
• ISSN: 2051-1426
• DOI: 10.1136/jitc-2023-SITC2023.0437

BackgroundClonal neoantigens are formed early in cancer evolution and have been identified as a subset of patient specific mutations that are associated with improved clinical benefit, representing great promise as targets for next generation T cell therapies. Cell therapies targeting multiple clonal neoantigens represent a unique personalised approach to treating solid cancer, as they are present on all cancer cells, minimising the risk of tumour escape, and absent from healthy tissue. Process 2 of the VELOSTM manufacturing platform has successfully demonstrated the feasibility of generating clonal neoantigen-reactive T cell (cNeT) products for the treatment of advanced NSCLC, (NCT04032847) and melanoma (NCT03997474) in two first-in-human studies. Here we demonstrate that implementation of an optimised VELOSTM platform (Process 2b) in clinical manufacturing can generate a significant dose boost of highly potent and reactive CD8+ and CD4+ cNeT for clinical use compared to both Process 1 and Process 2.MethodBriefly, tumour-infiltrating lymphocytes (TIL) were isolated from tumour fragments and Dendritic Cells (DCs) generated from whole blood, prior to cryopreservation. Patient-specific clonal neoantigens were predicted using our proprietary PELEUSTM bioinformatic platform, enabling manufacture of synthetic peptides for each patient. The co-culture of TIL and peptide loaded DCs allows the selective expansion of cNeT, prior to a polyclonal T cell boost step.ResultsHere we present clinical manufacturing data on 21 tumour samples (13 NSCLC and 8 melanoma) generated with Process 2b and demonstrate a 5-fold increase in the median CD3+ TIL yield compared to 33 TIL intermediates (13 NSCLC and 20 melanoma) generated with Process 2 (30M vs. 147M). Improvements in TIL yield at the pre-expansion step have driven a 10-fold increase in the median cNeT dose (17M vs. 167M) following co-culture in 15 clinical batches manufactured with VELOSTM Process 2b (14 – 6,347M) compared to 17 batches manufactured with Process 2 (1.4 – 6,409M). Median clonal reactivity was 16% (0.2 – 96%) with products manufactured with Process 2b compared to 10% (0 – 97.6%) with Process 2. Furthermore, peptide deconvolution identified products with multiple single T cell reactivities to clonal neoantigens demonstrating a highly polyclonal product (mean number of unique variants: 7, range 0 – 90).ConclusionsWe demonstrate that optimised VELOSTM Process 2b incorporating the PELEUSTM platform for prediction of clonal neoantigens can generate significantly higher cNeT doses and in some cases >1B in concert with accurately identifying the active drug component for the treatment of advanced NSCLC and melanoma.