Abstract 1508: Characterization of a novel clonal neoantigen reactive T cell (cNeT) product through a comprehensive translational research program
Authors: Epstein Michael , Pike Rebecca , Leire Emma , Middleton Jen , Wileman Megan , Ouboussad Lylia , Manning Leah , Oakes Theres , Pekle Eva , Baker Amy , Brown Mark , Melandri Daisy , Becker Pablo , Ramirez Anabel , Hadjistephanou Natasa , Turaljic Samra , Jamal-Hanjani Mariam , Forster Martin , Ali Iraj , Robertson Jane , Peggs Karl , Quezada Sergio 
Published: July 2021

Adoptive cell therapy (ACT) using ex vivo expanded tumor infiltrating lymphocytes (TIL) has shown great promise as a treatment for metastatic melanoma and has the potential to deliver durable responses in other solid tumors. Clonal neoantigens, which are derived from mutations occurring very early in the tumor development, are present in all cancer cells within a patient and therefore could be the optimal targets for TIL-based therapies. Recently it was shown that the number of clonal neoantigens within a tumor is associated with improved clinical outcomes following checkpoint inhibition in patients with non-small cell lung cancer (NSCLC) and melanoma. An approach that targets multiple clonal neoantigens with specific T cells has the potential to demonstrate high specificity and efficacy whilst mitigating the risk of immune escape.

Achilles Therapeutics is developing a personalized ACT product, ATL001, to target clonal neoantigens, which are identified using tumor exome sequencing and the PELEUS™ bioinformatics platform. Clonal neoantigen reactive T cells (cNeTs) are then manufactured from TIL using the VELOS™ manufacturing process. Two Phase I/IIa clinical trials of ATL001 are ongoing in patients with advanced NSCLC and metastatic or recurrent melanoma.

In common with the development of other ACT products, the key to characterizing and improving cNeT products relies on evaluating a diverse set of exploratory endpoints in early clinical trials, including understanding the procedural, clinical and biological factors that influence cNeT manufacturing rate and product reactivity; monitoring the expansion, persistence and phenotype of the infused cells in vivo and identifying potential biomarkers of clinical activity or safety of cNeTs in treated patients. These insights may suggest further improvements to cNeT product development in ensuing iterations.

The evaluation of these endpoints requires the collection of a rich longitudinal dataset that traces each patient's journey from tissue procurement and cNeT manufacture, to final product infusion and follow up. The data collected will include clinical and disease characteristics, tumor microenvironment insights from exome sequencing and immunohistochemistry of procured tumor, and metrics from the VELOS™ manufacturing process, along with a comprehensive immune-monitoring programme comprising immuno-sequencing, immunophenotyping, bespoke ctDNA panels and reactivity assays at specified timepoints, all to be evaluated against clinical outcomes data. The amalgamation of diverse streams of data requires the development of robust processes and systems for data collection, processing and storage. Furthermore, the evaluation of multiple exploratory endpoints will require integration and modelling of baseline covariates, time-series immune-monitoring and efficacy data, all of which will be described

Citation Format: Michael Epstein, Rebecca Pike, Emma Leire, Jen Middleton, Megan Wileman, Lylia Ouboussad, Leah Manning, Theres Oakes, Eva Pekle, Amy Baker, Mark Brown, Daisy Melandri, Pablo Becker, Anabel Ramirez, Natasa Hadjistephanou, Samra Turaljic, Mariam Jamal-Hanjani, Martin Forster, Iraj Ali, Jane Robertson, Karl Peggs, Sergio Quezada. Characterization of a novel clonal neoantigen reactive T cell (cNeT) product through a comprehensive translational research program [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1508.