On July 6, 2023 Autolus Therapeutics plc (Nasdaq: AUTL), a clinical-stage biopharmaceutical company developing next-generation programmed T cell therapies, reported a publication in Nature Medicine1 entitled: ‘Transcriptional hallmarks of persisting CD19 CAR T-cells in children with leukaemia,’ describing new findings from the original Obecabtagene autoleucel (obe-cel) study (CARPALL2) in Pediatric B-cell Acute Lymphoblastic Leukemia (Press release, Autolus, JUL 6, 2023, View Source [SID1234633070]).
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Long-term CAR T cell persistence is associated with durable responses in some cancers, including B-cell acute lymphoblastic leukemia (B-ALL). Obe-cel, Autolus’ CD19 CAR, was designed to maximize CAR T cell persistence by tuning the affinity to CD19 to result in more physiological signaling.
The transcriptional mechanisms behind long-term persistence of antigen-specific T cells are not fully understood. The long-term persistence of obe-cel CAR T cells in patients allows their isolation by flow-cytometric sorting from peripheral blood at very late time-points (including several years) after infusion. This has enabled researchers at University College London, working in collaboration with the Wellcome Sanger Institute, to perform detailed single-cell analysis on long-term persisting CAR T cells from patients treated in the CARPALL study2, the first clinical study of obe-cel in pediatric B-ALL.
Publishing her findings in Nature Medicine today, Dr Sara Ghorashian described how long-term persistence was associated with a particular T cell population which was CD4/CD8 double-negative, but expressed the transcription factor TOX and Granzyme K. This phenotype emerged across all clones and subsets of T-cells, suggesting that CAR T-cells converge transcriptionally to this state to maintain persistence. This finding fits with the newly described TPEX sub-population found in chronic viral infections.
"Long-term CAR T cell persistence is required for durable responses in B-ALL but is not well understood," said Dr Martin Pule, Chief Scientific Officer and Founder of Autolus: "Dr Ghorashian has exploited the ability to isolate obe-cel CAR T-cells from patients at late time-points to further our understanding of which transcriptional states drive long-term persistence. These findings will allow us to work towards further refining CAR T manufacturing to favor these transcriptional states."