Sir Peter MacCallum Department of Oncology - Research Publications

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Author: Beavis, Paul × Author: D'Souza, Criselle × Author: Darcy, Phillip × Author: Harrison, Simon × End date: 2023 × Start date: 2020 × Type: Journal Article ×

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    TSTEM-like CAR-T cells exhibit improved persistence and tumor control compared with conventional CAR-T cells in preclinical models
    Meyran, D ; Zhu, JJ ; Butler, J ; Tantalo, D ; MacDonald, S ; Nguyen, TN ; Wang, M ; Thio, N ; D'Souza, C ; Qin, VM ; Slaney, C ; Harrison, A ; Sek, K ; Petrone, P ; Thia, K ; Giuffrida, L ; Scott, AM ; Terry, RL ; Tran, B ; Desai, J ; Prince, HM ; Harrison, SJ ; Beavis, PA ; Kershaw, MH ; Solomon, B ; Ekert, PG ; Trapani, JA ; Darcy, PK ; Neeson, PJ (AMER ASSOC ADVANCEMENT SCIENCE, 2023-04-05)
    Patients who receive chimeric antigen receptor (CAR)-T cells that are enriched in memory T cells exhibit better disease control as a result of increased expansion and persistence of the CAR-T cells. Human memory T cells include stem-like CD8+ memory T cell progenitors that can become either functional stem-like T (TSTEM) cells or dysfunctional T progenitor exhausted (TPEX) cells. To that end, we demonstrated that TSTEM cells were less abundant in infused CAR-T cell products in a phase 1 clinical trial testing Lewis Y-CAR-T cells (NCT03851146), and the infused CAR-T cells displayed poor persistence in patients. To address this issue, we developed a production protocol to generate TSTEM-like CAR-T cells enriched for expression of genes in cell replication pathways. Compared with conventional CAR-T cells, TSTEM-like CAR-T cells had enhanced proliferative capacity and increased cytokine secretion after CAR stimulation, including after chronic CAR stimulation in vitro. These responses were dependent on the presence of CD4+ T cells during TSTEM-like CAR-T cell production. Adoptive transfer of TSTEM-like CAR-T cells induced better control of established tumors and resistance to tumor rechallenge in preclinical models. These more favorable outcomes were associated with increased persistence of TSTEM-like CAR-T cells and an increased memory T cell pool. Last, TSTEM-like CAR-T cells and anti-programmed cell death protein 1 (PD-1) treatment eradicated established tumors, and this was associated with increased tumor-infiltrating CD8+CAR+ T cells producing interferon-γ. In conclusion, our CAR-T cell protocol generated TSTEM-like CAR-T cells with enhanced therapeutic efficacy, resulting in increased proliferative capacity and persistence in vivo.
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    Myeloma natural killer cells are exhausted and have impaired regulation of activation
    D'Souza, C ; Keam, SP ; Yeang, HXA ; Neeson, M ; Richardson, K ; Hsu, AK ; Canfield, R ; Bezman, N ; Robbins, M ; Quach, H ; Ritchie, DS ; Harrison, SJ ; Trapani, JA ; Prince, HM ; Beavis, PA ; Darcy, PK ; Neeson, PJ (FERRATA STORTI FOUNDATION, 2021-09)
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