• Qin, Mengfei
• Trapani, Joseph
• Butler, Jeanne
• Desai, Jayesh
• Thio, Niko
• Wang, Minyu
• Harrison, Aaron
• Macdonald, Sean
• Harrison, Simon J.
• Petrone, Pasquale
• Sek, Kevin
• Giuffrida, Lauren
• Terry, Rachael L.
• Kershaw, Michael
• Meyran, Deborah
• Thia, Kevin
• Prince, H. Miles
• Tantalo, Daniela
• Tran, Ben

Abstract

<jats:p>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<jats:sup>+</jats:sup>memory T cell progenitors that can become either functional stem-like T (T<jats:sub>STEM</jats:sub>) cells or dysfunctional T progenitor exhausted (T<jats:sub>PEX</jats:sub>) cells. To that end, we demonstrated that T<jats:sub>STEM</jats:sub>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 T<jats:sub>STEM</jats:sub>-like CAR-T cells enriched for expression of genes in cell replication pathways. Compared with conventional CAR-T cells, T<jats:sub>STEM</jats:sub>-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<jats:sup>+</jats:sup>T cells during T<jats:sub>STEM</jats:sub>-like CAR-T cell production. Adoptive transfer of T<jats:sub>STEM</jats:sub>-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 T<jats:sub>STEM</jats:sub>-like CAR-T cells and an increased memory T cell pool. Last, T<jats:sub>STEM</jats:sub>-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<jats:sup>+</jats:sup>CAR<jats:sup>+</jats:sup>T cells producing interferon-γ. In conclusion, our CAR-T cell protocol generated T<jats:sub>STEM</jats:sub>-like CAR-T cells with enhanced therapeutic efficacy, resulting in increased proliferative capacity and persistence in vivo.</jats:p>

Topics

• phase
• laser emission spectroscopy