PuSH - Publikationsserver des Helmholtz Zentrums München: T-cells expressing a highly potent PRAME-specific T-cell receptor in combination with a chimeric PD1-41BB co-stimulatory receptor show a favorable preclinical safety profile and strong anti-tumor reactivity.

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Sailer, N.* ; Fetzer, I.* ; Salvermoser, M.* ; Braun, M.* ; Brechtefeld, D.* ; Krendl, C.* ; Geiger, C.* ; Mutze, K.* ; Nößner, E. ; Schendel, D.J.* ; Bürdek, M.* ; Wilde, S.* ; Sommermeyer, D.*

T-cells expressing a highly potent PRAME-specific T-cell receptor in combination with a chimeric PD1-41BB co-stimulatory receptor show a favorable preclinical safety profile and strong anti-tumor reactivity.

Cancers 14:1998 (2022)

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The hostile tumor microenvironment (TME) is a major challenge for the treatment of solid tumors with T-cell receptor (TCR)-modified T-cells (TCR-Ts), as it negatively influences T-cell efficacy, fitness, and persistence. These negative influences are caused, among others, by the inhibitory checkpoint PD-1/PD-L1 axis. The Preferentially Expressed Antigen in Melanoma (PRAME) is a highly relevant cancer/testis antigen for TCR-T immunotherapy due to broad expression in multiple solid cancer indications. A TCR with high specificity and sensitivity for PRAME was isolated from non-tolerized T-cell repertoires and introduced into T-cells alongside a chimeric PD1-41BB receptor, consisting of the natural extracellular domain of PD-1 and the intracellular signaling domain of 4-1BB, turning an inhibitory pathway into a T-cell co-stimulatory pathway. The addition of PD1-41BB to CD8+ T-cells expressing the transgenic PRAME-TCR enhanced IFN-γ secretion, improved cytotoxic capacity, and prevented exhaustion upon repetitive re-challenge with tumor cells in vitro without altering the in vitro safety profile. Furthermore, a single dose of TCR-Ts co-expressing PD1-41BB was sufficient to clear a hard-to-treat melanoma xenograft in a mouse model, whereas TCR-Ts without PD1-41BB could not eradicate the PD-L1-positive tumors. This cutting-edge strategy supports development efforts to provide more effective TCR-T immunotherapies for the treatment of solid tumors.

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