Clinical-scale 10-day TCR-T cell manufacturing using IL-2/7/15 and TGF-β promotes early memory and tissue-resident-like phenotypes and robust antitumor activity in vitro

BackgroundAdoptive cell therapy (ACT) using TCR-engineered T (TCR-T) cells is a promising strategy for treating solid tumors. One factor that influences the efficacy of ACT is the type of T cells used, with T cells displaying younger, less differentiated or tissue resident phenotypes associated with greater antitumor activity.

We aimed to develop a rapid, clinical-scale protocol to generate younger and more potent TCR-T cells for therapy.MethodsPatient-derived PBMC were stimulated, CD8+ enriched, retrovirally transduced to express KRAS G12D-targeting TCRs, and expanded for 10 days in the presence of a novel cytokine cocktail (CKT) containing IL-2, IL-7, IL-15, and TGF-β. The impact of CKT on the phenotype, effector function, and in vitro antitumor activity was evaluated and compared to TCR-T cells manufactured with IL-2.

This process was then adapted for clinical-scale manufacturing.ResultsTCR-T cells generated with CKT displayed an increased frequency of early memory (Tn/scm) and tissue-resident (Trm)-like T cells with decreased KLRG1 expression compared to IL-2 manufactured TCR-T cells.