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In this study we report the functional comparison of T cell receptor (TCR)-engineered major histocompatibility complex (MHC) class I-restricted CD4 + versus CD8 + T cells targeting a peptide from six transmembrane epithelial antigen of the prostate 1 (STEAP1) in the context of HLA-A*02:01. STEAP1 is a tumor-associated antigen, which is overexpressed in many cancers, including Ewing sarcoma (EwS). Based on previous observations, we postulated strong antitumor potential of tumor-redirected CD4 + T cells transduced with an HLA class I-restricted TCR against a STEAP1-derived peptide. We compared CD4 + T cell populations to their CD8 + counterparts in vitro using impedance-based xCELLigence and cytokine/granzyme release assays. We further compared antitumor activity of STEAP 130 -TCR transgenic (tg) CD4 + versus CD8 + T cells in tumor-bearing xenografted Rag2 -/- gc -/- mice. TCR tgCD4 + T cells showed increased cytotoxic features over time with similar functional avidity compared to tgCD8 + cells after 5-6 weeks of culture. In vivo, local tumor control was equal. Assessing metastatic organotropism of intraveniously (i.v.) injected tumors, only tgCD8 + cells were associated with reduced metastases. In this analysis, EwS-redirected tgCD4 + T cells contribute to local tumor control, but fail to control metastatic outgrowth in a model of xenografted EwS.

MHC Class I-Restricted TCR-Transgenic CD4+ T Cells Against STEAP1 Mediate Local Tumor Control of Ewing Sarcoma In Vivo