CRS free T cell therapy: T cell membrane anchored and tumor targeted IL12 (ATTIL12)-T cell therapy eliminates large tumors, overcomes heterogeneity, and avoids adverse effects

Abstract

Abstract Adoptive transfer of genetic engineered T cells becomes an effective approach in treating hematologic malignancies, but shows poor responses against solid tumors due to multifactorial reasons. Interleukin-12 exhibits robust T cell activating and anti-tumor efficacy. However, its clinical application was impeded due to the lethal adverse effects. We demonstrated previously that tumor targeted IL-12 (ttIL12) gene therapy avoids the toxicity of wildtype IL12 and effectively eliminate tumor metastasis. In this study, we developed a second generation of ttIL12— membrane-anchored ttIL-12 (attIL12)—to modify naive T cells, CD19CAR-T cells and OT1 T cells. This attIL12-modified T cells silent the toxicity of both IL12 and CAR-T cells associated cytokine release syndrome (CRS). Surprisingly, this ATTIL12-T cell therapy is able to eliminate multiple types of tumors with either homo- or hetero-generous environment or large size. We are in full speed to prepare a phase I clinical trial.