SmartCAR-T - Reprogramming of the tumor microenvironment with modular engineered CAR-T cells to augment the efficacy of immunotherapy
Background & Hypothesis: We are pursuing the development of cancer immunotherapy with T cells expressing synthetic Chimeric Antigen Receptors (CARs). CAR-T cells are poorly prepared to withstand the physical and immunological barriers in the hostile tumor microenvironment (TME). Principal TME components that diminish CAR-T cell function include stromal fibroblasts and regulatory immune cells. We hypothesize that CAR- T cells can be instructed by advanced gene-engineering to remove (seek & destroy) or modify (seek & modulate) negative TME influences, thereby ‘paving their own way’ for delivering antitumor efficacy. Specific Aims: Aim 1. To determine key components in the TME of multiple myeloma (MM) and small cell lung cancer (SCLC) as exemplary hematologic and solid tumors. Aim 2. To develop SmartCAR-Ts which destroy or modulate the TME in MM and SCLC. Aim 3. To determine the gain in antitumor function of SmartCAR-T cells and extrapolate insights to other tumor entities. Methods: We will perform systematic multi-omics analyses on MM aspirates and SCLC biopsies to describe TME state and dynamics, high-content imaging to comprehend TME composition, spatial organization and super-resolution microscopy to quantify TME biomarkers. We have established a CAR pipeline for MM (SLAMF7, BCMA), SCLC (ROR1, CD133) and ROR2 (cross-entity); and expression cassettes with co-receptors to destroy negative components in the TME and with inducible soluble factors cytokines and immune fusion proteins to modulate the TME. Expected Results & Impact: We anticipate that SmartCAR-T cells will confer more potent and durable antitumor reactivity. We will deliver a platform that can be rapidly adjusted to other tumor types. The TME-response functions are integrated into SmartCAR-T cells as a ‘stand alone, single shot treatment‘ without the need for expensive combination therapy. This allows scalable economic production and broad patient access in a sustainable way for health care systems.
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This project has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under grant agreement No. 964264.