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.
Funded by the European Union under the Horizon Europe Framework Programme - Grant Agreement Nº: 101095654. Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the European Union or European Health and Digital Executive Agency (HADEA). Neither the European Union nor the granting authority can be held responsible for them.