INCAR · Innovative CAR immune cell communities to break solid tumor barriers

Glioblastoma is the most common and most aggressive primary brain tumor in adults. It is paradigmatic for many incurable, poorly immunologic solid tumors that desperately need more effective therapies. Cellular immunotherapies with engineered immune cells expressing synthetic chimeric antigen receptors (CAR) to recognize cancer cells have great therapeutic potential. However, significant barriers related to cell manufacturing, immune cell migration and activation in the tumor environment and failure to engage the host immune system, have hindered the breakthrough of CAR cell therapies against solid tumors like glioblastoma. Our recent research shows encouraging results by combining different CAR immune cell types or arming them to co-express additional factors. Yet due to technical limitations, such multicellular CAR immune cell networks remain largely unexplored and the most potent factors for improving CAR immune cell efficacy in glioblastoma are still to be identified. The overarching goal of this proposal is to break barriers of current CAR cell therapies in solid tumors with a focus on glioblastoma. To achieve this, we will employ innovative cell engineering strategies to create multicellular CAR immune cell networks and evaluate their safety and efficacy in advanced human model systems and orthotopic immunocompetent mouse models using cutting-edge technologies such as functional single-cell profiling (Aim 1). Furthermore, we will use in vivo cell labeling and time-resolved single-cell RNA sequencing to decipher the dynamics of a CAR cell therapy-associated host immune response and harness this for combination therapies (Aim 2) and conduct novel gain-of-function screens in primary immune cells to identify the most potent co-factor for enhancing CAR cell efficacy (Aim 3). Altogether our project will deliver novel cell therapy concepts and technical solutions to address unmet medical needs and provide novel insights in cancer-immune interactions.