Drivers and Brakes of CAR T Cell Efficacy Determined by the Tumor Immune Microenvironment

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Cancer immunotherapies with chimeric antigen receptor (CAR) T cells have shown dramatic clinical efficacy in patients with B cell neoplasms. Thus, their clinical use is expected to increase considerably in the near future. However, for poorly understood reasons, not all patients with lymphoma benefit from these expensive therapies. The ability to stratify patients into probable responders vs. non-responders prior to immunotherapy will improve treatment efficacy, limit patient exposure to adverse effects, and mitigate the significant economic costs associated with these therapies. We and others have previously demonstrated that effective antitumoral immunity requires complex, spatially coordinated interactions between different cellular elements within the tumor immune microenvironment (TIME). There is evidence that patient response to immunotherapy is attributed to specific characteristics of the TIME, such as the composition, spatial arrangement, and activation states of immune cell types in it. Therefore, a better understanding of the TIME, and of how immunotherapies come into effect in live, intact human tissues, is critical for the selection of successful immunotherapies for our patients. The overarching aim of the CAR-TIME project is to explore and visualize the cellular and molecular mechanisms of CAR T cell efficacy in lymphoma, determined by CAR T cell interactions with the TIME. This shall be achieved by creating a high-dimensional map of the TIME of diffuse large B cell lymphoma, performing live tissue cultures treated with immunotherapies, and establishing a novel live cell microscopy platform to interrogate intact human lymphoma tissue treated with CAR T cells. Drug perturbations, multidimensional imaging technologies, RNA sequencing and integrative bioinformatics analysis will illuminate mechanisms of therapy response vs. resistance, reveal novel predictive biomarkers, and inform future combination immunotherapy strategies to improve patient outcomes.