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Summary: Current in vitro and in vivo assays used to study immunotherapeutic interventions lack human immune components that mimic the tumor microenvironment to investigate drug potency and limitations of efficacy. Herein, we describe an ex vivo pleural effusion culture (ePEC) assay, using malignant pleural-effusion-derived soluble and cellular factors that differentially affected the cytotoxicity of chimeric antigen receptor (CAR) T cells. Following identification of CAR T cell-suppressive factors, blocking of individual factors reveals their contribution to compromising T cell efficacy. ePEC is a human component assay that can be utilized for developing next-generation cell and antibody therapies that counteract immunosuppression. Motivation: In vitro assays that are currently being used in a pre-clinical setting to test CAR T cell functional activity do not reflect the activity seen when used in a patient’s immunosuppressive environment. We used patient-derived malignant pleural effusions to provide an ex vivo milieu that allowed us to determine CAR T cell functional activity in an immunosuppressive environment.