Abstract: According to the National Cancer Institute, every 9 minutes a person in the USA dies from a blood cancer1. While initial responses are achievable with conventional chemotherapy, relapsed/refractory disease remains a significant problem. Chimeric antigen receptor (CAR) T cell-based immunotherapy is a revolutionarily new approach against these stubborn cancers. Although several clinical trials have shown remarkable efficacy, there remains a subset of patients who do not respond to CAR T therapy and/or experience toxicity as a result of immune activation in the form of cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome (ICANS)2-6. As preserving of this a result, managing these iatrogenic toxicities while still high on-target efficacy has become a fundamental part of the ongoing development immunotherapy. To date, several studies have demonstrated the strong interplay between commensal microbiota and its effect on both the innate and adaptive immune system, such as the regulation of T cell function7-18. Studies suggest that the intestinal microbiota may be a crucial host factor that modulates the response to immunotherapy7,8,19-21. Lymphodepleting conditioning and administration of antibiotics regularly disrupt the natural intestinal flora leading to dysbiosis and expansion of unfavorable antibiotic-resistance pathogenic taxa22. Although the microbiome has been associated with clinical response in allogeneic-hematopoietic stem cell transplants, checkpoint blockade, and adoptive T cell therapy10,20,23-26, it is still unknown as to how microbiome manipulations affect CAR T cell therapy response. Preliminary data from our center shows that exposure to antibiotics prior to CAR T cell infusion decreases overall survival and progression free survival of patients. Additionally, we have found that specific bacterial taxa in the baseline stool of patients prior to CAR T cell infusion, are associated with complete response. These enhanced preliminary studies support outcome of CAR T cell therapy. a causal role for the intestinal microbiota in The central hypothesis for this project is that strategic microbiota modulation can enhance CAR T cell therapy response by preserving favorable taxa for improved effector function of CAR T cells via a pro-inflammatory milieu. This hypothesis will be tested by pursuing two project aims: 1) Investigating the role of the intestinal microbiota on CAR T Cell therapy response; and 2) Evaluating the impact of broad-spectrum antibiotics on CAR T cell effector function.