Towards Safer and More Effective CART Cell Therapy Through the Modulation of Myeloid Cytokines

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PROJECT SUMMARY Despite the impressive activity of chimeric antigen receptor T (CART) cell therapy in the treatment of B-cell malignancies, the therapy is limited by the development of toxicities, including cytokine release syndrome (CRS) and neurotoxicity, as well as by lower rates of durable responses. The in vivo expansion of CART cells is a critical determinant of their antitumor activity as well as of the development of toxicities. Over the last 5 years, we have focused our work on addressing limitations related to CART complexity, toxicity, and resistance. We utilized companion dogs as a proof-of-concept model to test engineered allogeneic human CART cells as a therapy for spontaneous disease including diffuse large B-cell lymphoma (DLBCL). We engineered canine CD20-targeting xenogeneic human CART cells (T-cell receptor alpha (TRAC)- and beta-2 microglobulin (B2M)- disrupted), developed and optimized a canine-specific lymphodepleting regimen, and tested the safety of xenogeneic CART cells in healthy beagles. Then, to track CART cell fates and functions in real time in vivo, we developed and recently published the utility of sodium iodide symporter (NIS) as a platform to detect CART cell expansion, trafficking, and toxicity in mouse models. In this application, we propose to utilize our NIS reporter system, novel canine lymphodepletion regimen, and established canine clinical trial expertise to test NIS+ human CART cells in companion dogs. We hypothesize that 18F-tetrafluoroborate (TFB) PET imaging of NIS+ canine CD20-targeting xenogeneic human CART cells is a sensitive strategy to detect CART cell rejection, expansion, and trafficking to tumor sites in canine patients with DLBCL. To test this hypothesis, we have designed two specific aims. In Aim 1, we will study the utility of TFB-PET imaging of NIS+ CART cells to measure CART expansion, rejection, and trafficking in canine patients with DLBCL. We will determine how quantitative PET signal (qPET) correlates with quantitative PCR (qPCR) measurement of the CAR transgene in peripheral blood and lymph node samples. In Aim 2, we will determine how TFB-PET imaging of CART cell expansion and trafficking correlates with their activity and toxicity. Completion of these aims will validate qPET imaging as a non-invasive platform to study CART dynamics in canine lymphoma and provide additional rationale to propose a first-in-human clinical trial of NIS+ CART cells in patients with lymphoma.