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Safety of multiple doses of car T cells

      Chimeric antigen receptor (CAR) T cells have demonstrated promising results for cancers in pre-clinical models and early phase trials. However, some groups have observed serious adverse events (SAEs) and toxicities attributable to the administration of CAR T cells, the most clinically significant being cytokine release syndrome (CRS). In addition, a recent case report described a patient who developed an anaphylaxis reaction to CAR T cells, ultimately attributed to receipt of multiple doses of cells. As there are a number of ongoing clinical trials at our institution utilizing CAR T cells to treat various hematologic and solid malignancies and several patients have received multiple doses, we performed a retrospective review to assess whether early or late infusion toxicities were observed with subsequent infusions. We identified 45 of over 200 patients who received more than one dose of CAR T cells between January 2009 and December 2014. We assessed patient characteristics including type of malignancy, disease status at the time of subsequent infusions, cell product (autologous vs. allogeneic), presence or absence of prior lymphodepletion, number of infusions, dosing schedule, and the relationship to development of CRS. Each characteristic was examined for any correlation to developing a SAE. Our results indicate that at our institution, repeated CAR T cell infusions are well tolerated, with the majority of grade 3-4 adverse events being hematologic and electrolyte abnormalities. Furthermore, the majority of SAEs reported after repeated CAR T cell infusions were attributed as unrelated to the infusion itself. However, further evaluation of a larger cohort is necessary to determine whether an association between the timing of repeated infusions and CRS and other SAEs exists. These findings and our continued evaluation of patients receiving multiple infusions will help us to ensure the safety of administering multiple doses of CAR T cells in the future.
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