Blood-brain barrier breakdown, central nervous system cell damage, and infiltrated T cells as major adverse effects in CAR-T-related deaths: a literature review

Background CAR-T-related deaths observed worldwide are rare. The underlying pathogenetic mechanisms are the subject of study, as are the findings that enable diagnosis. A systematic literature search of the PubMed database and a critical review of the collected studies were conducted from the inception of this database until January 2023. The aim of the study is to determine when death is related to CAR-T cell therapy and to develop a shareable diagnostic algorithm.Methods The database was searched by combining and meshing the terms ("CAR-t" OR "CART") AND ("Pathology" OR "Histology" OR "Histological" OR "Autopsy") AND ("Heart" OR "Cardiac" OR "Nervous System" OR "Kidney" OR "Liver") with 34 results and also the terms: [(Lethal effect) OR (Death)] AND (CAR-T therapy) with 52 results in titles, abstracts, and keywords [all fields]. One hundred scientific articles were examined, 14 of which were additional records identified through other sources. Fifteen records were included in the review.Results Neuronal death, neuronal edema, perivascular edema, perivascular and intraparenchymal hemorrhagic extravasation, as well as perivascular plasmatodendrosis, have been observed in cases with fatal cerebral edema. A cross-reactivity of CAR-T cells in cases of fatal encephalopathy can be hypothesized when, in addition to the increased vascular permeability, there is also a perivascular lymphocyte infiltrate, which appears to be a common factor among most authors.Conclusion Most CAR-T-related deaths are associated with blood-brain barrier breakdown, central nervous system cell damage, and infiltrated T cells. Further autopsies and microscopic investigations would shed more light on the lethal toxicity related to CAR-T cells. A differential diagnosis of CAR-T-related death is crucial to identifying adverse events. In this article, we propose an algorithm that could facilitate the comparison of findings through a systematic approach. Despite toxicity cases, CAR-T therapy continues to stand out as the most innovative treatment within the field of oncology, and emerging strategies hold the promise of delivering safer therapies in future

Identification of a serum and urine extracellular vesicle signature predicting renal outcome after kidney transplant

Background A long-standing effort is dedicated towards the identification of biomarkers allowing the prediction of graft outcome after kidney transplant. Extracellular vesicles (EVs) circulating in body fluids represent an attractive candidate, as their cargo mirrors the originating cell and its pathophysiological status. The aim of the study was to investigate EV surface antigens as potential predictors of renal outcome after kidney transplant. Methods We characterized 37 surface antigens by flow cytometry, in serum and urine EVs from 58 patients who were evaluated before, and at 10-14 days, 3 months and 1 year after transplant, for a total of 426 analyzed samples. The outcome was defined according to estimated glomerular filtration rate (eGFR) at 1 year. Results Endothelial cells and platelets markers (CD31, CD41b, CD42a and CD62P) in serum EVs were higher at baseline in patients with persistent kidney dysfunction at 1 year, and progressively decreased after kidney transplant. Conversely, mesenchymal progenitor cell marker (CD1c, CD105, CD133, SSEEA-4) in urine EVs progressively increased after transplant in patients displaying renal recovery at follow-up. These markers correlated with eGFR, creatinine and proteinuria, associated with patient outcome at univariate analysis and were able to predict patient outcome at receiver operating characteristics curves analysis. A specific EV molecular signature obtained by supervised learning correctly classified patients according to 1-year renal outcome. Conclusions An EV-based signature, reflecting the cardiovascular profile of the recipient, and the repairing/regenerative features of the graft, could be introduced as a non-invasive tool for a tailored management of follow-up of patients undergoing kidney transplant