A New Era in Endothelial Injury Syndromes: Toxicity of CAR-T Cells and the Role of Immunity

Abstract

Immunotherapy with chimeric antigen receptor T (CAR-T cells) has been recently approved for patients with relapsed/refractory B-lymphoproliferative neoplasms. Along with great efficacy in patients with poor prognosis, CAR-T cells have been also linked with novel toxicities in a significant portion of patients. Cytokine release syndrome (CRS) and neurotoxicity present with unique clinical phenotypes that have not been previously observed. Nevertheless, they share similar characteristics with endothelial injury syndromes developing post hematopoietic cell transplantation (HCT). Evolution in complement therapeutics has attracted renewed interest in these life-threatening syndromes, primarily concerning transplant-associated thrombotic microangiopathy (TA-TMA). The immune system emerges as a key player not only mediating cytokine responses but potentially contributing to endothelial injury in CAR-T cell toxicity. The interplay between complement, endothelial dysfunction, hypercoagulability, and inflammation seems to be a common denominator in these syndromes. As the indications for CAR-T cells and patient populations expand, there in an unmet clinical need of better understanding of the pathophysiology of CAR-T cell toxicity. Therefore, this review aims to provide state-of-the-art knowledge on cellular therapies in clinical practice (indications and toxicities), endothelial injury syndromes and immunity, as well as potential therapeutic targets.

Noninfectious lung complications of hematopoietic cell transplantation

“…Cytokine release syn drome (CRS) can include respi ra tory com pro mise, with infil trates, hyp oxia, and endo the lial dys func tion that closely mim ics CLS. [36][37][38] A large inter na tional study showed that 25% of patients with CART had sig nifi cant pul mo nary com pro mise. 39 Risk fac tors for CRS include high dis ease bur den, con cur rent infec tions, and lymphodepletion prior to CART.…”

The Role of Myeloid-Derived Suppressor Cells (MDSCs) in Graft-versus-Host Disease (GVHD)

“…Furthermore, translational studies are highly needed in this field to confirm the role of MDSC in the pathogenesis of GVHD. While entering the era of CAR-T cell and other upcoming cellular therapies [ 108 ], appreciating the interactions between effector immune cells and MDSCs in order to be able to define the ideal conditions for harvesting is of paramount importance.…”

Influence of Culture Conditions on Ex Vivo Expansion of T Lymphocytes and Their Function for Therapy: Current Insights and Open Questions

“…Endothelial cell activation is one of the CAR T cell therapy–associated toxicity ( Gavriilaki et al, 2020 ). Persistent activation of endothelial cells CRS during CAR T cell therapy has also been described to result in endothelial dysfunction ( Page and Liles, 2013 ; Gust et al, 2017 ).…”