CD19-targeted chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia

Abstract

Relapsed and refractory acute lymphoblastic leukemia (ALL) remains difficult to treat, with minimal improvement in outcomes seen in more than 2 decades despite advances in upfront therapy and improved survival for de novo ALL. Adoptive transfer of T cells engineered to express a chimeric antigen receptor (CAR) has emerged as a powerful targeted immunotherapy, showing striking responses in highly refractory populations. Complete remission (CR) rates as high as 90% have been reported in children and adults with relapsed and refractory ALL treated with CAR-modified T cells targeting the B-cell–specific antigen CD19. Distinct CAR designs across several studies have produced similar promising CR rates, an encouraging finding. Even more encouraging are durable remissions observed in some patients without additional therapy. Duration of remission and CAR-modified T-cell persistence require further study and more mature follow-up, but emerging data suggest these factors may distinguish CAR designs. Supraphysiologic T-cell proliferation, a hallmark of this therapy, contributes to both efficacy and the most notable toxicity, cytokine release syndrome (CRS), posing a unique challenge for toxicity management. This review will discuss the current landscape of CD19 CAR clinical trials, CRS pathophysiology and management, and remaining challenges.

Cytotoxic protein from the mushroom Coprinus comatus possesses a unique mode for glycan binding and specificity

“…Its cytotoxicity toward Jurkat cells is mediated by the activation of caspase cascade that is presumably induced by specific LDNF/Y3 interactions. T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy, and the long-term survival of T-ALL patients remains extremely poor due to the remission and recurrence (55,56). The critical need of an improved treatment regimen of aggressive acute T-cell leukemia lends obvious significance to Y3 for developing potential novel treatment and diagnosis options.…”

CART‐cells merge into the fast lane of cancer care

“…Once collected, T-cells are genetically modified and expanded ex-vivo for clinical use. While lenti-and retroviral vectors are the methods of gene transfer in the represented studies, other methods such as electroporation or RNA-based methods can be employed [11,16]. Different cell culture manufacturing systems have been developed which may impact the final phenotypic composition of the CAR T-cell product [17][18][19].…”

“…Given the life threatening nature of CRS, it is helpful to try and identify disease, patient or therapy related factors which may predict for the severity of CRS. Disease type (ALL) and disease burden (in ALL) are strongly correlative with the severity of CRS [1,4,16]. Unlike more traditional agents, there is not an obvious dose: toxicity relationship with CD19-CAR T-cell therapy where the infusion dose grossly underestimates the final expanded active dose, and dose is only one of many factors which may correlate with peak in vivo expansion.…”

“…Indeed, many of the clinical manifestations of CRS overlap with those of macrophage activation syndrome/hemophagocytic lymphohistiocytosis [37]. An area of ongoing investigation is whether cytokine profiles can be used to predict severity of CRS and be used to guide pre-emptive anti-cytokine directed treatment [1,16].…”

Axicabtagene ciloleucel, a first-in-class CAR T cell therapy for aggressive NHL

“…In such cases of CRS, administration of the IL-6-receptor antagonist tocilizumab and, if necessary, corticosteroids is recommended [51,52]. Treatment with tocilizumab results in a rapid reversal of symptoms [51,52], and it has been hypothesized that prophylactic treatment, including early tocilizumab administration, may play a role in reducing CAR T therapy-related CRS [56]. In the ZUMA-1 trial, 43% of patients received tocilizumab and 27% received corticosteroids for management of cytokine release syndrome and/or neurologic events [41].…”