Abstract
SummaryChimeric antigen receptor (CAR) T cells are genetically engineered cells containing fusion proteins combining an extracellular epitope-specific binding domain, a transmembrane and signaling domains of the T cell receptor. The CD19-CAR T cell product tisagenlecleucel has been approved by the US Food and Drug Administration and the European Medicines Agency for therapy of children and young adults under 25 years with relapsed/refractory B‑cell acute lymphoblastic leukemia (ALL) due to a high overall response rate of 81% at 3 months after therapy. The rates of event-free and overall survival were 50 and 76% at 12 months. Despite the high initial response rate with CD19-CAR‑T cells in B‑ALL, relapses occur in a significant fraction of patients. Current strategies to improve CAR‑T cell efficacy focus on improved persistence of CAR‑T cells in vivo, use of multispecific CARs to overcome immune escape and new CAR designs. The approved CAR‑T cell products are from autologous T cells generated on a custom-made basis with an inherent risk of production failure. For large scale clinical applications, universal CAR‑T cells serving as “off-the-shelf” agents would be of advantage. During recent years CAR‑T cells have been frequently used for bridging to allogeneic hematopoietic stem cell transplantation (HSCT) in patients with relapsed/refractory B‑ALL since we currently are not able to distinguish those CAR‑T cell induced CRs that will persist without further therapy from those that are likely to be short-lived. CAR‑T cells are clearly of benefit for treatment following relapse after allogeneic HSCT. Future improvements in CAR‑T cell constructs may allow longer term remissions without additional HSCT.
Highlights
First-line chemotherapy for patients with B-cell acute lymphoblastic leukemia (B-ALL) younger than 65 years is intensive chemotherapy, e.g., Hoelzer protocol or hyper-CVAD (1)
Novel therapeutic options including blinatumomab and inotuzumab ozogamicin (InO) have resulted in higher response rates and longer survival (OS) than conventional chemotherapy [1]. Response to these agents enables patients to undergo hematopoietic stem cell transplantation (HSCT) as has been recently reported by Marks and colleagues where 101 of 236 patients (43%) with relapsed/refractory B-ALL given InO, an anti-CD22 antibody conjugated to calicheamicin, proceeded to HSCT [2]
In a prospective randomized phase III study more patients with relapsed/refractory B-ALL treated with blinatumomab, a bispecific T cell engager targeted to CD19 and CD3, compared to standard-of-care chemotherapy (SOC) achieved complete remission (CR), CR with partial (CRh), or incomplete (CRi) hematologic recovery and minimal residual disease (MRD)-negativity [3]
Summary
First-line chemotherapy for patients with B-cell acute lymphoblastic leukemia (B-ALL) younger than 65 years is intensive chemotherapy, e.g., Hoelzer protocol or hyper-CVAD (1). Novel therapeutic options including blinatumomab and inotuzumab ozogamicin (InO) have resulted in higher response rates and longer survival (OS) than conventional chemotherapy [1]. Response to these agents enables patients to undergo HSCT as has been recently reported by Marks and colleagues where 101 of 236 patients (43%) with relapsed/refractory B-ALL given InO, an anti-CD22 antibody conjugated to calicheamicin, proceeded to HSCT [2]. Current second-generation CAR-T constructs are combined with additional costimulatory domains such as CD28, 4-1BB, and OX40 This enables a strong antigen-specific T cell activation without the need of TCR-MHC interactions. The rates of event-free survival (EFS) and OS were 73 and 90% at 6 months and 50 and 76% at
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