At the Bench: Chimeric antigen receptor (CAR) T cell therapy for the treatment of B cell malignancies

Abstract

The chimeric antigen receptor (CAR) represents the epitome of cellular engineering and is one of the best examples of rational biologic design of a synthetic molecule. The CAR is a single polypeptide with modular domains, consisting of an antibody-derived targeting moiety, fused in line with T cell-derived signaling domains, allowing for T cell activation upon ligand binding. T cells expressing a CAR are able to eradicate selectively antigen-expressing tumor cells in a MHC-independent fashion. CD19, a tumor-associated antigen (TAA) present on normal B cells, as well as most B cell-derived malignancies, was an early target of this technology. Through years of experimental refinement and preclinical optimization, autologously derived CD19-targeting CAR T cells have been successfully, clinically deployed, resulting in dramatic and durable antitumor responses but not without therapy-associated toxicity. As CD19-targeted CAR T cells continue to show clinical success, work at the bench continues to be undertaken to increase further the efficacy of this therapy, while simultaneously minimizing the risk for treatment-related morbidities. In this review, we cover the history and evolution of CAR technology and its adaptation to targeting CD19. Furthermore, we discuss the future of CAR T cell therapy and the need to ask, as well as answer, critical questions as this treatment modality is being translated to the clinic.

NKG2D/NKG2-Ligand Pathway Offers New Opportunities in Cancer Treatment

“…For instance, CAR-T cells were shown to be potent against CD19-expressing hematologic tumors in several trials (103, 104). However, the safety of CAR-T cells remains a major obstacle, and CARs must be optimized to increase efficacy and limit treatment-related morbidities due to cytokine-release syndrome (105). Up to now, the use of CAR-T cells for treating solid tumors has been limited by the lack of appropriate tumor antigens (106).…”

Anti-tumor Efficacy of CD19 CAR-T in a Raji B Cell Xenografted Mouse Model

“…Chimeric antigen receptor (CAR)-T-cell therapy exploits an antibody-dependent, major histocompatibility complex–independent antigen recognition paradigm to specifically target cancer cells using genetically engineered T cells. It is one of the most sought-after tools for treating hematologic malignancies ( Daniyan and Brentjens, 2016 ; Posey et al, 2016). Recently, extensive studies have revealed the molecular mechanisms of CAR-T activation, such as charged lipids and ions–regulated CD28 conformation and signaling ( Yang et al, 2017 ) and LAT-independent formation of CAR microclusters ( Dong et al, 2020 ); SILAC-based phosphoproteomics revealed unique signaling circuits of CAR-Ts, and the distance of synapse from CAR-T/tumor cells was found to affect T-cell function ( Xiao et al, 2022 ).…”

Understanding and Managing Large B Cell Lymphoma Relapses after Chimeric Antigen Receptor T Cell Therapy

“…Chimeric antigen receptor (CAR) T cell therapy in DLBCL and its variants provides a new treatment option for patients who relapse after 2 or more lines of therapy. Commercially available CAR T cells are produced by transducing autologous T cells with a gene encoding a hybrid receptor comprising an extracellular target binding domain, a transmembrane domain, and intracellular signaling domains that can eliminate CD19 expressing tumor via effector and cytolytic processes [6,7]. Second-generation CD19-directed CAR T cell therapies, those containing both a CD3-z signaling domain and a costimulatory domain, were evaluated in relapsed/refractory B cell lymphomas, and durable objective responses were observed in single-arm, multicenter, pivotal phase 2 trials.…”