Clinical practice: chimeric antigen receptor (CAR) T cells: a major breakthrough in the battle against cancer

Abstract

Chimeric antigen receptor (CAR) T cell therapy has come of age, offering a potentially curative option for patients who are refractory to standard anti-cancer treatments. The success of CAR T cell therapy in the setting of acute lymphoblastic leukemia and specific types of B cell lymphoma led to rapid regulatory approvals of CD19-directed CAR T cells, first in the United States and subsequently across the globe. Despite these major milestones in the field of immuno-oncology, growing experience with CAR T cells has also highlighted the major limitations of this strategy, namely challenges associated with manufacturing a bespoke patient-specific product, intrinsic immune cell defects leading to poor CAR T cell function as well as persistence, and/or tumor cell resistance resulting from loss or modulation of the targeted antigen. In addition, both onand off-tumor immunotoxicities and the financial burden inherent in conventional cellular biomanufacturing often hamper the success of CAR T cell-based treatment approaches. Herein, we provide an overview of the opportunities and challenges related to the first form of gene transfer therapy to gain commercial approval in the United States. Ongoing advances in the areas of genetic engineering, precision genome editing, toxicity mitigation methods and cell manufacturing will improve the efficacy and safety of CAR T cells for hematologic malignancies and expand the use of this novel class of therapeutics to reach solid tumors.

Cas9-mediated knockout of Ndrg2 enhances the regenerative potential of dendritic cells for wound healing

“…By contrast, adoptive cell transfer using a patient’s own T cells or DCs has been successfully translated to the clinic and has led to oncologic breakthroughs in recent years 62 . Combining gene editing with immunotherapy enabled the development of CAR-T-cell therapy, which has demonstrated unsurpassed effectivity against hematologic malignancies, even in patients who are refractory to multiple lines of therapy 63 . In addition to T cells, using a patient’s own DCs to treat solid tumors and a variety autoimmune conditions has demonstrated adequate safety profiles and strong therapeutic efficacy 11 , 13 , 15 , 17 , 18 .…”

Cas9-Mediated Knockout of Ndrg2 Enhances the Regenerative Potential of Dendritic Cells for Wound Healing

“…57 Combining gene editing with immunotherapy enabled the development of CAR T cell therapy, which demonstrated unsurpassed effectivity against hematologic malignancies and a potential cure for patients who are refractory to standard chemotherapies. 58 In addition to T cells, using a patient's own DCs to treat solid tumors and multiple auto-immune conditions has demonstrated adequate safety profiles and strong therapeutic efficacy. 11,13,15,17,18 Gene editing of DCs for non-therapeutic use has previously been performed using lentiviral vector-based approaches.…”

Gene-circuit therapy on the horizon: synthetic biology tools for engineered therapeutics

“…Such solutions exploit antigen specificity to recognize cancer cells, thus extending the spectrum of T cell activation beyond the capabilities of major histocompatibility complex (MHC). Development of CARs was a breakthrough in efficient T cell immunotherapy that is currently in clinical practice (Maude et al, 2015;Holzinger et al, 2016;Lundh et al, 2020;Lanitis et al, 2020). However, even these advanced engineered therapeutics suffer from the adverse effects of transgene overexpression, cell-cell variability, and the lack of contextual control of expression levels.…”