From bench to bedside: the history and progress of CAR T cell therapy

Abstract

Chimeric antigen receptor (CAR) T cell therapy represents a major breakthrough in cancer care since the approval of tisagenlecleucel by the Food and Drug Administration in 2017 for the treatment of pediatric and young adult patients with relapsed or refractory acute lymphocytic leukemia. As of April 2023, six CAR T cell therapies have been approved, demonstrating unprecedented efficacy in patients with B-cell malignancies and multiple myeloma. However, adverse events such as cytokine release syndrome and immune effector cell-associated neurotoxicity pose significant challenges to CAR T cell therapy. The severity of these adverse events correlates with the pretreatment tumor burden, where a higher tumor burden results in more severe consequences. This observation is supported by the application of CD19-targeted CAR T cell therapy in autoimmune diseases including systemic lupus erythematosus and antisynthetase syndrome. These results indicate that initiating CAR T cell therapy early at low tumor burden or using debulking strategy prior to CAR T cell infusion may reduce the severity of adverse events. In addition, CAR T cell therapy is expensive and has limited effectiveness against solid tumors. In this article, we review the critical steps that led to this groundbreaking therapy and explore ongoing efforts to overcome these challenges. With the promise of more effective and safer CAR T cell therapies in development, we are optimistic that a broader range of cancer patients will benefit from this revolutionary therapy in the foreseeable future.

Synthetic G protein-coupled receptors for programmable sensing and control of cell behavior

“…Cortical neurons were extracted from embryonic day 18 Sprague Dawley rat embryos (Charles River Laboratories, strain 400) by dissociation in Hank’s balanced salt solution with calcium and magnesium (Gibco). Cortical tissue was digested in papain according to the manufacturer’s protocol (Worthington), then 5 × 10 5 cells were plated onto each dish in neuronal culture medium at 37 °C under 5% CO2. The neuronal culture medium is neurobasal (Gibco) supplemented with 2% (v/v) B27 supplement (Life Technologies), 0.5% (v/v) fetal bovine serum, 1% (v/v) GlutaMAX, 1% (v/v) penicillin-streptomycin, and 1% (v/v) sodium pyruvate (Gibco, 100 mM).…”

“…Engineering modular synthetic receptors capable of recapitulating this transmembrane signaling is a key challenge for reprogramming cell behavior. Synthetic receptors derived from T cell receptors (CARs 1,2 ) and the Notch receptor (synNotch 3 ) have enabled diverse applications in medicine 4,5 and basic research. 6,7 However, these platforms are limited by their inherent mechanisms of activation (antigen-induced clustering and force, respectively) which restrict both antigen and output scope.…”

Update on Thrombosis Risk in Patients with Cancer: Focus on Novel Anticancer Immunotherapies

“…46 Currently, numerous different CAR T-cell-based therapies are in development or undergoing clinical testing in a variety of hematologic and solid cancers. 47 Importantly, upon application of CAR T cells, the anticancer effect is frequently accompanied by a strong systemic inflammatory stimulus, which can prompt a cytokine release syndrome (CRS). 48 Clinically, CRS presents mostly with fewer and hypotension, with severe cases characterized by rapid clinical deterioration, shock, and high mortality.…”

Potential and pitfalls of repurposing the CAR-T cell regimen for the treatment of autoimmune disease

“…The initial optimisation of CAR-T cell adoptive immunotherapy was carried out in oncology with the greatest advance in the treatment of B cell malignancies and subsequent activity in the development of CAR-T cells for other malignancies 9. The first clinical breakthrough for CAR-T cell therapy in cancer occurred when CAR-T cells targeting the B cell marker CD19 were found to exhibit robust, persistent antitumour activity in vivo and achieved complete remission in patients with chronic lymphocytic leukaemia 10.…”