Driving CAR T-cells forward

Abstract

The engineered expression of chimeric antigen receptors (CARs) on the surface of T cells enables the redirection of T-cell specificity. Early clinical trials using CAR T cells for the treatment of patients with cancer showed modest results, but the impressive outcomes of several trials of CD19-targeted CAR T cells in the treatment of patients with B-cell malignancies have generated an increased enthusiasm for this approach. Important lessons have been derived from clinical trials of CD19-specific CAR T cells, and ongoing clinical trials are testing CAR designs directed at novel targets involved in haematological and solid malignancies. In this Review, we discuss these trials and present strategies that can increase the antitumour efficacy and safety of CAR T-cell therapy. Given the fast-moving nature of this field, we only discuss studies with direct translational application currently or soon-to-be tested in the clinical setting.

Combination therapy with L-arginine and α-PD-L1 antibody boosts immune response against osteosarcoma in immunocompetent mice

“…Numerous studies are focusing using CD8 C T-cells for cancer immunotherapy, including osteosarcoma. [17][18][19] However, the underlying mechanisms affecting Tcell activation, differentiation, function and survival are still largely unknown. Any method which can facilitate T-cell activity will undoubtedly help in cancer immunotherapy.…”

Immune targets and neoantigens for cancer immunotherapy and precision medicine

“…First, approximately 40%-50% of patients who received CD19-CAR T cell therapy will have recurrence within one year, and the underlying mechanisms remain unclear. The second issue is that CAR T cell therapy does not yet work well in solid cancers, even though many CAR T cell therapies target surface molecules expressed by solid cancers [46]. Thus, immune suppression in the tumor microenvironment is a major obstacle for T-cellbased immunotherapy.…”

“…Since the first report of CD19-CAR T cell therapy [48], this immunotherapy strategy has been successfully extended to treating patients with many types of chemotherapy-refractory B cell malignancies, including acute lymphoblastic B cell leukemias (ALLs), chronic lymphocytic leukemias (CLLs), aggressive B cell lymphoma, and marginal zone lymphoma [41,43,194,195]. A major toxicity associated with CAR T cell therapy is cytokine release syndrome (CRS) resulting from an exuberant release of cytokines such as IFN-γ and IL-6 from infused T cells when they encounter CD19-positive tumor cells [46,47]. Clinical symptoms of CRS include high fevers, kidney failure, electrolyte abnormalities, hypotension, cardiac dysfunction, and seizures.…”

“…It should be noted that these checkpoint blockade therapies rely on the presence of tumor-specific T cells at tumor sites, which is highly correlated with PD-L1 expression on cancer cells [38]. Furthermore, recent clinical trials, using antigen-specific T cell receptor (TCR) for the treatment of patients with synovial sarcoma, metastatic melanoma or myeoloma, and CD19-chimeric antigen receptor (CAR) for leukemia and lymphoma, have shown promising clinical responses [40][41][42][43][44][45][46][47][48].…”

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

“…CARs are synthetic immunoreceptors whose extracellular domain is typically an antibody-derived single chain variable fragment (scFv) that recognizes a tumor cell surface protein. The scFv is linked to intracellular signaling components derived from T lymphocytes, including the key intracellular signaling domain of the TCR CD3f subunit [3]. Although essential for T cell activation, signaling via CD3f is not sufficient for optimal T cell function.…”