CAR-modified T-cell therapy for cancer: an updated review

Abstract

The use of chimeric antigen receptor (CAR)-modified T cells is a promising approach for cancer immunotherapy. These genetically modified receptors contain an antigen-binding moiety, a hinge region, a transmembrane domain, and an intracellular costimulatory domain resulting in T-cell activation subsequent to antigen binding. Optimal tumor removal through CAR-modified T cells requires suitable target antigen selection, co-stimulatory signaling domain, and the ability of CAR T cells to traffic, persist, and retain antitumor function after adoptive transfer. There are several elements which can improve antitumor function of CAR T cells, including signaling, conditioning chemotherapy and irradiation, tumor burden of the disease, T-cell phenotype, and supplementary cytokine usage. This review outlines four generations of CAR. The pre-clinical and clinical studies showed that this technique has a great potential for treatment of solid and hematological malignancies. The main purpose of the current review is to focus on the pre-clinical and clinical developments of CAR-based immunotherapy.

Use of Chimeric Antigen Receptor T Cells in Allogeneic Hematopoietic Stem Cell Transplantation

“…The outcome is also poor for a patient with a higher burden of disease [34]. In addition, it is very difficult to collect sufficient T cells for the construction of CAR-T cells from patients who have an extremely high leukemia burden [23,35].…”

High-throughput cancer hypothesis testing with an integrated PhysiCell-EMEWS workflow

“…In future work, we plan to integrate and explore other key features of the immune system, such as inflammatory responses, cross-talk between different immune cell types, and molecular-level mechanisms for MHC function and immune-mediated cancer cell apoptosis [53,47,48,21]. The models also need extension to directly model new treatments such as the role of PD-1 and PD-L1 in CAR T-cell therapies [19,20]. In our next steps, we will extend the modeling framework to incorporate these effects, and import it into the EMEWS framework.…”

“…Recent successes of cancer immunotherapies-such as CAR (chimeric antigen receptor) T-cell treatments [20,21]-have brought heightened attention to cancer immunology. In some patients, immune cell therapies have been impressively successful, while other patient populations have demonstrated disappointing outcomes; this variability of patient response arises in part from the poorly-understood, complex interactions between cancer and the immune system [22][23][24][25][26][27].…”

Harnessing the immune system to improve cancer therapy

“…Second and third generation CARs contained additional co-stimulatory domains such as CD28 and/or CD137, which improved cytokine production by and in vivo persistence of infused CAR-modified T cells, respectively. Recently developed T cells redirected for universal cytokine-mediated killing (47). CAR T-meso in patients with mesothelin-expressing tumors and CAR T cells secreting IL-12 for recurrent ovarian cancer are among the most promising constructs (48).…”