Tuning CARs: recent advances in modulating chimeric antigen receptor (CAR) T cell activity for improved safety, efficacy, and flexibility

Abstract

Cancer immunotherapies utilizing genetically engineered T cells have emerged as powerful personalized therapeutic agents showing dramatic preclinical and clinical results, particularly in hematological malignancies. Ectopically expressed chimeric antigen receptors (CARs) reprogram immune cells to target and eliminate cancer. However, CAR T cell therapy's success depends on the balance between effective anti-tumor activity and minimizing harmful side effects. To improve CAR T cell therapy outcomes and mitigate associated toxicities, scientists from different fields are cooperating in developing next-generation products using the latest molecular cell biology and synthetic biology tools and technologies. The immunotherapy field is rapidly evolving, with new approaches and strategies being reported at a fast pace. This comprehensive literature review aims to provide an up-to-date overview of the latest developments in controlling CAR T cell activity for improved safety, efficacy, and flexibility.

CAR-T Cells Immunotherapies for the Treatment of Acute Myeloid Leukemia—Recent Advances

“…EM is composed of intracellular signaling domains and an extracellular peptide epitope binding domain, which is physiologically absent on the cell surface, so UniCAR cells are devoid of cytotoxic activity until the administration of TM composed of a peptide epitope and a tumor specific antigen-binding domain. The administration of TMs targets the UniCAR cell to the tumor cell, and enables the activation of cytotoxic mechanisms (see Figure 3) [46,47]. Cartellieri et al created the UniCAR platform targeting CD123 and CD33.…”

“…In order to improve the safety of therapy, the iC9 suicide gene can be included in the CAR construct. In the event of significant toxicity and other adverse effects after the infusion of CAR-T cells, the activation of iC9 can be triggered by administering a neutral molecule to the patient, which will result in the elimination of therapeutic cells from the recipient's body [47,113]. The disadvantage of this solution is the permanent loss of CAR-T cells.…”

“…The disadvantage of this solution is the permanent loss of CAR-T cells. An alternative solution to this problem may be the regulation of CAR gene expression, thanks to which it will be possible to control the number of CARs expressed on CAR-T cells using biophysical or chemical inducers (e.g., Tet-ON technology enables the control of CAR gene expression depending on the dose of the administered tetracycline) [47]. The enhancement of the safety profile of CAR-T cells can also be obtained by overexpressing the runt-related transcription factor 3 (RUNX3) gene in them.…”

“…UniCAR cells are devoid of cytotoxic activity until TMs are administered, which targets them to the tumor cell and enables the activation of cytotoxic mechanisms; therefore, the elimination of TMs from the body in the event of side effects prevents the activation of UniCAR cells. The advantage of UniCAR cells over CAR cells is the ability to target the same UniCAR cells to different tumor antigens by modifying only the target module, and their increased safety profile [46,47]. The modification of UniCAR cells is the RevCAR technology, in which the size of the gene encoding the CAR construct is reduced by swapping the locations of the peptide epitope and the peptide epitope-binding domain [68].…”

Bispecific T-Cell Engagers and Chimeric Antigen Receptor T-Cell Therapies in Glioblastoma: An Update

“…Furthermore, universal CARs (UniCAR) include a binding moiety that can bind multiple different antigen-targeting modules for easy retargeting and control. Many others exist, but a discussion of these designs is beyond the scope of this review, and multiple excellent reviews discuss them at length [ 166 , 240 , 241 ].…”