Chimeric Antigen Receptor T-cell Therapy in Cancer: A Critical Review

Abstract

Targeted cancer therapy acts on targeted molecules, is less toxic to normal cells, and acts more specifically on cancer cells. The two primary strategies for preventing malignancy growth are the blocking of T-cell repression signals or forwarding of T-cell to tumor target with both T and tumor-specific antibodies. The CAR comprises three domains, the extracellular antigen recognition domain and the intracellular T-cell signaling domain, which participate in activating T-cells. The two most common adverse effects of CAR T-cell treatment are cytokine release syndrome (CRS) and cell-associated neurotoxicity syndrome (CANS). The adaptability of intracellular signaling domains inside CARs allows the cell to counterbalance the downregulation of co-stimulatory molecules produced by tumor cells, either indirectly or directly. The major disadvantage of CAR-T cell therapy is off-target toxicity. Treatment with CARs expressing CD3, CD123, Lewis Y, CLL-1, CD44v6, FLT3, and folate receptors showed promising results in preclinical models of acute myeloid leukemia (AML). A recent study has revealed that B7-H3 CAR-T cells exhibit significant anticancer efficacy in a variety of solid tumor preclinical models, including PDAC, ovarian cancer, neuroblastoma, and various pediatric malignancies. The notion of SUPRA CAR, with its unique capacity to alter targets without the need to re-engineer, is a recent innovation in CAR. Given the importance of NK cells in tumor development and metastatic defence, NK cell-based immunotherapies, including adoptive transfer of NK cells, have garnered a lot of interest. With the advancement of improved cellular manufacturing methods, novel cellular engineering strategies, precision genome editing technologies, and combination therapy approaches, we firmly believe that CAR-T cells will soon become an off-the-shelf, cost-effective, and potentially curative therapy for oncogenesis.

Case report: Donor-derived CLL-1 chimeric antigen receptor T-cell therapy for relapsed/refractory acute myeloid leukemia bridging to allogeneic hematopoietic stem cell transplantation after remission

“…Treatment after relapse remains a challenge, especially for AML that relapses after HSCT, with no standard therapies and only a series of palliative treatments (18,19). In recent years, the success of CD19 CAR-T therapy in B-cell malignancies has led to the exploration of the efficacy and safety of CAR-T therapy in AML, the targets of which include LewisY, CD44V6, CD33, CD123, and CLL-1 (4,8,(20)(21)(22)(23)(24). Although more expressed in leukemic stem cells (LSCs), CD33 and CD123 are also frequently expressed in normal HSCs, and their suppression can lead to long-term or even permanent myelosuppression (25).…”

Broadening the horizon: potential applications of CAR-T cells beyond current indications

“…After initial hopes that CAR-T cells could present a potentially universal therapeutic approach for malignant diseases, researchers are currently understanding that CAR-T cells are most likely just one of several options in personalized therapies ( 21 ). Therefore, other innovative immunotherapeutic strategies are being investigated, including different immune cell groups, oncolytic viruses, technologies like T-cell engagers, T-cell receptor (TCR) engineering, and combinations of these technologies with CAR-T cells ( 22 ).…”