Novel CAR T therapy is a ray of hope in the treatment of seriously ill AML patients

Abstract

Acute myeloid leukemia (AML) is a serious, life-threatening, and hardly curable hematological malignancy that affects the myeloid cell progenies and challenges patients of all ages but mostly occurs in adults. Although several therapies are available including chemotherapy, allogeneic hematopoietic stem cell transplantation (alloHSCT), and receptor-antagonist drugs, the 5-year survival of patients is quietly disappointing, less than 30%. alloHSCT is the major curative approach for AML with promising results but the treatment has severe adverse effects such as graft-versus-host disease (GVHD). Therefore, as an alternative, more efficient and less harmful immunotherapy-based approaches such as the adoptive transferring T cell therapy are in development for the treatment of AML. As such, chimeric antigen receptor (CAR) T cells are engineered T cells which have been developed in recent years as a breakthrough in cancer therapy. Interestingly, CAR T cells are effective against both solid tumors and hematological cancers such as AML. Gradually, CAR T cell therapy found its way into cancer therapy and was widely used for the treatment of hematologic malignancies with successful results particularly with somewhat better results in hematological cancer in comparison to solid tumors. The AML is generally fatal, therapy-resistant, and sometimes refractory disease with a disappointing low survival rate and weak prognosis. The 5-year survival rate for AML is only about 30%. However, the survival rate seems to be age-dependent. Novel CAR T cell therapy is a light at the end of the tunnel. The CD19 is an important target antigen in AML and lymphoma and the CAR T cells are engineered to target the CD19. In addition, a lot of research goes on the discovery of novel target antigens with therapeutic efficacy and utilizable for generating CAR T cells against various types of cancers. In recent years, many pieces of research on screening and identification of novel AML antigen targets with the goal of generation of effective anti-cancer CAR T cells have led to new therapies with strong cytotoxicity against cancerous cells and impressive clinical outcomes. Also, more recently, an improved version of CAR T cells which were called modified or smartly reprogrammed CAR T cells has been designed with less unwelcome effects, less toxicity against normal cells, more safety, more specificity, longer persistence, and proliferation capability. The purpose of this review is to discuss and explain the most recent advances in CAR T cell-based therapies targeting AML antigens and review the results of preclinical and clinical trials. Moreover, we will criticize the clinical challenges, side effects, and the different strategies for CAR T cell therapy.

Challenges and Advances in Chimeric Antigen Receptor Therapy for Acute Myeloid Leukemia

“…Fourth generation CAR T-cells, sometimes known as "T-cells redirected for universal cytokine-mediated killing" or "TRUCKs", are less defined in the literature, but are designed to additionally secrete cytokines into the tumor microenvironment and may co-express additional proteins such as chemokine receptors, switch receptors, and bispecific T-cell engagers (BiTEs) [9,10]. Adoptive transfer of autologous CAR T-cells should result in T-cell activation upon recognition of its target antigen, and subsequent killing of the cancer cell via perforin, granzyme, and recruitment of natural cancer-specific immune responses [11].…”

“…An advantage of using antibody-derived scFvs in CAR T-cells is that they function in a major histocompatibility complex (MHC) independent manner [11,12]. However, intracellular antigens are not typically accessible to CARs, as these can only be recognized after being processed and presented by MHC molecules [13].…”

“…CD7 is transmembrane protein estimated to be expressed by 30% of adult AML patients [11]. When present, it is typically associated with a more aggressive disease course and resistance to chemotherapy [85].…”

Targeting the Tumor Microenvironment in Acute Myeloid Leukemia: The Future of Immunotherapy and Natural Products

“…Wilms Tumor 1 (WT1) is overexpressed in most AML patients and studies have demonstrated that increased WT1 is associated with resistance to therapy, higher incidence of relapse, and poor overall survival. WT1 CAR T cells have also exhibited the ability to lyse WT1 primary tumor cells [ 100 ]. CD33 and CD123 in particular are of interest and explained further below [ 101 ].…”

Molecular Mechanisms and Therapies of Myeloid Leukaemia

“…Recently, treatments have included the use of chimeric antigen receptor T-cells (CAR-T) [ 36 ]. CAR-T cells have a recombinant receptor that can bind to antigens and kill targeted cancerous cells.…”