Emerging CAR T Cell Strategies for the Treatment of AML

Abstract

Engineered T cells expressing chimeric antigen receptors (CARs) on their cell surface can redirect antigen specificity. This ability makes CARs one of the most promising cancer therapeutic agents. CAR-T cells for treating patients with B cell hematological malignancies have shown impressive results. Clinical manifestation has yielded several trials, so far five CAR-T cell therapies have received US Food and Drug Administration (FDA) approval. However, emerging clinical data and recent findings have identified some immune-related toxicities due to CAR-T cell therapy. Given the outcome and utilization of the same proof of concept, further investigation in other hematological malignancies, such as leukemias, is warranted. This review discusses the previous findings from the pre-clinical and human experience with CAR-T cell therapy. Additionally, we describe recent developments of novel targets for adoptive immunotherapy. Here we present some of the early findings from the pre-clinical studies of CAR-T cell modification through advances in genetic engineering, gene editing, cellular programming, and formats of synthetic biology, along with the ongoing efforts to restore the function of exhausted CAR-T cells through epigenetic remodeling. We aim to shed light on the new targets focusing on acute myeloid leukemia (AML).

Allogeneic stem cell transplantation in the treatment of acute myeloid leukemia: An overview of obstacles and opportunities

“…Another potential future strategy is to target AML-associated, e.g. , WT1 or PR1, rather than AML-specific antigens using peptide vaccines[ 137 , 190 , 191 ]. However, at present, allo-HSCT remains the standard of care for individuals diagnosed with AML and who display evidence of intermediate or unfavorable risk, and the potential benefits of CAR-T cell therapy in conjunction with pharmacological agents and/or allo-HSCT in the management of AML remains to be decided in future studies[ 192 ].…”

Neoantigen-specific TCR-T cell-based immunotherapy for acute myeloid leukemia

“…The TCR complex is a heterodimer consisting of alpha and beta chains. Unlike TCR, CARs are synthetic receptors created from a combination of an antibody-derived single-chain variable fragment (scFV), a T-cell receptor-derived CD3ζ domain, a transmembrane domain, and one or more intracellular co-stimulatory domains (such as CD28, 4-1BB/CD137, ICOS, and/or OX40) that have evolved across five generations [ 136 ]. Other than that, safety switches have been introduced to TCR and CAR constructs [ 132 , 137 ].…”

“…Modified T cells are potential for “On-target, off-tumor” toxicity in cases where the antigenic target is co-expressed on normal cells, such as CAR-T cells targeting leukemia-associated antigens and TCR-T cells targeting TAAs [ 136 ]. Neoantigens are only found in malignant cells, therefore employing them as targets might help with this problem.…”

Oncolytic Viruses for the Treatment of Bladder Cancer: Advances, Challenges, and Prospects

“…Chimeric antigen receptor T cells (CAR-T), tumor-infiltrating lymphocytes (TILs), and T-cell receptor (TCR) transgenic T cells are the three main ACT treatment techniques [ 125 ]. In CAR-T therapy, T cells are equipped with chimeric antigen receptors, which can recognize and eliminate tumor cells [ 126 ]. Although several clinical trials for BC patients are using CAR-T technology, CAR-T cell research for the treatment of BC is still in its infancy [ 127 ].…”