Chimeric antigen receptors for adoptive T cell therapy in acute myeloid leukemia

Abstract

Currently, conventional therapies for acute myeloid leukemia (AML) have high failure and relapse rates. Thus, developing new strategies is crucial for improving the treatment of AML. With the clinical success of anti-CD19 chimeric antigen receptor (CAR) T cell therapies against B-lineage malignancies, many studies have attempted to translate the success of CAR T cell therapy to other malignancies, including AML. This review summarizes the current advances in CAR T cell therapy against AML, including preclinical studies and clinical trials, and discusses the potential AML-associated surface markers that could be used for further CAR technology. Finally, we describe strategies that might address the current issues of employing CAR T cell therapy in AML.

Keywords: Acute myeloid leukemia; Chimeric antigen receptors; Immunotherapy.

Fig. 1

The process of CAR T cell activation and killing of tumor targets. T cells are collected from patients and then selected and activated by a CD3/CD28 antibody. The CAR gene was transferred by viral vectors or non-viral systems. When CAR recognizes its antigen on tumor cells and binds it, the intracellular signaling domains within the CAR produce a series of signal transduction cascades, and then, the CAR T cell is activated. The activation of cytotoxic CD8+ CAR T cells releases TNF-α, INF-γ, granzyme and perforin, which directly kill tumor cells. In addition, tumor killing can also be mediated by the activation of other components of the immune system through cytokines released by CD4+ CAR T cells. Notably, the defining characteristic of CAR T cells is that they produce long-term memory CAR T cells after the initial activation, which will be of great benefit to the long-term tumor eradication and the prevention of tumor relapse

Fig. 2

The four generations of CAR production. The extracellular domain of CAR includes a single chain variable fragment (scFv) (H (heavy) and L (light) chain) that is spliced by a linker. A hinge (e.g., hinge region of human immunoglobulin D molecule) ensures flexibility and connects to the transmembrane domain (TM). The TM is routinely the constant region of the human G immunoglobulin, whereas the intracellular domain includes only the CD3ζ signaling domain known as the “1st-generation CAR”. Subsequently, to augment T cell persistence and proliferation [28], CD3ζ as well as the costimulatory endo-domains 41BB- or CD28-signaling domains were incorporated into the “2nd-generation CAR”. The intracellular domain includes CD3ζ plus two costimulatory domains 41BB- and CD28-signaling domains that were included in the “3rd-generation CARs” [31, 32]. So-called TRUCK T cells are known as the “4th-generation CAR”, which is additionally modified with an inducible expression cassette for a transgenic protein

Fig. 3

The main evolution of CAR T cell therapy for treating AML. CIK, cytokine induced killer; EBV-CTL, human Epstein Barr Virus-cytotoxic lymphocyte; EGFRt, a tag derived from the epidermal growth factor receptor, is the antigen of the clinically available antibody cetuximab; DAP10, a type of natural adaptive protein, provides a costimulatory signal similar to that of CD28 [113]; ATRA, all-trans retinoic acid, a drug that up-regulates the expression of the target antigen, resulting in improved anti-leukemia activity; GoCART, a structure comprising a proliferation-deficient first generation CAR and a ligand-dependent activation switch (e.g., iMC) that efficiently eradicates CD123+ AML cells when co-stimulated with systemic rimiducid administration. iMC, inducible MyD88/CD40 is a ligand (rimiducid)-dependent costimulatory switch [114]

Fig. 4

Creating a better CAR-expressing T cell. mAb, antibody monoclonal antibody; scFv, single chain antibody fragment; allo-HSCT, allogenic haemopoietic stem cell transplantation; iCasp9, inducible caspase 9; IL12, interleukin-12; LAG3, lymphocyte activating 3; mRNA, messenger ribonucleic acid; PD1, programmed death 1; EGFRt, truncated epidermal growth factor receptor; TRUCKS, T cells redirected for universal cytokine-mediated eliminating antigen-negative cancer cells

Fig. 5

Different types of “Dual targeting” approaches. a The CD3ζ and costimulatory domains are separated in individual molecules targeting two diverse tumor antigens, an event known as trans-signaling CARs. These proteins will be activated when both antigens are identified [–117]. b The “ON-switch” CAR T cell requires a small molecule drug to activate an “ON-switch” such that the engaging antigen and intracellular signaling domain will be connected [118]. c The mechanism of “notch CAR” recognizes combinatorial antigens by using a synthetic Notch receptor for one antigen that drives the inducible expression of the CAR target to a second antigen; this system requires a tumor cell to express both antigens before recognition by the CAR T cells [119]. d An inhibitory CAR replaces the CD28- CD3ζ chain with an inhibitory domain, which limits the excess activation signal from other CARs [120, 121]. e “PD1CD28” switch CAR T cells express a switch receptor construct comprising the PD1 extracellular domain and the CD28 costimulatory domain; this allows PD-L1 binding to enhance CAR T cell cytokine secretion and proliferation [122]. f Dual-signaling CAR, T cells are respectively modified by two distinct CAR molecules with two different scFvs and the same intracellular signaling domain [108, 109]. g Tandem CARs comprise two different linked scFvs to allow for targeting of two different antigens using a single construct [112]. h This is a hypothetical strategy to reduce CRS and was inspired by the “PD1CD28” switch CAR T cells