Adoptive T-cell therapy for Leukemia

Abstract

Allogeneic stem cell transplantation (alloSCT) is the most robust form of adoptive cellular therapy (ACT) and has been tremendously effective in the treatment of leukemia. It is one of the original forms of cancer immunotherapy and illustrates that lymphocytes can specifically recognize and eliminate aberrant, malignant cells. However, because of the high morbidity and mortality that is associated with alloSCT including graft-versus-host disease (GvHD), refining the anti-leukemia immunity of alloSCT to target distinct antigens that mediate the graft-versus-leukemia (GvL) effect could transform our approach to treating leukemia, and possibly other hematologic malignancies. Over the past few decades, many leukemia antigens have been discovered that can separate malignant cells from normal host cells and render them vulnerable targets. In concert, the field of T-cell engineering has matured to enable transfer of ectopic high-affinity antigen receptors into host or donor cells with greater efficiency and potency. Many preclinical studies have demonstrated that engineered and conventional T-cells can mediate lysis and eradication of leukemia via one or more leukemia antigen targets. This evidence now serves as a foundation for clinical trials that aim to cure leukemia using T-cells. The recent clinical success of anti-CD19 chimeric antigen receptor (CAR) cells for treating patients with acute lymphoblastic leukemia and chronic lymphocytic leukemia displays the potential of this new therapeutic modality. In this review, we discuss some of the most promising leukemia antigens and the novel strategies that have been implemented for adoptive cellular immunotherapy of lymphoid and myeloid leukemias. It is important to summarize the data for ACT of leukemia for physicians in-training and in practice and for investigators who work in this and related fields as there are recent discoveries already being translated to the patient setting and numerous accruing clinical trials. We primarily focus on ACT that has been used in the clinical setting or that is currently undergoing preclinical testing with a foreseeable clinical endpoint.

Keywords: Adoptive cellular therapy; Chimeric antigen receptor; Engineered T-cell; Immunotherapy; Leukemia; Stem cell transplant; T-cell; Tumor antigen.

Figure 1

Graphic representations of the various T-cell approaches used to target leukemia antigens. (a) Conventional T-cells target peptides that are presented in the context of an MHC molecule. (b) Modified Ectopic α/β T-cells target the same epitope as a conventional TCR (MHC-peptide) but with an engineered (often higher affinity) TCR from an autologous, allogeneic, or xenogeneic cell. (c) CAR T-cells contain a synthetic polypeptide that contains the single chain variable fragment (scFv) of an antibody as the antigen-binding domain, a hinge, a transmembrane region, a costimulatory (Costim) domain, and a CD3ζ signaling domain. CARs recognize extracellular antigens that are not MHC-bound. (d) A TCR-like CAR utilizes the scFv fragment of a TCR-mimicking Ab, which recognizes a peptide antigen in the context of an MHC molecule, but with a much higher affinity than conventional or most engineered TCRs.

Figure 2

Diagram of ACT within the alloSCT platform. T-cell depleted SCT would eliminate the need for post-SCT immunosuppressive medications that can limit the efficacy of modified T-cells. Since allogeneic cells are used, the endogenous specificity of the T-cells would be pre-selected (CMV, EBV, varicella, etc.) or other GvHD prevention measures would need to be incorporated, such as naïve T cell depletion.