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.
Highlights
T-lymphocytes are critical cells of the immune system that eliminate both infectious pathogens and abnormal, malignant cells
The importance of T-cells in the elimination of leukemia was first supported by trials comparing T-cell replete versus T-cell depleted allogeneic stem cell transplant, where a higher incidence of disease relapse was observed for recipients of T-cell depleted transplants, but with the advantage of a lower incidence of graft-versus-host disease (GvHD) [1,2,3,4,5,6]
The data for this effect are strongest in chronic myeloid leukemia (CML), though evidence for T-lymphocyte targeting of malignant cells within other leukemia diagnoses – acute
Summary
T-lymphocytes are critical cells of the immune system that eliminate both infectious pathogens and abnormal, malignant cells. A recent trial at the NIH tested the adoptive transfer of polyclonal tumor-derived lymphocytes for the treatment of relapsed CLL or lymphoma after alloSCT [82] The rationale underlying this approach is that T-cells found within tumor specimens are enriched for tumor antigen-specific cytotoxic T-lymphocytes (CTLs), which can be made more potent by ex vivo costimulation and expansion. Targeting leukemia antigens in the clinic CD19 Trials of anti-CD19 CAR T-cell therapy in patients with B-cell malignancies have generated exciting clinical results and underscore the tremendous potential of antigenspecific ACT for leukemia These trials – spearheaded by groups at the NIH, Baylor College of Medicine, the University of Pennsylvania, and at Memorial Sloan Cancer Center (MSKCC) – have laid the foundation for this new therapeutic modality that is certain to gain importance in the treatment of ALL, CLL and B-cell lymphomas.
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