Immunology of chronic myeloid leukemia: current concepts and future goals

Abstract

Although chronic myeloid leukemia is a rare malignancy, it has developed into a model system for the study of a variety of aspects of cancer biology and immunology. The introduction of tyrosine kinase inhibitors has resulted in a significant prolongation of the survival rates of chronic myeloid leukemia patients but has not resulted in a cure. There is a growing conviction that this aim can be achieved through immunotherapy. For this concept to be successful, a considerable increase in the present understanding of chronic myeloid leukemia immunology is required. The authors attempt to review and evaluate the current findings that demonstrate a number of immunological aberrations in patients prior to the start of any therapy and their normalization after achieving remission. They also discuss the recent clinical trials with experimental therapeutic vaccines and then present their own strategy on how to address the problem.

CML patients with deep molecular responses to TKI have restored immune effectors and decreased PD-1 and immune suppressors

“…18 More recently, the goal in CML treatment is to induce a durable DMR as a prelude to successful TFR, with a lack of overt relapse in such patients attributed to immunological control of CML. 19 Several studies of combination TKI therapy and IFN-a have been completed recently, with several reporting increased rates of DMR.…”

Immune Effector Recovery in Chronic Myeloid Leukemia and Treatment-Free Remission

“…The resultant constitutively active tyrosine kinase, Bcr-Abl, mediates phosphorylation and activation of downstream signaling pathways, causing altered cell adhesion, inhibition of apoptosis, differentiation arrest, and proteasomal degradation of key proteins, which lead to the phenotype of the disease (1). CML is considered to be one of the cancers most sensitive to immunological manipulation (2). Tyrosine kinase inhibitors (TKIs) imatinib, nilotinib, and dasatinib are used as first-line treatment in CML.…”

“…TKIs also exert significant off-target multikinase inhibitory effects, albeit with differing potencies. Cumulative data suggest that TKIs exhibit a dual mode of action; direct oncokinase inhibition interspersed with concomitant immunomodulatory effects, particularly against key suppressor MDSC and Treg populations, conferring immune system re-activation and restoring effector-mediated immune surveillance (2, 13, 20–24). In this review, we discuss an immunological timeline to successful TFR in CML; an initial period of immune dysfunction in newly diagnosed CML patients, followed by restoration of immune effector responses and release of immune suppressors, albeit with differing frequencies in concert with differing levels of molecular response achieved on TKI.…”

Intracellular Cytokines Produced by Stimulated CD3+ Cells from Chronic Myeloid Leukemia Patients

“…It remains to be determined whether this was an artefact or the expression of an increased activity of T cells following the removal of tumor cells and their immunosuppressive effects. In spite of these rather strong suggestions, one can still imagine that the suppression described is an important part of the multistep process of CML disease development, as we discussed previously [15]. It is noteworthy that the results obtained indicate suppression/restoration of cytokine production concerning INF-γ, TNF-α, and IL-2, i.e., proinflammatory Th1 cytokines.…”