Targeting the silent minority: emerging immunotherapeutic strategies for eradication of malignant stem cells in chronic myeloid leukaemia

Abstract

Standard allogeneic stem cell transplantation (alloSCT) has provided a cure for chronic myeloid leukaemia (CML) over the last 25 years, but is only an option for a minority of patients. It was hoped that the introduction of imatinib mesylate (IM), a specific tyrosine kinase inhibitor that targets the Bcr-Abl oncogene product, would provide long-term remission or even cure for those patients without a donor, but studies have shown that IM does not eliminate leukaemic stem cells in CML patients. To overcome this problem of molecular persistence, research is underway to combine reduced intensity stem cell transplant or non-donor-dependent immunotherapies with IM with the aim of increasing cure rate, reducing toxicity and improving quality of life. The alternative approach is to combine IM or second-generation agents with other novel drugs that interrupt key signalling pathways activated by Bcr-Abl. This article will focus on the latest immunotherapy and molecularly targeted therapeutic options in CML and how they may be combined to improve the outcome for CML patients in the future.

Fig. 1

Immunotherapeutic approaches for the treatment of CML post-IM. Diagnosis of CP CML is by detection of Ph⁺ or Bcr-Abl⁺ cells in PB and BM. It is now clear that there is also a population of quiescent leukaemic stem cells resident in PB and BM. IM therapy induces CCR and establishes MRD in the majority of patients. However IM-resistant quiescent cells remain and if therapy is withdrawn or resistance occurs, these cells eventually proliferate and induce relapse. AlloSCT or RISCT offer the best chance for lasting remission or cure, with or without supplementary graded DLI. In patients without a suitable donor, several immunotherapy approaches are being investigated. These include vaccination with Bcr-Abl peptides, HSP complexes, or adoptive therapy with expanded tumour-specific CTLs. Leukaemic APCs naturally expressing tumour antigens, or DCs primed with additional tumour antigens are also being studied as vaccine agents. Interleukin 2 (IL-2) and IFN-α can be used singly or as an adjunct to IM therapy as immunostimulatory agents, improving overall response through a variety of mechanisms.

Fig. 2

DC types available for clinical use. DCs may be generated from Ph⁺ or Ph⁻ precursors. Circulating DCs, CD34⁺ cells and monocytes are collected by apheresis and enriched using magnetic beads coated with monoclonal antibodies specific for surface markers. DCs may be generated from CD34⁺ cells by ex vivo culture with cytokine cocktails such as GM-CSF, FlT-3 and TNF-α. Monocytes can be converted to fully mature DCs via a two-stage process. Monocytes are cultured with cytokine cocktails such as GM-CSF and IL-4/IL-13/IFN-α to produce immature monocyte-derived DCs (MoDCs), antigen primed and then cultured with TNF-α/prostaglandin E₂/CD40L cocktails to generate fully mature DCs.

Fig. 3

Signal transduction pathways affected by Bcr-Abl and sites of inhibition. Bcr-Abl can affect many downstream signalling pathways including Jak/Stat, PI3K/Akt and Ras/Raf/MEK/ERK. Sites of inhibition and their inhibitors are indicated in the figure. Inh inhibitor, FTI farnesyl transferase inhibitor.