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Combined application of targeted therapy and immunotherapy in chronic myeloid leukaemia

Periodic Report Summary 2 - IMMUNOTHERAPY IN CML (Combined application of targeted therapy and immunotherapy in chronic myeloid leukaemia)

The tyrosine kinase inhibitors (TKIs) imatinib, nilotinib, and dasatinib are remarkably effective as single-agent therapy for chronic myeloid leukemia (CML) in chronic phase (CP). To date, very few in vivo human studies have addressed the long-term impact of these molecular-targeted drugs on the immune function. Data from in vitro and animal studies have documented seemingly contradictory effects of imatinib on the immune response, ranging from impaired antigen-specific T-cell responses to reversal of T-cell tolerance and potentiation of antitumor immune responses. An understanding of the potential in vivo immunomodulatory mechanisms of TKIs is imperative before one could embark on clinical trials of vaccination against leukaemia antigens. In order to gain insight into the effects of TKIs on vaccine-induced cellular and humoral immune responses, we proposed to first characterize T- and B-cell responses to vaccination against influenza and pneumococcus in CP-CML patients receiving imatinib, dasatinib, and nilotinib and healthy controls. In order to perform these studies 51 CP-CML patients in complete cytogenetic response (CCyR) on standard-dose imatinib (n = 26), dasatinib (n = 13), or nilotinib (n = 12) and 24 adult controls were recruited in this study during 2 influenza seasons (2008 and 2009). Peripheral blood mononuclear cells (PBMCs) and serum samples were collected from all patients and donors prior to vaccination, and at 4 weeks and at 2 to 3 months postimmunization. All patients and adult controls gave informed written consent, and the local institutional ethics board approved the study protocol. The assays to determine influenza-specific CD8+ and CD4+ T-cell responses by flow cytometry and pneumococcal serum titers for immunoglobulins IgM and IgG levels were established in the laboratory. Initial analysis of samples has revealed significant impairment of humoral responses to pneumococcus, with normal T cell responses to the influenza antigen. Further studies to understand the mechanisms underlying impaired B cell responses are under way.
These data support the development of clinical protocols to induce cellular immune response against leukaemia antigens. Based on these data, we were successful in obtaining funding from Cancer Research UK to support a clinical study of PR1 and WT1 peptide vaccination in patients with CML on imatinib.