IMMUNOTHERAPY IN CML · Combined application of targeted therapy and immunotherapy in chronic myeloid leukaemia

Periodic Report Summary 1 - IMMUNOTHERAPY IN CML (Combined application of targeted therapy and immunotherapy in chronic myeloid leukaemia)

In order to optimize immunotherapeutic strategies a better understanding of the underlying mechanisms limiting successful anti-leukaemia immune responses are needed. The tyrosine kinase inhibitors (TKI) imatinib (IM), nilotinib (NIL) and dasatinib (DAS) are remarkably effective as single-agent therapy for chronic myeloid leukemia (CML) in chronic phase (CP). However little is known of their potential impact on the immune response. No human in vivo studies are available to assess how these molecularly-targeted drugs affect immune function in patients, and data from in vitro and animal studies with imatinib have been contradictory, ranging from impaired antigen-specific T-cell response to enhanced stimulation of tolerant T cells. To characterize the in vivo immunomodulatory effects of TKI, we recruited 51 patients with CP-CML in complete cytogenetic response (CCyR) on standard dose IM (n=26), DAS (n=14) or NIL (n=12) and 28 adult controls during two influenza seasons (2008 and 2009). Patients and controls were immunized with an influenza vaccine (Ph. Eur. 2008/2009 or Ph. Eur. 2009/2010, CSL biotherapies) and with the 23-valent polysaccharide pneumococcal vaccine (Pneumovax II; Sanofi Pasteur MSD). Following vaccination, Flu-specific T cells were detected in 24/51 (47.0%) patients on TKI and 15/24 (62.5%) healthy controls (p=0.16). We also assessed IgM responses to Pneumococcal vaccination in 45 patients and 12 healthy controls. Four weeks postimmunization, 11/12 (92%) controls achieved IgM pneumococcal Ab titers >80 U/ml compared to only 23/45 (53%) CML patients on TKI (p=0.010). The pneumococcal IgM titers were significantly lower in patients with CML on TKI compared to healthy controls (median, 89.0 U/ml, range 5-200 vs 200 U/ml, range 58-200, p=0.0006), suggesting that CML patients on TKI have impaired IgM responses to vaccination. To further characterize the humoral immune response to Pneumovax, we stratified CML patients based on their pneumococcal IgM titers. We found a significantly lower percentage of IgM memory B cell subset in CML patients who failed to mount a significant pneumococcal IgM response compared to patients who achieved a pneumococcal IgM response (median, 6.25% vs 16.4%, p=0.0059) and healthy controls (median, 6.25% vs 14.3%, p=0.0086). Furthermore, we found a significant correlation between anti-pneumococcal IgM titers and IgM memory B cell percentage (Spearman rank correlation test, r=0.61, p<.0001), To investigate a putative role of TKI for the loss of IgM memory B cell subsets in CML patients, we determined the frequencies of IgM memory B cells in paired samples collected from 15 CML-CP patients at diagnosis (i.e. prior to initiating IM) and once CCyR was achieved. We found a significant decrease in the percentage of IgM memory B cells in CML-CP patients treated with IM compared to the pre-treatment sample (median 9.4%, vs. 15.2% respectively, p=0.0023). In summary, patients with CML on TKI can mount effective T-cell immune responses to influenza vaccination. Our data suggest that TKI (IM, DAS and NIL) impair T-cell independent humoral immune responses, namely IgM responses to vaccination. This is associated with a loss of IgM memory B cell subsets. Further investigations to understand the mechanisms by which TKIs may impact B-cell subsets are underway. These results are of particular interest in terms of the long-term effects of TKI on tumour immune surveillance and susceptibility to infections and may have implication for vaccination strategies in CML patients.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз