Breaking T-cell tolerance in chronic lymphocytic leukaemia

摘要: CLL is an incurable B-cell malignancy associated with profound tumour cell-mediated immune dysfunction. It therefore represents a challenging disease for the successful application of immunotherapeutic strategies aimed at promoting anti-tumour T-cell responses. In this study, extensive immunophenotypic analysis T-cells from blood patients was performed, in order to better characterise their dysfunctional status within disease. Analysis patient samples revealed skewing towards highly differentiated effector memory phenotype as well expression markers exhaustion/senescence (CD28- and CD57+) immunosuppressive molecules (PD-1 CD200). addition study expansion CD8+ subset leading inversion normal CD4:CD8 ratio. The presence inverted ratio subsequently shown be shorter time first treatment reduced progression-free survival. Characterisation identified several that could targeted therapeutically break tolerance potentially restore Investigation PD-1 CD200 showed they are over expressed patients, suggesting may involved maintaining However, blockade PD-1-PDL-1 CD200-CD200R signalling pathways failed enhance responses vitro. alternative approach use bi-specific antibody targeting CD19 CD3 called blinatumomab. vitro testing blinatumomab can induce activation, release pro-inflammatory cytokines granzyme B secretion both CD4+ T-cells. addition, mediate dependent killing cells requiring formation T-cell:CLL cell conjugates. Finally provided clear evidence strongly advocates progression into clinical trials novel therapeutic agent CLL.