Kurzfassung

Although the clinical outcome for patients with acute myeloid leukemia (AML) has improved, chemo-resistance and relapse remain major caveats of cancer–associated mortality and highlight the need for alternative treatment approaches. In this regard, accumulating data evidence that AML is susceptible to immuno-attack by both the innate and adaptive immune system. However, in the AML microenvironment both cytotoxic T cells and NK cells are largely exhausted or suppressed by the presence of...Although the clinical outcome for patients with acute myeloid leukemia (AML) has improved, chemo-resistance and relapse remain major caveats of cancer–associated mortality and highlight the need for alternative treatment approaches. In this regard, accumulating data evidence that AML is susceptible to immuno-attack by both the innate and adaptive immune system. However, in the AML microenvironment both cytotoxic T cells and NK cells are largely exhausted or suppressed by the presence of immune suppressive factors such as regulatory T cells, anti-inflammatory cytokines, checkpoint receptor interactions and metabolic alterations. One therapeutic approach to overcome insufficient immunity has been the introduction of genetically-engineered chimeric antigen receptors (CAR) into T cells, and lately also into NK cells. However, the biologic heterogeneity of AML and the significant potential for off-target toxicity due to target antigen expression on healthy hematopoietic stem cells, as shown e.g. for CD33, CD44v6, CD123 and CD135, so far constitutes a major obstacle in the design of new CAR-T/NK cells. We therefore have studied the expression of B7-H6, an antigen that is largely expressed on tumor but not normal hematopoietic cells and recognized by the NK-natural cytotoxicity receptor NKp30, on AML cell lines and primary AML samples derived from patients and found expression on a considerable amount of AML samples. Moreover, we developed high avidity NKp30-based CARs by introducing single point mutations in the B7H6 binding region of NKp30 and can elicit potent reactivity against B7H6 positive AML lines in vitro using NKp30 CAR redirected NK92 cells. Further functional studies in vitro and in vivo in established AML xenograft models will be performed in collaboration with the group of PD Dr. Dr. Andre at the Children’s University Hospital in Tübingen to elaborate the therapeutic potential of high avidity NKp30 CAR redirected NK cells for cellular therapy in AML.» weiterlesen» einklappen