Anaplastic lymphoma kinase-targeted immunotherapy strategies as treatment for neuroblastoma (360G-Wellcome-102803_Z_13_Z)

Chimeric antigen receptors (CARs) consist of the antigen recognizing domain of an antibody linked to intracellular portions of T-cell signalling receptors. Adoptive immunotherapy with T-cells engineered to express CARs has shown promise in a phase I study in neuroblastoma and recently has led to unprecedented responses in patients with chemotherapy resistant leukaemias. Our CAR strategies in neuroblastoma to date have focussed on disialoganglioside GD2. We aim to broaden this approach to anapl astic lymphoma kinase (ALK), a tyrosine kinase present on the majority of neuroblastomas while largely absent from normal tissue. Aim of this fellowship is to develop an ALK-targeting CAR strategy against neuroblastoma. I will generate ALK-binders using a hybrid vaccination/phage display strategy. With these I will perform extensive target validation of ALK. I will identify a binder which results in the optimal CAR recognizing ALK on neuroblastoma. Next, I will explore combining this anti-ALK C AR with small molecule ALK-inhibitors as these may increase ALK surface expression. Further, I will explore restricting CAR-activity to cells expressing both GD2 and ALK; as presence of these antigens in normal tissue appears distinct this may avoid on-target off-tumour toxicity. I intend to lead this work onto a phase I study of ALK-based CAR-therapy.