Next generation engineered T-cell therapy for brain lymphoma (360G-Wellcome-200145_Z_15_Z)

Primary Central Nervous System Lymphoma (PCNSL) confers long-term survival in only 30% of patients and relapsed disease is currently unsalvageable. Histologically, the majority of cases are diffuse large B cell lymphomas (DLBCL). Chimeric Antigen Receptor (CAR) therapy is an emerging modality and CD19 directed CAR T-cells (CAR19) are remarkably efficacious in relapsed B-cell cancers (including systemic DLBCL). Indeed, studies have reported CAR19 trafficking to the central nervous system (CNS) with clearance of disease from this site. For these reasons, CAR19 T-cells in PCNSL DLBCL are therapeutically attractive, but face particular considerations. Firstly, the value of clinical experimentation would be greatly increased by means of tracking CAR T-cells non-invasively. Secondly, the CNS is intolerant of rapid immune activation so it is imperative that CAR T-cells must be controlled to limit toxicity. We propose a phase I study in patients with relapsed PCNSL using advanced T-cell engineering to generate a trackable CAR19 (using radiotracers) where cytotoxicity can be switched on/off using an exogenous small molecule.Tracking T-cells will permit the exploration of optimal conditioning regimens to maximise CAR T-cell trafficking to sites of CNS disease. We believe that this work will spearhead CAR T-cell therapy of more common brain cancers such as glioma.