C04: Engineering CAR T cells to better find and eradicate neuroblastoma

Despite the constant improvement of neuroblastoma treatment regimens, primary treatment resistance or relapse continue to occur, resulting in rapidly progressing disease. One route with potential to more completely eradicate tumor cells is to integrate immunotherapies, such as CAR T cells, into treatment regimens. The limited T cell infiltration into an immunosuppressive microenvironment containing tumor cells that heterogeneously express antigen has hampered neuroblastoma eradication by CAR T cells  so far. Key to overcoming these present hurdles are (i) a detailed knowledge of the cellular composition in the primary/metastatic lesion, including immune components and the general principles of T-tumor cell co-evolution and (ii) a detailed molecular and functional exploration of the inhibitory tumor microenvironment (TME). The parallel identification of novel suitable target structures (antigens) on the (metastatic) neuroblastoma cell could also speed development of effective immunotherapies. We hypothesize that understanding the interplay between neuroblastoma evolution, metastasis and the TME will enable us to develop CAR T cells overcoming current hurdles preventing their success against neuroblastoma. Project C04 aims to close these essential knowledge gaps by characterizing the neuroblastoma TME using single-cell technologies in two immunocompetent neuroblastoma mouse models at different disease sites (Task 1). Subsequently, we will employ key tumor microenvironmental cues that are crucial for cell tissue-directed trafficking and persistence to improve CAR T cell homing to and survival within primary/metastatic sites (Task 2). In a parallel approach, we will validate suitable tumor-specific antigens (identified in CRC1588 cooperations) and develop novel CAR T cell constructs against the top 3 targets (Task 3). As a first step towards clinical exploitation of our results in subsequent early clinical trials, we will pursue first preclinical evaluation steps of the novel CAR T cell constructs in vitro and in vivo (Task 4).

PhD positions and place of work: 2

1 wet-lab (PI Annette Künkele, Charité Berlin)

1 wet-lab (PI Uta Höpken, MDC Berlin)