Small cell lung cancer (SCLC) is an aggressive disease with very limited treatment options. SCLC responsiveness to immuno-oncology agents suggests this indication may be amenable to a T-cell based therapy. Genetically modified T cells that express chimeric antigen receptors (CARs) have shown impressive efficacy in multiple hematological malignancies. To translate this approach for SCLC treatment, we are exploring Delta-like ligand 3 (DLL3) as a therapeutic target. DLL3 is highly expressed in SCLC and several other types of neuroendocrine cancers, with limited normal tissue RNA expression in brain, pituitary and testis. A large panel of antibodies that bind to DLL3 were generated, formatted into CARs, and tested in in vitro short-term and long-term cytotoxicity assays using target cells that express high, medium or low levels of DLL3. A subset of CAR T cells were highly active and displayed long-term killing potential. These were tested in vivo and robust efficacy was seen in both subcutaneous and systemic SCLC models. To understand the potential for toxicity in pituitary and brain, subcutaneous or intracranial tumors expressing DLL3 were implanted in mice and human/mouse cross-reactive DLL3 CAR T cells were injected into the tumor-bearing animals. In both models, T cell infiltration into intermediate and posterior pituitary was detected. However, no tissue damage in brain or pituitary was observed and hormone-secretion function of pituitary was not ablated. We believe toxicity is significantly derisked but as an additional safety assurance, CAR T cells were further engineered to contain an off-switch, by which CAR T cells are eliminated upon administration of Rituximab. Multiple off-switch CAR formats were evaluated, and optimal formats determined independently for each CAR. In summary, DLL3 is a target for SCLC with limited normal tissue expression and toxicity. Multiple DLL3 CAR T cells have been characterized. A subset of these CAR T cells showed robust in vitro and in vivo activity and were chosen for further evaluation as potential clinical candidates.
Citation Format: Yi Zhang, Silvia Tacheva-Grigorova, Zea Melton, Bryan Smith, Tao Sai, Tom Van Blarcom, Rafael Amado, Barbra Sasu, Siler Panowski. Screening and characterization of AlloCAR T targeting DLL3 for the treatment of small cell lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6599.