Targeting refractory/recurrent neuroblastoma and osteosarcoma with anti-CD3×anti-GD2 bispecific antibody armed T cells
Maxim Yankelevich, Archana Thakur, Shakeel Modak, Roland Chu, Jeffrey W. Taub, Alissa Martin, Dana L. Schalk, Amy Schienshang, Sarah A. Whitaker, Katie Rea, Daniel W. Lee, Qin Liu, Anthony F. Shields, Nai‐Kong V. Cheung, Lawrence G. Lum
Abstract
Background The survival benefit observed in children with neuroblastoma (NB) and minimal residual disease who received treatment with anti-GD2 monoclonal antibodies prompted our investigation into the safety and potential clinical benefits of anti-CD3×anti-GD2 bispecific antibody (GD2Bi) armed T cells (GD2BATs). Preclinical studies demonstrated the high cytotoxicity of GD2BATs against GD2+cell lines, leading to the initiation of a phase I/II study in recurrent/refractory patients. Methods The 3+3 dose escalation phase I study ( NCT02173093 ) encompassed nine evaluable patients with NB (n=5), osteosarcoma (n=3), and desmoplastic small round cell tumors (n=1). Patients received twice-weekly infusions of GD2BATs at 40, 80, or 160×10 6 GD2BATs/kg/infusion complemented by daily interleukin-2 (300,000 IU/m 2 ) and twice-weekly granulocyte macrophage colony-stimulating factor (250 µg/m 2 ). The phase II segment focused on patients with NB at the dose 3 level of 160×10 6 GD2BATs/kg/infusion. Results Of the 12 patients enrolled, 9 completed therapy in phase I with no dose-limiting toxicities. Mild and manageable cytokine release syndrome occurred in all patients, presenting as grade 2–3 fevers/chills, headaches, and occasional hypotension up to 72 hours after GD2BAT infusions. GD2-antibody-associated pain was minimal. Median overall survival (OS) for phase I and the limited phase II was 18.0 and 31.2 months, respectively, with a combined OS of 21.1 months. A phase I NB patient had a complete bone marrow response with overall stable disease. In phase II, 10 of 12 patients were evaluable: 1 achieved partial response, and 3 showed clinical benefit with prolonged stable disease. Over 50% of evaluable patients exhibited augmented immune responses to GD2+targets post-GD2BATs, as indicated by interferon-gamma (IFN-γ) EliSpots, Th1 cytokines, and/or chemokines. Conclusions This study demonstrated the safety of GD2BATs up to 160×10 6 cells/kg/infusion. Coupled with evidence of post-treatment endogenous immune responses, our findings support further investigation of GD2BATs in larger phase II clinical trials.