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Targeting refractory/recurrent neuroblastoma and osteosarcoma with anti-CD3×anti-GD2 bispecific antibody armed T
Maxim Yankelevich1,2, Archana Thakur3, Shakeel Modak4
1St. Christopher's Hospital for Children, Philadelphia, Pennsylvania, USA yankelevic@gmail.com LGL4F@uvahealth.org.
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 160×106 GD2BATs/kg/infusion complemented by daily interleukin-2 (300,000 IU/m2) and twice-weekly granulocyte macrophage colony-stimulating factor (250 µg/m2). The phase II segment focused on patients with NB at the dose 3 level of 160×106 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 160×106 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.
Insights
Anti-CD3xanti-GD2 bispecific antibody armed T cells (GD2BATs) show safety and efficacy in treating pediatric cancers like neuroblastoma. This therapy demonstrated manageable side effects and improved survival rates, supporting further clinical trials.
Area of Science:
- Immunotherapy
- Pediatric Oncology
- Antibody Engineering
Background:
- Neuroblastoma (NB) patients with minimal residual disease benefit from anti-GD2 monoclonal antibodies.
- Preclinical studies show high cytotoxicity of anti-CD3xanti-GD2 bispecific antibody armed T cells (GD2BATs) against GD2+ cell lines.
Purpose of the Study:
- Investigate the safety and clinical benefits of GD2BATs in children with recurrent/refractory neuroblastoma and other solid tumors.
- Evaluate the maximum tolerated dose and preliminary efficacy of GD2BATs in a phase I/II clinical trial.
Main Methods:
- A phase I dose-escalation study (NCT02173093) enrolled 9 patients with NB, osteosarcoma, and desmoplastic small round cell tumors.
- Patients received GD2BATs infusions (40-160x10^6 cells/kg/infusion) with interleukin-2 and granulocyte macrophage colony-stimulating factor.
- Phase II focused on NB patients at the dose level of 160x10^6 GD2BATs/kg/infusion.
Main Results:
- No dose-limiting toxicities were observed in phase I; mild, manageable cytokine release syndrome occurred in all patients.
- Median overall survival was 18.0 months (phase I) and 31.2 months (phase II), with a combined 21.1 months.
- One NB patient achieved complete bone marrow response; 3 out of 12 evaluable phase II patients showed clinical benefit with prolonged stable disease. Over 50% demonstrated augmented immune responses.
Conclusions:
- GD2BATs are safe up to 160x10^6 cells/kg/infusion.
- Evidence of post-treatment endogenous immune responses supports further investigation.
- Larger phase II clinical trials are warranted to further evaluate GD2BATs efficacy.
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