Targeting refractory/recurrent neuroblastoma and osteosarcoma with anti-CD3×anti-GD2 bispecific antibody armed T cells Journal Article
| Authors: | Yankelevich, M.; Thakur, A.; Modak, S.; Chu, R.; Taub, J.; Martin, A.; Schalk, D.; Schienshang, A.; Whitaker, S.; Rea, K.; Lee, D. W.; Liu, Q.; Shields, A. F.; Cheung, N. K. V.; Lum, L. G. |
| Article Title: | Targeting refractory/recurrent neuroblastoma and osteosarcoma with anti-CD3×anti-GD2 bispecific antibody armed T cells |
| 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-I 3) 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. © 2024 BMJ Publishing Group. All rights reserved. |
| Keywords: | osteosarcoma; adult; child; unclassified drug; overall survival; clinical trial; fatigue; diarrhea; side effect; antineoplastic agents; positron emission tomography; antineoplastic agent; anorexia; t lymphocyte; t-lymphocytes; interleukin 2; low drug dose; neutrophil count; phase 2 clinical trial; nausea; vomiting; granulocyte macrophage colony stimulating factor; pathology; monoclonal antibody; chill; drug dose escalation; fever; hypoxia; hypotension; insomnia; antibodies, monoclonal; karnofsky performance status; immunotherapy; neuroblastoma; cd4+ t lymphocyte; headache; phase 1 clinical trial; lymphocyte count; peripheral blood mononuclear cell; blurred vision; platelet count; desmoplastic small round cell tumor; sore throat; apheresis; refractory neuroblastoma; bispecific antibody; humans; human; article; recurrent neuroblastoma; adoptive cell therapy - act; gd2bi |
| Journal Title: | Journal for ImmunoTherapy of Cancer |
| Volume: | 12 |
| Issue: | 3 |
| ISSN: | 2051-1426 |
| Publisher: | Biomed Central Ltd |
| Date Published: | 2024-03-01 |
| Start Page: | e008744 |
| Language: | English |
| DOI: | 10.1136/jitc-2023-008744 |
| PUBMED: | 38519053 |
| PROVIDER: | scopus |
| PMCID: | PMC10961524 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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