GD2 or HER2 targeting T cell engaging bispecific antibodies to treat osteosarcoma
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RESEARCH
GD2 or HER2 targeting T cell engaging bispecific antibodies to treat osteosarcoma Jeong A. Park and Nai‑Kong V. Cheung*
Abstract Background: The cure rate for metastatic osteosarcoma has not substantially improved over the past decades. Clinical trials of anti-HER2 trastuzumab or anti-GD2 dinutuximab for metastatic or refractory osteosarcoma were not successful, and neither was immune checkpoint inhibitors (ICIs). Methods: We tested various target antigen expressions on osteosarcoma cell lines using flow cytometry and ana‑ lyzed in vitro T cell engaging BsAb (T-BsAb)-dependent T cell-mediated cytotoxicity using 4-h 51Cr release assay. We tested in vivo anti-tumor activities of T-BsAb targeting GD2 or HER2 in established osteosarcoma cell line or patientderived xenograft (PDX) mouse models carried out in BALB-Rag2−/−IL-2R-γc-KO (BRG) mice. We also generated ex vivo BsAb-armed T cells (EATs) and studied their tumor-suppressive effect against osteosarcoma xenografts. In order to improve the anti-tumor response, ICIs, anti-human PD-1 (pembrolizumab) or anti-human PD-L1 (atezolizumab) anti‑ bodies were tested their synergy with GD2- or HER2-BsAb against osteosarcoma. Results: GD2 and HER2 were chosen from a panel of surface markers on osteosarcoma cell lines and PDXs. Anti-GD2 BsAb or anti-HER2 BsAb exerted potent anti-tumor effect against osteosarcoma tumors in vitro and in vivo. T cells armed with anti-GD2-BsAb (GD2-EATs) or anti-HER2-BsAb (HER2-EATs) showed significant anti-tumor activities as well. Anti-PD-L1 combination treatment enhanced BsAb-armed T cell function in vivo and improved tumor control and survival of the mice, when given sequentially and continuously. Conclusion: Anti-GD2 and anti-HER2 BsAbs were effective in controlling osteosarcoma. These data support the clinical investigation of GD2 and HER2 targeted T-BsAb treatment in combination with immune checkpoint inhibitors, particularly anti-PD-L1, in patients with osteosarcoma to improve their treatment outcome. Keywords: Osteosarcoma, Immunotherapy, Bispecific antibody, Disialogangliosides, Human epidermal growth factor receptor-2, T cell arming, Ex vivo bispecific antibody-armed T cells (EATs), Programmed cell death protein 1 (PD-1), Programmed cell death-1 ligand 1(PD-L1) Introduction Osteosarcoma is the most common primary bone tumor in childhood and adolescence. With the introduction of multiagent chemotherapy, overall survival has improved to 60–70% [1]. However, survival rates have remained stagnant, and the prognosis for patients with metastatic or relapsed disease remains poor, with *Correspondence: [email protected] Department of Pediatrics, Memorial Sloan Kettering Cancer Center, 1275 York Ave, Box 170, New York, NY, USA
a 5-year overall survival rate of 20% [2–4]. Since the provocative observations of Dr. Coley on bacterial toxins inducing tumor regression [5], many immunotherapy attempts have been made in soft tissue and bone sarcomas, but success has been very limited [6, 7]. The EURAMOS-1 clinical trial, which
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