Abstract
BackgroundThe 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).MethodsWe tested various target antigen expressions on osteosarcoma cell lines using flow cytometry and analyzed 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 patient-derived 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) antibodies were tested their synergy with GD2- or HER2-BsAb against osteosarcoma.ResultsGD2 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.ConclusionAnti-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.
Highlights
Osteosarcoma is the most common primary bone tumor in childhood and adolescence
We previously described T cell engaging bispecific antibodies (T-BsAbs) using sequences of anti-CD3 and anti-disialoganglioside [GD2] or antiepidermal growth factor receptor-2 [human epidermal growth factor receptor-2 (HER2)] antibody structured on IgG-[L]-scFv format with silenced Fc, exerting potent anti-tumor activities [19, 20]
GD2 and/or HER2 was overexpressed on majority of osteosarcoma cell lines To identify potential therapeutic targets for osteosarcoma, we conducted a literature review and assessed the expression of surface target antigens, GD2, GD3, HER2, B7H3 (CD276), high molecular weight melanoma antigen (HMW-M), gene name chondroitin-sulfate proteoglycan-4 (CSPG4), glycoprotein A33 (GPA33), L1 cell adhesion molecule (L1CAM), glypican-3 (GPC-3), Lewis Y, prostate-specific antigen (PSA), Globo H, interleukin 11 receptor-α (IL-11Rα), Programmed cell death-1 receptor ligand-1 (PD-L1), prostate-specific membrane antigen (PSMA), and insulin-like growth factor 2 receptor (IGF2R), reported to be overexpressed by osteosarcoma [32,33,34,35]
Summary
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]. 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 incorporated IFN-α2b, failed to show the benefit [8], and antibody-based immunotherapies have not succeeded in improving outcome including trastuzumab or dinutuximab in clinical trials. 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)
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