Immunotherapy targeting HER2 with genetically modified T cells eliminates tumor-initiating cells in osteosarcoma

Abstract

Despite radical surgery and multi-agent chemotherapy, less than one third of patients with recurrent or metastatic osteosarcoma (OS) survive. The limited efficacy of current therapeutic approaches to target tumor-initiating cells (TICs) may explain this dismal outcome. The purpose of this study was to assess the impact of modified T cells expressing a human epidermal growth factor receptor (HER2)-specific chimeric antigen receptor in the OS TIC compartment of human established cell lines. Using the sarcosphere formation assay, we found that OS TICs were resistant to increasing methotrexate concentrations. In contrast, HER2-specific T cells decreased markedly sarcosphere formation capacity and the ability to generate bone tumors in immunodeficient mice after orthotopic transplantation. In vivo, administration of HER2-specific T cells significantly reduced TICs in bulky tumors as judged by decreased sarcosphere forming efficiency in OS cells isolated from explanted tumors. We demonstrate that HER2-specific T cells target drug resistant TICs in established OS cell lines, suggesting that incorporating immunotherapy into current treatment strategies for OS has the potential to improve outcomes.

MicroRNA-126 enhances the sensitivity of osteosarcoma cells to cisplatin and methotrexate

“…At present, the majority of studies advocate the comprehensive treatment of osteosarcoma, including the use of surgery, radiotherapy, chemotherapy and immune therapy (24)(25)(26). Chemotherapy was first used for the palliative treatment of advanced cases and achieved effects to a certain degree, thus promoting its application in the adjuvant treatment of early-stage patients to prevent metastasis.…”

The contribution of immune infiltrates and the local microenvironment in the pathogenesis of osteosarcoma

“…Numerous immunotherapies were assessed to modulate the tumor microenvironment and to reactivate a prolonged and efficient immune response [6]. Adoptive cell therapies based on TIL as described above and generating antigen-specific lymphocytes [103][104][105], dendritic cells [106][107][108][109][110][111][112], NK cells [113][114][115][116][117][118] were developed mostly in vitro and in pre-clinical model of osteosarcoma. Several clinical trials are currently in progress for evaluating their therapeutic efficacy in patients (Table 1).…”

Tandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape

“…Adoptive transfer of chimeric antigen receptor-grafted (CARgrafted) (1) T cells has induced tumor regression in several preclinical models of glioblastoma (GBM) (2)(3)(4), osteosarcoma (5,6), and neuroblastoma (7). However, only sporadic clinical responses have been observed in early-phase clinical trials for these tumors (8)(9)(10)(11).…”