Abstract 3500: T cells redirected against HER2 for the adoptive immunotherapy for HER2-positive osteosarcoma

Abstract

INTRODUCTION: The prognosis for patients with advanced osteosarcoma (OS) has not improved over the last two decades. Hence novel biologically-based therapies, such as immunotherapy, are needed for these patients. We have shown in preclinical studies that T cells, genetically modified with a HER2-specific chimeric antigen receptor (CAR; HER2-CAR T cells), kill HER2+ OS cells ex vivo and induce regression of HER2+ OS xenografts in animal models. Based on these findings we developed a Phase I/II clinical study with HER2-CAR T cells in patients with metastatic and/or recurrent OS. METHODS: The primary objective of this clinical trial is to determine the safety of escalating doses of HER2-CAR T cells in patients with advanced HER2+ OS. The secondary objective is to determine the expansion, persistence and anti-tumor effects of infused HER2-CAR T cells. RESULTS: 43 (78%) out of 55 screened OS patients had HER2+ tumors. Twenty one HER2-CAR T-cell lines have been generated to date by retroviral transduction. Median HER2-CAR expression was 67.4% (range 50.7-85.6%) and HER2-CAR T cells killed HER2+ OS cells in contrast to non-transduced T cells (p <0.0001). The median CD4+:CD8+ T-cell ratio was 1:1.3, and T-cell products contained naïve (CD45RA+; median: 11.8%; range 2.4-33.2%), effector memory (CD45RO+/CCR7-/CD62L-; median: 29.3%; range: 7.8-67.5%), and central memory T cells (CD45RO+/CD62L+; median 55.9%; range: 21.9-87.9%). Nine patients have been infused so far at HER2-CAR T-cell doses between 10⁴/m² to 1x10⁶/m². Infusions were well tolerated without systemic side effects, and no increase of proinflammatory cytokines (IL-2, IFN-γ, GM-CSF, TNF-α) was observed in the patients’ plasma post infusion. HER2-CAR T cells were detectable for up to 3 months post infusion. CONCLUSION: HER2-CAR T cells have shown promising antitumor activity in preclinical OS animal models. We are currently evaluating the safety and efficacy of HER2-CAR T cells in a Phase I/II clinical study. Initial safety data at low T-cell dose levels are encouraging, warranting further active exploration of HER2-CAR T-cell based therapies for OS and other HER2+ malignancies.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3500. doi:1538-7445.AM2012-3500