Phase I/II Study of Treatment of Stage IV Breast Cancer with OKT3 x Trastuzumab–Armed Activated T Cells

Rationale Metastatic breast cancer (MBC) is incurable with use of standard treatment modalities, with a median survival of 1-2 years after recurrence.1,2 Standard treatment regimens and high-dose chemotherapy with peripheral blood stem cell transplantation (HDC-SCT) have reached dose-limiting toxicities (DLTs) and are not curative for stage IV breast cancer. Therefore, nontoxic immunologic strategies are needed to improve overall survival (OS), progression-free survival (PFS), and quality of life of patients with stage IV disease. In an earlier phase II study, 23 women with stage IIIB/IV breast cancer were treated with HDC-SCT (n = 20) or dose-dense therapy (n = 3) followed by immunotherapy consisting of multiple infusions of anti-CD3 activated T cells (ATCs), lowdose interleukin (IL)–2, and granulocyte-macrophage colony-stimulating factor (GM-CSF).3 The OS rate was 70% and PFS was 50% at 30 months in the group that either received HDC-SCT or dose-dense therapy followed by immunotherapy, whereas 21 women in a historical control group treated with HDC-SCT without immunotherapy had an OS of 50% and a PFS of 15% (P = 0.09). These data suggest that specific targeting of ATCs would enhance an antitumor effect. One strategy is to arm ATCs with a bispecific antibody (BiAb) with specificity directed at CD3 (T-cell receptor) and HER2/neu, which redirects the nonspecific non–major histocompatibility complex (MHC)–restricted cytotoxicity exhibited by ATCs to target HER2-expressing tumors. We hypothesized that the targeting of ex vivo expanded T cells with anti-CD3 × anti-HER2/neu (ie, HER2BiAb) may thwart tumor escape, increase the frequency of tumor-specific cytotoxic T lymphocytes (CTLs), and immunize the patient against autologous breast cancer antigens. This article addresses the following preclinical questions Submitted: Mar 3, 2003; Revised: Apr 17, 2003; Accepted: Apr 15 , 2003 Address for correspondence: Lawrence G. Lum, MD, Roger Williams Hospital, North Campus, Room G01, 825 Chalkstone Ave, Providence, RI 02908 Fax: 401-456-2398; e-mail: llum@rwmc.org 1Immunotherapy and Blood and Stem Cell Transplantation Programs, Adele R. Decof Cancer Center 2Department of Radiation Oncology, Adele R. Decof Cancer Center, Roger Williams Medical Center 3Department of Pathology 4Department of Research Roger Williams Medical Center, Providence, RI 5Boston University School of Medicine, MA Phase I/II Study of Treatment of Stage IV Breast Cancer with OKT3 x Trastuzumab–Armed Activated T Cells