Immune responses to transgene and retroviral vector in patients treated with ex vivo–engineered T cells

作者：C. B. H. W. Lamers, Ralph A. Willemsen, Pascal van Elzakker, Sabine van Steenbergen‐Langeveld, Marieke Broertjes, Jeannette Oosterwijk‐Wakka, Egbert Oosterwijk, Stefan Sleijfer, Reno Debets, Jan W. Gratama · 发表于：Blood · 年份：2010 · DOI：10.1182/blood-2010-07-294520 · 被引用次数：371 · 研究领域：CAR-T cell therapy research、CRISPR and Genetic Engineering、Virus-based gene therapy research

Adoptive transfer of immune effector cells that are gene modified by retroviral transduction to express tumor-specific receptors constitutes an attractive approach to treat cancer. In patients with metastatic renal cell carcinoma, we performed a study with autologous T cells genetically retargeted with a chimeric antibody receptor (CAR) directed toward carbonic anhydrase IX (CAIX), an antigen highly expressed in renal cell carcinoma. In the majority of patients, we observed distinct humoral and/or cellular anti-CAIX-CAR T-cell immune responses in combination with a limited peripheral persistence of transferred CAIX-CAR T cells in the majority of patients. Humoral immune responses were anti-idiotypic in nature and neutralized CAIX-CAR-mediated T-cell function. Cellular anti-CAIX-CAR immune responses were directed to the complementarity-determining and framework regions of the CAR variable domains. In addition, 2 patients developed immunity directed against presumed retroviral vector epitopes. Here, we document the novel feature that therapeutic cells, which were ex vivo engineered by means of transduction with a minimal γ-retroviral vector, do express immunogenic vector-encoded epitopes, which might compromise persistence of these cells. These observations may constitute a critical concern for clinical ex vivo γ-retroviral gene transduction in general and CAR-retargeted T-cell therapy in particular, and underscore the need to attenuate the immunogenicity of both transgene and ...