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

Cor Lamers, Ralph Willemsen, Pascal Elzakker, Sabine Langeveld, M Broertjes, J Oosterwijk-Wakka, E Oosterwijk, Stefan Sleijfer, Reno Debets, Jan willem Gratama

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259 Citations (Scopus)


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 gamma-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 gamma-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 vector. (Blood. 2011;117(1):72-82)
Original languageUndefined/Unknown
Pages (from-to)72-82
Number of pages11
Issue number1
Publication statusPublished - 2011

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