Local immunotherapy of glioma patients with a combination of 2 bispecific antibody fragments and resting autologous lymphocytes: Evidence for in situT-cell activation and therapeutic efficacy

After adoptive transfer of pre-activated lymphocytes into the operation cav ity of glioma patients, tumor regression and improved survival have been re ported in some patients. Results were most impressive when bispecific antib odies with tumor x CD3 specificity were also applied. In this study, we att empted to avoid time-consuming pre-activation procedures for adoptively tra nsferred cells by using a combination of bispecific antibodies directed to the EGF receptor (EGFR) on tumor cells and to CD3 and CD28 on T cells. Elev en patients with high-grade malignant glioma received 3 injections of 2 bis pecific antibody fragments (EGFR x CD3 and EGFR x CD28) together with fresh ly isolated autologous lymphocytes via an Ommaya reservoir. Intracavitary f luid aspirated during immunotherapy was examined for markers of T-cell acti vation. Increased levels of soluble IL-2 receptor and TNF-alpha were detect ed in the intracavitary fluid of all patients tested. Two of the 11 treated patients experienced a beneficial response to therapy as defined by a tran sient contrast enhancement in subsequent MRI scans and prolonged survival. Side effects were transient and consisted of fever, nausea, headache and ag gravation of pre-existing neurologic deficits. These adverse effects were m ost likely due to the antibody construct containing anti-CD3 specificity. T wo patients developed cerebral edema and required steroid treatment. (C) 20 01 Wiley-Liss, inc.