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

Abstract

After adoptive transfer of pre‐activated lymphocytes into the operation cavity of glioma patients, tumor regression and improved survival have been reported in some patients. Results were most impressive when bispecific antibodies with tumor × CD3 specificity were also applied. In this study, we attempted to avoid time‐consuming pre‐activation procedures for adoptively transferred 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. Eleven patients with high‐grade malignant glioma received 3 injections of 2 bispecific antibody fragments (EGFR × CD3 and EGFR × CD28) together with freshly isolated autologous lymphocytes via an Ommaya reservoir. Intracavitary fluid aspirated during immunotherapy was examined for markers of T‐cell activation. Increased levels of soluble IL‐2 receptor and TNF‐α were detected in the intracavitary fluid of all patients tested. Two of the 11 treated patients experienced a beneficial response to therapy as defined by a transient contrast enhancement in subsequent MRI scans and prolonged survival. Side effects were transient and consisted of fever, nausea, headache and aggravation of pre‐existing neurologic deficits. These adverse effects were most likely due to the antibody construct containing anti‐CD3 specificity. Two patients developed cerebral edema and required steroid treatment. © 2001 Wiley‐Liss, Inc.

Stereotaxic administrations of allogeneic human Vγ9Vδ2 T cells efficiently control the development of human glioblastoma brain tumors

“…Clinical trials of adoptive immunotherapy of GBM with human T lymphocytes were based on either intravascular or intracavitary administrations. [34][35][36] However, the survival and activity of T cells within the cerebro-spinal fluid remains unclear as no studies have been performed to describe their behavior or their ability to move and infiltrate the brain parenchyma. Our approach is based on the direct injection of allogeneic amplified gd T cells in the parenchyma, all around the resection cavity.…”

Anti-CD3 × Anti-Epidermal Growth Factor Receptor (EGFR) Bispecific Antibody Redirects T-Cell Cytolytic Activity to EGFR-Positive Cancers In vitro and in an Animal Model

“…BiAbs created to redirect CD3-, CD16-, or CD64-positive effector cells to numerous tumor-associated antigens (25 -40), including EGFR (41,42), have shown promising antitumor effects in both preclinical and clinical studies (reviewed in ref. 18).…”

Effective Eradication of Glioblastoma Stem Cells by Local Application of an AC133/CD133-Specific T-cell–Engaging Antibody and CD8 T Cells

“…Tumor regressions and prolonged survival in the majority of patients were reported in a study where lymphokine-activated killer cells preloaded with chemically cross-linked bsAbs with anti-glioma activity (but unknown specificity) were locally applied with Ommaya reservoirs (30). Also, resting T cells preloaded with chemically prepared EGFR-specific T-cell-recruiting antibody fragments were applied in a similar way and evidence for clinical activity was observed in some patients (31). We have observed that T-cell-recruiting bsAbs are rapidly internalized after binding to T cells, which would adversely affect the efficacy of T cells preloaded with bsAbs.…”