Clinical Evaluation of Dendritic Cell Vaccination for Patients with Recurrent Glioma: Results of a Clinical Phase I/II Trial

Abstract

Purpose: To investigate the safety and the immunologic and clinical responses of dendritic cell therapy for patients with recurrent malignant glioma. Experimental Design: Twenty-four patients with recurrent malignant glioma (6 grade 3 and 18 grade 4 patients) were evaluated in a phase I/II clinical study of dendritic cell therapy. All patients were resistant to the standard maximum therapy. The patient's peripheral blood dendritic cells were generated with granulocyte macrophage colony-stimulating factor, plus interleukin 4 with or without OK-432, and pulsed with an autologous tumor lysate. Dendritic cells were injected intradermally, or both intratumorally and intradermally every 3 weeks. Results: The protocols were well tolerated with only local redness and swelling at the injection site in several cases. Clinical responses were as follows: 1patient with partial response, 3 patients with minor response, 10 patients with stable disease, and 10 patients with progressive disease. The patients whose dendritic cells were matured with OK-432 had longer survival times than the dendritic cells from patients without OK-432 maturation. The patients with both intratumoral and intradermal administrations had a longer survival time than the patients with intradermal administration only. Increased ELISPOT and delayed-type hypersensitivity responses after vaccination could provide good laboratory markers to predict the clinical outcome of patients receiving dendritic cell vaccination. The overall survival of patients with grade 4 glioma was 480 days, which was significantly better than that in the control group. Conclusions: This study showed the safety and clinical response of autologous tumor lysatepulsed dendritic cell therapy for patients with malignant glioma. Dendritic cell therapy is recommended for further clinical studies in malignant glioma patients.

Synergistic Induction of Antigen-Specific CTL by Fusions of TLR-Stimulated Dendritic Cells and Heat-Stressed Tumor Cells

“…We used the TLR4-agonist OK-432 to stimulate ImmDCs, which were then fused with heat-treated tumor cells. Because OK-432 is an agent of good manufacturing practice grade and has been widely used in patients with cancer (33)(34)(35)(36)(37), an important aspect of our work is its potential clinical relevance. Interestingly, OK/HS-FCs expressed significantly higher levels of CD86 and intracellular HSPs (HSP70, HSP90, and HSC70).…”

TLR Ligands in the Local Treatment of Established Intracerebral Murine Gliomas

“…Although all studies led to the induction of antitumor CTLs and lymphocyte infiltration into tumors in situ, survival benefit remained low. Objective tumor regressions appeared to relate to the absence of a bulky tumor mass secreting TGF-␤2 and, importantly, on the maturation status of DCs inside and around the tumor (7,8). Therapeutic strategies combining abrogation of local immunosuppression with potent immune stimulation are therefore of particular interest in the search for efficient treatments of malignant gliomas.…”

Danger signals in tumor cells: a risk factor for autoimmune disease?

“…Immunizing with dendritic cells (DCs) loaded with whole-tumor-cell preparations also bears in theory the potential risk of inducing autoimmunity against self-antigens of the tumor. However, such an approach seems to be safe and not associated with autoimmunity as for example for cutaneous T lymphoma [30] or for glioma [31]. The first clinical trial using a DC-based cancer vaccine for glioma patients consisting in DCs pulsed with acid-eluted peptides from cultured autologous Editorial tumor cells and injected intradermally into the deltoid region three-times biweekly also showed no significant side effect and autoimmune syndromes [32].…”