Dendritic cells are essential for priming but inefficient for boosting antitumour immune response in an orthotopic murine glioma model

Abstract

The prognosis of malignant gliomas remains dismal and alternative therapeutic strategies are required. Immunotherapy with dendritic cells (DCs) pulsed with tumour antigens emerges as a promising approach. Many parameters influence the efficacy of DC-based vaccines and need to be optimised in preclinical models. The present study compares different vaccine schedules using DCs loaded with tumour cell lysate (DC-Lysate) for increasing long-term survival in the GL26 orthotopic murine glioma model, focusing on the number of injections and an optimal way to recall antitumour immune response. Double vaccination with DC-Lysate strongly prolonged median survival compared to unvaccinated animals (mean survival 87.5 days vs. 25 days; p < 0.0001). In vitro data showed specific cytotoxic activity against GL26. However, late tumour relapses frequently occurred after 3 months and only 20% of mice were finally cured at 7 months. While one, two or three DC injections gave identical survival, a boost using only tumour lysate after initial DC-Lysate priming dramatically improved long-term survival in vaccinated mice, compared to the double DC-Lysate group, with 67.5% of animals cured at 7 months (p < 0.0001). In vitro data showed better specific CTL response and also the induction of specific anti-GL26 antibodies in the DC-Lysate/Lysate group, which mediated Complement Dependent Cytotoxicity. These experimental data may be of importance for the design of clinical trials that currently use multiple DC injections.

Vaccination Elicits Correlated Immune and Clinical Responses in Glioblastoma Multiforme Patients

“…Curiously, these endogenous responders were not more likely to exhibit vaccine-enhanced responses of similar or higher magnitudes, suggesting that prior antitumor responses failed to boost stronger secondary responses in these patients. This is consistent with a recent report that DC vaccination effectively primes, but poorly boosts, antiglioma responses in mice (47), although endogenous responses were not directly considered in this report. Moreover, endogenous responses correlated inversely with vaccine-enhanced IFN-g responses, consistent with the notion that endogenous responsiveness may proportionally diminish vaccine responses.…”

Postoperative Adjuvant Dendritic Cell–Based Immunotherapy in Patients with Relapsed Glioblastoma Multiforme

“…In contrast, injection of DC for the priming, followed by boosts with tumor cell lysate alone generated the most effective antitumor effects. This vaccination methodology allowed better cytotoxic T-lymphocyte responses and also triggered an antitumor humoral response (41). Moreover, in renal cell carcinoma, the immunogenicity and survival benefit of intradermal tumor cell lysate administration has been shown (42).…”

Mouse Models of Brain Tumors and Their Applications in Preclinical Trials

“…A number of other strategies yet to be tested in GEM models of brain tumorigenesis include histone deacetylase inhibitors (54), immune modulation (55,56), angiogenetic therapy (58), monoclonal antibodies (59,60), small interfering RNA approaches (52), and differentiation therapy (61). These therapies are interesting for their flexibility, which allows tailoring treatment to specific tumors and their environment by choosing antigens, antibodies, appropriate toxin or isotope conjugates, or administration methods.…”