Sequential delivery of interferon-α gene and DCs to intracranial gliomas promotes an effective antitumor response

Abstract

Effective presentation of tumor antigens by dendritic cells (DCs) is considered to be essential for the induction of antitumor T-cell responses. Apoptotic and necrotic tumors have been noted to be a robust antigen source for DCs. Because glioma cells undergo apoptosis after transfection with the type I interferon (IFN) gene and type I IFNs promote the stimulatory activity of DCs, we hypothesized that transfection of glioma cells with type I IFN genes and provision of DCs would promote particularly effective antitumor activity by both facilitating apoptosis of glioma cells and the presentation of the glioma antigens, thereby inducing specific immune responses against glioma cells. We have previously reported the proof of this hypothesis in vitro and in a subcutaneous tumor model. Here we report an extension of this approach in intracranial (i.c.) gliomas using adenoviral IFN-a (Ad-IFN-a) vector. Mice bearing day-5 i.c. GL261 glioma received sequential intratumoral (i.t.) delivery of Ad-IFN-a and bone marrow-derived syngeneic DCs. This treatment prolonged survival in that nine of 17 animals survived long term (460 days versus 0 of 10 control animals). Specific CTL activity was demonstrated following this regimen in the cervical lymph nodes, and the therapeutic efficacy was dependent upon CD8+ cells. Furthermore, these animals were protected against subsequent rechallenge with GL261 gliomas. DCs injected i.t. survived in the tumor and migrated into cervical lymph node. In vitro migration assays revealed the ability of DCs to migrate toward the tumor, suggesting that i.t. injected DCs migrate through the glioma. Taken together, this combination of gene therapy and cellular immunotherapy may be an effective future strategy for treating human gliomas.

Fundamentals of Gene and Viral Therapy for Malignant Gliomas

“…IFN-inhibits cell cycle progression and induces apoptosis in tumor cells thereby leading to enhanced immune system reaction by increasing expression of MHC-1 (King 2005 andYang 2004). IFN-has shown to regress glioma in animal model when co-delivered with DCs into the tumor (Tsugawa 2004).…”

Beyond retrovirus infection: HIV meets gene therapy

“…Scherr et al (2005) used HIV vectors to investigate the potential therapeutic applications of RNAi as stable gene transfer systems for K562 cancer cell lines and for CD34+ cells from chronic myeloid leukemia patients and have shown that stable RNAi may represent an useful approach to cancer gene therapy. Not only HIV-based vectors have been evaluated in this context, with for instance, adeno-associated vectors having been used in intratumoral injection in order to promote antitumor response (Tsugawa et al, 2004). However, it seems more appropriate to employ a viral vector able to induce immune responses which constitute by themselves a therapeutic approach for cancer.…”

Dendritic cell therapy with interferon-α synergistically suppresses outgrowth of established tumors in a murine colorectal cancer model

“…Therefore, the combined use of DC-based immunotherapy with IFN-a gene therapy is considered reasonable. Recently, Tsugawa et al 30 reported that combined use of DC with adenoviral vector encoding IFN-a elicits antitumor response in a murine intracranial gliomas model. In this study, as a preliminary investigation of the combined therapy, we investigated the effects of bone marrow-derived DCs and IFN-a-expressing colorectal cancer cells on the proliferation of allogeneic splenocytes.…”