Purpose: We previously reported that autologous dendritic cells pulsed with acid-eluted tumor peptides can stimulateTcell^mediated antitumor immune responses against brain tumors in animal models. As a next step in vaccine development, a phase I clinical trial was established to evaluate this strategy for its feasibility, safety, and induction of systemic and intracranial

Purpose: To assess the feasibility, safety, and toxicity of autologous tumor lysate-pulsed dendritic cell (DC) vaccination and toll-like receptor (TLR) agonists in patients with newly diagnosed and recurrent glioblastoma. Clinical and immune responses were monitored and correlated with tumor gene expression profiles.Experimental Design: Twenty-three patients with glioblastoma (WHO grade IV) were enrolled in this dose-escalation study and received three biweekly injections of glioma lysate-pulsed DCs followed by booster vaccinations with either imiquimod or poly-ICLC adjuvant every 3 months until tumor progression. Gene expression profiling, immunohistochemistry, FACS, and cytokine bead arrays were performed on patient tumors and peripheral blood mononuclear cells.Results: DC vaccinations are safe and not associated with any dose-limiting toxicity. The median overall survival from the time of initial surgical diagnosis of glioblastoma was 31.4 months, with a 1-, 2-, and 3-year survival rate of 91%, 55%, and 47%, respectively. Patients whose tumors had mesenchymal gene expression signatures exhibited increased survival following DC vaccination compared with historic controls of the same genetic subtype. Tumor samples with a mesenchymal gene expression signature had a higher number of CD3 þ and CD8 þ tumor-infiltrating lymphocytes compared with glioblastomas of other gene expression signatures (P ¼ 0.006). Conclusion: Autologous tumor lysate-pulsed DC vaccination in conjunction with TLR agonists is safe as adjuvant therapy in newly diagnosed and recurrent glioblastoma patients. Our results suggest that the mesenchymal gene expression profile may identify an immunogenic subgroup of glioblastoma that may be more responsive to immune-based therapies. Clin Cancer Res; 17(6); 1603-15. Ó2010 AACR.

Multiple sclerosis patients who become pregnant experience a significant decrease in relapses that may be mediated by a shift in immune responses from T helper 1 to T helper 2. Animal models of multiple sclerosis have shown that the pregnancy hormone, estriol, can ameliorate disease and can cause an immune shift. We treated nonpregnant female multiple sclerosis patients with the pregnancy hormone estriol in an attempt to recapitulate the beneficial effect of pregnancy. As compared with pretreatment baseline, relapsing remitting patients treated with oral estriol (8 mg/day) demonstrated significant decreases in delayed type hypersensitivity responses to tetanus, interferon-gamma levels in peripheral blood mononuclear cells, and gadolinium enhancing lesion numbers and volumes on monthly cerebral magnetic resonance images. When estriol treatment was stopped, enhancing lesions increased to pretreatment levels. When estriol treatment was reinstituted, enhancing lesions again were significantly decreased. Based on these results, a larger, placebo-controlled trial of estriol is warranted in women with relapsing remitting multiple sclerosis. This novel treatment strategy of using pregnancy doses of estriol in multiple sclerosis has relevance to other autoimmune diseases that also improve during pregnancy.

Together, these studies elucidate the role that TIMs play in mediating adaptive immune resistance in the GBM microenvironment and provide evidence that they can be manipulated pharmacologically with agents that are clinically available. Development of immune resistance in response to active vaccination in GBM can be reversed with dual administration of CSF-1Ri and PD-1 mAb.

Interferon-alpha and IFN-gamma can significantly upregulate the MHC Class I molecules that are expressed on the cell surface of human GBM cells as well as the potentially immunogenic peptides bound to the MHC. These results may help explain the molecular basis for increased immunogenicity with IFN treatment of human GBMs and might provide added insight into the design of future antitumor vaccines for human brain tumors.