Enhancement of Cancer Radiation Therapy by Use of Adenovirus-Mediated Secretable Glucose-Regulated Protein 94/gp96 Expression

Abstract

Tumor-derived glucose-regulated protein 94 (GRP94/gp96) has shown great promise as a tumor vaccine. However, current protein-based approaches require the availability of large quantities of tumor tissue, which are often not possible. In addition, the efficacy of immunotherapy is often not ideal when used alone. In this study, we explored the therapeutic efficacy of a combined GRP94/gp96-based genetic immunotherapy and radiation therapy strategy in the weakly immunogenic and highly metastatic 4T1 murine mammary cancer model. An adenovirus encoding a modified, secretable form of GRP94 gene (AdsGRP94) was constructed and evaluated in various antitumor experiments. Lethally irradiated, virus-infected cells were used as vaccines. Adenoviral vectors were also injected directly into tumors in conjunction with tumor irradiation. Vaccination with lethally irradiated, AdsGRP94-infected 4T1 cells completely prevented subsequent tumor growth from challenge inoculations of as many as 10 7 cells per mouse. In established tumor models, vaccinations alone had minimal effect on local and metastatic tumor growth. However, when vaccination was combined with radiation therapy and i.t. AdsGRP94 injections, local tumor growth and pulmonary metastasis were markedly inhibited. In some cases, complete tumor regression was observed. In these cases, the mice were resistant to subsequent tumor challenge and remain tumor free up to 10 months after initial therapy. Our results indicate that combined AdsGRP94-based immunotherapy and radiation therapy may be a potentially effective strategy for cancer treatment. (Cancer Res 2005; 65(20): 9126-31)

Modulated electro-hyperthermia enhances dendritic cell therapy through an abscopal effect in mice

“…Thus, one key molecule, by which the abscopal effect induces systemic antitumor immune reaction, may be GP96. As others have reported, GP96 potentially boosts the activity of the systemic antitumor effect by these CTLs, and this mechanism could be one explanation for the abscopal effect (34)(35)(36).…”

Glucose regulated proteins in cancer progression, Drug resistance and immunotherapy

“…4,51 Based on this model, therapeutic strategy was developed to use irradiated and genetically modified tumor cells overexpressing a secreted form of GRP94 as a vaccine. 52,53 While this results in suppression of tumor growth, the efficacy is improved by low dose cyclophosphamide which inhibits the induction of suppressive regulatory T cells. 53…”

Triplex Profiling of Functionally Distinct Chaperones (ERp29/PDI/BiP) Reveals Marked Heterogeneity of the Endoplasmic Reticulum Proteome in Cancer

“…4,5,8 Endoplasmin (GRP94, gp96), another stress-sensitive chaperone related to BiP, has prominence in cancer immunotherapy and as a target of the anticancer agent, geldanamycin. 7,10,11 The redox sensor PDI is essential for disulfide bond formation and, due to its broad overexpression, has been proposed as a cancer biomarker. 12,13 These classical ER-marker proteins are recognized to hold strong mechanistic, therapeutic, and prognostic potential given their status as multifaceted sensors of cell pathophysiology and drug exposure.…”