Low dose of GRP78-targeting subtilase cytotoxin improves the efficacy of photodynamic therapy in vivo

Abstract

Photodynamic therapy (PDT) exerts direct cytotoxic effects on tumor cells, destroys tumor blood and lymphatic vessels and induces local inflammation. Although PDT triggers the release of immunogenic antigens from tumor cells, the degree of immune stimulation is regimen-dependent. The highest immunogenicity is achieved at sub-lethal doses, which at the same time trigger cytoprotective responses, that include increased expression of glucose-regulated protein 78 (GRP78). To mitigate the cytoprotective effects of GRP78 and preserve the immunoregulatory activity of PDT, we investigated the in vivo efficacy of PDT in combination with EGF-SubA cytotoxin that was shown to potentiate in vitro PDT cytotoxicity by inactivating GRP78. Treatment of immunocompetent BALB/c mice with EGF-SubA improved the efficacy of PDT but only when mice were treated with a dose of EGF-SubA that exerted less pronounced effects on the number of T and B lymphocytes as well as dendritic cells in mouse spleens. The observed antitumor effects were critically dependent on CD8+ T cells and were completely abrogated in immunodeficient SCID mice. All these results suggest that GRP78 targeting improves in vivo PDT efficacy provided intact T-cell immune system.

A HER2-Targeting Antibody–Drug Conjugate, Trastuzumab Deruxtecan (DS-8201a), Enhances Antitumor Immunity in a Mouse Model

“…Because the parental anti-hHER2 antibody of DS-8201a does not cross-react with mouse HER2, we prepared a mouse cell line that stably expresses the human target gene (22)(23)(24) and used those cells for an immunocompetent mouse tumor model. The human HER2 gene was introduced into CT26.WT cells, and the expression level of human HER2 on the resultant CT26.…”

[Fam-] trastuzumab deruxtecan (DS-8201a)-induced antitumor immunity is facilitated by the anti–CTLA-4 antibody in a mouse model

“…Since the parental anti-hHER2 antibody of [fam-] trastuzumab deruxtecan does not bind to mouse ERBB2, we prepared a mouse cell line that stably expresses the human target gene [21–23] and used those cells to construct an immunocompetent mouse tumor model. The human HER2 gene was introduced into EMT6 mouse breast cancer cells and the expression level of human HER2 in the EMT6-hHER2 cells was determined by flow cytometry analysis.…”