A Novel Combination Immunotherapy for Cancer by IL-13Rα2–Targeted DNA Vaccine and Immunotoxin in Murine Tumor Models

Abstract

Optimum efficacy of therapeutic cancer vaccines may require combinations that generate effective antitumor immune responses, as well as overcome immune evasion and tolerance mechanisms mediated by progressing tumor. Previous studies showed that IL-13Rα2, a unique tumor-associated Ag, is a promising target for cancer immunotherapy. A targeted cytotoxin composed of IL-13 and mutated Pseudomonas exotoxin induced specific killing of IL-13Ra2+ tumor cells. When combined with IL-13Rα2 DNA cancer vaccine, surprisingly, it mediated synergistic antitumor effects on tumor growth and metastasis in established murine breast carcinoma and sarcoma tumor models. The mechanism of synergistic activity involved direct killing of tumor cells and cell-mediated immune responses, as well as elimination of myeloid-derived suppressor cells and, consequently, regulatory T cells. These novel results provide a strong rationale for combining immunotoxins with cancer vaccines for the treatment of patients with advanced cancer.

Targeting of interleukin-13 receptor α2 for treatment of head and neck squamous cell carcinoma induced by conditional deletion of TGF-β and PTEN signaling

“…To examine for any immunological changes in the treated mice, some animals were sacrificed three days after the last dose of IL-13-PE, and FACS analysis was performed using the splenocytes. The MDSCs, a heterogeneous population of myeloid cells known to promote tumor immune evasion, were detected with FACS analysis using the monocyte/macrophage markers CD11b+ and the granulocyte antigen Gr-1+ [17]. The Tgfbr1f/f/Ptenf/f mice lacking the K14-CreER tam transgene to cause conditional deletion were also analyzed as normal controls without tumors.…”

“…Quantification of MDSCs (CD11b+ GR-1+) by FACS analysis was performed as previously described [17]. Essentially, 1 x 10 6 splenocytes were evaluated using FITC-conjugated anti-CD11b and PerCP-Cy5.5–conjugated anti–Gr-1 Abs (e-Bioscience, San Diego, CA).…”

Strategies targeting the IL-4/IL-13 axes in disease

“…It has been reported that IL-13Ra2 is overexpressed in a variety of human tumors, including glioblastoma, head and neck, pancreatic, kidney, ovarian, breast, and Kaposi's sarcoma [291]. Therefore, IL-13Ra2 is recognized as a tumor associated antigen which can be used to target cancer cells for killing by immunotoxin conjugates [292,293]. A similar approach using IL-4-Pseudomonas exotoxin was also tested in patients with recurrent malignant glioma with an acceptable safety and toxicity profile [294].…”

Cytokine Stimulation of Epithelial Cancer Cells: The Similar and Divergent Functions of IL-4 and IL-13

“…Even without considering the biological pathways involved, the high level expression of IL4Rα (also known as CD124) or IL13Rα2 on several types of tumor cells has allowed tumor cell-selective delivery of various toxins or lytic peptides resulting in reduced tumor load (30). So, is it plausible to target the IL4R or IL13Rα2 signaling pathways in patients as anti-cancer therapy?…”