A novel combination immunotherapy for cancer by IL-13Rα2-targeted DNA vaccine and immunotoxin in murine tumor models.
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-13Rα2(+) 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.
Tumor Vaccines and Biotechnology Branch, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Bethesda, MD 20892, USA.
Hideyuki
H
Nakashima
Masaki
M
Terabe
Jay A
JA
Berzofsky
Syed R
SR
Husain
Raj K
RK
Puri
D036002:ADP Ribose Transferases / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D000818:Animals; D001427:Bacterial Toxins / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005098:Exotoxins / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D005260:Female; D018390:Gene Targeting / Q000379:methods*; D007167:Immunotherapy / Q000379:methods*; D053663:Interleukin-13 Receptor alpha2 Subunit / Q000096:biosynthesis / Q000235:genetics / Q000627:therapeutic use*; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012513:Sarcoma, Experimental / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D019444:Vaccines, DNA / Q000276:immunology / Q000627:therapeutic use*; D037521:Virulence Factors / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D001427:Bacterial Toxins; D019496:Cancer Vaccines; D005098:Exotoxins; D053663:Interleukin-13 Receptor alpha2 Subunit; D019444:Vaccines, DNA; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A