Use of radiolabeled monoclonal antibody to enhance vaccine-mediated antitumor effects.
Radiolabeled monoclonal antibodies (mAb) have demonstrated measurable antitumor effects in hematologic malignancies. This outcome has been more difficult to achieve for solid tumors due, for the most part, to difficulties in delivering sufficient quantities of mAb to the tumor mass. Previous studies have shown that nonlytic levels of external beam radiation can render tumor cells more susceptible to T cell-mediated killing. The goal of these studies was to determine if the selective delivery of a radiolabeled mAb to tumors would modulate tumor cell phenotype so as to enhance vaccine-mediated T-cell killing. Here, mice transgenic for human carcinoembryonic antigen (CEA) were transplanted with a CEA expressing murine carcinoma cell line. Radioimmunotherapy consisted of yttrium-90 (Y-90)-labeled anti-CEA mAb, used either alone or in combination with vaccine therapy. A single dose of Y-90-labeled anti-CEA mAb, in combination with vaccine therapy, resulted in a statistically significant increase in survival in tumor-bearing mice over vaccine or mAb alone; this was shown to be mediated by engagement of the Fas/Fas ligand pathway. Mice receiving the combination therapy also showed a significant increase in the percentage of viable tumor-infiltrating CEA-specific CD8(+) T cells compared to vaccine alone. Mice cured of tumors demonstrated an antigen cascade resulting in CD4(+) and CD8(+) T-cell responses not only for CEA, but for p53 and gp70. These results show that systemic radiotherapy in the form of radiolabeled mAb, in combination with vaccine, promotes effective antitumor response, which may have implications in the design of future clinical trials.
Chakraborty
Mala
M
Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Room 8B09, Bethesda, MD 20892, USA.
Gelbard
Alexander
A
Carrasquillo
Jorge A
JA
Yu
Sarah
S
Mamede
Marcelo
M
Paik
Chang H
CH
Camphausen
Kevin
K
Schlom
Jeffrey
J
Hodge
James W
JW
D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000951:Antigens, Neoplasm / Q000276:immunology; D019496:Cancer Vaccines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D019337:Hematologic Neoplasms / Q000532:radiotherapy*; D051379:Mice; D008822:Mice, Transgenic; D016499:Radioimmunotherapy / Q000379:methods*; D012680:Sensitivity and Specificity; D014018:Tissue Distribution; D016896:Treatment Outcome; D015854:Up-Regulation / Q000276:immunology; D015021:Yttrium Radioisotopes / Q000493:pharmacokinetics / Q000627:therapeutic use; D019014:fas Receptor / Q000276:immunology
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D015021:Yttrium Radioisotopes; D019014:fas Receptor