| Abstract: |
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. © 2008 Springer-Verlag. |
| Keywords: |
cancer survival; controlled study; treatment outcome; drug efficacy; drug potentiation; monotherapy; nonhuman; sensitivity and specificity; antigen expression; cd8+ t lymphocyte; animal cell; mouse; phenotype; animals; mice; animal tissue; cell viability; radiation; carcinoembryonic antigen; fas antigen; animal experiment; animal model; combination chemotherapy; antineoplastic activity; cell line, tumor; protein p53; transgenic mouse; mice, transgenic; monoclonal antibody; antibodies, monoclonal; hematologic neoplasms; statistical significance; cellular immunity; immunotherapy; antigens, neoplasm; cancer vaccine; drug distribution; isotope labeling; tissue distribution; cancer vaccines; cd4+ t lymphocyte; tumor cell; single drug dose; up-regulation; radioimmunotherapy; colon adenocarcinoma; glycoprotein; yttrium radioisotopes; carcinoma cell; vaccine; lymphocyte count; cell killing; recombinant vaccine; cell transplantation; mab; antigens, cd95; y-90; col 1 monoclonal antibody y 90; glycoprotein gp 70
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