Two distinct pathways of immuno-modulation improve potency of p53 immunization in rejecting established tumors

• Published in: Cancer research (Chicago, Ill.) Ill.), 2004-08, Vol.64 (15), p.5407-5414
• Main Authors: DAFTARIAN, Pirouz, SONG, Guang-Yun, ALI, Saima, FAYNSOD, Moshe, LONGMATE, Jeff, DIAMOND, Don J, ELLENHORN, Joshua D. I
• Format: Article
• Language: English
• Subjects: Adjuvants, Immunologic - pharmacology; Adjuvants, Immunologic - therapeutic use; Animals; Antibodies, Monoclonal - metabolism; Antigens, CD; Antigens, Differentiation - chemistry; Antineoplastic agents; Biological and medical sciences; CD8-Positive T-Lymphocytes - immunology; Cells, Cultured; Colonic Neoplasms - genetics; Colonic Neoplasms - immunology; Colonic Neoplasms - therapy; Combined Modality Therapy; Cricetinae; CTLA-4 Antigen; Cytotoxicity Tests, Immunologic; DNA-Binding Proteins - genetics; DNA-Binding Proteins - physiology; Drug Synergism; Female; Homozygote; Humans; Immunization; Interleukin-6 - genetics; Interleukin-6 - physiology; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Mammary Neoplasms, Animal - genetics; Mammary Neoplasms, Animal - immunology; Mammary Neoplasms, Animal - therapy; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Oligodeoxyribonucleotides - pharmacology; Pharmacology. Drug treatments; Receptors, Cell Surface - genetics; Receptors, Cell Surface - physiology; Sarcoma, Experimental - genetics; Sarcoma, Experimental - immunology; Sarcoma, Experimental - therapy; Signal Transduction; Toll-Like Receptor 9; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - pharmacology; Tumors
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-04-0169

The p53 gene product is overexpressed by almost 50% of cancers, making it an ideal target for cancer immunotherapy. We previously demonstrated rejection of established p53-overexpressing tumors without stimulating autoimmunity by immunization with modified vaccinia Ankara-expressing murine p53 (MVAp53). Tumor rejection was enhanced through antibody-mediated CTL-associated antigen 4 (CTLA-4) blockade. We examined the role of synthetic oligodeoxynucleotides (ODN) containing unmethylated cytosine-phosphate-guanine (CpG) motifs (CpG ODN) in enhancing MVAp53-mediated tumor rejection. CpG ODN with MVAp53 resulted in tumor rejection in BALB/c mice bearing poorly immunogenic 11A-1 murine mammary carcinomas or Meth A sarcomas and C57Bl/6 mice bearing MC-38 colon carcinomas. The effect was similar to that seen in tumor-bearing mice treated with MVAp53 along with CTLA-4 blockade. Monoclonal antibody depletion experiments demonstrated that the adjuvant effects of CpG ODN and CTLA-4 blockades were CD8 dependent. CpG ODN were partially natural killer cell dependent and ineffective in Toll-like Receptor 9(-/-) and interleukin 6(-/-) mice, whereas CTLA-4 blockade was partially CD4 dependent and functional in Toll-like Receptor 9(-/-) and interleukin 6(-/-) mice. In addition, when administered with MVAp53, both adjuvants enhanced p53-specific cytotoxicity and demonstrated an additive effect when combined. The combination of CpG ODN and CTLA-4 blockade worked synergistically to reject palpable 11A-1 and MC-38 tumors. These experiments demonstrate the potential for augmenting MVAp53-mediated antitumor immunity using CpG ODN and CTLA-4 blockade. This cell-free immunotherapy approach is a candidate for evaluation in cancer patients.