Two distinct pathways of immuno-modulation improve potency of p53 immunization in rejecting established tumors.
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.
Laboratory of Vaccine Research, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.
Pirouz
P
Daftarian
Guang-Yun
GY
Song
Saima
S
Ali
Moshe
M
Faynsod
Jeff
J
Longmate
Don J
DJ
Diamond
Joshua D I
JD
Ellenhorn
D000276:Adjuvants, Immunologic / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000737:chemistry; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D060908:CTLA-4 Antigen; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D003131:Combined Modality Therapy; D006224:Cricetinae; D003601:Cytotoxicity Tests, Immunologic; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D004357:Drug Synergism; D005260:Female; D006720:Homozygote; D006801:Humans; D007114:Immunization; D015850:Interleukin-6 / Q000235:genetics / Q000502:physiology; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D015674:Mammary Neoplasms, Animal / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology; D012513:Sarcoma, Experimental / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D015398:Signal Transduction; D051217:Toll-Like Receptor 9; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000494:pharmacology*
D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; C408982:CPG-oligonucleotide; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D009838:Oligodeoxyribonucleotides; D011956:Receptors, Cell Surface; C495371:TLR9 protein, human; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D016159:Tumor Suppressor Protein p53