Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 5407-5414 |
| Number of pages | 8 |
| Journal | Cancer Research |
| Volume | 64 |
| Issue number | 15 |
| DOIs | |
| State | Published - Aug 1 2004 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Cancer Research
- Oncology
Cite this
Two distinct pathways of immuno-modulation improve potency of p53 immunization in rejecting established tumors. / Daftarian, Pirouz; Song, Guang Yun; Ali, Saima; Faynsod, Moshe; Longmate, Jeff; Diamond, Don J.; Ellenhorn, Joshua D I.
In: Cancer Research, Vol. 64, No. 15, 01.08.2004, p. 5407-5414.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Two distinct pathways of immuno-modulation improve potency of p53 immunization in rejecting established tumors
AU - Daftarian, Pirouz
AU - Song, Guang Yun
AU - Ali, Saima
AU - Faynsod, Moshe
AU - Longmate, Jeff
AU - Diamond, Don J.
AU - Ellenhorn, Joshua D I
PY - 2004/8/1
Y1 - 2004/8/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=3442883353&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=3442883353&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-04-0169
DO - 10.1158/0008-5472.CAN-04-0169
M3 - Article
C2 - 15289349
AN - SCOPUS:3442883353
VL - 64
SP - 5407
EP - 5414
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0099-7013
IS - 15
ER -