CTLA-4 blockade enhances the therapeutic effect of an attenuated poxvirus vaccine targeting p53 in an established murine tumor model. Export

@article{citeulike:2309448, abstract = {p53 is overexpressed by half of all cancers, and is an attractive target for a vaccine approach to immunotherapy. p53 overexpression is frequently the result of point mutations, which leaves the majority of the protein in its wild-type form. Therefore, the majority of p53 sequence is wild type, making it a self-protein for which tolerance plays a role in limiting immune responses. To overcome tolerance to p53, we have expressed wild-type murine p53 in the nonpathogenic attenuated poxvirus, modified vaccinia virus Ankara (recombinant modified vaccinia virus Ankara expressing wild-type murine p53 (rMVAp53)). Mice immunized with rMVAp53 vaccine developed vigorous p53-specific CTL responses. rMVAp53 vaccine was evaluated for its ability to inhibit the outgrowth of the syngeneic murine sarcoma Meth A, which overexpresses mutant p53. Mice were inoculated with a lethal dose (5 x 10(5) cells injected s.c.) of Meth A tumor cells and vaccinated by i.p. injection 3 days later with 5 x 10(7) PFU of rMVAp53. The majority of mice remained tumor free and resistant to rechallenge with Meth A tumor cells. We wished to determine whether rMVAp53 immunization could effect the rejection of an established, palpable Meth A tumor. In subsequent experiments, mice were injected with 10(6) Meth A tumor cells, and treated 6 days later with anti-CTLA-4 Ab (9H10) and rMVAp53. The majority of treated mice had complete tumor regression along with lasting tumor immunity. In vivo Ab depletion confirmed that the antitumor effect was primarily CD8 and to a lesser extent CD4 dependent. These experiments demonstrate the potential of a novel cell-free vaccine targeting p53 in malignancy.}, address = {Division of General and Oncologic Surgery, City of Hope National Medical Center, Duarte, CA 91010, USA.}, author = {Espenschied, J. and Lamont, J. and Longmate, J. and Pendas, S. and Wang, Z. and Diamond, D. J. and Ellenhorn, J. D.}, citeulike-article-id = {2309448}, citeulike-linkout-0 = {http://view.ncbi.nlm.nih.gov/pubmed/12626601}, citeulike-linkout-1 = {http://www.hubmed.org/display.cgi?uids=12626601}, day = {15}, issn = {0022-1767}, journal = {J Immunol}, keywords = {cancer, p53, retrovirus}, month = {March}, number = {6}, pages = {3401--3407}, posted-at = {2008-01-31 03:27:34}, priority = {2}, title = {CTLA-4 blockade enhances the therapeutic effect of an attenuated poxvirus vaccine targeting p53 in an established murine tumor model.}, url = {http://view.ncbi.nlm.nih.gov/pubmed/12626601}, volume = {170}, year = {2003} }

TY - JOUR ID - citeulike:2309448 L3 - citeulike-article-id:2309448 N2 - p53 is overexpressed by half of all cancers, and is an attractive target for a vaccine approach to immunotherapy. p53 overexpression is frequently the result of point mutations, which leaves the majority of the protein in its wild-type form. Therefore, the majority of p53 sequence is wild type, making it a self-protein for which tolerance plays a role in limiting immune responses. To overcome tolerance to p53, we have expressed wild-type murine p53 in the nonpathogenic attenuated poxvirus, modified vaccinia virus Ankara (recombinant modified vaccinia virus Ankara expressing wild-type murine p53 (rMVAp53)). Mice immunized with rMVAp53 vaccine developed vigorous p53-specific CTL responses. rMVAp53 vaccine was evaluated for its ability to inhibit the outgrowth of the syngeneic murine sarcoma Meth A, which overexpresses mutant p53. Mice were inoculated with a lethal dose (5 x 10(5) cells injected s.c.) of Meth A tumor cells and vaccinated by i.p. injection 3 days later with 5 x 10(7) PFU of rMVAp53. The majority of mice remained tumor free and resistant to rechallenge with Meth A tumor cells. We wished to determine whether rMVAp53 immunization could effect the rejection of an established, palpable Meth A tumor. In subsequent experiments, mice were injected with 10(6) Meth A tumor cells, and treated 6 days later with anti-CTLA-4 Ab (9H10) and rMVAp53. The majority of treated mice had complete tumor regression along with lasting tumor immunity. In vivo Ab depletion confirmed that the antitumor effect was primarily CD8 and to a lesser extent CD4 dependent. These experiments demonstrate the potential of a novel cell-free vaccine targeting p53 in malignancy. IS - 6 JF - J Immunol SN - 0022-1767 AD - Division of General and Oncologic Surgery, City of Hope National Medical Center, Duarte, CA 91010, USA. EP - 3407 TI - CTLA-4 blockade enhances the therapeutic effect of an attenuated poxvirus vaccine targeting p53 in an established murine tumor model. VL - 170 SP - 3401 KW - cancer KW - p53 KW - retrovirus AU - Espenschied, J AU - Lamont, J AU - Longmate, J AU - Pendas, S AU - Wang, Z AU - Diamond, DJ AU - Ellenhorn, JD PY - 2003/03/15/ UR - http://view.ncbi.nlm.nih.gov/pubmed/12626601 ER -