Tumor vaccines expressing Flt3 ligand synergize with CTLA-4 blockade to reject preimplanted tumors Journal Article
| Authors: | Curran, M. A.; Allison, J. P. |
| Article Title: | Tumor vaccines expressing Flt3 ligand synergize with CTLA-4 blockade to reject preimplanted tumors |
| Abstract: | The transformation of a healthy cell into a malignant neoplasm involves numerous genetic mutations and aberrations in gene expression. As few of these changes are shared between individuals or types of cancer, the best source for eliciting broad-spectrum tumor immunity remains each patient's own tumor. Previously, we have shown that combining blockade of the T-cell-negative costimulatory molecule CTL-associated antigen 4 (CTLA-4) and vaccination with irradiated B16 tumor expressing granulocyte macrophage colony-stimulating factor (GM-CSF; Gvax) promotes rejection of established murine melanomas. Here we show that, like GM-CSF, the cytokine Flt3 ligand (Flt3L) expressed in B16 and coupled with CTLA-4 blockade promotes both prophylactic and therapeutic rejection of B16. When administered at the site of growing tumor, Gvax fails to prevent tumor outgrowth in any mice, whereas the B16-Flt3L vaccine (Fl3vax) induces the rejection of 75% of melanomas implanted 3 days before vaccination. Relative to Gvax, Fl3vax promotes greater infiltration of both the vaccine site and the tumor site by CD8<sup>+</sup> T cells and "sentinel" and plasmacytoid dendritic cells. Gvax and Fl3vax did not synergize when used in combination in treating B16 melanoma even in the context of CD25<sup>+</sup> regulatory T-cell depletion. Further, we show that a combination of Flt3L expression and CTLA-4 blockade can also promote the rejection of established TRAMP prostate adenocarcinomas, proving that the utility of this treatment extends beyond melanoma. Engineering Flt3L to be constitutively secreted and attaching an IgG2a tail yielded a B16 vaccine that, when combined with CTLA-4 blockade, prevented the outgrowth of significantly more 5-day implanted B16-BL6 tumors than did Gvax. ©2009 American Association for Cancer Research. |
| Keywords: | controlled study; protein expression; unclassified drug; drug efficacy; nonhuman; adjuvant therapy; cd8+ t lymphocyte; animal cell; mouse; tumor localization; melanoma; dendritic cell; granulocyte macrophage colony stimulating factor; animal experiment; animal model; add on therapy; prophylaxis; vaccination; irradiation; prostate adenocarcinoma; graft rejection; tumor growth; cytotoxic t lymphocyte antigen 4; flt3 ligand; flt3 ligand vaccine; gamma interferon inducible protein 10; granulocyte macrophage colony stimulating factor vaccine; immunoglobulin g2a; monocyte chemotactic protein 3; tumor vaccine; cd25+ t lymphocyte; t cell depletion |
| Journal Title: | Cancer Research |
| Volume: | 69 |
| Issue: | 19 |
| ISSN: | 0008-5472 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2009-10-01 |
| Start Page: | 7747 |
| End Page: | 7755 |
| Language: | English |
| DOI: | 10.1158/0008-5472.can-08-3289 |
| PROVIDER: | scopus |
| PMCID: | PMC2756314 |
| PUBMED: | 19738077 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 5" - "Export Date: 30 November 2010" - "CODEN: CNREA" - "Source: Scopus" |
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