A vascular endothelial growth factor receptor-2 inhibitor enhances antitumor immunity through an immune-based mechanism.
OBJECTIVE
Given the complex tumor microenvironment, targeting multiple cellular components may be the most effective cancer treatment strategy. Therefore, we tested whether antiangiogenic and immune-based therapy might synergize by characterizing the activity of DC101, an antiangiogenic monoclonal antibody specific for vascular endothelial growth factor receptor-2 (VEGF-R2), alone and with HER-2/neu (neu)-targeted vaccination.


METHODS
Neu-expressing breast tumors were measured in treated nontolerant FVB mice and immune-tolerant neu transgenic (neu-N) mice. Neu-specific and tumor cell-specific immune responses were assessed by intracellular cytokine staining, ELISPOT, and CTL assays.


RESULTS
DC101 decreased angiogenesis and increased tumor cell apoptosis. Although DC101 increased serum levels of the immunosuppressive cytokine VEGF, no evidence of systemic immune inhibition was detected. Moreover, DC101 did not impede the influx of tumor-infiltrating lymphocytes. In FVB mice, DC101 inhibited tumor growth in part through a T cell-dependent mechanism, resulting in both increased tumor-specific CD8(+) T cells and tumor regression. Combining DC101 with neu-specific vaccination accelerated tumor regression, augmenting the lytic activity of CD8(+) cytotoxic T cells. In tolerant neu-N mice, DC101 only delayed tumor growth without inducing frank tumor regression or antigen-specific T-cell activation. Notably, mitigating immune tolerance by inhibiting regulatory T cell activity with cyclophosphamide revealed DC101-mediated augmentation of antitumor responses in vaccinated neu-N mice.


CONCLUSIONS
This is the first report of DC101-induced antitumor immune responses. It establishes the induction of tumor-specific T-cell responses as one consequence of VEGF-R2 targeting with DC101. These data support the development of multitargeted cancer therapy combining immune-based and antiangiogenic agents for clinical translation.
Manning
Elizabeth A
EA
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Ullman
John G M
JG
Leatherman
James M
JM
Asquith
Justin M
JM
Hansen
Timothy R
TR
Armstrong
Todd D
TD
Hicklin
Daniel J
DJ
Jaffee
Elizabeth M
EM
Emens
Leisha A
LA
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D017951:Antigen Presentation; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D019496:Cancer Vaccines; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D006801:Humans; D007107:Immune System; D016246:Lymphocytes, Tumor-Infiltrating / Q000378:metabolism; D051379:Mice; D009389:Neovascularization, Pathologic; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D019496:Cancer Vaccines; C511761:DC101 monoclonal antibody; D040301:Vascular Endothelial Growth Factor Receptor-2