title: Combined antiangiogenic and immune therapy of prostate cancer.
abstract: Experimental studies of antiangiogenic or immune therapy of cancer have generated a great deal of optimism. However, the results of clinical testing of these therapies are below expectations. We hypothesized that the antitumor efficacy can be increased when immune destruction of tumor cell is combined with destruction of tumor vasculature by antiangiogenic drugs. In the present study the therapeutic efficacy of combined antiangiogenic and immune therapy has been tested against the highly aggressive, MHC class I negative murine RM1 prostate tumor. SU6668 was used as the antiangiogenic drug and recombinant murine B7.2-IgG fusion protein was used to stimulate T cell-mediated immune destruction of tumor cells. SU6668 is an inhibitor of the tyrosine kinase activity of three angiogenic receptors VEGFR2 (Flk-1/KDR), PDGFRbeta and FGFR1 that play a crucial role in tumor-induced vascularization. Our studies show that B7.2-IgG treatment of mice with established RM1 prostate tumors resulted in a significant inhibition of tumor growth. Both CD4+ and CD8+ T cells were responsible for this effect. SU6668 therapy substantially inhibited tumor vascularization and tumor growth. When tumor-bearing mice were treated with SU6668 in combination with B7.2-IgG, the antitumor effects were substantially higher than in mice treated separately with SU6668 or B7.2-IgG. Prolonged treatment of mice with SU6668 did not inhibit the immunoreactivity of T lymphocytes. On the contrary, T cells from mice treated with a combination of SU6668 and B7.2-IgG showed higher proliferative responses and cytokine production following anti-CD3 stimulation than T cells of mice treated separately with these modalities. These results indicate that antiangiogenic and immune therapies using SU6668 and B7.2-IgG are compatible and manifest complementary antitumor effects. Combined antiangiogenic and immune therapy might represent a new strategy for cancer treatment.
authors.affiliation: Department of Pathology, University of Pittsburgh Cancer Institute, PA 15213, USA.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Huang
authors.forename: Tatiana
authors.initials: T
authors.lastname: Raskovalova
authors.forename: Anna
authors.initials: A
authors.lastname: Lokshin
authors.forename: Alyssa
authors.initials: A
authors.lastname: Krasinskas
authors.forename: Jason
authors.initials: J
authors.lastname: Devlin
authors.forename: Simon
authors.initials: S
authors.lastname: Watkins
authors.forename: Stanley F
authors.initials: SF
authors.lastname: Wolf
authors.forename: Elieser
authors.initials: E
authors.lastname: Gorelik
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D017252:CD3 Complex; D045744:Cell Line, Tumor; D007074:Immunoglobulin G / Q000627:therapeutic use; D007167:Immunotherapy; D007211:Indoles / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D000078183:Oxindoles; D011422:Propionates; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000276:immunology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011758:Pyrroles / Q000627:therapeutic use*; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000187:drug effects / Q000502:physiology
chemical_list: D020533:Angiogenesis Inhibitors; D017252:CD3 Complex; D007074:Immunoglobulin G; D007211:Indoles; D000078183:Oxindoles; D011422:Propionates; D011758:Pyrroles; D011993:Recombinant Fusion Proteins; C412603:orantinib; D011505:Protein-Tyrosine Kinases