Antibodies to vascular endothelial growth factor enhance the efficacy of cancer immunotherapy by improving endogenous dendritic cell function

Inadequate function of dendritic cells (DCs) in tumor-bearing hosts is one mechanism of tumor escape from immune system control and may compromise the efficacy of cancer immunotherapy, Vascular endothelial growth factor (VEGF ), produced by most tumors, not only plays an important role in tumor angio genesis but also can inhibit the maturation of DCs from hematopoietic proge nitors, Here, we investigate a novel combination of antiangiogenic and immu notherapy based on this dual role of VEGF, Two s.c. mouse tumor models were used: D459 cells, expressing mutant human p53; and MethA sarcoma with poin t mutations in the endogenous murine p53 gene. Therapy with anti-mouse VEGF antibody (10 mu g i.p. twice a week over 4 weeks) was initiated when tumor s became palpable. Treatment of established tumors with anti-VEGF antibody alone did not affect the rate of tumor growth. However, anti-VEGF antibody significantly improved the number and function of lymph node and spleen DCs in these tumor-bearing animals. To investigate the possible effects of thi s antibody on the immunotherapy of established tumors, tumor-bearing mice w ere immunized with DCs pulsed with the corresponding mutation-specific p53 peptides, together with injections of anti-VEGF antibody. Therapy with pept ide-pulsed DCs alone resulted in considerable slowing of tumor growth but o nly during the period of treatment, and tumor growth resumed after the end of the therapy. Combined treatment with peptide-pulsed DCs and anti-VEGF an tibody resulted in a prolonged and much more pronounced antitumor effect. T his effect was associated with the induction of significant anti-p53 CTL re sponses only in this group of mice. These data suggest that inhibition of V EGF may be a valuable adjuvant in the immunotherapy of cancer.