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Antibodies to Vascular Endothelial Growth Factor Enhance the Efficacy of Cancer Immunotherapy by Improving Endogenous Dendritic Cell Function
Ist Teil von
Clinical cancer research, 1999-10, Vol.5 (10), p.2963-2970
Ort / Verlag
Philadelphia, PA: American Association for Cancer Research
Erscheinungsjahr
1999
Quelle
MEDLINE
Beschreibungen/Notizen
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 angiogenesis but also can inhibit the maturation of DCs from hematopoietic progenitors.
Here, we investigate a novel combination of antiangiogenic and immunotherapy 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 point mutations in the endogenous
murine p53 gene. Therapy with anti-mouse VEGF antibody (10 μg i.p. twice a week over 4 weeks) was initiated when tumors 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 this antibody on the immunotherapy of established tumors, tumor-bearing mice were immunized with DCs
pulsed with the corresponding mutation-specific p53 peptides, together with injections of anti-VEGF antibody. Therapy with
peptide-pulsed DCs alone resulted in considerable slowing of tumor growth but only during the period of treatment, and tumor
growth resumed after the end of the therapy. Combined treatment with peptide-pulsed DCs and anti-VEGF antibody resulted in
a prolonged and much more pronounced antitumor effect. This effect was associated with the induction of significant anti-p53
CTL responses only in this group of mice. These data suggest that inhibition of VEGF may be a valuable adjuvant in the immunotherapy
of cancer.