Effects of the anti-VEGF monoclonal antibody bevacizumab in a preclinical model and in patients with refractory and multiple relapsed Hodgkin lymphoma.
No curative treatment is currently available for refractory or relapsed Hodgkin lymphoma (HL) after high-dose chemotherapy. Thus, new drugs with different modes of action are needed. Vascular endothelial growth factor (VEGF), a key regulator of tumor-angiogenesis, is elevated in sera of patients with HL. Hodgkin and Reed-Sternberg cells also express the growth-stimulating VEGF-R2 receptor suggesting that VEGF could contribute to the pathophysiology of this malignancy. We investigated the effects of the humanized anti-VEGF monoclonal antibody bevacizumab (BV) against human HL xenografts in severe combined immune deficiency mice and in a compassionate use program in HL patients with multiple relapsed and progressive diseases. After a 4-week run-in phase of single agent BV, combined gemcitabine and BV therapy was administered. In the animal model, BV delayed the growth of HL tumors significantly (P=0.0004). Out of 5 patients included, BV alone had biologic effects as determined by tumor size, blood flow, fluorodeoxyglucose-uptake, and serum markers CCL17/thymus and activation-related chemokine, and sCD30 in 4 patients. The combination of BV and gemcitabine led to partial or complete remission in 3 of 5 patients. Accordingly, VEGF deprivation by the anti-VEGF antibody BV has antitumor activity in established HL tumors in a preclinical model. Furthermore, BV single agent therapy has biologic effects in HL patients indicating clinical activity. On the basis of these results, a prospective clinical study has been initiated to further investigate the impact of this antiangiogenic approach in HL.
Reiners
Katrin S
KS
Laboratory of Immunotherapy, Department of Internal Medicine I, University Hospital Cologne, Cologne, Germany.
Gossmann
Axel
A
von Strandmann
Elke Pogge
EP
Böll
Boris
B
Engert
Andreas
A
Borchmann
Peter
P
D000328:Adult; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab; D048708:Cell Growth Processes / Q000187:drug effects / Q000276:immunology; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D005260:Female; D006689:Hodgkin Disease / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D006801:Humans; D007167:Immunotherapy; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D047368:Tumor Burden / Q000187:drug effects / Q000276:immunology; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology* / Q000378:metabolism; D000093542:Gemcitabine
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D042461:Vascular Endothelial Growth Factor A; D003841:Deoxycytidine; D000068258:Bevacizumab; D000093542:Gemcitabine