Effects of the Anti-VEGF Monoclonal Antibody Bevacizumab in a Preclinical Model and in Patients With Refractory and Multiple Relapsed Hodgkin Lymphoma

Abstract

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.