Immunotherapy Targeting Folate Receptor Induces Cell Death Associated with Autophagy in Ovarian Cancer

Purpose: Cancer cells are highly dependent on folate metabolism, making them susceptible to drugs that inhibit folate receptor activities. Targeting overexpressed folate receptor alpha (FR alpha) in cancer cells offers a therapeutic opportunity. We investigated the functional mechanisms of MORAB-003 (farletuzumab), a humanized mAb against FR alpha, in ovarian cancer models. Experimental Design: We first examined FR alpha expression in an array of human ovarian cancer cell lines and then assessed the in vivo effect of MORAB-003 on tumor growth and progression in several orthotopic mouse models of ovarian cancer derived from these cell lines. Molecular mechanisms of tum or cell death induced by MORAB-003 were investigated by cDNA and protein expression profiling analysis. Mechanistic studies were performed to determine the role of autophagy in MORAB-003-induced cell death. Results: MORAB-003 significantly decreased tumor growth in the high-FR alpha IGROV1 and SKOV3ip1 models but not in the low-FR alpha A2780 model. MORAB-003 reduced proliferation, but had no significant effect on apoptosis. Protein expression and cDNA microarray analyses showed that MORAB-003 regulated an array of autophagy-related genes. It also significantly increased expression of LC3 isoform II and enriched autophagic vacuolization. Blocking autophagy with hydroxychloroquine or bafilomycin A1 reversed the growth inhibition induced by MORAB-003. In addition, alteration of FOLR1 gene copy number significantly correlated with shorter disease-free survival in patients with ovarian serous cancer. Conclusions: MORAB-003 displays prominent antitumor activity in ovarian cancer models expressing FR alpha at high levels. Blockade of folate receptor by MORAB-003 induced sustained autophagy and suppressed cell proliferation. (C) 2014 AACR.