Abstract LB-133: Vaccination with dendritic cells pulsed with autologous oxidized whole tumor lysate induced strong and long-lasting anti-tumor immunity in recurrent ovarian cancer patients

Abstract

Abstract Background Despite surgical and chemotherapeutic advances, the death rate from ovarian cancer has not changed over the past two decades. We report here an enhanced, more rapid and more immunogenic dendritic cell vaccine platform developed for clinical testing. Furthermore we report the application of this novel immunotherapy platform comprising of dendritic cell (DC)-based autologous whole tumor antigen vaccination in a pilot study of patients with recurrent ovarian cancer. Methods To determine the optimal tumor lysate preparation for loading DCs, ovarian tumor lines (SKOV3, OVCAR5 and A1847) were prepared by HOCl-oxidation, UVB-irradiation or freeze and thaw. Normal donor DCs were evaluated for tumor lysate uptake, cytokine and chemokine productions and phenotype after maturation with lipopolysaccharides (LPS) and interferon (IFN)-gamma. The optimal lysate preparation, was used in a phase I study where five patients with recurrent, progressive stage III and IV ovarian cancer with available tumor lysate from secondary debulking surgery underwent intranodal vaccination with OC-DC, an autologous DC preparation pulsed with HOCl-oxidized autologous tumor cells (5-10 x 106 DC per dose, 5 doses). Feasibility, safety, and biological and clinical efficacy were evaluated. Results Normal donor DCs pulsed with HOCl-oxidized tumor lines demonstrated the highest tumor lysate uptake, matured efficiently after LPS and IFN-gamma stimulation, and produced higher levels of proinflammatory cytokines and chemokines including IL-1, IL-6, IL-8, IL-12, IP-10, MIP-1alpha and MIG. In vitro, these lysates loaded DCs primed T cell responses against ovarian tumor associated antigens and effectively expanded against tumor specific T cells from donors and patients. Therapy was feasible and well tolerated in all five subjects. Vaccination with OC-DC produced limited grade 1 toxicities and elicited tumor-specific T cell responses. Moreover specific HLA-A2-restricted responses to HER-2/neu, MUC1, NYESO-1, mesothelin and WT1 were documented following vaccination and HER-2/neu specific T cells were expanded following 10 days of in vitro culture. Patients exhibiting immune response demonstrated clinical benefit including two patients who demonstrated remission inversion on vaccine maintenance. Conclusions We developed a DC-HOCl oxidized whole tumor lysate vaccine which was safe and well-tolerated by all patients. The DC vaccine was highly proinflammatory and elicited cellular and humoral anti-tumor responses establishing a platform for immune-combinatorial therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-133. doi:1538-7445.AM2012-LB-133