Abstract A26: Monocyte depletion to amplify tumor vaccine immunity in a dog non-Hodgkin lymphoma model

Background. Spontaneously-developing B cell lymphoma in dogs closely resembles non-Hodgkin lymphoma (NHL) in humans in many respects, including tumor biology, predictors of tumor progression, and development of resistance to chemotherapy. The canine NHL model therefore provides a strong platform for evaluation of therapeutics for human NHL, including assessment of novel immunotherapeutic approaches. We reported recently that inflammatory monocytes exerted potent suppressive effects on vaccine responses and that monocyte depletion at the time of immunization could significantly enhance tumor vaccine immunity, as assessed by studies in rodent tumor models. The present study was conducted to determine whether the monocyte depletion approach could also effectively augment tumor vaccine immunity in the canine spontaneous NHL model. Approach. A pilot study involving 20 dogs with NHL was conducted to assess the vaccine enhancing effects of monocyte depletion. Autologous lymphoma vaccines were prepared from lymph node biopsy specimens obtained from dogs with multicentric B cell NHL. To prepare tumor vaccines, cell membrane antigens were extracted from the tumor tissues and mixed with a liposomal-TLR adjuvant, and the resulting autologous tumor vaccine was administered s.c. Dogs enrolled in the study were randomized to receive the lymphoma vaccine alone or the vaccine administered together with i.v. liposomal clodronate as a transient monocyte depleting agent. Tumor remission was first induced using doxorubicin and dogs each received a total of 6 tumor vaccines over an 18-week period, administered along with concurrent doxorubicin chemotherapy. Cellular and humoral immune responses were evaluated using PBMC. Results. Immunization with the autologous lymphoma vaccine induced measurable cellular immune responses, including increased IFN-g recall responses to tumor antigens, increased tumor-specific CTL activity, and increased anti-tumor antibody responses. Immunization combined with monocyte depletion induced significant enhancement of both cellular and humoral immune responses to vaccination, compared to dogs that received the tumor vaccine alone. However, augmentation of vaccine immunity waned at the completion of the vaccination period, and disease-free intervals were not significantly different between the vaccine only and vaccine + liposomal clodronate groups of dogs. Conclusions. We concluded that transient monocyte depletion at the time of vaccination significantly enhanced vaccine immunity in dogs with NHL, though the vaccine enhancing effects were transient. Additional studies of monocyte targeted therapeutics for tumor vaccine enhancement to generate more durable vaccine immunity appear to be warranted based on the results of this feasibility study in a canine model of NHL. Citation Format: Steven Dow, Leah Mitchell, Amanda Guth, Dan Regan, Jenna Burton, Robyn Elmslie. Monocyte depletion to amplify tumor vaccine immunity in a dog non-Hodgkin lymphoma model. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr A26.