Abstract
Cell-based active immunotherapy for cancer is a promising novel strategy, with the first dendritic cell (DC) vaccine achieving regulatory approval for clinical use last year. Manufacturing remains arduous, especially for DC vaccines, and the prospect of using cell-based immunotherapy in the adjuvant setting or in combination with chemotherapy remains largely untested. Here, we used a comparative oncology approach to test the safety and potential efficacy of tumor RNA-loaded, CD40-activated B cells in privately owned dogs presenting with non-Hodgkin's lymphoma (NHL), a clinical scenario that represents not only a major problem in veterinary medicine but also a bona fide spontaneous animal model for the human condition. When administered to NHL dogs in remission after induction chemotherapy, CD40-B cells electroporated ex vivo with autologous tumor RNA safely stimulated immunity in vivo. Although chemotherapy plus CD40-B vaccination did not improve time-to-progression or lymphoma-specific survival compared to dogs treated with chemotherapy alone, vaccination potentiated the effects of salvage therapy and improved the rate of durable second remissions as well as subsequent lymphoma-specific survival following salvage therapy. Several of these relapsed dogs are now long-term survivors and free of disease for more than a year. Overall, these clinical and immunological results suggest that cell-based CD40 cancer vaccination is safe and synergizes with chemotherapy to improve clinical outcome in canine NHL. More broadly, our findings underscore the unique value of clinical investigations in tumor-bearing companion animals.
Highlights
With the recent FDA approval of the dendritic cell vaccine sipuleucel-T for the treatment of advanced prostate cancer [1], there has been renewed efforts to further optimize secondgeneration cell-based therapies aimed at stimulating anti-tumor immunity for the treatment of cancer [2,3]
These dogs were selected based on the fact that they were treated with the same induction chemotherapy regimen as the vaccinated group (Group 2) and were confirmed to be in complete clinical and cytological remission at the end of the chemotherapy protocol but they did not receive CD40-B cell vaccines
The aim of this study was to determine whether tumor RNAtransfected CD40-activated B cells could safely induce anti-tumor immunity and impact the natural history of spontaneous non-Hodgkin’s lymphoma (NHL) in dogs after remission induction with chemotherapy
Summary
With the recent FDA approval of the dendritic cell vaccine sipuleucel-T for the treatment of advanced prostate cancer [1], there has been renewed efforts to further optimize secondgeneration cell-based therapies aimed at stimulating anti-tumor immunity for the treatment of cancer [2,3]. Dendritic cells in most models are the cells responsible for physiological T cell priming in vivo, B cells can act as APC and can be licensed by CD40 activation [9,10]. CD40-activated B cells (CD40-B), like DC, can prime naıve T cell responses against neoantigens ex vivo and can boost memory T cell responses [9,10,11], suggesting that antigen-loaded, CD40-B may represent a viable alternative to DC in cell-based vaccination strategies. CD40-B can augment antigen-specific effector T cell responses in vitro against viral and tumor associated antigens, little is known whether these alternative APC can stimulate effective anti-tumor immune responses in vivo
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