Dendritic cells are potent antigen presenting cells capable of stimulating tumor immunity. Despite their promise as vectors for cancer vaccines, limited clinical efficacy has been observed to date. We have identified a fundamental metabolic pathway that is triggered within the melanoma microenvironment and that results in the potent suppression of dendritic cell function.
After identifying a fatty acid transporter as playing a critical role in this pathway, we have determined that the pharmacological inhibition of this transporter is capable of reversing this process of dendritic cell tolerization and significantly enhancing T cell activation. Based on these findings, we now propose to engineer a dendritic cell-based cancer vaccine that has been genetically silenced for this transporter and to test the impact of this modification both in a transgenic melanoma model as well as in advanced melanoma patients who are refractory to checkpoint inhibitor immunotherapy. In addition to generating more potent ex vivo DC-based vaccines, this work is aimed at validating this recently identified fatty acid transporter as a genetic target for future in vivo DC-targeted treatment strategies.
An ultimate goal of cancer immunotherapy is to activate tumor-specific T cells through therapeutic vaccinations to eradicate pre-established tumor. However, tumor-specific T cell tolerance remains one of the major barriers in cancer immunotherapy. Thus, to elicit effective anti-tumor immunity, it is necessary to develop vaccine strategies capable of overcoming T cell tolerance.
In the previous application funded by Alliance for Cancer Gene Therapy, we have demonstrated an essential role of the innate immune system in shaping adaptive immune responses. In a series of 10 peer-reviewed publications, we have identified several parameters that are critical for the potency of a vaccine in overcoming T cell tolerance: 1) the ability of the vaccine to activate multiple innate immune pathways, leading to production of both type I interferons (IFNs) and pro-inflammatory cytokines; 2) the ability to activate both plasmacytoid dendritic cells (pDCs) and conventional DCs (cDCs); and 3) the ability to activate other innate immune cells such as NK cells, which further enhances adaptive immune responses.
Based on these important parameters, we have demonstrated in a murine model of pre-established lymphoma that DC vaccines co-administered with the TLR9 ligand, CpG in vivo are effective in activating tumor-specific T cell response and treating pre-established lymphoma. This is probably related to the ability of CpG to activate both cDCs and pDCs and to produce pro-inflammatory cytokines and type I IFNs, respectively. In addition, CpG can also activate NK cells.
In this application, we will test the central hypothesis that DC vaccines co-administered with CpG in vivo are effective in activating tumor-specific CD8+ T cell response in patients with lymphoma through the following three specific aims: 1) To perform and analyze FDA required bio-distribution and toxicology studies in mice; 2) To obtain full regulatory approval and GMP manufacturing of DC vaccines to support the trial; and 3) To conduct a pilot phase I to study the safety and immunological efficacy of Epstein-Barr virus (EBV)-derived tumor antigen (LMP2) loaded DC vaccines in patients with EBV-associated lymphoma. We plan to administer LMP2-loaded DC vaccines twice intravenously.
The boost vaccination will be administered 4 weeks after the first vaccination. GMP-grade CpG will be given intramuscularly with each vaccination. We will determine the safety and feasibility of the treatment by determining 1) clinical toxicology; 2) tumor antigen-specific immune responses; 3) although a secondary goal, anti-tumor effect will also be measured. In summary, this will be the first clinical trial designed to enhance anti-tumor immunity using a combined strategy of tumor.
