Clinical trials with tumor cell-based vaccines to stimulate broad unbiased tumor specific adaptive responses have shown promise but none have yet shown sufficient clinical efficacy. One critical shortcoming of these cellular vaccines has been the limited number of activated antigen presenting cells that can marshal multiple cell types to destroy the malignant cells. In order to increase these activated anti-tumor APCs and the subsequent T-cell responses, we formulated cyclic di-nucleotides (CDN), a novel class of pathogen associated molecular pattern (PAMP) molecules that activate Stimulator of Interferon Genes (STING) signaling adaptor molecule, into a tumor cell vaccine (STINGVAX). STINGVAX resulted in significant anti-tumor response in vivo in multiple murine models, including the treatment of palpable and established B16 tumor. Another shortcoming of many of the cancer immunotherapy clinical trial is the presence of immune checkpoint pathways that can prevent an effective adaptive immune response. We combined TLR agonists formulated tumor cell vaccine (TEGVAX), with a blocking anti-PD-1 antibody that targets the PD-1/B7-H1 immune checkpoint pathway, and we were able to induce regression of established B16 tumor. We hypothesize that multiple PAMP molecules formulated with cellular vaccines can augment anti-tumor cytokine responses, which can be paired with immune checkpoint blockade molecules to limit the adaptive immune resistance of the tumor microenvironment. Our long-term goal is to introduce optimally formulated STINGVAX in clinical trials as a critical component of a combinatorial cancer vaccine regimen that incorporates maximal activation of tumor specific T-cells with antibodies that block the immune checkpoint pathways. Toward this goal, we propose to optimize the formulation of STINGVAX using in vivo treatment assays in murine models. Second, we propose to examine how STINGVAX increases the number of activated antigen presenting cells to prime and polarize anti-tumor T-cells. Third, we propose to utilize magnetovaccination MRI imaging method to study the enhanced trafficking of activated dendritic cells that is induced by STINGVAX. Magnetovaccination has a high translation potential to quantify APC trafficking. Lastly, we propose to combine STINGVAX with blocking anti-PD-1 antibody to limit the adaptive resistance of immune escape and thereby develop a combinatorial immunotherapy regiment for cancer patients.
In concordance with the mission statement of NIH and NCI, this proposal seeks to obtain knowledge of cancer immunotherapy and to apply these findings to enhance the health of cancer patients. We propose to develop and to optimize tumor cell based combinatorial immunotherapy for solid tumors such as melanoma.
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|Fu, Juan; Kanne, David B; Leong, Meredith et al. (2015) STING agonist formulated cancer vaccines can cure established tumors resistant to PD-1 blockade. Sci Transl Med 7:283ra52|
|Fu, Juan; Malm, Ian-James; Kadayakkara, Deepak K et al. (2014) Preclinical evidence that PD1 blockade cooperates with cancer vaccine TEGVAX to elicit regression of established tumors. Cancer Res 74:4042-52|