@article{smith_griffith_zaharoff_2019, title={Analyzing the effects of instillation volume on intravesical delivery using biphasic solute transport in a deformable geometry}, volume={36}, ISSN={["1477-8602"]}, DOI={10.1093/imammb/dqy004}, abstractNote={Ailments of the bladder are often treated via intravesical delivery-direct application of therapeutic into the bladder through a catheter. This technique is employed hundreds of thousands of times every year, but protocol development has largely been limited to empirical determination. Furthermore, the numerical analyses of intravesical delivery performed to date have been restricted to static geometries and have not accounted for bladder deformation. This study uses a finite element analysis approach with biphasic solute transport to investigate several parameters pertinent to intravesical delivery including solute concentration, solute transport properties and instillation volume. The volume of instillation was found to have a substantial impact on the exposure of solute to the deeper muscle layers of the bladder, which are typically more difficult to reach. Indeed, increasing the instillation volume from 50-100 ml raised the muscle solute exposure as a percentage of overall bladder exposure from 60-70% with higher levels achieved for larger instillation volumes. Similar increases were not seen for changes in solute concentration or solute transport properties. These results indicate the role that instillation volume may play in targeting particular layers of the bladder during an intravesical delivery.}, number={2}, journal={MATHEMATICAL MEDICINE AND BIOLOGY-A JOURNAL OF THE IMA}, author={Smith, Sean G. and Griffith, Boyce E. and Zaharoff, David A.}, year={2019}, month={Jun}, pages={139–156} }
 @article{ravindranathan_nguyen_kurtz_frazier_smith_koppolu_rajaram_zaharoff_2018, title={Tumor-derived granulocyte colony-stimulating factor diminishes efficacy of breast tumor cell vaccines}, volume={20}, ISSN={["1465-542X"]}, DOI={10.1186/s13058-018-1054-3}, abstractNote={Although metastasis is ultimately responsible for about 90% of breast cancer mortality, the vast majority of breast-cancer-related deaths are due to progressive recurrences from non-metastatic disease. Current adjuvant therapies are unable to prevent progressive recurrences for a significant fraction of patients with breast cancer. Autologous tumor cell vaccines (ATCVs) are a safe and potentially useful strategy to prevent breast cancer recurrence, in a personalized and patient-specific manner, following standard-of-care tumor resection. Given the high intra-patient and inter-patient heterogeneity in breast cancer, it is important to understand which factors influence the immunogenicity of breast tumor cells in order to maximize ATCV effectiveness.The relative immunogenicity of two murine breast carcinomas, 4T1 and EMT6, were compared in a prophylactic vaccination-tumor challenge model. Differences in cell surface expression of antigen-presentation-related and costimulatory molecules were compared along with immunosuppressive cytokine production. CRISPR/Cas9 technology was used to modulate tumor-derived cytokine secretion. The impacts of cytokine deletion on splenomegaly, myeloid-derived suppressor cell (MDSC) accumulation and ATCV immunogenicity were assessed.Mice vaccinated with an EMT6 vaccine exhibited significantly greater protective immunity than mice vaccinated with a 4T1 vaccine. Hybrid vaccination studies revealed that the 4T1 vaccination induced both local and systemic immune impairments. Although there were significant differences between EMT6 and 4T1 in the expression of costimulatory molecules, major disparities in the secretion of immunosuppressive cytokines likely accounts for differences in immunogenicity between the cell lines. Ablation of one cytokine in particular, granulocyte-colony stimulating factor (G-CSF), reversed MDSC accumulation and splenomegaly in the 4T1 model. Furthermore, G-CSF inhibition enhanced the immunogenicity of a 4T1-based vaccine to the extent that all vaccinated mice developed complete protective immunity.Breast cancer cells that express high levels of G-CSF have the potential to diminish or abrogate the efficacy of breast cancer ATCVs. Fortunately, this study demonstrates that genetic ablation of immunosuppressive cytokines, such as G-CSF, can enhance the immunogenicity of breast cancer cell-based vaccines. Strategies that combine inhibition of immunosuppressive factors with immune stimulatory co-formulations already under development may help ATCVs reach their full potential.}, journal={BREAST CANCER RESEARCH}, author={Ravindranathan, Sruthi and Nguyen, Khue G. and Kurtz, Samantha L. and Frazier, Haven N. and Smith, Sean G. and Koppolu, Bhanu Prasanth and Rajaram, Narasimhan and Zaharoff, David A.}, year={2018}, month={Oct} }
 @article{smith_baltz_koppolu_ravindranathan_nguyen_zaharoff_2017, title={Immunological mechanisms of intravesical chitosan/interleukin-12 immunotherapy against murine bladder cancer}, volume={6}, ISSN={["2162-402X"]}, DOI={10.1080/2162402x.2016.1259050}, abstractNote={ABSTRACT There is a critical unmet clinical need for bladder cancer immunotherapies capable of inducing durable antitumor immunity. We have shown that four intravesical treatments with a simple co-formulation of interleukin-12 and the biopolymer chitosan not only destroy orthotopic bladder tumors, but also promote a potent long-lasting systemic immune response as evidenced through tumor-specific in vitro killing assays, complete protection from rechallenge, and abscopal antitumor responses at distant non-treated tumors. This study investigates the immunological kinetics underlying these results. We show through depletion studies that CD8+ T cells are required for initial tumor rejection, but CD4+ T cells protect against rechallenge. We also show that even a single intravesical treatment can eliminate tumors in 50% of mice with 6/9 and 7/8 mice eliminating tumors after three or four treatments respectively. We then performed immunophenotyping studies to analyze shifts in immune cell populations after each treatment within the tumor itself as well as in secondary lymphoid organs. These studies demonstrated an initial infiltration of macrophages and granulocytes followed by increased CD4+ and CD8+ effector-memory cells. This was coupled with a decreased level of regulatory T cells in peripheral lymph nodes as well as decreased myeloid-derived suppressor cell infiltration in the bladder. Taken together, these data demonstrate the ability of properly delivered interleukin-12-based therapies to engage adaptive immunity within the tumor itself as well as throughout the body and strengthen the case for clinical translation of chitosan/interleukin-12 as an intravesical treatment for bladder cancer.}, number={1}, journal={ONCOIMMUNOLOGY}, author={Smith, Sean G. and Baltz, John L. and Koppolu, Bhanu Prasanth and Ravindranathan, Sruthi and Nguyen, Khue and Zaharoff, David A.}, year={2017} }
 @article{jayanthi_koppolu_nguyen_smith_felber_kumar_zaharoff_2017, title={Modulation of Interleukin-12 activity in the presence of heparin}, volume={7}, ISSN={["2045-2322"]}, DOI={10.1038/s41598-017-05382-1}, abstractNote={Abstract}, journal={SCIENTIFIC REPORTS}, author={Jayanthi, Srinivas and Koppolu, Bhanu Prasanth and Nguyen, Khue G. and Smith, Sean G. and Felber, Barbara K. and Kumar, Thallapuranam Krishnaswamy Suresh and Zaharoff, David A.}, year={2017}, month={Jul} }