RESUMO
Introduction: Immunotherapy is revolutionizing the management of multiple cancer types. However, only a subset of patients responds to immunotherapy. One mechanism of resistance is the absence of immune infiltrates within the tumor. In situ vaccine with local means of tumor destruction that can induce immunogenic cell death have been shown to enhance tumor T cell infiltration and increase efficacy of immune checkpoint blockade. Methods: Here, we compare three different forms of localize tumor destruction therapies: radiation therapy (RT), vascular targeted photodynamic therapy (VTP) and cryoablation (Cryo), which are known to induce immunogenic cell death, with their ability to induce local and systemic immune responses in a mouse 4T1 breast cancer model. The effects of combining RT, VTP, Cryo with anti-PD1 was also assessed. Results: We observed that RT, VTP and Cryo significantly delayed tumor growth and extended overall survival. In addition, they also induced regression of non-treated distant tumors in a bilateral model suggesting a systemic immune response. Flow cytometry showed that VTP and Cryo are associated with a reduction in CD11b+ myeloid cells (granulocytes, monocytes, and macrophages) in tumor and periphery. An increase in CD8+ T cell infiltration into tumors was observed only in the RT group. VTP and Cryo were associated with an increase in CD4+ and CD8+ cells in the periphery. Conclusion: These data suggest that cell death induced by VTP and Cryo elicit similar immune responses that differ from local RT.
RESUMO
Locally advanced urothelial cancer has high recurrence and progression rates following surgical treatment. This highlights the need to develop neoadjuvant strategies that are both effective and well-tolerated. We hypothesized that neoadjuvant sub-ablative vascular-targeted photodynamic therapy (sbVTP), through its immunotherapeutic mechanism, would improve survival and reduce recurrence and progression in a murine model of urothelial cancer. After urothelial tumor implantation and 17 days before surgical resection, mice received neoadjuvant sbVTP (WST11; Tookad Soluble, Steba Biotech, France). Local and systemic response and survival served as measures of therapeutic efficacy, while immunohistochemistry and flow cytometry elucidated the immunotherapeutic mechanism. Data analysis included two-sided Kaplan-Meier, Mann-Whitney, and Fischer exact tests. Tumor volume was significantly smaller in sbVTP-treated animals than in controls (135 mm3 vs. 1222 mm3, P < 0.0001) on the day of surgery. Systemic progression was significantly lower in sbVTP-treated animals (l7% vs. 30%, P < 0.01). Both median progression-free survival and overall survival were significantly greater among animals that received sbVTP and surgery than among animals that received surgery alone (P < 0.05). Neoadjuvant-treated animals also demonstrated significantly lower local recurrence. Neoadjuvant sbVTP was associated with increased early antigen-presenting cells, and subsequent improvements in long-term memory and increases in effector and active T-cells in the spleen, lungs, and blood. In summary, neoadjuvant sbVTP delayed local and systemic progression, prolonged progression-free and overall survival, and reduced local recurrence, thereby demonstrating therapeutic efficacy through an immune-mediated response. These findings strongly support its evaluation in clinical trials.
