Abstract 6659: Oncolytic herpes simplex virus expressing XCL1 and FLT3L modulate the intratumoral immune response and improve the anti-tumor efficacy in a metastatic breast tumor model

Abstract Patients with metastatic breast cancer (MBC) have a dismal prognosis, with a 5-year survival rate of only 26%. The inadequate infiltration of immune cells targeting the tumor microenvironment (TME) is a key factor contributing to this low survival rate. Immune effector cells, including CD8+ cytotoxic T cells, NKT cells, and NK cells, play a crucial role in targeting tumor cells. The activation of immune effector cells relies on the presence of conventional type I dendritic cells (cDC1), which present tumor-specific antigenic peptides on their surface. Recent studies have identified the chemokine XCL1 and growth factor FLT3L as critical factors involved in the intratumoral recruitment and expansion of dendritic cells. To enhance the activity of cDC1 in the TME we designed an oncolytic herpes simplex virus (oHSV) expressing XCL1 and FLT3L. The recombinant oHSV, rQ1-XF, was generated by incorporating LoxP sites into the viral genome through recombination with a carrier plasmid carrying the polycistronic cassette. To enhance the intratumoral penetration of oHSV injected intravenously in primary tumors and MBC lesions in the lung, we employed the cancer drug ganetespib, which can increase the permeability of tumor blood vessels. In comparison to untreated mice, ganetespib combined with rQ1-XF reduced the size of primary tumors and induced a short but significant increase in the survival of mice. Additionally, compared to the ganetespib alone treatment, ganetespib combined with rQ1-XF reduced MBC burden in the lung. The flow cytometry analysis of immune cells revealed an increased infiltration of CD11c+CD11b- dendritic cells in primary tumors treated with oHSV combination therapy compared to the ganetespib only control. A similar trend was also observed in CD4 T cells and CD8 T cells in primary tumors. As expected, there was a negative correlation between tumor burden and the infiltration of CD4+ T cells and CD8+ T cells in primary tumors. Ganetespib combined with oHSV also reduced the infiltration of CD4+ regulatory T cells (Tregs) in primary tumors, however the number of Tregs increased with primary tumor size as well as tumor burden in the lung. This could potentially lead to reduced efficacy of tumor-infiltrating dendritic cells in activating effector T cells in tumors treated with ganetespib and rQ1-XF. Moreover, the combination therapy did not yield significant alterations in the populations of DCs, CD4+ T cells, and CD8+ T cells in lungs with metastatic lesions. Further studies are underway to investigate whether the depletion of Treg cells in combination with rQ1-XF enhances effector T cell activation against metastatic breast tumor cells. The findings of this study will provide valuable insights into the effectiveness of using XCL1 and FLT3L-armed oncolytic viruses in patients with MBC. Citation Format: Himanshu Soni, Liqun Gu, Sylvie Roberge, Heena Kumra, Hiroshi Nakashima, E. Antonio Chiocca, Yves Boucher. Oncolytic herpes simplex virus expressing XCL1 and FLT3L modulate the intratumoral immune response and improve the anti-tumor efficacy in a metastatic breast tumor model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6659.