Abstract A085: Evaluating the immune modulating effects of standard chemotherapies and macrophage-targeted therapy in a humanized patient-derived xenograft model of high grade ovarian cancer
Authors: Mara P. Steinkamp, Danielle Burke, Parisa Nikeghbal, Irina Lagutina
Journal: Cancer Research (2024)

Abstract Tumor infiltrating immune cells play a role in ovarian cancer growth and response to therapies. However, nearly all preclinical testing is performed in either immunocompromised mice engrafted with human cancer cells or in syngeneic mouse models where the mouse immune response can differ from the patient’s immune response. To assess the immune modulating effects of therapies while leveraging the genetic heterogeneity of PDX models, we are using humanized ovarian cancer patient-derived xenografts (huPDX) that are transplanted with human hematopoietic stem cells to reconstitute a human immune system. Our previous work demonstrated that high grade serous ovarian cancer PDX engrafted into the peritoneal cavity of the humanized NBSGW model release cytokines that recruit human tumor associated macrophages (TAMs) and tumor infiltrating T cells to the tumor microenvironment. Here we use our huPDX models to determine how engrafted human immune cells alter response to frontline chemotherapies. A platinum-sensitive OvCa PDX model, PDX3-Luc2, was engrafted into humanized mice and tumors were grown for two weeks before treating for two weeks with twice weekly 12 mg/kg carboplatin, 6 mg/kg low-dose daily paclitaxel or the combination. To assess the impact of TAMs on response to chemotherapies, a group of huPDX was treated with 160 mg/kg CSF1R inhibitor, BLZ945, alone or in combination with low-dose paclitaxel. Tumor burden was quantified using bioluminescent in vivo imaging. Response was assessed based on change in tumor burden from the pre-treatment time point to one and two weeks of treatment. Tumor burden was compared to a control untreated huPDX group and to non-humanized PDX (non-huPDX) mice treated with the same regimen of carboplatin, paclitaxel or the combination. Tumor burden increased faster in the huPDX untreated controls compared to the non-huPDX controls indicating that the human immune cells are pro-tumorigenic in this model. Single agent paclitaxel and combination carboplatin and paclitaxel were more effective at reducing tumor burden in huPDX compared to non-huPDX with 1 week of treatment. However, after two weeks of treatment, tumor burden was reduced more consistently in non-huPDX mice suggesting that the immune cells shift roles during treatment. Spectral flow analysis of immune cells from the ascites fluid of huPDX mice after 2 weeks of treatment identified differences in immune cell infiltrate between treatment groups. Paclitaxel treated huPDX ascites contained more myeloid cells and fewer T cells. Surprisingly, BLZ945 treatment alone did not have an impact on immune cell infiltrates. However, combined treatment with paclitaxel and BLZ945 abrogated the effect of paclitaxel on myeloid cell recruitment and increased human B cell infiltration. Recent studies have suggested that increased B cell infiltration may aid in anti-tumor immunity. This study demonstrates that huPDX mouse models can explore the immunomodulatory effects of therapies and will be useful for testing novel treatment strategies to harness the anti-tumor immune response. Citation Format: Mara P. Steinkamp, Danielle Burke, Parisa Nikeghbal, Irina Lagutina. Evaluating the immune modulating effects of standard chemotherapies and macrophage-targeted therapy in a humanized patient-derived xenograft model of high grade ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A085.