Grant: Travel Awards - Institute Community Support

Ovarian cancer (OC) is the most lethal gynecologic malignancy and treatment strategies have remained unchanged for decades. Immune checkpoint inhibitors (ICI) have shown impressive clinical efficacy in several cancers, yet the response in OC has been limited. This is likely due to a hostile tumor microenvironment (TME) characterized by disrupted blood flow, reduced oxygen, and factors that inhibit the tumor's immune response. Our group has shown that Fc3TSR, a fragment of the thrombospondin-1 protein, eliminates dysfunctional blood vessels in the tumor, resulting in improved blood supply. Concurrent with this, Fc3TSR facilitates the uptake of therapeutic compounds and trafficking of immune cells to the tumor. The result of this is tumor shrinkage and regression of advanced disease. Here, we determined whether combined Fc3TSR and ICI, anti-PD1, facilitate disease regression compared to anti-PD1 alone. Tumors were induced with the injection of one million ovarian surface epithelial cells under the ovarian bursa of C57BL/6 mice, and were allowed to develop to advanced stage characterized by a primary tumor, numerous metastatic lesions, and early ascites. At this stage, mice either received saline (control) or Fc3TSR once weekly for two weeks prior to two injections of saline (control) or anti-PD-1 administered five days apart. Mice treated with Fc3TSR demonstrated normalized blood vessels and reduced tumor hypoxia compared to controls. Combined anti-PD1+Fc3TSR therapy reduced primary tumor burden and metastasis compared to anti-PD1 alone and controls. Subsequent work will determine the ability of anti-PD1+Fc3TSR to alter the environment within the tumor to improve the uptake of immune cells and enhance their ability to kill tumor cells. We demonstrate a novel approach to remodel the TME to improve the anti-tumor effects of ICI therapy. By addressing main impediments to therapeutic success, we believe Fc3TSR may improve the efficacy of immunotherapy in OC.