The Perfect Combination: Enhancing Patient Response to PD-1-Based Therapies in Epithelial Ovarian Cancer

Abstract

Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy, with an overall 5-year survival of only 47%. As the development of novel targeted therapies is drastically necessary in order to improve patient survival, current EOC clinical trials have heavily focused on immunotherapeutic approaches, centered upon programmed cell death 1 (PD-1) inhibitors. While PD-1 monotherapies have only exhibited modest responses for patients, it has been theorized that in order to enhance EOC patient response to immunotherapy, combinatorial regimens must be investigated. In this review, unique challenges to EOC PD-1 response will be discussed, along with a comprehensive description of both preclinical and clinical studies evaluating PD-1-based combinatorial therapies. Promising aspects of PD-1-based combinatorial approaches are highlighted, while also discussing specific preclinical and clinical areas of research that need to be addressed, in order to optimize EOC patient immunotherapy response.

Immune Modeling Analysis Reveals Immunologic Signatures Associated With Improved Outcomes in High Grade Serous Ovarian Cancer

“…Finally, results from our immune modeling analysis revealed PVRL2 as the most abundantly expressed immune factor. PVRL2 has been previously shown to be overexpressed in ovarian cancer (29,30,40), which we confirmed in a small independent cohort. It is a member of the nectin and nectin-like family that contains receptors such as DNAM-1 (CD226), CD96, T cell immunoreceptor with Ig and ITIM domains (TIGIT), and poliovirus receptor related immunoglobin (PVRIG).…”

“…Next, we performed PVRL2 fluorescent immunohistochemistry on benign/normal (n = 5) and HGSOC (n = 15) samples. Mean and maximum intensity was 1.6-fold and 2.4-fold greater, respectively, in HGSOC compared to normal/benign tissue (p = 0.0021, p = <0.00001) ( Figures 5D-F), which is in agreement with published studies (29,30).…”

“…In addition to PD-1, CTLA-4 is one of the most clinically studied immune checkpoint receptors in EOC, with six open Phase I/II clinical trials evaluating the combination of anti-PD-1/PD-L1 and CTLA-4 therapy ( 31 ). While the clinical significance of targeting CTLA-4 has been well-studied, its prognostic value has not previously been investigated in HGSOC.…”

“…T regs are known to play a particularly important role in ovarian cancer pathogenesis. Intriguingly, it has been reported that response to immunotherapy is exceptionally challenging due to the fact that EOC tumors exhibit elevated levels of highly activated T regs ( 31 ), with a distinct phenotype exhibiting higher levels of FOXP3, PD-1, 4-1BB, and ICOS compared to melanoma tumoral T regs , while also displaying increased suppressive capabilities against cytotoxic T cell proliferation ( 34 ). Despite T regs contributing to challenges with immunotherapy response in EOC, our study identified T regs as part of the multidimensional biomarker for the long PFS group of patients.…”

Intra-Tumoral Nerve-Tracing in a Novel Syngeneic Model of High-Grade Serous Ovarian Carcinoma

“…Moreover, standard-of-care treatment consists predominantly of chemotherapy. While some ovarian cancer patients benefit from new therapeutics (targeted, immunotherapies), the majority do not [ 5 ]. The emergence of faithful pre-clinical models provides a means with which to test new therapeutics or therapy combinations to advance treatment for this aggressive disease.…”