Photoimmunotherapy of Ovarian Cancer: A Unique Niche in the Management of Advanced Disease

Abstract

Ovarian cancer (OvCa) is the leading cause of gynecological cancer-related deaths in the United States, with five-year survival rates of 15–20% for stage III cancers and 5% for stage IV cancers. The standard of care for advanced OvCa involves surgical debulking of disseminated disease in the peritoneum followed by chemotherapy. Despite advances in treatment efficacy, the prognosis for advanced stage OvCa patients remains poor and the emergence of chemoresistant disease localized to the peritoneum is the primary cause of death. Therefore, a complementary modality that is agnostic to typical chemo- and radio-resistance mechanisms is urgently needed. Photodynamic therapy (PDT), a photochemistry-based process, is an ideal complement to standard treatments for residual disease. The confinement of the disease in the peritoneal cavity makes it amenable for regionally localized treatment with PDT. PDT involves photochemical generation of cytotoxic reactive molecular species (RMS) by non-toxic photosensitizers (PSs) following exposure to non-harmful visible light, leading to localized cell death. However, due to the complex topology of sensitive organs in the peritoneum, diffuse intra-abdominal PDT induces dose-limiting toxicities due to non-selective accumulation of PSs in both healthy and diseased tissue. In an effort to achieve selective damage to tumorous nodules, targeted PS formulations have shown promise to make PDT a feasible treatment modality in this setting. This targeted strategy involves chemical conjugation of PSs to antibodies, referred to as photoimmunoconjugates (PICs), to target OvCa specific molecular markers leading to enhanced therapeutic outcomes while reducing off-target toxicity. In light of promising results of pilot clinical studies and recent preclinical advances, this review provides the rationale and methodologies for PIC-based PDT, or photo-immunotherapy (PIT), in the context of OvCa management.

Flow-induced Shear Stress Confers Resistance to Carboplatin in an Adherent Three-Dimensional Model for Ovarian Cancer: A Role for EGFR-Targeted Photoimmunotherapy Informed by Physical Stress

“…To improve selective delivery, the PS can be attached to a variety of targeting moieties, such as carbohydrates, peptides, folic acid and antibodies, or nanocarriers that target markers that are overexpressed on cancer cells [48,97,136,[145][146][147][148][149]. PIT involves the use of an antibody-based PIC to enhance PS selectivity and has been shown to be effective in a variety of cancer types, including ovarian cancer [49,60,61,[67][68][69][70][94][95][96][97]. The efficacy of anti-EGFR targeted PIT in adherent 3D tumors grown under flow-induced shear stress was investigated for the first time in this proposal.…”

“…On day 6, 1 µM-BPD equivalent of PIC in complete culture medium was pumped through the channels at 2 µL/min for 24 h, based on extensive studies demonstrating the kinetics of PIC processing and delivery of photochemically available photosensitizers [49,[59][60][61][67][68][69][70]. On day 7, the syringes were replaced with complete culture medium and the medium was pumped for an additional 4 h before PIT application to ensure that the PIC-containing medium inside the channels was replaced with fresh culture medium.…”

“…Here, a low-dose approach is leveraged to target EGFR overexpression in tumors grown under flow-induced shear stress ( Figure 6). This approach builds on an extensive body of published studies [49,[59][60][61][67][68][69][70][94][95][96][97], demonstrating the ability of photodynamic therapy (PDT) and a targeted variant, photoimmunotherapy (PIT), to selectively induce photodamage and induce cytotoxicity in a manner that is mechanistically-distinct from traditional chemotherapy. Whether this approach is effective in targeting molecular and phenotypic changes in 3D ovarian tumors grown under flow-induced shear stress was investigated for the first time in this study.…”

“…Whether this approach is effective in targeting molecular and phenotypic changes in 3D ovarian tumors grown under flow-induced shear stress was investigated for the first time in this study. A well-established anti-EGFR PIC [49,60,61,[67][68][69][70] was used to target and deliver a photosensitizing agent, in this case, BPD, to 3D ovarian tumors. Figure 6A shows normalized viable tumor area in static 3D cultures following incubation with PIC (1 µM BPD equivalent) for 24 h and subsequent irradiation with increasing energy densities ranging from 10-50 J/cm 2 @ 50 mW/cm 2 .…”

Development and Verification of an Immune-Related Gene Pairs Prognostic Signature in Ovarian Cancer

“…Despite improved treatment outcomes in recent years, the prognosis of patients with advanced OV remains poor. The emergence of chemoresistant diseases confined to the peritoneum is the leading cause of death (4).…”