Abstract 2603: Targeting chemo-resistant ovarian cancer with a first-in-class, first-in-human immune-oncology agents containing granzyme B

Abstract

Abstract Ovarian cancer (OC) is the fifth leading cause of cancer-related mortality in women. The current standard of care consists of debulking surgery with platinum-taxane maintenance chemotherapy. However, OC will recur in most patients, resulting in a five-year survival rate of 45%. In the past decades, there have been several developments in front-line maintenance therapy including bevacizumab or PARP inhibitors. While these therapies have shown effectiveness in prolonging progression free survival, this has not translated into improvements in overall survival. It is, therefore, essential to develop more effective maintenance therapies and most of the current efforts are focused on targeted approaches and immune therapeutics. Though immunotherapeutic strategies have induced durable responses in patients with melanoma, lung cancer, and other malignancies, the OC response to immunotherapy is limited as there is a significant subset of patients who do not respond. Our laboratory has developed several fully human granzyme B (GrB) based fusion proteins against key OC targets including folate receptor 1 (GrB-Fc-mov018) and fibroblast growth factor-inducible 14 (GrB-Fc-IT4) which retain high specificity of the targeting agent, combined with the GrB specific activity, a pro-apoptotic mechanism of action, and a robust in vivo efficacy. We assessed the in vitro cytotoxicity of GrB-based constructs against a panel of OC cell lines sensitive (OVCAR8, SKOV3, A2780, HeyA8) or resistant (SKOV3-TX, A2780/Cl-16, HeyA8-MDR) to common chemotherapeutic agents. SKOV3-TX cells were >10 fold more resistant to Paclitaxel than the parental SKOV3 cells while A2780/Cl-16 were 11-fold more resistant to Cisplatin than the parental A2780 cells. In contrast, none of the chemo-resistant cell lines showed resistance to the GrB-based constructs and the IC50 values observed were similar to those of the parental cell lines in the low nanomolar range (<50 nM). Moreover, target expression analysis did not show significant differences between parental and chemo-resistant cell lines. A pilot in vivo efficacy study of GrB-Fc-IT4 and GrB-Fc-mov018 against a subcutaneous, established ovarian tumor (OVCAR8) xenograft showed promising growth inhibition of established tumors compared to vehicle controls. In vivo studies evaluating the response to different treatments of mice bearing chemo-resistant ovarian tumors are ongoing. Our results suggest that the mechanism of resistance developed to conventionally used chemotherapeutic agents such as Paclitaxel, Doxorubicin, Cisplatin or Mitomycin do not confer resistance to GrB-based constructs. Hence, we speculate that GrB-based constructs could be an effective therapy in OC patients with immune-excluded tumors that have developed resistance to conventional treatment. Research conducted, in part, by the Clayton Foundation for Research. Citation Format: Ana Alvarez-Cienfuegos, Lawrence H. Cheung, Khalid A. Mohamedali, Michael G. Rosenblum. Targeting chemo-resistant ovarian cancer with a first-in-class, first-in-human immune-oncology agents containing granzyme B [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 2603.