Abstract 5591: Anti-FolRα ADC STRO-002 induces immunogenic cell death (ICD) to enhance anti-tumor activity
Authors: Abrahams Cristina L. , McGeehan Andrew , Smith Jennifer , Yuan Robert , Doshi Kshama A. , Zhou Sihong , Li Xiaofan , Tran Cuong , Yin Gang , Molina Arturo , Bedard Kristin , Hallam Trevor 
Published: June 2022

Abstract
STRO-002 is an antibody-drug conjugate (ADC) composed of an anti-folate receptor alpha (FolRα) antibody conjugated to a tubulin-targeting hemiasterlin (SC209) warhead via a cleavable linker currently in clinical studies for ovarian and endometrial cancer. FolRα exhibits minimal expression in normal tissues but is overexpressed in several cancers such as ovarian, endometrial, and NSCLC. We previously showed that STRO-002 induces in vitro hallmarks of immunogenic cell death (ICD), such as increased calreticulin exposure and HMGB1 and ATP release in a FolRα dependent manner. Follow-up vaccination studies with murine MC38 tumor cells engineered to express human FolRα (MC38-hFolRa) were performed to further explore the significance of STRO-002-induced ICD and protective immunity in vivo. A single vaccination with STRO-002 or SC209 in vitro-treated MC38-hFolRa cells in immunocompetent mice resulted in 60% of animals rejecting a subsequent rechallenge with living MC38-hFolRa cells, while relapse was observed in most control mice. Including an additional booster vaccination further increased the proportion ( 90%) of animals remaining tumor free after rechallenge. These results demonstrate that tumor cells pre-treated with STRO-002 or SC209 undergo potent immunogenic cell damage which can, in turn, mount protective immunity in vivo.
The ability of STRO-002 to induce ICD that elicits an effective and robust anti-tumor immune response may translate into several advantages in the clinic. Induction of ICD is likely to offer a complementary anti-tumor mechanism in combination therapy regimens such as with check point inhibitors or VEGF blockade. We have demonstrated that STRO-002 in combination with avelumab in MC38-hFolRα-bearing mice significantly enhanced efficacy and durable anti-tumor immunity. More recent rechallenge studies reveal that this combination treatment suppresses growth of not only MC38-hFolRα but also MC38 wild-type tumor cells, indicating formation of immunological memory with signs of epitope spreading. Additionally, co-administration of STRO-002 with anti-VEGF therapy demonstrates improved TGI compared to monotherapy (p &lt; 0.0001) in human ovarian OV-90 tumors.
The potent cytotoxic and immunostimulatory properties of STRO-002 may also contribute to enhancing efficacy in indications with low FolRα expression. Such tumor types include endometrial and NSCLC, in which STRO-002 has displayed potent monotherapy activity in preclinical studies. In a panel of endometrial PDX models, STRO-002 was significantly efficacious in 9/17 (53%) FolRα-positive tumors, including models with moderate and weak FolRα levels. In a NSCLC PDX model, a single dose of STRO-002 induced tumor regression and suppressed tumor growth for up to three months post-dose. In conclusion, the induction of ICD by STRO-002 has potential to increase anti-tumor activity in cancers with low FolRα expression.
Citation Format: Cristina L. Abrahams, Andrew McGeehan, Jennifer Smith, Robert Yuan, Kshama A. Doshi, Sihong Zhou, Xiaofan Li, Cuong Tran, Gang Yin, Arturo Molina, Kristin Bedard, Trevor Hallam. Anti-FolRα ADC STRO-002 induces immunogenic cell death (ICD) to enhance anti-tumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5591.