Abstract LBA026: Survivin peptides formulated in the DPX delivery platform rather than standard emulsions, elicit a robust, sustained T cell response to survivin in advanced and recurrent ovarian cancer patients

Abstract

Abstract Despite improvements in peptide-based tumor antigen discovery, success in eliciting a clinically meaningful T cell response to these peptides has been limited. The choice of antigen delivery platform strongly impacts the quality, quantity, and durability of induced immune responses. DPX is a unique, water-free, lipid-based formulation that can deliver peptides, proteins, and small molecules specifically to antigen presenting cells (APCs), eliciting a targeted, robust, and sustained T cell-based immune response. DPX allows for antigenic peptides to remain at the site of injection without significant diffusion into surrounding tissues, in direct contrast to most emulsion-based delivery methods. Maveropepimut-S (MVP-S; formerly known as DPX-Survivac) is a DPX formulation that incorporates 5 HLA-restricted peptides derived from the anti-apoptotic protein survivin, which is commonly overexpressed in advanced cancers including ovarian cancer. Prior efforts with these same peptides emulsified in Montanide ISA 51 VG provided limited clinical benefit and no objective responses (Lennerz 2014). We now show in pre-clinical models that, when packaged in DPX, these peptides elicit higher avidity, more abundant and cytolytically-active survivin-specific T cells than standard emulsion-based formulations. Early clinical studies with MVP-S in advanced ovarian cancer patients have shown a persistent, survivin-specific T cell response, which in a subset of patients lasted more than 2 years. The recently completed phase 2 study of MVP-S and low-dose cyclophosphamide (CPA) in advanced and recurrent ovarian cancer subjects (DeCidE1), provided encouraging clinical benefit across multiple measures (ORR = 26% & DCR = 79% on target lesions, mOS = 19.9 months in evaluable patients). We now show that majority of patients in this study had survivin-specific T cells on treatment by in vitro tetramer staining (87%) and ex vivo ELISPOT analyses (56%). Importantly, 75% of patients deriving clinical benefit had active survivin-specific T cells by ex vivo ELISPOT analyses. Immunophenotyping of the longitudinally collected PBMCs showed evidence of sustained T cell proliferation by tetramer staining across time and did not show increased expression of immunosuppressive markers (e.g., PD-1, Tim3), suggesting that MVP-S induced T cells remain active over time. TCRβ analyses of tumor TCR repertoires further showed the ability of de novo elicited survivin-specific T cells to infiltrate on-treatment tumours. Collectively, these preclinical and clinical data show that MVP-S treatment effectively elicits a robust, persistent, survivin-specific T cell response. These data also provide compelling evidence that clinical benefit in DeCidE1 patients is most evident in those with survivin-specific T cells. Finally, these data further underscore the unique capacity of DPX technology to effectively elicit peptide-specific, T cell based immune responses when conventional formulations do not. Citation Format: Yogesh Bramhecha, Oliver Dorigo, Valarmathy Kaliaperumal, Heather Torrey, Walead Ebrahimizadeh, Kelcey Patterson, Brennan Dirk, Moamen Bydoun, Barry Kennedy, Aurelio Lobo, Genevieve Weir, Jeremy Graff, Stephan Fiset, Olga Hrytsenko. Survivin peptides formulated in the DPX delivery platform rather than standard emulsions, elicit a robust, sustained T cell response to survivin in advanced and recurrent ovarian cancer patients [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr LBA026.