Maintenance vigil immunotherapy in newly diagnosed advanced ovarian cancer: Efficacy assessment of homologous recombination proficient (HRP) patients in the phase IIb VITAL trial.

5502 Background: In the VITAL (NCT02346747) trial, maintenance therapy with Vigil, an autologous tumor cell vaccine transfected with a DNA plasmid encoding GMCSF and bi-shRNA-furin for TGFβ expression control, following frontline platinum-based chemotherapy led to a recurrence-free survival (RFS) benefit in patients with advanced high-grade ovarian cancer (HR=0.69, 90% CI 0.44–1.07, p=0.078) and significantly in BRCA-wt patients (HR=0.51, 90% CI 0.30-0.88, p=0.020) ( Rocconi et al. Lancet Oncol. 2020). Here we report post-hoc HR deficiency (HRD) subgroup analysis and identification of an additional molecular subgroup sensitive to Vigil therapy involving STRING analysis. Methods: This double-blind, placebo-controlled, Phase 2b study randomized 92 patients with newly diagnosed stage III/IV ovarian cancer with a complete clinical response (CR) to frontline surgery and chemotherapy. Patients received 1 x 10e7 cells/ml of Vigil or placebo intradermally once a month for up to 12 doses or disease progression. RFS was the primary endpoint assessed by blinded independent central review. HRD status was determined according to the Myriad Genetics myChoice CDx assay (HRD score < 42 for proficient). Using tumor annotated DNA polymorphism data, a protein-protein interaction network was constructed using the STRING database. Properties of this network including topological distance and the identification of hub genes were used to predict a target molecular population sensitive to Vigil. Results: In the per-protocol population (PP, n=91), 62 BRCA-wt patients were tested for HRD status. Forty-five patients were HR proficient (HRP) and 17 patients were HR deficient (HRD). No HRP patients in the Vigil group reported treatment related Grade 3 or higher adverse events. From the time of study randomization median RFS was improved with Vigil (n=25) in HRP patients compared to placebo (n=20) (Table 1). Similarly, overall survival (OS) benefit was observed in the Vigil group compared to placebo (Table 1). Improved RFS was demonstrated for a subset of patients with STRING predicted molecular profile. Conclusions: Vigil immunotherapy as frontline maintenance in Stage III/IV ovarian cancer is well tolerated and showed clinical benefit in both BRCA-wt and HRP molecular profile patients. Results suggest a unique molecular network that enhances sensitivity to Vigil therapy. Clinical trial information: NCT02346747. [Table: see text]

Engineering autologous tumor cell vaccine to locally mobilize antitumor immunity in tumor surgical bed

Autologous tumor cell–based vaccines (ATVs) are emerging as a transformable approach for personalized immunotherapy, but their therapeutic efficacy remains unsatisfying in patients with cancer. Here, we design a photodynamic therapy (PDT)–motivated ATV (P-ATV) in Fmoc-KCRGDK–phenylboronic acid (FK-PBA) hydrogel, which mobilizes local immune activation to inhibit relapse of postoperative tumors. The FK-PBA targeting overexpressed sialic acid on tumor cells can enable on-demand gelation in residue tumor areas and maintain continuous vaccination in surgical bed. Unlike neoantigen-based vaccine or adoptive cell therapy that takes several months to prepare, P-ATV can be easily manufactured within a few days and efficiently boost neoepitope-specific CD8+ T cells to activate personalized immunotherapy. This simple and powerful approach of engineered ATVs provides an alternative strategy for personalized immunotherapy and is readily transformable to various kinds of cell-based antigens to inhibit the relapse of postoperative tumors.

Intratumoral administration of DNA-damaging chemotherapy-treated tumor cells to enhance therapeutic benefit of systemic immune checkpoint blockade in mouse cancer models.

77 Background: Immune checkpoint inhibition or ICI (antibodies to PD-1 and CTLA4), has shown promise in the treatment of some tumor types, especially in inducing durable remissions in advanced stage cancer patients. However, the majority of patients do not respond to ICI. Identifying combinations to enhance response to ICI is an urgent medical need. Methods: Murine tumor cell lines B16-Ova and MC-38-Ova were treated with DNA-damaging chemotherapeutic drugs, co-cultured with primary murine bone marrow derived dendritic cells (BMDC) followed by addition of OT-1 CD8+ T-cells and flow cytometric analysis of IFN-γ+ CD8+ T-cells. Mice bearing B16-Ova or MC-38 flank tumors were injected intra-tumorally with ex vivo chemotherapy-treated B16-Ova cells with or without systemic ICI. Tumor cross-sectional area was measured using calipers. Intra-tumoral DC and circulating H2-Kb/SIINFEKL-specific CD8+ T-cells were analyzed by flow cytometry. Results: Etoposide and mitoxantrone-treated B16-Ova and MC-38-Ova tumor cells, when co-cultured with BMDC, efficiently promote IFN- γ induction in OT-1 CD8+ T-cells. This was abrogated by co-treatment of tumor cells with Necrostatin-1 but not ZVAD-FMK. Intra-tumoral injection of ex vivo etoposide-treated tumor cells, with systemic ICI, increases the numbers of intra-tumoral CD103+ DC, the frequency of circulating H2-Kb/SIINFEKL-specific CD8+ T-cells and significantly improves survival. The tumor cell vaccine/systemic ICI combination, but not ICI alone, induced complete tumor regressions in a subset of mice. This is abrogated in BATF3-deficient mice. Conclusions: Etoposide and mitoxantrone-treated tumor cells efficiently promote BMDC-mediated CD8+ T-cell priming, in a tumor cell RIPK1 activity-dependent but caspase-independent manner. Intra-tumoral administration of the DNA-damage induced tumor cell vaccine in vivo, in combination with systemic ICI, enhances anti-tumor CD8+ T-cell responses, tumor-free and overall survival, and anti-tumor immunological memory. This enhancement in therapeutic efficacy is dependent on BATF3+ DC in vivo.