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Background Current standard of care for advanced biliary tract cancer (BTC) is gemcitabine, cisplatin plus anti‐PD1/PD‐L1, but response rates are modest. The purpose of this study was to explore the efficacy and safety of durvalumab (anti‐PD‐L1) and tremelimumab (anti‐CTLA‐4), with and without an interventional radiology (IR) procedure in advanced BTC. Methods Eligible patients with advanced BTC who had received or refused at least one prior line of systemic therapy were treated with tremelimumab and durvalumab for four combined doses followed by monthly durvalumab alone with and without an IR procedure until the progression of disease or unacceptable toxicity. Objective response was assessed through CT or MRI by Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) every 8 weeks. Adverse events (AEs) were recorded and managed. The primary endpoint was 6‐month progression‐free survival (PFS). Results Twenty‐three patients with advanced BTC were enrolled; 17 patients were assigned to treatment with durvalumab and tremelimumab (Durva/Treme); and 6 patients were treated with the combination of durvalumab, tremelimumab plus IR procedure (Durva/Treme + IR). The best clinical responses in the Durva/Treme arm were partial response (n = 1), stable disease (n = 5), progressive disease (n = 5), and in the Durva/Treme + IR arm: partial response (n = 0), stable disease (n = 3), progressive disease (n = 3). The median PFS was 2.2 months (95% CI: 1.3–3.1 months) in the Durva/Treme arm and 2.9 months (95% CI: 1.9–4.7 months) in the Durva/Treme + IR arm (p = 0.27). The median OS was 5.1 months (95% CI: 2.5–6.9 months) in the Durva/Treme arm and 5.8 months (95% CI: 2.9–40.1 months) in the Durva/Treme + IR arm (p = 0.31). The majority of AEs were grades 1–2. Conclusion Durva/Treme and Durva/Treme + IR showed similar efficacy. With a manageable safety profile. Larger studies are needed to fully characterize the efficacy of Durva/Treme ± IR in advanced BTC. The purpose of this study was to explore the efficacy and safety of two ICIs, durvalumab and tremelimumab, with and without an interventional radiology (IR) procedure in patients with advanced BTC. Durva/Treme + IR showed no difference in efficacy compared with Durva/Treme alone, but the safety profile of both cohorts was manageable. Larger studies are needed to fully characterize efficacy of Durva/Treme with or without IR in advanced BTCs.

BackgroundOncolytic immunotherapy represents a unique therapeutic platform for the treatment of cancer. Here, we evaluated the safety and efficacy of the combination of pexastimogene devacirepvec (PexaVec) plus durvalumab (anti-programmed death ligand 1) with and without tremelimumab (anti-cytotoxic T-lymphocyte associated protein 4) in patients with standard chemotherapy refractory mismatch repair proficient (pMMR) metastatic colorectal cancer (mCRC) in a phase I/II trial.MethodsAdult patients with histologically confirmed advanced pMMR mCRC, who had progressed on at least two prior lines of systemic chemotherapy were studied in four cohorts. Patients received four doses of PexaVec IV at a dose of 3×108 plaque forming units (pfu) (dose level 1) or 1×109 pfu (dose level 2) every 2 weeks. Twelve days after the first PexaVec administration, patients received either 1500 mg of durvalumab every 28 days alone or an additional single dose of 300 mg tremelimumab on day 1. Responses were assessed every 8 weeks by CT or MRI. AEs were recorded. The primary endpoints were safety and feasibility. Secondary endpoints included progression-free survival (PFS) and overall survival. Paired tumor samples and peripheral blood were collected to perform immune monitoring.ResultsThirty-four patients with mCRC enrolled on to the study: 16 patients in the PexaVec/durvalumab cohorts and 18 patients in the PexaVec/durvalumab/tremelimumab cohorts. Overall, the combination of PexaVec plus immune checkpoint inhibitors did not result in any unexpected toxicities. Most common toxicities observed were fever and chills after PexaVec infusion. Two cases of grade 3 colitis, one case of a grade 2 myositis and one case of grade 3 hypotension resulted in discontinuation of immune checkpoint inhibitor and PexaVec treatment, respectively. The median PFS in the PexaVec/durvalumab/tremelimumab cohorts was 2.3 months (95% CI: 2.2 to 3.2 months) vs 2.1 months (95% CI: 1.7 to 2.8 months; p=0.57) in the PexaVec/durvalumab cohorts. Flow cytometry analysis of peripheral blood mononuclear cells revealed an increase in Ki67+CD8+ T cells on treatment.ConclusionPexaVec in combination with durvalumab and tremelimumab is safe and tolerable. No unexpected toxicities were observed. The combination of PexaVec/durvalumab/tremelimumab demonstrated potential clinical activity in patients with pMMR mCRC, but further studies are needed to identify the predictive biomarkers.Trial registration numberNCT03206073.

BackgroundMicrosatellite stable colorectal liver metastases (MSS CLM) maintain an immunosuppressive tumor microenvironment (TME). Historically, immune-based approaches have been ineffective. VB-111 (ofranergene obadenovec) is a genetically-modified adenoviral vector targeting the TME; its unique dual mechanism induces an immune response and disrupts neovascularization. Checkpoint inhibition may synergize the immune response induced by viral-mediated anti-angiogenic gene therapy. We aimed to examine the safety and antitumor activity of VB-111 and nivolumab in patients with refractory MSS CLM and to characterize immunological treatment-response.MethodsThis was a phase II study of adult patients with histologically-confirmed MSS CLM who progressed on prior therapy. A priming dose of VB-111 1×1013 viral particles was given intravenously 2 weeks prior to starting biweekly nivolumab 240 mg and continued every 6 weeks. The combination continued until disease progression or unacceptable toxicity. The primary objectives were overall response rate and safety/tolerability. Secondary objectives included median overall survival and progression-free survival. Correlative studies were performed on paired tumor biopsies and blood.ResultsBetween August 2020 and December 2021, 14 patients were enrolled with median age 50.5 years (40–75), and 14% were women. Median follow-up was 5.5 months. Of the 10 evaluable patients, the combination of VB-111 and nivolumab failed to demonstrate radiographic responses; at best, 2 patients had stable disease. Median overall survival was 5.5 months (95% CI: 2.3 to 10.8), and median progression-free survival was 1.8 months (95% CI: 1.4 to 1.9). The most common grade 3–4 treatment-related adverse events were fever/chills, influenza-like symptoms, and lymphopenia. No treatment-related deaths were reported. Qualitative analysis of immunohistochemical staining of paired tumor biopsies did not demonstrate significant immune infiltration after treatment, except for one patient who had exceptional survival (26.0 months). Immune analysis of peripheral blood mononuclear cells showed an increase of PD-1highKi67highCD8+ T cells and HLA-DRhigh T cells after VB-111 priming dose. Plasma cytokines interleukin-10 and tumor necrosis factor-α increased after treatment with both drugs.ConclusionIn patients with MSS CLM, VB-111 and nivolumab did not improve overall response rate or survival but were tolerated with minimal toxicities. While challenging to distinguish between antiviral or antitumor, correlative studies demonstrated an immune response with activation and proliferation of CD8+ T cells systemically that was poorly sustained.Trial registration numberNCT04166383.

BackgroundMicrosatellite stable colorectal liver metastases (MSS CLM) maintain an immunosuppressive tumor microenvironment (TME). Historically, immune-based approaches have been ineffective. VB-111 is a genetically-modified adenoviral vector targeting the TME; its unique dual mechanism induces immune response and disrupts neovascularization.1–4 Checkpoint inhibition may synergize the immune response induced by viral-mediated anti-angiogenic gene therapy. We aimed to examine the safety and anti-tumor activity of VB-111 and nivolumab in patients with refractory MSS CLM and to characterize immunological treatment-response.MethodsThis is a phase II study of adult patients with histologically confirmed MSS CLM who progressed on prior therapy. A priming dose of VB-111 1x1013 viral particles was given intravenously two weeks prior to starting biweekly nivolumab 240mg and continued every 6 weeks. The combination was continued until disease progression or unacceptable toxicity. Primary endpoints were ORR and safety/tolerability. Secondary endpoints included mPFS and mOS. Correlative studies were performed on paired tumor biopsies and blood.ResultsBetween August 2020 and December 2021, fourteen patients were enrolled with median age 50.5y (40–75), and 14% were female. Of the ten evaluable patients, the combination of VB-111 and nivolumab failed to demonstrate radiographic responses; at best, two patients had stable disease. After median follow-up of 5.5 months (m), mOS was 5.5m (95%CI: 2.3–10.8m), and mPFS was 1.8m (95%CI: 1.4–1.9 m) (figure 1). The most common grade 3–4 treatment-related adverse events were fever/chills, flu-like symptoms, and lymphopenia. No treatment-related deaths were reported. Qualitative analysis of immunohistochemical staining of paired tumor biopsies did not demonstrate significant immune infiltration after treatment, except for one patient who had exceptional survival (25.7m). Immune analysis of PBMCs showed an increase of PD1highKi67highCD8+ T-cells and HLA-DRhigh T-cells after VB-111 priming dose (figure 2). Plasma cytokines IL-10 and TNFα increased after treatment with both drugs.ConclusionsIn patients with MSS CLM, VB-111 and nivolumab did not improve objective response rate or survival but was tolerated with minimal toxicities. While challenging to distinguish between anti-viral or anti-tumor, correlative studies demonstrated an antigen-specific immune response with activation and proliferation of CD8+ T-cells systemically; however, this was poorly sustained and immune infiltration was sparsely seen within on-treatment tumor biopsies[5]. With its transient immunogenicity and limited clinical efficacy, a single priming dose may not be the optimal strategy for viral-mediated therapies; rather, multiple sequential doses of viral vector and earlier administration of checkpoint inhibition may be required to elicit a stronger immune response to result in tumor killing.Abstract 585 Figure 1Kaplan-Meier survival analyses of progression-free survival (PFS) and overall survival (OS). All patients who received at least one dose of both study drugs were included (n=12); one patient was excluded due to disease progression prior to nivolumab initiation, and one patient was taken off protocol due to malignant bowel perforation with abdominal sepsis. Time-to-event started from date of enrollment until disease progression or death, respectively. After median potential follow-up of 22.9 months, median progression-free survival was 1.8 months (95% CI 1.4–1.9), and median overall survival was 5.5 months (95% CI 2.3–10.8). MSS mCRC = microsatellite stable metastatic colorectal cancer, PFS = progression- free survival, and OS = overall survival.Abstract 585 Figure 2Immune and T cell profiling of peripheral blood mononuclear cells (PBMC) after treatment with VB-111 and nivolumab. PBMCs were collected at baseline, after receiving VB-111 alone (C2D1), and after receiving both VB-111 and nivolumab (C4D1). A high-dimensional full-spectrum flow cytometry panel for immunophenotyping was performed to study different immune cell subsets and activation status. The stacked bar graphs show the frequency of distinct immune (top) and T cell (bottom) clusters across treatment by patient with their best radiographic response shown below. T cell cluster 5 represents proliferating T cells (PD1high Ki67highCD8+ T-cells), which in a conventional supervised analysis (not shown) demonstrated a statistically significant increase after VB-111 that decreased at next time point, two weeks later (n=9, p<0.05, Friedman test).

The roles of women have been and remain central to the functioning of the family farm business. However, a gap in recent literature on farm women, in general, exists and research is limited regarding women’s farm business roles and their satisfaction with their farm business financial situation. The purpose of this study was to explore factors that impact farm women’s perceptions of farm business financial satisfaction. Results indicated that the importance of financial solvency and satisfaction with one’s farm role were positively associated with women’s farm business financial satisfaction. Holding a primary decision-making role was negatively associated with farm business financial satisfaction. Implications for educators, professionals who work with farm women, and researchers are discussed.