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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.

Patients with advanced hepatocellular carcinoma (HCC) have historically had few options and faced extremely poor prognoses if their disease progressed after standard-of-care tyrosine kinase inhibitors (TKIs). Recently, the standard of care for HCC has been transformed as a combination of the immune checkpoint inhibitor (ICI) atezolizumab plus the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab was shown to offer improved overall survival in the first-line setting. Immunotherapy has demonstrated safety and efficacy in later lines of therapy as well, and ongoing trials are investigating novel combinations of ICIs and TKIs, in addition to interventions earlier in the course of disease or in combination with liver-directed therapies. Because HCC usually develops against a background of cirrhosis, immunotherapy for liver tumors is complex and oncologists need to account for both immunological and hepatological considerations when developing a treatment plan for their patients. To provide guidance to the oncology community on important concerns for the immunotherapeutic care of HCC, the Society for Immunotherapy of Cancer (SITC) convened a multidisciplinary panel of experts to develop a clinical practice guideline (CPG). The expert panel drew on the published literature as well as their clinical experience to develop recommendations for healthcare professionals on these important aspects of immunotherapeutic treatment for HCC, including diagnosis and staging, treatment planning, immune-related adverse events (irAEs), and patient quality of life (QOL) considerations. The evidence- and consensus-based recommendations in this CPG are intended to give guidance to cancer care providers treating patients with HCC.

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.

Background Advanced biliary tract carcinoma (BTC) carries a poor prognosis, and effective treatment options are limited in the second-line setting. While chemotherapy combined with PD-I blockade has demonstrated modest clinical activity, primary and acquired resistance remain major challenges. Preclinical studies indicate that CD40-mediated activation of antigen-presenting cells can enhance antitumor immunity and improve response to immune checkpoint inhibition, particularly when combined with chemotherapy. Methods This is an ongoing Phase I/II, single-arm, open-label study evaluating the safety and efficacy of the CD40 agonist antibody CDX-1140 in combination with capecitabine and oxaliplatin (CAPOX) and pembrolizumab in patients with advanced BTC who have progressed following prior systemic therapy. The Phase I portion uses a dose-escalation design to determine the recommended Phase II dose (RP2D) of CDX-1140 in combination with CAPOX and pembrolizumab. Phase II evaluates clinical efficacy at the RP2D. The primary Phase II endpoints are 6-month progression-free survival (PFS) and overall response rate (ORR) per RECIST vl.l. Secondary objectives include safety and overall survival. Exploratory endpoints include immune profiling of blood and tumor tissue, assessment of PD-Ll expression, cytokine analyses, multiplex immunohistochemistry, and genomic and transcriptomic analyses including ctDNA. Status The protocol plans to enroll up to 60 participants across two U.S. sites, with efficacy assessed by 6-month PFS and ORR. The phase I portion is completed, and we are currently enrolling on the phase II portion of the trial. We will present preliminary clinical results. Trial Registration NCT05849480

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).

BackgroundHepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality. The combination of tremelimumab and durvalumab is now a standard treatment option for advanced HCC.ObjectiveTo study immune responses in HCC patients treated with tremelimumab and durvalumab.DesignWe treated 28 HCC patients with durvalumab, tremelimumab and locoregional therapies. We performed a high-dimensional multiomics analysis including whole exome sequencing, single-cell RNA seq, CO-Detection by indEXing, flow cytometry and multiplex cytokine/chemokine analysis of patients’ blood and tumour samples and integrated this data to elucidate immune correlatives and response mechanisms. Mice with syngeneic HCC were treated with anti-PD-L1 plus anti-CTLA4 for hepatic lymphocytes, tumour-infiltrating lymphocytes and peripheral blood mononuclear cell analysis.ResultsThe median overall survival was 19.2 months. Tumour tissue analysis revealed enhanced interferon responses, with stronger effects in responders. Gene set variation analysis indicated enhanced antigen presentation in responders. Spatial analysis revealed that non-responder tumours had higher numbers of Tregs located in neighbourhoods enriched with immune cells and expressed higher levels of ICOS and PD-1. Conversely, non-responder PD1+CD8+T in these Treg-enriched neighbourhoods expressed lower ICOS. Cell-communication analysis demonstrated that Treg-CD8+T interaction was enhanced in non-responder tissue. Peripheral blood analysis showed increased classical monocytes in responders and Tregs in non-responders. Treg-CD8+T interaction was confirmed in preclinical models. Finally, single-patient computational analysis from the all-across analysis was performed on 860 features, which led to the identification of multiomics feature sets including Treg features.ConclusionOur study provides a blueprint for in-depth analysis of immune correlates in immunotherapy studies and demonstrates the importance of Treg distribution in HCC.Trial registration numbers NCT02821754 and the EudraCT identifier: 2019-002767-98.