tbuckley/cabot-search huggingface dataset:
CVM-1118: A potent oral anti-vasculogenic mimicry (VM) agent in combination with nivolumab in patients with unresectable advanced hepatocellular carcinoma (HCC)—A phase IIa study.
Authors: Chia-Jui Yen, Yi-Hsiang Huang, Kun-Yun Yeh, Pei-Jer Chen, Sheng-Nan Lu, John Gutheil, Teresa J. Melink, Yen-Ling Chen, Chun-Man Chen, Ting-Yu Chao, Yi-Wen Chu, Du-Shieng Chien
Journal: Journal of Clinical Oncology (2024)

e16150 Background: CVM-1118 is a potent anti-tumor new chemical entity with multiple mechanisms of action including induction of apoptosis, cell cycle arrest, and inhibition of VM network formation. This study evaluated the anti-tumor effect and safety profile of CVM-1118 plus nivolumab in patients with progressive unresectable advanced HCC following the first-line therapy with TKIs. Methods: Eligible pts had unresectable advanced HCC and were refractory to prior systemic therapy (e.g., sorafenib, lenvatinib, regorafenib, and/or ramucirumab), with the exception of prior immunotherapy. Patients received oral CVM-1118 at 200 mg BID (400 mg daily) in combination with intravenous nivolumab at 240 mg Q2W in 28-day cycles. The primary endpoint of objective response rate was evaluated using mRECIST. The secondary endpoints were overall response rate (ORR) (per RECIST 1.1), progression free survival (PFS), disease control rate (DCR), and duration of overall response (DoR). Results: A total of 31 evaluable pts were enrolled (25 M/6 F; median age 65 y, range 44–80 y). All patients were Child Pugh A, BCLC stage B (13%, n = 4) or C (87%, n = 27) at the start of treatment. The median number of prior lines of therapy was 1 (range 1–2). The duration of CVM-1118 and nivolumab treatment ranged from 1.5–15.0 mos (median 3.1 mos) with 5/31 (16%) pts remaining on treatment for ≥ 4.6 mos (range 4.67–15.0 mos). The best ORR was 19.4% (mRECIST) (2 CR (6%), 4 PR (13%)), with remaining responses including 11 SD (36%) and 14 PD (45%). The DCR was 54.8% (95% CI 37.3–72.3%), the median PFS was 3.53 mos (95% CI 1.9–5.4 mos) and the median DoR was 10.4 mos (95% CI 2.8–13.7 mos). The most common treatment-related AEs ³ grade 3 included AST increased (12.9%), neutrophil count decreased (9.7%), anemia (6.5%), and WBC decreased (6.5%). As opposed to therapy with atezolizumab plus bevacizumab, gastrointestinal hemorrhage and hypertension were not observed in this study. Pharmacokinetics data demonstrated that CVM-1118 was rapidly metabolized to CVM-1125 in all pts following administration. On Day 1, the mean drug exposure of CVM-1125 was C max 564 ng/mL and the AUC 0-24 was 2154 ng·hr/mL. Intersubject variability of drug exposure appeared to be high; the T 1/2 of CVM-1125 was ~1.7 hr. Conclusions: CVM-1118 combined with nivolumab demonstrated clinical activity in advanced HCC pts with a safety profile that appears favorable compared to atezolizumab plus bevacizumab. These data support further development of the combination of CVM-1118 and nivolumab in pts with unresectable advanced HCC. Clinical trial information: NCT05257590 .
Hepatocellular carcinoma etiology drives survival outcomes: A population-based analysis.
Authors: Hannah M. Cranford, Patricia Denise Jones, Qinran Liu, Tulay Koru-Sengul, Isildinha M. Reis, Paulo S. Pinheiro
Journal: Journal of Clinical Oncology (2024)

e16142 Background: Previous studies on survival differences according to etiology of hepatocellular carcinoma (HCC) (5-year observed survival of 23%) are limited to hospital-based series and restricted cohorts. We performed a population-based survival analysis by major HCC etiologies, inclusive of hepatitis-C virus (HCV), hepatitis-B virus (HBV), alcohol-related liver disease (ALD), and non-alcoholic fatty liver disease (NAFLD) as singular causes, in addition to unexplored dual etiological groups, (HCV&amp;HBV, HCV&amp;ALD, and HBV&amp;ALD), and accounting for age at diagnosis, tumor characteristics, and socio-demographics. Methods: All 19,956 cases of HCC diagnosed in Florida during 2005–2018 from the Florida cancer registry were linked for HCC etiology using Agency for Healthcare Administration and Florida Department of Health viral hepatitis data. Survival analysis was performed for the 15,759 linked HCC cases, comparing HCC etiologic groups (4 single and 3 dual). Results included age-adjusted 5-year survival, Kaplan-Meier curves, and adjusted hazard ratios from Cox regression models. Results: The leading single etiology was ‘HCV only’ (n=4,983; 31.6%); the leading dual etiology was ‘HCV&amp;ALD’ (n=2,694; 17.1%). The age-adjusted 5-year survival was low (&lt;22%) across all HCC etiologies; however, non-ALD causes showed higher survival [‘HCV only’ (21.5%; 95%CI:20.2%–22.8%), ‘HBV only’ (20.2%; 95%CI:16.6%–23.9%), ‘NAFLD only’ (19.9%; 95%CI:18.7%–21.2%)] than ALD-related etiologies [‘ALD only’ (14.4%; 95%CI:12.7%–16.0%), ‘HCV&amp;ALD’ (10.4%; 95%CI:9.0%–11.9%), ‘HBV&amp;ALD’ (8.1%; 95%CI:2.2%–14.1%)]. Compared to the reference category ‘HCV only,’ age-adjusted hazard ratios were 1.69 (95%CI: 1.41–2.03; p-value&lt;0.0001) for ‘HBV&amp;ALD,’ 1.33 (95%CI:1.26–1.40; p-value&lt;0.0001) for ‘HCV&amp;ALD,’ and 1.35 (95%CI:1.28–1.43; p-value&lt;0.0001) for ‘ALD only.’ Multivariable analysis including additional factors showed minimal variation from these results. Conclusions: Significant differences in survival based on HCC etiology are important for prevention, surveillance, and targeted treatments based on etiologic-specific biomarkers. Specific pathophysiological mechanisms for ALD in addition to viral hepatitis could be responsible for poorer outcomes for dual etiologies involving alcohol use, compared to viral etiology alone. To increase overall survival, improved screening is needed for patients with multiple HCC risk factors. [Table: see text]
Crosstalk between epitranscriptomic and epigenomic modifications and its implication in human diseases
Authors: Chengyu Li, Kexuan Chen, Qianchen Fang, Shaohui Shi, Jiuhong Nan, Jialin He, Yafei Yin, Xiaoyu Li, Jingyun Li, Lei Hou, Xinyang Hu, Manolis Kellis, Xikun Han, Xushen Xiong
Journal: Cell Genomics (2024)

Crosstalk between N
Hepatic artery infusion chemotherapy (HAIC) plus sintilimab and bevacizumab biosimilar (IBI305) in initial unresectable hepatocellular carcinoma (HCC): A retrospective study.
Authors: Xihao Zhang, Yang Liu, Linlin Fu, Yayue Liu, Qi Qi, Rentao Li, Yunlong Cui, Wei Lu, Huikai Li
Journal: Journal of Clinical Oncology (2024)

e16185 Background: Combining sintilimab with IBI305 has shown significant survival benefits over sorafenib in first-line HCC treatment. Our prior study has indicated improved outcomes with sintilimab and bevacizumab biosimilar (IBI305) in combination with HAIC for HCC (Clinical trial: NCT05029973). This study aims to evaluate combining HAIC with sintilimab and IBI305 for initial unresectable HCC in real word. Methods: Eligible patients (pts) had histologically or cytologically diagnosed or clinically confirmed HCC, with China liver cancer staging (CNLC) stage Ib-IIIb, no prior systemic treatment, Child-Pugh A or B, and ECOG 0 or 1. Patients were administered FOLOFOX-HAIC, combined with intravenous Sintilimab (200 mg, Q3W) and intravenous IBI305 (7.5 mg/kg, Q3W). Primary endpoints included objective response rate (ORR) and disease control rate (DCR) per modified Response Evaluation Criteria in Solid Tumors (mRECIST). Secondary endpoints included surgical conversion rate, R0 resection rate, and pathological complete response (pCR) rate. Results: Data were collected from 106 patients (from Apr, 2021 to Jul, 2023), median age 61, with the majority being male (91, 85.9%), ECOG 0 (106, 100%), and classified as Child-Pugh A (82, 77.4%). CNLC staging: Ib (19), IIa (2), IIb (20), IIIa (42), IIIb (23). HBV infection: 84 (79.3%), HCV: 3 (2.8%). AFP levels were &gt; 400ng/ml in 53 patients (50.0%), with tumor diameters &gt; 10 cm in 47 patients (44.3%). Single tumors were noted in 35 patients (33.0%), vascular invasion in 60 patients (56.6%), and extrahepatic metastasis in 26 patients (24.5%). Among the 106 patients evaluable for response, ORR was 39.6% with 42 patients demonstrating partial responses (PR); DCR was 96.2% (102/106), comprising 42 PR, 60 stable disease (SD). The surgical conversion rate was 40.56% (43/106), achieving R0 resection in all 43 patients and complete pathological response (pCR) in 9/43(20.9%) patients and major pathological response (MPR) in 12/43 (27.9%). The 1-year progression-free survival (PFS) and overall survival (OS) rates were 54.5% and 74%, respectively. The 2-year PFS and OS rates were 41.4% and 58.6%, respectively. No new safety signals were observed, and no treatment-related adverse events (TRAEs) led to death. Conclusions: Combining HAIC with Sintilimab and IBI305 as conversion therapy for unresectable HCC shows promising benefits with manageable safety.
Sleeping Beauty mRNA-LNP enables stable rAAV transgene expression in mouse and NHP hepatocytes and improves vector potency
Authors: Philip M Zakas, Sharon C Cunningham, Ann Doherty, Eva B van Dijk, Raed Ibraheim, Stephanie Yu, Befikadu D Mekonnen, Brendan Lang, Elizabeth J English, Gang Sun, Miles C Duncan, Matthew S Benczkowski, Robert C Altshuler, Malvenderjit Jagjit Singh, Emily S Kibbler, Gulen Y Tonga, Zi Jun Wang, Z Jane Wang, Guangde Li, Ding An, James B Rottman, Yashvi Bhavsar, Cormac Purcell, Rachit Jain, Ryan Alberry, Nathaniel Roquet, Yanfang Fu, Robert J Citorik, Jacob R Rubens, Michael C Holmes, Cecilia Cotta-Ramusino, William Querbes, Ian E Alexander, William E Salomon
Journal: Molecular Therapy (2024)
Long-term survival outcomes with regular recurrence surveillance following surgical resection in early-stage hepatocellular carcinoma: Insights from a multicenter prospective study.
Authors: Tian Yang, Lan-Qing Yao, Han Liu, Yong-Kang Diao, Yi-Fan Wu, Chao Li, Ying-Jian Liang, Yong-Yi Zeng, Ming-Da Wang, Feng Shen, Guo-Yue Lv
Journal: Journal of Clinical Oncology (2024)

e16259 Background: While surgical resection stands as the primary curative approach for early-stage hepatocellular carcinoma (HCC), the looming risk of recurrence significantly impacts long-term outcomes. This study investigates the influence of regular recurrence surveillance on the long-term prognosis of HCC patients after curative surgical resection. Methods: In this large multicenter observational study, patients who underwent curative resection for early-stage (BCLC stage 0/A) HCC were divided into two cohorts: those adhering to a structured surveillance protocol (regular check-ups every 2-3 months for the first two years, followed by biannual check-ups) and those with irregular or no recurrence surveillance. Key metrics compared between these groups included overall survival (OS), time-to-recurrence (TTR), and post-recurrence survival (PRS). Results: The study encompassed 1,544 patients, with 786 (50.9%) adhering to regular surveillance for postoperative recurrence. Patients under regular surveillance, as opposed to those with irregular/no surveillance, demonstrated a comparable TTR (median: 61.4 vs. 66.2 months, P = 0.161). However, they exhibited significantly improved OS (median: 113.4 vs. 94.5 months, P = 0.010) and PRS (median: 37.9 vs. 16.3 months, P &lt; 0.001) in cases of recurrence. Multivariable Cox-regression analysis identified regular recurrence surveillance as an independent protective factor, significantly enhancing OS (HR: 0.777; 95% CI: 0.663-0.910; P = 0.002) and PRS (HR: 0.523; 95% CI: 0.428-0.638; P &lt; 0.001). Conclusions: Regular recurrence surveillance markedly improves OS and PRS in patients undergoing surgical resection for early-stage HCC. This study underscores the critical importance of adherence to a structured surveillance regimen in HCC management, potentially enhancing opportunities for subsequent curative interventions and improving long-term survival outcomes. [Table: see text]
Efficacy and safety of lenvatinib plus durvalumab combined with hepatic arterial infusion chemotherapy for unresectable intrahepatic cholangiocarcinoma.
Authors: Rongce Zhao, Jing Zhou, Shaohua Li, Wei Wei, Rongping Guo
Journal: Journal of Clinical Oncology (2024)

e16184 Background: The prognosis for unresectable intrahepatic cholangiocarcinoma (ICC) is poor and the efficacy of traditional chemotherapy remains unsatisfactory. Hepatic arterial infusion chemotherapy (HAIC) with oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX) is effective in patients with unresectable ICC. In this study, we determined the preliminary clinical efficacy and safety of lenvatinib plus durvalumab combined with FOLFOX-HAIC in patients with untreated, unresectable ICC. Methods: Between July 2021 and July 2023, patients with unresectable ICC who initially received lenvatinib plus durvalumab combined with FOLFOX-HAIC at the Sun Yat-Sen University Cancer Center (SYSUCC) were retrospectively reviewed for eligibility. Efficacy was evaluated by tumor response rate and survival, and safety was assessed by the frequency of key adverse events (AEs). Results: A total of 28 eligible patients were enrolled. The objective response rates (ORRs) based on mRECIST and RECIST 1.1 criteria were 65.2% and 39.1%, respectively. The median OS was 17.9 months (95% CI, 5.7–30.1) and the median PFS was 11.9 months (95% CI, 6.7–17.1). Most patients (92.9%) experienced adverse events (AEs), whereas 46.5% (13/28) experienced grade 3 or 4 AEs. Conclusions: Lenvatinib plus durvalumab combined with FOLFOX-HAIC showed promising antitumor activity and manageable AEs in patients with treatment-naive unresectable ICC. This regimen may be suitable as a novel first-line treatment option for this patient population.
Cadonilimab in combined with gemcitabine and cisplatin in advanced biliary tract cancer (BicureX): A phase II, single-arm clinical trial.
Authors: Ji Ma, Tao Wang, Yidi Chen, Yi Yang, Yiwen Qiu, Shu Shen, Cheng Yi, Wentao Wang
Journal: Journal of Clinical Oncology (2024)

e16158 Background: PD-1 or PD-L1 inhibitors plus chemotherapy as the first-line treatment has been proven to be effective in improving the prognosis of advanced biliary tract cancer (BTC) patients. However, there is still considerable demand for further improvement of BTC patients’ prognosis. This trial aims to evaluate the efficacy and safety of Cadonilimab (PD-1/CTLA-4, a bi-specific antibody) plus gemcitabine and cisplatin for patients with advanced BTC in first -line treatment. Methods: In this phase II, single-arm trial, we will enroll 65 patients with previously untreated, unresectable, locally advanced or metastatic BTC, including intrahepatic or extrahepatic cholangiocarcinoma (ICC/ECC) and gallbladder carcinoma (GBC). Participants received Cadonilimab (10 mg/kg, days 1, every three weeks) plus gemcitabine (1000 mg/m 2 , days 1, 8, Q3W), and cisplatin (25 mg/m 2 , days 1, 8, Q3W) for up to eight cycles, followed by Cadonilimab (10 mg/kg, days 1, Q3W) until disease progression or unacceptable toxicity. Treatment response was evaluated with image-based assessment according to response evaluation criteria insolid tumors (RECIST) version 1.1. by two experienced experts and further explored multiple methods, such as 3D visualisation and Spectral computed tomography Scan. The primary endpoint was the objective response rate (ORR); the secondary endpoints are disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Exploratory endpoints included associations between response, molecular characteristics, and the immune microenvironment. Results: Between June 30, and January 31, 2024, a total of 30 patients have undergone at least one imaging evaluation. 66.7% of these patients were diagnosed with ICC, 23.3% with GBC, and 10% with ECC. The mean age was 58.4 years, and 60% of the patients were male. 24 (80%) patients had metastasis. Among them, 1 (3.3%) patient acheived complete response (CR), 15 (50%) patients had partial response (PR) and 8 (26.7%) patients presented with stable disease (SD). The ORR was 53.3% and the DCR was 80%. The most common treatment-related adverse events (TRAEs) of any grade were rash (80%) and anaemia (76.7%). Grade 3 TRAEs were observed in 66.7% of the patients. The most frequent grade 3 TRAEs were anaemia (33.3%), and leukocytopenia (33.3%). No grade 4 or 5 events were observed. All patients were microsatellite stable (MSS), and the median TMB was 2.88 (0-109.44) Muts/Mb. Conclusions: Cadonilimab plus gemcitabine and cisplatin shown a promising efficacy and acceptable safety profile as first-line treatment for advanced BTC patients. Clinical trial information: NCT05978609 .
Delivery Room Oxygen for Preterm Infants—Uncertainty Persists
Authors: Alyssa R. Thomas, Elizabeth E. Foglia
Journal: JAMA Pediatrics (2024)

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Envafolimab combined with lenvatinib and gemcitabine plus cisplatin in advanced biliary tract cancer as first-line treatment: A single-arm, open-label, phase II study (ENLIGHTEN study).
Authors: Ming Kuang, Lixia Xu, Mengping Zhang, Gaomin Zheng, Chuankai Zhang, Ying Zhang, Tianhong Su, Jifei Wang, Fang Wang, Fengjie Wang, Huanwei Chen
Journal: Journal of Clinical Oncology (2024)

e16188 Background: The prognosis of advanced biliary tract cancer (BTC) remains unsatisfactory despite first-line treatment with PD-1/PD-L1 inhibitors in combination with gemcitabine and cisplatin. Lenvatinib (LEN), an anti-angiogenic multi-kinase inhibitor, has recently demonstrated promising antitumor activity in various tumors. This study aimed to determine the efficacy and safety of envafolimab (PD-L1 inhibitor) and LEN in combination with gemcitabine and cisplatin as first-line treatment in advanced BTCs. Methods: This prospective, open-label, single-arm, Simon’s two-stage, phase II study in patients with advanced BTC is ongoing at two centers. All patients received subcutaneous envafolimab (400mg, Q3W) and LEN (8 mg/day, orally once daily) combined with gemcitabine (1000mg/m 2 , IV, days 1, 8, Q3W) plus cisplatin (25mg/m 2 , IV, days 1, 8, Q3W) up for 6-8 cycles, followed by maintenance envafolimab and LEN until disease progression (PD) or unacceptable toxicity. The primary endpoint was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1). A Simon’s two-stage phase II optimal design was used with following statistical assumptions: If 4 or more patients had partial response (PR) in 10 patients in stage 1, the cohort would expand to a total of 39 patients, and the outcomes would be positive if 15 or more patients achieved PR. The secondary endpoints included overall survival (OS), progression-free survival (PFS), disease control rate (DCR), and safety. Results: Between October 2022 and October 2023, 20 patients were enrolled, and included for efficacy and safety analysis. All patients received at least two doses of study medication. Of the first 10 patients enrolled, confirmed responses were noted in 4 patients, and the trial continued to accrual. The ORR and DCR were 45% and 80%, respectively. Nine patients (9/20, 45%) exhibited PR, seven patients (7/20, 35%) showed stable disease (SD), and four patients (4/20, 20%) experienced PD. The most common grade 3/4 treatment-related adverse events (TRAEs) were GGT increased (n = 3, 15%) and platelet decreased (n = 2, 10%). No unacceptable toxicity or treatment-related deaths occurred. Conclusions: Envafolimab and LEN in combination with gemcitabine and cisplatin seems to be an effective and tolerable treatment option in advanced BTC. Survival data is immature and will be updated in the future. Clinical trial information: NCT05410197 .
Effect of BCL9/BCL9L inhibition–derived Th1 cells on dendritic cells–mediated antigen presentation in hepatocellular carcinoma and on the efficacy of CAR-T immunotherapy.
Authors: Yuanyuan Zhu, Mei Feng, Feng Wang, Andrew X. Zhu, Di Zhu, Enfeng Zhao
Journal: Journal of Clinical Oncology (2024)

e16180 Background: Hepatocellular carcinoma (HCC) is an aggressive malignancy with limited treatment options. The emerging field of tumor immunotherapy, primarily focusing on CD8 + T cells and the tumor microenvironment (TME), has garnered substantial attention. CD4 + T cells, on the other hand, play a crucial role in maintaining immune equilibrium and orchestrating immune responses through interactions with various cell types. As crucial participants and coordinators in innate and adaptive immune responses, the role of CD4 + T cells in tumor development remain further exploration. Conventional dendritic cells (cDCs) are thought to perform antigen presentation to prime CD4 + T cells or CD8 + T cells. However, the reverse regulatory impact of CD4 + T cells on cDCs remains poorly understood. Methods: Initially, we examined the role of CD4 + T cell subsets in HCC development using TCGA database. Subsequently, we established Cd4-Cre Bcl9 fl/fl Bcl9l fl/fl mice to explore the impact of T cell-specific Bcl9/Bcl9l deficiency on HCC development. We further investigate the impact of Bcl9/Bcl9l deficiency in CD4 + T cells on the therapeutic efficacy of mouse CAR-T treatment. Moreover, using single-cell RNA sequencing (scRNA-seq) databases from Bcl9/Bcl9l KO tumor-bearing mice and HCC patients, we investigated the regulatory role of CD4 + T cells on the function of cDCs. Finally, we validated the mechanism by which CD4 + T cells regulate cDCs function in a mouse HCC model and explored their influence on tumor-specific CD8 + T cells response. Results: We found elevated Th1 cell infiltration in various cancers including liver hepatocellular carcinoma (LIHC). High Th1 infiltration is associated with a favorable prognosis in LIHC, but there is a significant negative correlation between the expression of B-cell lymphoma 9/B-cell lymphoma 9-like (BCL9/BCL9L) and the infiltration of Th1 cells. We found that blocking T cell-intrinsic BCL9/BCL9L increased frequencies of Th1 cells, thereby suppressing HCC tumor growth. The enrichment of Th1 cells inversely regulates innate immune response to augment cDCs activation. BCL9/BCL9L inhibition amplifies CD4 + T cell and cDCs crosstalk and promotes cDCs antigen presentation. The reinforced cross-presentation of tumor antigens by cDCs promotes activation and proliferation of CD8 + T cells. Moreover, genetic editing of BCL9/BCL9L in CD4 + T cells can enhance the anti-tumor immunity by promoting CAR-T cell toxicity. Conclusions: Thus, BCL9/BCL9L inhibition orchestrate an adaptive immune to innate immune circuit wherein Th1 cells triggers cDCs antigen presentation in turn activate tumor-specific CD8 + T cells response to promote cancer immunity.