Immune checkpoint inhibitors and anti-vascular endothelial growth factor antibody/tyrosine kinase inhibitors with or without transarterial chemoembolization as first-line treatment for advanced hepatocellular carcinoma (CHANCE2201): a target trial emulation study.

Background: The role of transarterial chemoembolization (TACE) in the treatment of advanced hepatocellular carcinoma (HCC) is unconfirmed. This study aimed to assess the efficacy and safety of immune checkpoint inhibitors (ICIs) plus anti-vascular endothelial growth factor (anti-VEGF) antibody/tyrosine kinase inhibitors (TKIs) with or without TACE as first-line treatment for advanced HCC. Methods: This nationwide, multicenter, retrospective cohort study included advanced HCC patients receiving either TACE with ICIs plus anti-VEGF antibody/TKIs (TACE-ICI-VEGF) or only ICIs plus anti-VEGF antibody/TKIs (ICI-VEGF) from January 2018 to December 2022. The study design followed the target trial emulation framework with stabilized inverse probability of treatment weighting (sIPTW) to minimize biases. The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), objective response rate (ORR), and safety. The study is registered with ClinicalTrials.gov, NCT05332821. Findings: Among 1244 patients included in the analysis, 802 (64.5%) patients received TACE-ICI-VEGF treatment, and 442 (35.5%) patients received ICI-VEGF treatment. The median follow-up time was 21.1 months and 20.6 months, respectively. Post-application of sIPTW, baseline characteristics were well-balanced between the two groups. TACE-ICI-VEGF group exhibited a significantly improved median OS (22.6 months [95% CI: 21.2-23.9] vs 15.9 months [14.9-17.8]; P < 0.0001; adjusted hazard ratio [aHR] 0.63 [95% CI: 0.53-0.75]). Median PFS was also longer in TACE-ICI-VEGF group (9.9 months [9.1-10.6] vs 7.4 months [6.7-8.5]; P < 0.0001; aHR 0.74 [0.65-0.85]) per Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. A higher ORR was observed in TACE-ICI-VEGF group, by either RECIST v1.1 or modified RECIST (41.2% vs 22.9%, P < 0.0001; 47.3% vs 29.7%, P < 0.0001). Grade ≥3 adverse events occurred in 178 patients (22.2%) in TACE-ICI-VEGF group and 80 patients (18.1%) in ICI-VEGF group. Interpretation: This multicenter study supports the use of TACE combined with ICIs and anti-VEGF antibody/TKIs as first-line treatment for advanced HCC, demonstrating an acceptable safety profile. Funding: National Natural Science Foundation of China, National Key Research and Development Program of China, Jiangsu Provincial Medical Innovation Center, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, and Nanjing Life Health Science and Technology Project.

The pattern of tumor progression on first-line immune checkpoint inhibitor-based systemic therapy for Chinese advanced hepatocellular carcinoma -CLEAP 004 study.

Background: For decades, stratification criteria for first-line clinical studies have been highly uniform. However, there is no principle or consensus for restratification after systemic treatment progression based on immune checkpoint inhibitors (ICIs). The aim of this study was to assess the patterns of disease progression in patients with advanced hepatocellular carcinoma (HCC) who are not eligible for surgical intervention, following the use of immune checkpoint inhibitors. Methods: This is a retrospective study that involved patients with inoperable China liver stage (CNLC) IIIa and/or IIIb. The patients were treated at eight centers across China between January 2017 and October 2022. All patients received at least two cycles of first-line treatment containing immune checkpoint inhibitors. The patterns of disease progression were assessed using RECIST criteria 1.1. Different progression modes have been identified based on the characteristics of imaging progress. The study's main outcome measures were post-progression survival (PPS) and overall survival (OS). Survival curves were plotted using the Kaplan-Meier method to compare the difference among the four groups. Subgroup analysis was conducted to compare the efficacy of different immunotherapy combinations. Variations in the efficacy of immunotherapy have also been noted across patient groups exhibiting alpha-fetoprotein (AFP) levels equal to or exceeding 400ng/mL, in contrast to those with AFP levels below 400ng/mL. Results: The study has identified four distinct patterns of progress, namely p-IIb, p-IIIa, p-IIIb, and p-IIIc. Diverse patterns of progress demonstrate notable variations in both PPS and OS. The group p-IIb had the longest PPS of 12.7m (95% 9.3-16.1) and OS 19.6m (95% 15.6-23.5), the remaining groups exhibited p-IIIb at PPS 10.5 months (95%CI: 7.9-13.1) and OS 19.2 months (95%CI 15.1-23.3). Similarly, p-IIIc at PPS 5.7 months (95%CI: 4.2-7.2) and OS 11.0 months (95%CI 9.0-12.9), while p-IIIa at PPS 3.4 months (95%CI: 2.7-4.1) and OS 8.2 months (95%CI 6.8-9.5) were also seen. Additional stratified analysis was conducted and showed there were no differences of immunotherapy alone or in combination in OS (HR= 0.92, 95%CI: 0.59-1.43, P=0.68) and PPS (HR= 0.88, 95%CI: 0.57-1.36, P=0.54); there was no significant difference in PPS (HR=0.79, 95% CI: 0.55-1.12, P=0.15) and OS (HR=0.86, 95% CI: 0.61-1.24, P=0.39) for patients with AFP levels at or over 400ng/mL. However, it was observed that patients with AFP levels above 400ng/mL experienced a shorter median progression of PPS (8.0 months vs. 5.0 months) after undergoing immunotherapy. Conclusion: In this investigation of advanced hepatocellular carcinoma among Chinese patients treated with immune checkpoint inhibitors, we identified four distinct progression patterns (p-IIb, p-IIIa, p-IIIb and p-IIIc) that showed significant differences in PPS and OS. These findings demonstrate the heterogeneity of disease progression and prognosis after immunotherapy failure. Further validation in large cohorts is necessary to develop prognostic models that integrate distinct progression patterns to guide subsequent treatment decisions. Additionally, post-immunotherapy progression in patients with AFP levels ≥400ng/mL indicates a shortened median PPS. These findings provide valuable insights for future personalized treatment decisions.

Multi-cohort validation study of a four-gene signature for risk stratification and treatment response prediction in hepatocellular carcinoma.

BACKGROUND: The intricate molecular landscape of hepatocellular carcinoma (HCC) presents a significant challenge to achieving precise risk stratification through clinical genetic testing. At present, there is a paucity of robust gene signatures that could assist clinicians in making clinical decisions for patients with HCC. METHODS: We obtained gene expression profiles of patients with HCC from 20 independent cohorts available in public databases. A gene signature was developed by employing two machine learning algorithms. In addition to validating the signature with high-throughput data in public cohorts, we external validated the signature in 64 HCC cases by RT-PCR method. We compared genomic, transcriptomic and proteomic features between different subgroups. We also compared our signature to 130 gene signatures that have already been published. RESULTS: We developed a novel four-gene signature, designated as HCC4, that demonstrates significant potential for the prediction of survival outcomes in more than 1300 patients with HCC. The HCC4 also has potential for predicting recurrence and tumor volume doubling time, assessing transcatheter arterial chemoembolization and immunotherapy responses, and non-invasive detection of HCC. The high HCC4 score group shows a higher frequency of mutations in genes TP53, RB1 and TSC1/2, as well as increased activity of cell-cycle, glycolysis and hypoxia signaling pathways, higher cancer stemness score, and lower lipid metabolism activity. In seven HCC cohorts, HCC4 exhibited a higher average C-index in predicting overall survival compared to the 130 signatures previously published. Drug screening indicated that patients with high HCC4 scores were more sensitive to agents targeting AURKA, TUBB, JMJD6 and KIFC1. CONCLUSIONS: Our findings demonstrated that HCC4 is a powerful tool for improving risk stratification and for identifying HCC patients who are most likely to benefit from TACE treatment, immunotherapy, and other experimental therapies.

Efficacy and safety of hepatic arterial infusion chemotherapy combined with immune checkpoint inhibitors and tyrosine kinase inhibitors in advanced hepatocellular carcinoma: A systematic review and meta­analysis.

At present, hepatic arterial infusion chemotherapy (HAIC) for the treatment of hepatocellular carcinoma (HCC) is often applied to patients who are not suitable or are unwilling to undergo surgical treatment. However, to the best of our knowledge, the efficacy and safety of HAIC combined with immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) in HCC have not been fully demonstrated. Published studies involving the treatment of patients with HCC with HAIC, ICIs and TKIs were searched from public databases, including PubMed, Embase, the Cochrane Library and Sinomed. Efficacy and safety data for each study, including progression-free survival (PFS), overall survival (OS) and adverse events (AEs) were collected. The present study included 17 treatment groups from 15 studies, including 1,987 patients with HCC in the systematic review. The target population was dominated by those unsuitable for surgical treatment, with Barcelona Clinic Liver Cancer stage B or C, Eastern Cooperative Oncology Group performance status ≤2 and Child-Pugh score A or B. The results showed that the longest estimated median PFS (95% CI) in the HAIC + ICI/TKI therapy group (group C) was 9.37 months (95% CI, 6.81-11.93); in the HAIC therapy group (group B) was 7.45 months (95% CI, 6.45-8.46); and in the ICIs + other systemic therapies group (group A) was 5.92 months (95% CI, 5.31-6.54). There was no significant difference in the expected OS among the three groups, which may be because OS events were not reached in numerous studies during the follow-up time. The incidence of treatment-related adverse effects, such as increased AST [14/221 (6.33%)], increased ALT [13/221 (5.88%)], and decreased platelet count [13/221 (5.88%)], was not significantly increased in group C when compared with groups A or B (P>0.05). In conclusion, the effectiveness of HAIC + ICI/TKI for the treatment of advanced HCC was better than that of ICIs + other systemic therapies or HAIC alone. In addition, the incidence of AEs above grade 3 was not significantly higher compared with that in the other treatment groups, and the safety profile was good.

Expanding the applications of immune checkpoint inhibitors in advanced lung cancer beyond disease progression.

Background: Immunotherapy, particularly the utilization of immune checkpoint inhibitors (ICIs), assumes a pivotal role in the comprehensive management of advanced lung cancer. There has been substantial deliberation regarding the appropriateness of extending ICIs treatment beyond the point of disease progression. This study delves into the potential benefits of sustained utilization of ICIs subsequent to disease progression in patients. Methods: A retrospective analysis was conducted on a cohort of 248 patients diagnosed with advanced lung cancer who received treatment with ICIs. The study population comprised 99 patients in the treatment beyond progression (TBP) group and 42 patients in the non-treatment beyond progression (NTBP) group. Parameters including progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and disease control rate (DCR) were assessed. The Cox proportional hazard regression model was employed to analyze prognostic factors related to immunotherapy. Results: Patients undergoing primary treatment with PD-1/PD-L1 inhibitors exhibited a median progression-free survival (mPFS) of 5.3 months. In the context of disease progression, a comparison between the TBP and NTBP groups was performed with respect to mPFS. The results demonstrated that the TBP group manifested an mPFS of 8.6 months, contrasting with the NTBP group's mPFS of 4.0 months (p=0.028). The mean overall survival (mOS) in the TBP group exhibited a statistically significant increase in comparison to the NTBP group (14.1 months vs. 6.0 months, p=0.028). Evaluation of the objective response rate (ORR) between the TBP and NTBP groups revealed a substantial distinction. The TBP group displayed an ORR of 12.1%, while the NTBP group exhibited a lower ORR of 2.4%. The statistical analysis yielded a p-value of 0.068, signifying a notable trend towards significance. The disease control rate (DCR) was also assessed and exhibited a noteworthy variance between the two groups, with a higher DCR of 92.9% in contrast to 71.4% in the control group (p = 0.001). Conclusion: Subsequent to ICIs treatment, a subset of patients may derive continued benefits from anticancer therapy, notwithstanding the progression of their advanced lung cancer.

Guidelines for the Diagnosis and Treatment of Primary Liver Cancer (2022 Edition).

Background: Primary liver cancer, of which around 75-85% is hepatocellular carcinoma in China, is the fourth most common malignancy and the second leading cause of tumor-related death, thereby posing a significant threat to the life and health of the Chinese people. Summary: Since the publication of Guidelines for Diagnosis and Treatment of Primary Liver Cancer in China in June 2017, which were updated by the National Health Commission in December 2019, additional high-quality evidence has emerged from researchers worldwide regarding the diagnosis, staging, and treatment of liver cancer, that requires the guidelines to be updated again. The new edition (2022 Edition) was written by more than 100 experts in the field of liver cancer in China, which not only reflects the real-world situation in China but also may reshape the nationwide diagnosis and treatment of liver cancer. Key Messages: The new guideline aims to encourage the implementation of evidence-based practice and improve the national average 5-year survival rate for patients with liver cancer, as proposed in the "Health China 2030 Blueprint."

A phase II randomised controlled trial of adjuvant tumour-infiltrating lymphocytes for pretreatment Epstein-Barr virus DNA-selected high-risk nasopharyngeal carcinoma patients.

PURPOSE: The safety and objective clinical responses were observed in the phase I study using adjuvant autologous tumour-infiltrating lymphocytes (TILs) following concurrent chemoradiotherapy (CCRT) in nasopharyngeal carcinoma (NPC) patients. METHODS AND MATERIALS: One hundred fifty-six patients with stage III-IVb and pretreatment Epstein-Barr virus DNA levels of ≥4000 copies/ml were randomly assigned to receive CCRT combined with TIL infusion (n = 78) or CCRT alone (n = 78). All patients received CCRT and patients assigned to the TIL group received TIL infusion within 1 week after CCRT. The primary endpoint was investigator-assessed progression-free survival (PFS) at 3 years. RESULTS: After a median follow-up of 62.3 months, no significant difference was observed in the 3-year PFS rate between the CCRT plus TIL infusion group and CCRT alone group (75.6% versus 74.4%, hazard ratios, 1.08; 95% confidence intervals, 0.62-1.89). TIL infusion was safe without grade 3 or 4 adverse events and all the high-grade adverse effects were associated with myelosuppression caused by CCRT. Exploratory analysis showed that a potential survival benefit was observed with TILs in patients with lower levels of circulating CD8+TIM3+ cells, serum IL-8 or PD-L1. The infused TIL products in patients with favourable outcomes were associated with increased transcription of interferon-γ and a series of inflammatory related genes and a lower exhausted score. CONCLUSION: The primary objective of prolonging PFS with CCRT plus TILs in high-risk NPC patients was not met. These findings may provide evidence for the design of future trials investigating the combination of TILs plus immune checkpoint inhibitors based on CCRT in high-risk NPC patients. TRIAL REGISTRATION NUMBER: NCT02421640.

Chinese expert consensus recommendations for the administration of immune checkpoint inhibitors to special cancer patient populations.

Immune checkpoint inhibitors (ICIs) targeting programmed cell death 1, programmed cell death ligand 1, and cytotoxic T lymphocyte-associated antigen-4 have shown significantly durable clinical benefits and tolerable toxicities and have improved the survival of patients with various types of cancer. Since 2018, the National Medical Products Administration of China has approved 17 ICIs as the standard treatment for certain advanced or metastatic solid tumors. As ICIs represent a broad-spectrum antitumor strategy, the populations eligible for cancer immunotherapy are rapidly expanding. However, the clinical applications of ICIs in cancer patient populations with special issues, a term that refers to complex subgroups of patients with comorbidities, special clinical conditions, or concomitant medications who are routinely excluded from prospective clinical trials of ICIs or are underrepresented in these trials, represent a great real-world challenge. Although the Chinese Society of Clinical Oncology (CSCO) has provided recommendations for screening before the use of ICIs in special populations, the recommendations for full-course management remain insufficient. The CSCO Expert Committee on Immunotherapy organized leading medical oncology and multidisciplinary experts to develop a consensus that will serve as an important reference for clinicians to guide the proper application of ICIs in special patient populations. This article is a translation of a study first published in Chinese in The Chinese Clinical Oncology (ISSN 1009-0460, CN 32-1577/R) in May 2022 (27(5):442-454). The publisher of the original paper has provided written confirmation of permission to publish this translation in Therapeutic Advances in Medical Oncology.

Effect of different PD-1 inhibitor combination therapies for unresectable intrahepatic cholangiocarcinoma.

BACKGROUND: Immune checkpoint inhibitor (ICI) combination therapy offers a new option for treatment of unresectable intrahepatic cholangiocarcinoma (uICC). AIM: To compare the effect of different anti-PD-1 combination therapies as the first-line treatments for uICC. METHODS: This study included 318 patients who received chemotherapy alone (Chemo), anti-PD-1 plus chemotherapy (ICI-chemo), anti-PD-1 plus targeted therapy (ICI-target) or anti-PD-1 plus targeted therapy and chemotherapy (ICI-target-chemo) as first line for uICC from 22 centres in China. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR) and safety. RESULTS: Patients with ICI-chemo (median PFS [mPFS], 6.3 months; HR: 0.61, 95% CI: 0.42-0.88; p = 0.008; median OS [mOS], 10.7 months; HR: 0.61, 95% CI: 0.39-0.94; p = 0.026), ICI-target (7.2 months; HR: 0.54, 95% CI: 0.36-0.80; p = 0.002; 15.8 months; HR: 0.54, 95% CI: 0.35-0.84; p = 0.006) or ICI-target-chemo (6.9 months; HR: 0.65, 95% CI: 0.47-0.90; p = 0.009; 14.4 months; HR: 0.47, 95% CI: 0.31-0.70; p < 0.001) achieved better clinical outcomes than those with Chemo (3.8 months; 9.3 months). ICI-target was not inferior to ICI-chemo in survival outcomes (HR for PFS: 0.88, 95% CI: 0.55-1.42; p = 0.614; HR for OS: 0.89, 95% CI: 0.51-1.55; p = 0.680). ICI-target-chemo yielded similar prognoses as ICI-chemo (HR for PFS: 1.07, 95% CI: 0.70-1.62; p = 0.764; HR for OS: 0.77, 95% CI: 0.45-1.31; p = 0.328) and ICI-target (HR for PFS: 1.20, 95% CI: 0.77-1.88; p = 0.413; HR for OS: 0.86, 95% CI: 0.51-1.47; p = 0.583) but resulted in more adverse events (p < 0.001; p = 0.010). Multivariable and propensity score analyses supported these findings. CONCLUSIONS: Among patients with uICC, ICI-chemo or ICI-target provided more survival benefits than Chemo while achieving comparable prognoses and fewer adverse events than ICI-target-chemo.

Lactobacillus reuteri strain 8008 attenuated the aggravation of depressive-like behavior induced by CUMS in high-fat diet-fed mice through regulating the gut microbiota.

Objective: Gut microbiota play a key role in the pathogenesis of obesity and depression. Probiotics are a preventive strategy for obesity and a novel treatment for depression symptoms. However, the ameliorative or therapeutic effect of potential probiotic candidate Lactobacillus reuteri (L. reuteri) on obesity and depression comorbidity still remains unclear. We investigated the effects of chronic unpredictable mild stress (CUMS) in high-fat diet-fed mice and the effects of Lactobacillus reuteri strain 8008 on various disease indicators of obesity and depression comorbidity disease. Methods: Forty male C57BL/6 mice were randomized into 2 groups: the normal control (NC) group (n = 10) and the high-fat diet (HFD) group (n = 30), being fed with normal diet (ND) or high-fat diet (HFD) for 8 weeks, respectively. Then the obese mice fed with HFD were randomly allocated into 3 sub-groups: the HFD group (n = 10); the HFD + CUMS group (n = 10); the HFD + CUMS + L.r group (n = 10). The latter 2 subgroups underwent CUMS for 4 weeks to build the obesity and depression comorbidity mice model. During the duration of treatment, mice were gavaged with 0.5 mL PBS solution or L. reuteri (2 × 109 CFU/mL) once a day, respectively. The body weight, food intake, organ weight, behavioral indicators, histology, blood lipids, levels of inflammatory cytokines and tight junction proteins and abundance of colonic contents bacteria were measured. Results: The obesity and depression comorbidity mice model was successfully established after HFD feeding and chronic stress. The comorbid mice demonstrated inflammatory responses increase in liver and adipose tissues, worsened damage to the intestinal barrier as well as gut microbiota disorder. Gavaged with L. reuteri attenuated depressive-like behavior, improved blood lipids and insulin resistance, reduced inflammation in liver and adipose tissues, improved intestinal tight junctions as well as the microbiome dysbiosis in obesity and depression comorbidity mice. Conclusion: Lactobacillus reuteri strain 8008 could alleviate depressive-like behaviors and related indicators of obesity disorders by regulating the gut microbiota in obesity and depression comorbid mice.

Pembrolizumab Versus Placebo as Second-Line Therapy in Patients From Asia With Advanced Hepatocellular Carcinoma: A Randomized, Double-Blind, Phase III Trial.

PURPOSE: We evaluated the efficacy and safety of pembrolizumab in patients from Asia with previously treated advanced hepatocellular carcinoma (HCC). METHODS: In a double-blind, phase III trial, 453 patients with advanced HCC and progression during or after treatment with or intolerance to sorafenib or oxaliplatin-based chemotherapy were randomly assigned in a 2:1 ratio to receive pembrolizumab (200 mg) or placebo once every 3 weeks for ≤ 35 cycles plus best supportive care. The primary end point was overall survival (one-sided significance threshold, P = .0193 [final analysis]). Secondary end points included progression-free survival (PFS) and objective response rate (ORR; one-sided significance threshold, P = .0134 and .0091, respectively [second interim analysis]; RECIST version 1.1, by blinded independent central review). RESULTS: Median overall survival was longer in the pembrolizumab group than in the placebo group (14.6 v 13.0 months; hazard ratio for death, 0.79; 95% CI, 0.63 to 0.99; P = .0180). Median PFS was also longer in the pembrolizumab group than in the placebo group (2.6 v 2.3 months; hazard ratio for progression or death, 0.74; 95% CI, 0.60 to 0.92; P = .0032). ORR was greater in the pembrolizumab group (12.7% [95% CI, 9.1 to 17.0]) than in the placebo group (1.3% [95% CI, 0.2 to 4.6]; P < .0001). Treatment-related adverse events occurred in 66.9% of patients (grade 3, 12.0%; grade 4, 1.3%; grade 5, 1.0%) in the pembrolizumab group and 49.7% of patients (grade 3, 5.9%; grade 4, 0%; grade 5, 0%) in the placebo group. CONCLUSION: In patients from Asia with previously treated advanced HCC, pembrolizumab significantly prolonged overall survival and PFS, and ORR was greater versus placebo.

Cisplatin-Induced Anorexia and Pica Behavior in Rats Enhanced by Chronic Stress Pretreatment.

Background: Chemotherapy-induced nausea and vomiting severely impairs the treatment and prognosis of cancer patients. Depressive mood disorder might aggravate nausea and vomiting in cancer patients; however, the role of neurotransmitters and receptors involved in the mediation of emesis and nausea is still not well elaborated. Methods: The study was carried out based on the chronic unpredictable mild stress-induced depression-like phenotype rat model and cisplatin-induced pica rat model establishment. Forty male Sprague-Dawley rats were randomized into the non-treated control group and the chronic stress group, which were exposed to 8 weeks of stress. Each group was then sub-divided into vehicle subgroups (n = 10) and cisplatin subgroups (n = 10) which were given cisplatin to induce pica behavior. Kaolin and food intake were recorded after administration. The medulla oblongata and ileum tissues were obtained. Neurotransmitters involved in the mediation of emesis and nausea (5-HT, DA, SP, and AEA) were detected using an ELISA kit. Vomit-related receptors (5-HT3R, DA2R, NK1R, and CB1R) in tissues were assayed for mRNA and protein expression by RT-qPCR and Western blotting. Results: Behavioral test and sucrose preference validated that depression-like phenotype rat models were established successfully. The kaolin consumption test confirmed that chronic stress pretreatment aggravated anorexia and pica behavior. Vomiting-related molecules' data showed that chronic stress exposure increased 5-HT and SP levels in the medulla oblongata. Vomiting-related receptor expression data showed that chronic stress pretreatment upregulated 5-HT3R, DA2R, and NK1R expressions and downregulated the CB1R expression in the medulla oblongata. However, chronic stress pretreatment downregulated 5-HT3R, DA2R, and NK1R expressions and upregulated the CB1R expression in the ileum. Conclusion: Chronic stress pretreatment aggravates anorexia and vomiting progress, which might be via altering neurotransmitters and receptors involved in the mediation of emesis and the nausea level and expression in the central nervous system.

Phase I study of adjuvant immunotherapy with autologous tumor-infiltrating lymphocytes in locally advanced cervical cancer.

BACKGROUNDAdoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TILs) has achieved remarkable clinical efficacy in metastatic cancers such as melanoma and cervical cancer (CC). Here, we explored the safety, feasibility, and preliminary tumor response and performed translational investigations of adjuvant immunotherapy using infusion of autogenous TILs (auto-TILs) following concurrent chemoradiotherapy (CCRT) in patients with CC who had locally advanced disease.METHODSTwenty-seven patients with CC with stage III-IV disease were recruited in this single-center, phase I study. TILs were isolated from lesions in the uterine cervix and generated under good manufacturing practice (GMP) conditions and then infused after CCRT plus i.m. IL-2 injections.RESULTSTILs from 20 of the 27 patients were successfully expanded, with a feasibility of 74.1%. Twelve patients received TILs following CCRT. Adverse events (AEs) were primarily attributable to CCRT. Only 1 (8.3%) patient experienced severe toxicity with a grade 3 hypersensitivity reaction after TIL infusion. No autoimmune AEs, such as pneumonitis, hepatitis, or myocarditis, occurred, and there were no treatment-related mortalities. Nine of 12 patients (75.0%) attained a complete response, with a disease control duration of 9-22 months. Translational investigation showed that the transcriptomic characteristics of the infused TIL products and some immune biomarkers in the tumor microenvironment and serum of patients with CC at baseline were correlated with the clinical response.CONCLUSIONTIL-based ACT following CCRT was safe in an academic center setting, with potentially effective responses in patients with locally advanced CC. "Hot" inflammatory immune environments were beneficial to the clinical efficacy of TIL-based ACT as adjuvant therapy.TRIAL REGISTRATIONClinicalTrials.gov NCT04443296.FUNDINGNational Key R&D Program; Sci-Tech Key Program of the Guangzhou City Science Foundation; the Guangdong Province Sci-Tech International Key Program; the National Natural Science Foundation of China.

Chinese expert consensus on conversion therapy for hepatocellular carcinoma (2021 edition).

Recent advances in systemic and locoregional treatments for patients with unresectable or advanced hepatocellular carcinoma (HCC) have resulted in improved response rates. This has provided an opportunity for selected patients with initially unresectable HCC to achieve adequate tumor downstaging to undergo surgical resection, a 'conversion therapy' strategy. However, conversion therapy is a new approach to the treatment of HCC and its practice and treatment protocols are still being developed. Review the evidence for conversion therapy in HCC and develop consensus statements to guide clinical practice. Evidence review: Many research centers in China have accumulated significant experience implementing HCC conversion therapy. Preliminary findings and data have shown that conversion therapy represents an important strategy to maximize the survival of selected patients with intermediate stage to advanced HCC; however, there are still many urgent clinical and scientific challenges for this therapeutic strategy and its related fields. In order to summarize and learn from past experience and review current challenges, the Chinese Expert Consensus on Conversion Therapy for Hepatocellular Carcinoma (2021 Edition) was developed based on a review of preliminary experience and clinical data from Chinese and non-Chinese studies in this field and combined with recommendations for clinical practice. Sixteen consensus statements on the implementation of conversion therapy for HCC were developed. The statements generated in this review are based on a review of clinical evidence and real clinical experience and will help guide future progress in conversion therapy for patients with HCC.

Adaptor SH3BGRL drives autophagy-mediated chemoresistance through promoting PIK3C3 translation and ATG12 stability in breast cancers.

Acquired chemotherapy resistance is one of the main culprits in the relapse of breast cancer. But the underlying mechanism of chemotherapy resistance remains elusive. Here, we demonstrate that a small adaptor protein, SH3BGRL, is not only elevated in the majority of breast cancer patients but also has relevance with the relapse and poor prognosis of breast cancer patients. Functionally, SH3BGRL upregulation enhances the chemoresistance of breast cancer cells to the first-line doxorubicin treatment through macroautophagic/autophagic protection. Mechanistically, SH3BGRL can unexpectedly bind to ribosomal subunits to enhance PIK3C3 translation efficiency and sustain ATG12 stability. Therefore, inhibition of autophagy or silence of PIK3C3 or ATG12 can effectively block the driving effect of SH3BGRL on doxorubicin resistance of breast cancer cells in vitro and in vivo. We also validate that SH3BGRL expression is positively correlated with that of PIK3C3 or ATG12, as well as the constitutive occurrence of autophagy in clinical breast cancer tissues. Taken together, our data reveal that SH3BGRL upregulation would be a key driver to the acquired chemotherapy resistance through autophagy enhancement in breast cancer while targeting SH3BGRL could be a potential therapeutic strategy against breast cancer.Abbreviations: ABCs: ATP-binding cassette transporters; Act D: actinomycin D; ACTB/ß-actin: actin beta; ATG: autophagy-related; Baf A1: bafilomycin A1; CASP3: caspase 3; CHX: cycloheximide; CQ: chloroquine; Dox: doxorubicin; FBS: fetal bovine serum; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GEO: gene expression omnibus; GFP: green fluorescent protein; G6PD: glucose-6-phosphate dehydrogenase; GSEA: gene set enrichment analysis; IHC: immunochemistry; KEGG: Kyoto Encyclopedia of Genes and Genomes; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; 3-MA: 3-methyladenine; mRNA: messenger RNA; PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3; SH3BGRL: SH3 domain binding glutamate-rich protein-like; SQSTM1/p62: sequestosome 1; ULK1: unc-51 like autophagy activating kinase 1.

Salmonella flagella confer anti-tumor immunological effect via activating Flagellin/TLR5 signalling within tumor microenvironment.

mediated cancer therapy has achieved remarkable anti-tumor effects in experimental animal models, but the detailed mechanism remains unsolved. In this report, the active involvement of the host immune response in this process was confirmed by comparing the tumor-suppressive effects of Salmonella in immunocompetent and immunodeficient mice bearing melanoma allografts. Since flagella are key inducers of the host immune response during bacterial infection, flagella were genetically disrupted to analyse their involvement in Salmonella-mediated cancer therapy. The results showed that flagellum-deficient strains failed to induce significant anti-tumor effects, even when more bacteria were administered to offset the difference in invasion efficiency. Flagella mainly activate immune cells via Flagellin/Toll-like receptor 5 (TLR5) signalling pathway. Indeed, we showed that exogenous activation of TLR5 signalling by recombinant Flagellin and exogenous expression of TLR5 both enhanced the therapeutic efficacy of flagellum-deficient Salmonella against melanoma. Our study highlighted the therapeutic value of the interaction between Salmonella and the host immune response through Flagellin/TLR5 signalling pathway during Salmonella-mediated cancer therapy, thereby suggesting the potential application of TLR5 agonists in the cancer immune therapy.

Adaptor SH3BGRL promotes breast cancer metastasis through PFN1 degradation by translational STUB1 upregulation.

Metastatic recurrence is still a major challenge in breast cancer treatment, but the underlying mechanisms remain unclear. Here, we report that a small adaptor protein, SH3BGRL, is upregulated in the majority of breast cancer patients, especially elevated in those with metastatic relapse, indicating it as a marker for the poor prognosis of breast cancer. Physiologically, SH3BGRL can multifunctionally promote breast cancer cell tumorigenicity, migration, invasiveness, and efficient lung colonization in nude mice. Mechanistically, SH3BGRL downregulates the acting-binding protein profilin 1 (PFN1) by accelerating the translation of the PFN1 E3 ligase, STUB1 via SH3BGRL interaction with ribosomal proteins, or/and enhancing the interaction of PFN1 with STUB1 to accelerate PFN1 degradation. Loss of PFN1 consequently contributes to downstream multiple activations of AKT, NF-kB, and WNT signaling pathways. In contrast, the forced expression of compensatory PFN1 in SH3BGRL-high cells efficiently neutralizes SH3BGRL-induced metastasis and tumorigenesis with PTEN upregulation and PI3K-AKT signaling inactivation. Clinical analysis validates that SH3BGRL expression is negatively correlated with PFN1 and PTEN levels, but positively to the activations of AKT, NF-kB, and WNT signaling pathways in breast patient tissues. Our results thus suggest that SH3BGRL is a valuable prognostic factor and a potential therapeutic target for preventing breast cancer progression and metastasis.

Donafenib Versus Sorafenib in First-Line Treatment of Unresectable or Metastatic Hepatocellular Carcinoma: A Randomized, Open-Label, Parallel-Controlled Phase II-III Trial.

PURPOSE: Donafenib, a novel multikinase inhibitor and a deuterated sorafenib derivative, has shown efficacy in phase Ia and Ib hepatocellular carcinoma (HCC) studies. This study compared the efficacy and safety of donafenib versus sorafenib as first-line therapy for advanced HCC. PATIENTS AND METHODS: This open-label, randomized, parallel-controlled, multicenter phase II-III trial enrolled patients with unresectable or metastatic HCC, a Child-Pugh score ≤ 7, and no prior systemic therapy from 37 sites across China. Patients were randomly assigned (1:1) to receive oral donafenib (0.2 g) or sorafenib (0.4 g) twice daily until intolerable toxicity or disease progression. The primary end point was overall survival (OS), tested for noninferiority and superiority. Efficacy was primarily assessed in the full analysis set (FAS), and safety was assessed in all treated patients. RESULTS: Between March 21, 2016, and April 16, 2018, 668 patients (intention-to-treat) were randomly assigned to donafenib and sorafenib treatment arms; the FAS included 328 and 331 patients, respectively. Median OS was significantly longer with donafenib than sorafenib treatment (FAS; 12.1 v 10.3 months; hazard ratio, 0.831; 95% CI, 0.699 to 0.988; P = .0245); donafenib also exhibited superior OS outcomes versus sorafenib in the intention-to-treat population. The median progression-free survival was 3.7 v 3.6 months (P = .0570). The objective response rate was 4.6% v 2.7% (P = .2448), and the disease control rate was 30.8% v 28.7% (FAS; P = .5532). Drug-related grade ≥ 3 adverse events occurred in significantly fewer patients receiving donafenib than sorafenib (125 [38%] v 165 [50%]; P = .0018). CONCLUSION: Donafenib showed superiority over sorafenib in improving OS and has favorable safety and tolerability in Chinese patients with advanced HCC, showing promise as a potential first-line monotherapy for these patients.

Atezolizumab and bevacizumab for hepatocellular carcinoma: mechanism, pharmacokinetics and future treatment strategies.

Hepatocellular carcinoma (HCC) is a common cancer globally and a leading cause of cancer-related deaths. Although early-stage disease may be curable by resection, liver transplantation or ablation, many patients present with unresectable disease and have a poor prognosis. Combination treatment with atezolizumab (targeting PD-L1) and bevacizumab (targeting VEGF) in the recent IMbrave150 study was shown to be effective with an acceptable safety profile in patients with unresectable HCC. Herein, we discuss this novel combination in the context of the liver immune environment, summarize the mechanism and pharmacokinetics of atezolizumab and bevacizumab, and examine recent data on other immune checkpoint inhibitor combination strategies as well as future directions in the treatment of patients with advanced HCC.

Lay abstract Cancer of the liver is common worldwide and is one of the main causes of death from cancer. If caught early, liver cancer can be treated successfully, but most patients are diagnosed when their cancer has already spread and are less likely to survive. A new treatment method using two kinds of antibodies, atezolizumab and bevacizumab, has recently been shown in a clinical trial to be safe and to have a good effect in patients with advanced liver cancer. In this review, we look at how this new treatment works and discuss the results of other clinical trials using similar treatments. We also look ahead to how patients with advanced liver cancer might be treated in the future.