Guoying Wang

PURPOSE Lenvatinib (LEN) is a first-line therapy for patients with advanced hepatocellular carcinoma (HCC); however, it has shown modest survival benefits. Therefore, we aimed to compare clinical outcomes of LEN combined with transarterial chemoembolization (LEN-TACE) versus LEN monotherapy in patients with advanced HCC. MATERIALS AND METHODS This was a multicenter, randomized, open-label, parallel group, phase III trial. Patients with primary treatment-naive or initial recurrent advanced HCC after surgery were randomly assigned (1:1) to receive LEN plus on-demand TACE (LEN-TACE) or LEN monotherapy. LEN was initiated within 3 days after random assignment (initial dose: 12 mg once daily for patients ≥ 60 kg; 8 mg once daily for patients < 60 kg). TACE was initiated one day after LEN initiation. The primary end point was overall survival (OS). RESULTS Between June 2019 and July 2021, a total of 338 patients underwent random assignment at 12 centers in China: 170 to LEN-TACE and 168 to LEN. At a prespecified event-driven interim analysis after a median follow-up of 17.0 months, the median OS was significantly longer in the LEN-TACE group (17.8 v 11.5 months; hazard ratio, 0.45; P < .001). The median progression-free survival was 10.6 months in the LEN-TACE group and 6.4 months in the LEN group (hazard ratio, 0.43; P < .001). Patients in the LEN-TACE group had a higher objective response rate according to the modified RECIST (54.1% v 25.0%, P < .001). Multivariable analysis revealed that portal vein tumor thrombus and treatment allocation were independent risk factors for OS. CONCLUSION The addition of TACE to LEN improves clinical outcomes and is a potential first-line treatment for patients with advanced HCC.

Models that recapitulate the complexity of human tumors are urgently needed to develop more effective cancer therapies. We report a bank of human patient-derived xenografts (PDXs) and matched organoid cultures from tumors that represent the greatest unmet need: endocrine-resistant, treatment-refractory and metastatic breast cancers. We leverage matched PDXs and PDX-derived organoids (PDxO) for drug screening that is feasible and cost-effective with in vivo validation. Moreover, we demonstrate the feasibility of using these models for precision oncology in real time with clinical care in a case of triple-negative breast cancer (TNBC) with early metastatic recurrence. Our results uncovered a Food and Drug Administration (FDA)-approved drug with high efficacy against the models. Treatment with this therapy resulted in a complete response for the individual and a progression-free survival (PFS) period more than three times longer than their previous therapies. This work provides valuable methods and resources for functional precision medicine and drug development for human breast cancer.

<h3>Background</h3> Regulatory B (Breg) cells represent one of the B cell subsets that infiltrate solid tumors and exhibit distinct phenotypes in different tumor microenvironments. However, the phenotype, function and clinical relevance of Breg cells in human hepatocellular carcinoma (HCC) are presently unknown. <h3>Methods</h3> Flow cytometry analyses were performed to determine the levels, phenotypes and functions of TIM-1⁺Breg cells in samples from 51 patients with HCC. Kaplan-Meier plots for overall survival and disease-free survival were generated using the log-rank test. TIM-1⁺Breg cells and CD8⁺ T cells were isolated, stimulated and/or cultured in vitro for functional assays. Exosomes and B cells were isolated and cultured in vitro for TIM-1⁺Breg cell expansion assays. <h3>Results</h3> Patients with HCC showed a significantly higher TIM-1⁺Breg cell infiltration in their tumor tissue compared with the paired peritumoral tissue. The infiltrating TIM-1⁺Breg cells showed a CD5^highCD24⁻CD27^−/+CD38^+/high phenotype, expressed high levels of the immunosuppressive cytokine IL-10 and exhibited strong suppressive activity against CD8⁺ T cells. B cells activated by tumor-derived exosomes strongly expressed TIM-1 protein and were equipped with suppressive activity against CD8⁺ T cells similar to TIM-1⁺Breg cells isolated from HCC tumor tissue. Moreover, the accumulation of TIM-1⁺Breg cells in tumors was associated with advanced disease stage, predicted early recurrence in HCC and reduced HCC patient survival. Exosome-derived HMGB1 activated B cells and promoted TIM-1⁺Breg cell expansion via the Toll like receptor (TLR) 2/4 and mitogen-activated protein kinase (MAPK) signaling pathways. <h3>Conclusions</h3> Our results illuminate a novel mechanism of TIM-1⁺Breg cell-mediated immune escape in HCC and provide functional evidence for the use of these novel exosomal HMGB1-TLR2/4-MAPK pathways to prevent and to treat this immune tolerance feature of HCC.

Research models that replicate the diverse genetic and molecular landscape of breast cancer are critical for developing the next-generation therapeutic entities that can target specific cancer subtypes. Patient-derived tumorgrafts, generated by transplanting primary human tumor samples into immune-compromised mice, are a valuable method to model the clinical diversity of breast cancer in mice, and are a potential resource in personalized medicine. Primary tumorgrafts also enable in vivo testing of therapeutics and make possible the use of patient cancer tissue for in vitro screens. Described in this unit are a variety of protocols including tissue collection, biospecimen tracking, tissue processing, transplantation, and three-dimensional culturing of xenografted tissue, which enable use of bona fide uncultured human tissue in designing and validating cancer therapies.