Changqing Xie

Background: Combinatory therapeutic strategy containing immunochemotherapy as part of induction therapy components is one of the current trends in the treatment of high‐risk metastatic locally advanced nasopharyngeal carcinoma (NPC). However, the mechanism underlying the heterogeneity of response at the single‐cell level has not been underexplored.Methods: 18 bulks and 11 single‐cell RNA sequencing from paired before‐treatment and on‐treatment samples in patients with treatment‐naive high‐risk metastatic locally advanced NPCs were obtained. Following quality control, a total of 87 191 cells were included in the subsequence bioinformatics analysis.Results: Immunochemotherapy was associated with on‐treatment tumour microenvironment (TME) remodelling, including upregulation of anti‐TMEs signatures, downregulation of pro‐TMEs signatures, reversing CD8⁺ T exhaustion, and repolarizing proinflammatory TAMs. For the patients achieving a complete response, the cytotoxic activity of CD8⁺ T cells was stimulated and more interferon‐gamma was provided, which would be the key for TAMs proinflammatory repolarization and eventually promote the CD8⁺ T cells maturation in turn. Among patients who did not reach complete response, differentiation and hypoxia signatures for endothelial cells were elevated after therapy. These patients exhibited higher levels of immune checkpoint genes in malignant cells at the baseline (before treatment), and decreased tumour antigen presentation activity, which may underlie the resistance mechanism to therapy.Conclusions: This study pictures a map of TME modulation following immunochemotherapy‐based combination induction therapy and provides potential future approaches.Highlights: Immunochemotherapy remodeled T cell phenotypes. For the patients achieving complete response, more interferon gamma was provided by CD8⁺ T cells after therapy, which would be the key for TAMs pro‐inflammatory repolarization and eventually promote the CD8⁺ T cells maturation in turns. Among patients who did not reach complete response, malignant cells exhibited higher level of immune checkpoint genes before therapy, and decreased tumor antigen presentation activity, which may underlie the resistance mechanism to therapy.

Treatment options are limited for patients with recurrent or metastatic nasopharyngeal carcinoma (RM-NPC) after failure to anti-PD-1 therapy. Cadonilimab (AK104) is a humanized bispecific antibody that targets to PD-1 and CTLA-4. We aimed to evaluate the efficacy and safety of cadonilimab plus TPC chemotherapy (NAB-paclitaxel, cisplatin or lobaplatin, and capecitabine) in patients with RM-NPC who failed to at least one line of systemic chemotherapy and anti-PD-1 therapy. In this phase II clinical trial (ChiCRT2200067057), 25 patients were enrolled and received cadonilimab plus TPC chemotherapy every three weeks for up to six cycles followed by maintenance treatment of cadonilimab plus capecitabine. Here we report on the primary outcome of objective response rate (ORR) and secondary endpoints of progression-free survival, overall survival, duration of response, and safety. This trial met its prespecified primary endpoint of ORR (68%, 95% CI, 48-88), with 3 complete response (12%), 14 partial response (56%), 6 stable disease (24%). Grade ≥3 treatment-related adverse events were occurred in 12 (48%) patients, with the most common being anemia (6[24%]) and neutropenia (6[24%]). This phase II trial shows that cadonilimab in combination with TPC chemotherapy demonstrated satisfactory antitumoral efficacy and manageable toxicities in patients with systemic chemotherapy and anti-PD-1 therapy resistance RM-NPC.

The antiangiogenic agent apatinib has been shown to clinically improve responses to immune checkpoint inhibitors in several cancer types. Patients with N3 nasopharyngeal carcinoma have a high risk of distant metastasis, however, if the addition of immunotherapy to standard treatment could improve efficacy is unclear. In this phase II clinical trial (ChiCTR2000032317), 49 patients with stage T_anyN3M0 nasopharyngeal carcinoma were enrolled and received the combination of three cycles of induction chemotherapy, camrelizumab and apatinib followed by chemoradiotherapy. Here we report on the primary outcome of distant metastasis-free survival and secondary end points of objective response rate, failure-free survival, locoregional recurrence-free survival, overall survival and toxicity profile. After induction therapy, all patients had objective response, including 13 patients (26.5%) with complete response. After a median follow-up of 28.7 months, the primary endpoint of 1-year distant metastasis-free survival was met for the cohort (1-year DMFS rate: 98%). Grade≥3 toxicity appeared in 32 (65.3%) patients, with the most common being mucositis (14[28.6%]) and nausea/vomiting (9[18.4%]). In this work, camrelizumab and apatinib in combination with induction chemotherapy show promising distant metastasis control with acceptable safety profile in patients with stage T_anyN3M0 nasopharyngeal carcinoma.

Background: Microsatellite 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. Methods: This 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. Results: Between 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-1^highKi67^highCD8⁺ T cells and HLA-DR^high T cells after VB-111 priming dose. Plasma cytokines interleukin-10 and tumor necrosis factor-α increased after treatment with both drugs. Conclusion: In 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 number: NCT04166383.

Cholangiocarcinoma is a malignancy of the bile ducts that is driven by activities of cancer stem-like cells and characterized by a heterogeneous tumor microenvironment. To better understand the transcriptional profiles of cancer stem-like cells and dynamics in the tumor microenvironment during the progression of cholangiocarcinoma, we performed single-cell RNA analysis on cells collected from three different timepoints of tumorigenesis in a YAP/AKT mouse model. Bulk RNA sequencing data from TCGA (The Cancer Genome Atlas program) and ICGC cohorts were used to verify and support the finding. In vitro and in vivo experiments were performed to assess the stemness of cancer stem-like cells. We identified Tm4sf1high malignant cells as cancer stem-like cells. Across timepoints of cholangiocarcinoma formation in YAP/AKT mice, we found dynamic change in cancer stem-like cell/stromal/immune cell composition. Nevertheless, the dynamic interaction among cancer stem-like cells, immune cells, and stromal cells at different timepoints was elaborated. Collectively, these data serve as a useful resource for better understanding cancer stem-like cell and malignant cell heterogeneity, stromal cell remodeling, and immune cell reprogramming. It also sheds new light on transcriptomic dynamics during cholangiocarcinoma progression at single-cell resolution.

Antiangiogenic agent apatinib has shown synergetic antitumoral efficacy in combination with camrelizumab in several solid tumors. Immunotherapy combination with standard treatment regimen was reported benefit in nasopharyngeal carcinoma (NPC), however, N3 patients did not show the benefit. In this phase II clinical trial (ChiCTR2000032317), 49 eligible patients with stage T_anyN3M0 NPC were enrolled and received the combination of induction chemotherapy, camrelizumab and apatinib followed by chemoradiotherapy. After induction therapy, all patients had objective response, including 13 patients (26.5%) with complete response. After a median follow-up of 28.7 months, the primary endpoint of 1-year distant metastasis-free survival was met (98%, 95% confidence interval 88–100). The 2-year failure-free survival was 96%. Grade ≥ 3 toxicity appeared in 32 (65.3%) patients, with the most common being mucositis (14[28.6%]) and nausea/vomiting (9[18.4%]). Camrelizumab and apatinib in combination with induction chemotherapy shows promising distant metastasis control with acceptable safety profile in stage T_anyN3M0 NPC.

Colorectal cancers (CRCs) are prevalent worldwide, yet current treatments remain inadequate. Using chemical genetic screens, we identify that co-inhibition of topoisomerase I (TOP1) and NEDD8 is synergistically cytotoxic in human CRC cells. Combination of the TOP1 inhibitor irinotecan or its bioactive metabolite SN38 with the NEDD8-activating enzyme inhibitor pevonedistat exhibits synergy in CRC patient-derived organoids and xenografts. Mechanistically, we show that pevonedistat blocks the ubiquitin/proteasome-dependent repair of TOP1 DNA-protein crosslinks (TOP1-DPCs) induced by TOP1 inhibitors and that the CUL4-RBX1 complex (CRL4) is a prominent ubiquitin ligase acting on TOP1-DPCs for proteasomal degradation upon auto-NEDD8 modification during replication. We identify DCAF13, a DDB1 and Cullin Associated Factor, as the receptor of TOP1-DPCs for CRL4. Our study not only uncovers a replication-coupled ubiquitin-proteasome pathway for the repair of TOP1-DPCs but also provides molecular and translational rationale for combining TOP1 inhibitors and pevonedistat for CRC and other types of cancers.