TPP1 is associated with risk of advanced precursors and cervical cancer survival.

It is unclear how telomere-binding protein TPP1 interacts with human telomerase reverse transcriptase (hTERT) and influences cervical cancer development and progression. This study included all eligible 156 cervical cancers diagnosed during 2003-2008 and followed up through 2014, 102 cervical intraepithelial neoplasia (CIN) patients, and 16 participants with normal cervix identified at the same period. Correlation of expression of TPP1 and hTERT in these lesions was assessed using Kappa statistics. TPP1 was knocked down by siRNA in three cervical cancer cell lines. We assessed mRNA expression using quantitative real-time polymerase chain reaction and protein expression using tissue microarray-based immunohistochemical staining. We further analyzed the impact of TPP1 expression on the overall survival of cervical cancer patients by calculating the hazard ratio (HR) with 95% confidence intervals (CIs) using the multivariable-adjusted Cox regression model. Compared to the normal cervix, high TPP1expression was significantly associated with CIN 3 and cervical cancers (P<0.001 for both). Expressions of TPP1 and hTERT were highly correlated in CIN 3 (Kappa statistics = 0.50, P = 0.005), squamous cell carcinoma (Kappa statistics = 0.22, P = 0.011), and adenocarcinoma/adenosquamous carcinoma (Kappa statistics = 0.77, P = 0.001). Mechanistically, knockdown of TPP1 inhibited the expression of hTERT in both mRNA and protein levels. High expression of TPP1 (HR = 2.61, 95% CI 1.23-5.51) and co-high expression of TPP1 and hTERT (HR = 2.38, 95% CI 1.28-4.43) were independently associated with worse survival in cervical cancer patients. TPP1 and hTERT expression was correlated and high expression of TPP1 was associated with high risk of CIN 3 and cervical cancer and could predict a worse survival in cervical cancer.

Ficonalkib (SY-3505) in Advanced ALK-Positive NSCLC: A Multicenter, Open-Label, Single-Arm, Phase 1/2 Study.

INTRODUCTION: Treatment options for second-generation (2nd-gen) ALK tyrosine kinase inhibitor (TKI)-resistant patients are limited. We evaluated the safety, pharmacokinetics, and efficacy of ficonalkib (SY-3505), a third-generation (3rd-gen) ALK TKI, in patients with advanced ALK-positive non-small cell lung cancer. METHODS: This first-in-human, phase 1/2 study (Chinese Clinical Trial Registry identifier: ChiCTR1900025619; ClinicalTrials.gov identifier: NCT05257512) had two parts. Phase 1 included a dose-escalation phase (25-800 mg quaque die [QD]) and a dose-expansion phase (500 mg QD or 600 mg QD). Phase 2 enrolled patients treated at recommended phase 2 dose. Primary end points were safety in phase 1 and objective response rate (ORR) in phase 2. RESULTS: Between April 21, 2020, and August 31, 2023, a total of 127 patients with advanced ALK-positive non-small cell lung cancer were enrolled, with 62 in phase 1. Ficonalkib was well absorbed and tolerated, with one dose-limited toxicity event occurring at 800 mg QD. Treatment-related adverse events occurred in 85.5% of patients, with 19.4% experienced greater than or equal to grade 3 events. The ORR was 38.3% (23 of 60, 95% confidence interval [CI]: 26.1%-51.8%) in phase 1, and 600 mg QD was established as recommended phase 2 dose. In phase 2, a total of 65 patients received ficonalkib at 600 mg QD. In total, 88 patients received ficonalkib at 600 mg QD in phase 1/2, and all had received prior 2nd-gen ALK TKI treatment. Furthermore, 90.9% of the patients experienced treatment-related adverse events and 14.8% experienced greater than or equal to grade 3 events. The ORR in efficacy-assessable patients who received ficonalkib at 600 mg QD was 47.5% (38 of 80, 95% CI: 36.2%-59.0%), with an intracranial ORR of 37.5% (12 of 32, 95% CI: 21.1%-56.3%) in these patients with measurable brain lesions at baseline. CONCLUSIONS: Ficonalkib (SY-3505) was well tolerated, with favorable safety profiles and promising efficacy in patients resistant to prior 2nd-gen ALK TKI.

Modulation of gut microbiota: a novel approach to enhancing the effects of immune checkpoint inhibitors.

Although immune checkpoint inhibitors (ICIs) have greatly improved the prognosis of some cancer patients, the majority still fail to respond adequately, and the available biomarkers cannot reliably predict drug efficacy. The gut microbiota has received widespread attention among the various intrinsic and extrinsic factors contributing to drug resistance. As an essential regulator of physiological function, the impact of gut microbiota on host immunity and response to cancer therapy is increasingly recognized. Several studies have demonstrated significant differences in gut microbiota between responders and nonresponders. The gut microbiota associated with better clinical outcomes is called 'favorable gut microbiota'. Significantly, interventions can alter the gut microbiota. By shifting the gut microbiota to the 'favorable' one through various modifications, preclinical and clinical studies have yielded more pronounced responses and better clinical outcomes when combined with ICIs treatment, providing novel approaches to improve the efficacy of cancer immunotherapy. These findings may be attributed to the effects of gut microbiota and its metabolites on the immune microenvironment and the systemic immune system, but the underlying mechanisms remain to be discovered. In this review, we summarize the clinical evidence that the gut microbiota is strongly associated with the outcomes of ICI treatment and describe the gut microbiota characteristics associated with better clinical outcomes. We then expand on the current prevalent modalities of gut microbiota regulation, provide a comprehensive overview of preclinical and clinical research advances in improving the therapeutic efficacy and prognosis of ICIs by modulating gut microbiota, and suggest fundamental questions we need to address and potential directions for future research expansion.

Abnormal generation of IL-17A represses tumor infiltration of stem-like exhausted CD8+ T cells to demote the antitumor immunity.

BACKGROUND: Variated anti-cancer therapies are combined with immune checkpoint blockades (ICBs) for improving ICB therapeutic efficacy. Occurrence of tissue damage is common that triggers multiple inflammatory cytokine generation. Gastrointestinal organs are the commonly affected. We investigated the impact of acute colitis on tumor infiltration of antigen-specific CD8+ cytotoxic T lymphocytes (CTLs) for controlling tumor growth and responding to antibody against PD-1 (anti-PD-1). METHODS: Several tumor cell lines were inoculated into syngeneic mice subcutaneously or intra-hepatically. When tumor mass formed, activated CTLs were intravenously transferred into the tumor-bearing mice, that were given the drinking water containing 2% dextran sulfate sodium (DSS) for acute colitis induction. Tumor growth, infiltration of two exhausted CTL subsets, and the CTL interaction with tumor vascular endothelium were examined. RESULTS: Acute colitis dampened CTL-mediated antitumor effects, correlating with IL-17A elevation in the inflamed intestine. In the tumor bed, stem-like exhausted CTLs, which were defined as PD-1+Slamf6+Tim3-, expressed higher IL-17A receptor heterodimers and lower leukocyte function-associated antigen-1 (LFA-1) than terminally exhausted CTLs did, that were defined as PD-1+Slamf6-Tim3+. IL-17A stimulation reduced LFA-1 surface expression on stem-like exhausted CTLs and the counterpart ICAM-1 (intracellular adhesion molecule-1) on tumor vascular endothelium. IL-17A stimulation suppressed the extravasation across tumor vascular endothelium and self-renewal of stem-like, not the terminally exhausted CTLs. Administration of anti-IL-17A neutralizing antibody to the colitis mice restored the CTL tumor infiltration and enhanced anti-PD-1 treatment efficacy against tumors. In 33 hepatocellular carcinoma patients being treated with anti-PD-1 plus antibody against vascular endothelial growth factor, disease progression of 15 patients, that exhibited serum IL-17A increase 24 h post-therapy as compared to pre-therapy level, was poorer than that of 18 patients that exhibited serum IL-17A no-increase. CONCLUSIONS: Abnormal generation of IL-17A mainly repressed tumor infiltration of stem-like exhausted CTLs. ICB-based immunotherapeutic efficacy could be upgraded with administration of anti-IL-17A, when treatment-related IL-17A elevation occurred due to tissue damage, such as acute colitis.

Exploration of the immunogenetic landscape of hyperprogressive disease after combined immunotherapy in cancer patients.

The immune-genetic changes that occur in cancer patients experiencing hyperprogressive disease (HPD) during combined immunotherapy are unclear. In this study, HPD patients with pre- and post-HPD samples and non-HPD patients with solid tumors were molecularly characterized by genetic and tumor immune microenvironment (TiME) analyses of paired samples by whole-exome sequencing, RNA sequencing, and multiplex immunofluorescence. The genetic analysis of paired samples showed that almost all the tumor driver gene mutations were preserved between pre- and post-HPD tumors. HPD patients had higher frequencies of mutations in TP53 and CNN2, and a significantly higher mutant-allele tumor heterogeneity than non-HPD patients. Tumor IL-6 mRNA was upregulated in post-HPD samples vs. pre-HPD, accompanied by a potential immune suppressive TiME with an elevated M2/M1 ratio. Salvage treatment with irinotecan plus bevacizumab was effective in one HPD patient, who experienced prolonged survival. These genetic features and TiME characteristics might help identify the features of HPD after immunotherapy.

Nab-paclitaxel plus tegafur gimeracil oteracil potassium capsule (S-1) as first-line treatment for advanced biliary tract adenocarcinoma: a phase 2 clinical trial.

Background: This study aimed to evaluate the efficacy and safety of a new combination of nab-paclitaxel plus tegafur gimeracil oteracil potassium capsule (S-1) for patients with advanced biliary tract carcinoma (BTC). Methods: Patients were treated with nab-paclitaxel at a dose of 125 mg/m2 on day 1 and 8, and S-1, 80 to 120 mg/day on days 1-14 of a 21-day cycle. Treatments were repeated until disease progression or unacceptable toxicity occurred. The primary endpoint was objective response rate (ORR). The secondary endpoints were median progression-free survival (PFS), overall survival (OS), and adverse events (AEs). Results: The number of patients enrolled were 54, and 51 patients were evaluated for efficacy. A total of 14 patients achieved partial response (PR) with an ORR of 27.5%. The ORR varied by sites, with 53.8% (7/13) for gallbladder carcinoma, 18.4% (7/38) for cholangiocarcinoma. The most common grade 3 or 4 toxicities were neutropenia and stomatitis. The median PFS and OS were 6.0 and 13.2 months, respectively. Conclusions: The combination of nab-paclitaxel with S-1 showed explicit antitumor activities and favorable safety profile in advanced BTC and could serve as a potential non-platinum and -gemcitabine-based regimen.

NRP1 inhibition modulates radiosensitivity of medulloblastoma by targeting cancer stem cells.

BACKGROUND: Medulloblastoma (MB) is the most common pediatric malignant brain tumor. Despite current therapies, the morbidity and recurrent risk remains significant. Neuropilin-1 receptor (NRP1) has been implicated in the tumor progression of MB. Our recent study showed that NRP1 inhibition stimulated MB stem cells differentiation. Consequently, we hypothesized that targeting NRP1 in medulloblastoma could improve current treatments. METHODS: NRP1 inhibition with a novel peptidomimetic agent, MR438, was evaluated with radiotherapy (RT) in MB models (DAOY, D283-Med and D341-Med) in vitro on cancer stem-like cells as well as in vivo on heterotopic and orthotopic xenografts. RESULTS: We show that NRP1 inhibition by MR438 radiosensitizes MB stem-like cells in vitro. In heterotopic DAOY models, MR438 improves RT efficacy as measured by tumor growth and mouse survival. In addition, clonogenic assays after tumor dissociation showed a significant reduction in cancer stem cells with the combination treatment. In the same way, a benefit of the combined therapy was observed in the orthotopic model only for a low cumulative irradiation dose of 10 Gy but not for 20 Gy. CONCLUSIONS: Finally, our results demonstrated that targeting NRP1 with MR438 could be a potential new strategy and could limit MB progression by decreasing the stem cell number while reducing the radiation dose.

Pancancer analysis of a potential gene mutation model in the prediction of immunotherapy outcomes.

Background: Immune checkpoint blockade (ICB) represents a promising treatment for cancer, but predictive biomarkers are needed. We aimed to develop a cost-effective signature to predict immunotherapy benefits across cancers. Methods: We proposed a study framework to construct the signature. Specifically, we built a multivariate Cox proportional hazards regression model with LASSO using 80% of an ICB-treated cohort (n = 1661) from MSKCC. The desired signature named SIGP was the risk score of the model and was validated in the remaining 20% of patients and an external ICB-treated cohort (n = 249) from DFCI. Results: SIGP was based on 18 candidate genes (NOTCH3, CREBBP, RNF43, PTPRD, FAM46C, SETD2, PTPRT, TERT, TET1, ROS1, NTRK3, PAK7, BRAF, LATS1, IL7R, VHL, TP53, and STK11), and we classified patients into SIGP high (SIGP-H), SIGP low (SIGP-L) and SIGP wild type (SIGP-WT) groups according to the SIGP score. A multicohort validation demonstrated that patients in SIGP-L had significantly longer overall survival (OS) in the context of ICB therapy than those in SIGP-WT and SIGP-H (44.00 months versus 13.00 months and 14.00 months, p < 0.001 in the test set). The survival of patients grouped by SIGP in non-ICB-treated cohorts was different, and SIGP-WT performed better than the other groups. In addition, SIGP-L + TMB-L (approximately 15% of patients) had similar survivals to TMB-H, and patients with both SIGP-L and TMB-H had better survival. Further analysis on tumor-infiltrating lymphocytes demonstrated that the SIGP-L group had significantly increased abundances of CD8+ T cells. Conclusion: Our proposed model of the SIGP signature based on 18-gene mutations has good predictive value for the clinical benefit of ICB in pancancer patients. Additional patients without TMB-H were identified by SIGP as potential candidates for ICB, and the combination of both signatures showed better performance than the single signature.

Serum Concentration of CD137 and Tumor Infiltration by M1 Macrophages Predict the Response to Sintilimab plus Bevacizumab Biosimilar in Advanced Hepatocellular Carcinoma Patients.

PURPOSE: This study aimed to investigate the biomarkers of sintilimab (anti-PD-1) plus IBI305 (a bevacizumab biosimilar) in advanced hepatocellular carcinoma (HCC), as well as their safety and efficacy. PATIENTS AND METHODS: A total of 50 patients with advanced HCC received sintilimab (200 mg) plus IBI305 (7.5 or 15 mg/kg), treated every 3 weeks in a phase Ib clinical study. We performed baseline serum cytokine analysis using bead-based multiplex immunoassay and multiplex immunofluorescence on tissue specimens to discover novel biomarkers of response to VEGF/PD-1 combination therapy in HCC. RESULTS: The overall response rate was 34.0% (17/50). The median progression-free survival (PFS) and the median overall survival were 10.5 and 20.2 months, respectively. The incidence of grade 3 to 5 adverse events was lower in the 7.5 mg/kg (13.8%) than in the 15 mg/kg (28.6%) dose groups. Biomarker analysis showed that the serum CD137 concentration was significantly higher in patients with clinical benefit (CB) than in those without CB (median, 32.8 pg/mL vs. 19.8 pg/mL, P = 0.034). A markedly longer PFS was observed in patients with high CD137 concentrations compared with those with low concentrations (median, 14.2 months vs. 4.1 months, P = 0.001). The higher density of M1 macrophages (CD68+CD163-) in the stroma was also associated with higher efficacy (P = 0.033) and a longer PFS (P = 0.024). CONCLUSIONS: Sintilimab plus IBI305 was well tolerated and was effective therapy for advanced HCC. Both serum concentrations of CD137 and tumor infiltration of M1 macrophages may serve as potential predictive biomarkers. See related commentary by Cappuyns and Llovet, p. 3405.

Chinese expert recommendations on management of hepatocellular carcinoma during COVID-19 pandemic: a nationwide multicenter survey.

BACKGROUND: This study aimed to investigate the work status of clinicians in China and their management strategy alteration for patients with hepatocellular carcinoma (HCC) during the COVID-19 pandemic. METHODS: A nationwide online questionnaire survey was conducted in 42 class-A tertiary hospitals across China. Experienced clinicians of HCC-related specialties responded with their work status and management suggestions for HCC patients during the pandemic. RESULTS: 716 doctors responded effectively with a response rate of 60.1%, and 664 were included in the final analysis. Overall, 51.4% (341/664) of clinicians reported more than a 60% reduction of the regular workload and surgeons declared the highest proportion of workload reduction. 92.5% (614/664) of the respondents have been using online medical consultation to substitute for the "face-to-face" visits. Adaptive adjustment for the treatment strategy for HCC was made, including the recommendations of noninvasive and minimally invasive treatments such as transcatheter arterial chemoembolization for early and intermediate stage. Targeted therapy has been the mainstay for advanced stage and also as a bridge therapy for resectable HCC. DISCUSSION: During the COVID-19 pandemic, online medical consultation is recommended to avoid social contact. Targeted therapy as a bridge therapy is recommended for resectable HCC considering the possibility of delayed surgery.

Advanced development of biomarkers for immunotherapy in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common liver cancer and one of the leading causes of cancer-related deaths in the world. Mono-immunotherapy and combination therapy with immune checkpoint inhibitors (ICIs) and multitargeted tyrosine kinase inhibitors (TKIs) or anti-vascular endothelial growth factor (anti-VEGF) inhibitors have become new standard therapies in advanced HCC (aHCC). However, the clinical benefit of these treatments is still limited. Thus, proper biomarkers which can predict treatment response to immunotherapy to maximize clinical benefit while sparing unnecessary toxicity are urgently needed. Contrary to other malignancies, up until now, no acknowledged biomarkers are available to predict resistance or response to immunotherapy for HCC patients. Furthermore, biomarkers, which are established in other cancer types, such as programmed death ligand 1 (PD-L1) expression and tumor mutational burden (TMB), have no stable predictive effect in HCC. Thus, plenty of research focusing on biomarkers for HCC is under exploration. In this review, we summarize the predictive and prognostic biomarkers as well as the potential predictive mechanism in order to guide future research direction for biomarker exploration and clinical treatment options in HCC.

Evaluation of COVID-19 based on ACE2 expression in normal and cancer patients.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is now a serious public health problem. Angiotensin-converting enzyme 2 (ACE2) recognized as the receptor of SARS-CoV is also necessary for SARS-CoV-2. However, the impact of ACE2 on SARS-CoV-2 susceptibility and the situation of malignant tumor patients in this outbreak are unclear. So, it is important to understand the expressions of ACE2 in different normal tissues and cancers. The results showed that the kidneys, duodenum, intestine, gallbladder and testis had the highest ACE2 expressions, followed by the colon, rectum and seminal vesicles. The lungs had a very low expression. ACE2 expressions were upregulated in renal cancer, gastrointestinal tumor and lung cancer. ACE2 expression levels may affect SARS-CoV-2 infection and severity. A total of 3,421 cases with COVID-19 have been collected. Among them, 43 cases (1.26%) had malignant tumor coexisting conditions. The rate of severe events for malignant tumor patients was 39.02% (16/41), while the rate of severe events for all patients was 10.79% (194/1,798). The clinical symptoms and signs were studied for the following three systems: respiratory (31-92%), digestive (10-13%) and urinary systems (3.38%). It seems that symptom severity is not related to protein expression levels. This might be the reason for SARS-CoV-2 showing higher regeneration index and susceptibility. More research is needed to explore the mechanisms and treatments.

Stimulation of medulloblastoma stem cells differentiation by a peptidomimetic targeting neuropilin-1.

Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Despite the progress of new treatments, the risk of recurrence, morbidity, and death remains important. The neuropilin-1 (NRP-1) receptor has recently been implicated in tumor progression of MB, which seems to play an important role in the phenotype of cancer stem cells. Targeting this receptor appears as an interesting strategy to promote MB stem cells differentiation. Cancer stem-like cells of 3 MB cell lines (DAOY, D283-Med and D341-Med), classified in the more pejorative molecular subgroups, were obtained by in vitro enrichment. These models were characterized by an increase of NRP-1 and cancer stem cell markers (CD15, CD133 and Sox2), meanwhile a decrease of the differentiated cell marker Neurofilament-M (NF-M) was observed. Our previous work investigated potential innovative peptidomimetics that specifically target NRP-1 and showed that MR438 had a good affinity for NRP-1. This small molecule decreased the self-renewal capacity of MB stem cells for the 3 cell lines and reduced the invasive ability of DAOY and D283 stem cells while NRP-1 expression and cancer stem cell markers decreased at the same time. Possible molecular mechanisms were explored and showed that the activation of PI3K/AKT and MAPK pathways significantly decreased for DAOY cells after treatment. Finally, our results highlighted that targeting NRP-1 with MR438 could be a potential new strategy to differentiate MB stem cells and could limit medulloblastoma progression.

Electrolyte disorders assessment in solid tumor patients treated with anti-EGFR monoclonal antibodies: a pooled analysis of 25 randomized clinical trials.

The role of anti-epithelial growth factor receptor monoclonal antibodies (anti-EGFR MoAbs) in treatment-related electrolyte disorders is still controversial. Therefore, we conducted a meta-analysis of published randomized controlled trials (RCTs) to evaluate the incidences and overall risks of all-grade and grade 3/4 electrolyte disorder events. We searched relevant clinical trials from PubMed, EMBASE, and Web of Knowledge databases, meeting proceedings of American Society of Clinical Oncology and the European Society of Medical Oncology, as well as ClinicalTrials.gov. Eligible studies included phases II, III, and IV RCTs. Statistical analysis was performed to calculate the summary incidence, relative risk (RR), and 95 % confidence intervals (CIs) using fixed effects or random effects models based on the heterogeneity of included studies. A total of 16,411 patients from 25 RCTs were included in this meta-analysis. The all-grade incidence of hypomagnesemia related to anti-EGFR MoAbs was 34.0 % (95 % CI 28.0-40.5 %), and that for hypokalemia and hypocalcemia were 14.5 % (95 % CI 8.2-24.4 %) and 16.8 % (95 % CI 14.2-19.7 %), respectively. Compared with chemotherapy alone in colorectal cancer, addition of cetuximab increased the risk of grade 3/4 hypomagnesemia and grade 3/4 hypokalemia with RRs of 7.14 (95 % CI 3.13-16.27, p < 0.001) and 2.19 (95 % CI 1.14-4.23, p = 0.019). Additionally, colorectal cancer patients in panitumumab cases were more vulnerable to grade 3/4 hypomagnesemia and hypokalemia (RR 18.29, 95 % CI 7.29-48.41, p < 0.001, and RR 3.3, 95 % CI 1.32-8.25, p = .011). Treatment with anti-EGFR MoAbs is associated with significantly higher risks of electrolyte disorders such as hypomagnesemia, hypomagnesemia, and hypocalcemia, especially in colorectal cancer. Rigorous monitoring and early treatment of electrolyte disorders are proposed.