Comparing the difference of adverse events with HER2 inhibitors: a study of the FDA adverse event reporting system (FAERS).

Aim and background: This study attempted to identify similarities and differences in adverse events (AEs) between human epidermal growth factor receptor 2 (HER2) inhibitors, especially those related to hemorrhagic events and nervous system disorders. Methods: This study summarized the types, frequencies, and system organ classes (SOCs) of AEs of HER2 inhibitors. The US Food and Drug Administration Adverse Event Reporting System (FAERS) data from January 2004 through March 2022 was collected and analyzed. Disproportionality analyses were conducted to detect AEs signals for every HER2 inhibitor. The chi-square test, Wilcoxon test, and descriptive analysis were used to compare the differences of AEs for specific SOCs or drugs. Results: A total of 47,899 AE reports were obtained for eight HER2 inhibitors. Trastuzumab-related AEs were reported in the highest number and combination of regimens. In monotherapy, trastuzumab had the highest reported rate of cardiac disorders-related AEs (24.0%). However, small-molecule drugs exceeded other drugs in the reported rates of AEs related to gastrointestinal disorders, metabolism and nutrition disorders. The highest reported rates of respiratory disorders (47.3%) and hematologic disorders (22.4%) were associated with treatment with trastuzumab deruxtecan (T-DXd). Patients treated with trastuzumab emtansine (TDM-1) had the highest reported rate (7.28%) of hemorrhagic events, especially intracranial haemorrhage events. In addition, patients treated with TDM-1 with concomitant thrombocytopenia were likely to experience hemorrhagic events compared to other HER2 inhibitors (p < 0.001). The median time to onset of intracranial haemorrhage associated with trastuzumab (0.5 months) and TDM-1 (0.75 months) was short. However, there was no significant difference in median time to onset intracranial haemorrhage between patients in different age groups or with different outcomes. Disproportionality analysis results reveal that cerebral haemorrhage is a positive signal associated with T-DXd and TDM-1. In addition, tucatinib was the drug with the highest rate of reported nervous system disorders (31.38%). Memory impairment (83 cases) is a positive signal for tucatinib. Conclusion: The types and reporting rates of AEs associated with different HER2 inhibitors vary across multiple systems. In addition, hemorrhagic events concomitant with TDM-1 treatment and nervous system disorders concomitant with tucatinib treatment may be worthy of attention.

Efficacies of anlotinib monotherapy versus gemcitabine-based chemotherapy for patients with advanced soft tissue sarcoma after the failure of anthracycline-based chemotherapy.

OBJECTIVE: The purpose of this study was to compare the antitumor efficacy of anlotinib with gemcitabine-based chemotherapy as subsequent treatment regimens in patients with advanced non-specific soft tissue sarcoma (STS) after the failure of anthracycline-based chemotherapy. METHODS: Patients diagnosed with advanced STS who were treated with either anlotinib or gemcitabine-based chemotherapy between May 2009 and May 2023 in our center were eligible. All patients experienced disease progression or recurrence after the anthracycline-based chemotherapy. The primary endpoint was progression-free survival (PFS). Secondary endpoints were disease control rate (DCR), overall survival (OS) and safety. RESULTS: We included 49 patients receiving anlotinib and 45 patients receiving gemcitabine-based chemotherapy. The median follow-up time was 76.9 weeks (range 2.9-678.9 weeks). The DCR (65.3% vs. 57.8%; p = 0.610), PFS (24.0 weeks vs. 18.6 weeks; p = 0.669) and OS (79.4 weeks vs. 87.0 weeks; p = 0.471) of anlotinib and gemcitabine-based chemotherapy indicated similar clinical efficacy. Moreover, exploratory subgroup analyses showed that patients with STS originating from limbs and trunk were inclined to benefit from anlotinib treatment (median PFS: 31.3 weeks vs. 12.4 weeks; p = 0.045). ECOG PS was an independent predictor of the PFS [Hazard Ratio (HR) 0.31; 95% confidence interval (CI) 0.11-0.85; p = 0.023] and OS (HR 0.26, 95%CI 0.10-0.70; p = 0.008) in the anlotinib group. While neutrophil-to-lymphocyte ratio (NLR) was an independent prognostic factor of the PFS (HR 0.33, 95%CI 0.11-0.98; p = 0.045) in the gemcitabine-based chemotherapy group. The incidence of grade 3 or higher related AEs in anlotinib and gemcitabine-based chemotherapy was 20.4% (n = 10) and 20.0% (n = 9), respectively. CONCLUSION: Our research suggested that anlotinib and gemcitabine-based chemotherapy showed similar clinical efficacy and safety in the subsequent treatment of advanced STS after the failure of anthracycline-based chemotherapy.

Evaluation of cardiotoxicity of anthracycline-containing chemotherapy regimens in patients with bone and soft tissue sarcomas: A study of the FDA adverse event reporting system joint single-center real-world experience.

OBJECTIVES: To assess the occurrence of cardiotoxicity in patients with tumors receiving anthracycline-based chemotherapy, especially for sarcomas. METHODS: This study summarized the types and frequency of adverse events (AEs) for three anthracyclines from the FDA adverse event reporting system (FAERS) database. FAERS data from January 2004 to June 2022 were collected and analyzed. Disproportionality analyses, logistic regression, and descriptive analysis were used to compare the differences in cardiac disorders. A retrospective cohort study was conducted in a single center between December 2008 and May 2022. Our hospital-treated patients with bone and soft tissue sarcomas (BSTSs) with anthracycline-containing chemotherapy were analyzed. Serum markers, echocardiography, and electrocardiography have been used to evaluate cardiotoxic events. RESULTS: One hundred thousand and seventy-five AE reports were obtained for doxorubicin (ADM), epirubicin (EPI), and liposome doxorubicin (L-ADM) from the FAERS database. ADM (OR = 3.1, p < 0.001), EPI (OR = 1.5, p < 0.001), and sarcomas (OR = 1.8, p < 0.001) may increase the probability of cardiac disorders. Cardiac failure, cardiotoxicity, and cardiomyopathy were anthracyclines' top 3 frequent AEs. Among patients receiving ADM-containing therapy, those with ADM applied at doses ≥75 mg/m2 /cycle were more likely to develop cardiac disorders than the other subgroups (OR = 3.5, p < 0.001). Patients younger than 18 are more likely to benefit from dexrazoxane prevention of cardiac failure. Six hundred and eighty-three patients with BSTSs receiving anthracycline-based chemotherapy were analyzed in our center. Patients receiving ADM-containing chemotherapy were likelier to experience abnormalities in serum troponin-T and left ventricular ejection fraction (p < 0.05). 2.0% (6/300) of patients receiving ADM-containing chemotherapy required adjustment of the chemotherapy regimen because of cardiotoxicity, whereas none were in the EPI or L-ADM groups. CONCLUSIONS AND RELEVANCE: Among patients receiving anthracycline-containing therapy, patients with BSTSs were more likely to develop cardiac disorders than other tumors. In addition, patients with BSTSs receiving ADM chemotherapy had a higher likelihood of cardiotoxic events than those receiving EPI or L-ADM.

Association of NRAS mutations and tertiary lymphoid structure formation with clinical outcomes of adjuvant PD-1 inhibitors for acral melanoma.

OBJECTIVES: This study evaluates the efficacy of programmed death-1 (PD-1) inhibitors as adjuvant therapy for acral melanoma (AM) and the predictive value of genetic mutations and tertiary lymphoid structures (TLSs). METHODS AND RESULTS: A single-center retrospective longitudinal cohort study was conducted between October 1, 2018, and September 31, 2022. Patients with stages II-III completely resected AM were treated with at least two doses of adjuvant PD-1 inhibitors. A total of 44 participants were included in the final analysis, of which 41 patients with stage III. The median follow-up time, median relapse-free survival (RFS), and median distance metastasis-free survival (DMFS) for all patients were 18.4 months, 21.6 months, and 30.6 months, respectively. 21 (47.7%) and 20 (45.5%) patients were intravenously administered pembrolizumab and toripalimab, respectively. There were no significant differences in RFS (24.4 months vs. 18.9 months, p = 0.432) or DMFS (30.6 months vs. not reached, p = 0.865) between the pembrolizumab and toripalimab groups, respectively. The median DMFS (41.1 months vs. 9.0 months, p < 0.001) in the wild-type NRAS group was significantly longer than that in the NRAS mutation group. Overall, different levels of TLSs infiltration did not significantly affect patient survival. Only three people discontinued treatment due to adverse events. No treatment-related death occurred during the study period. CONCLUSION: Our study suggests that adjuvant toripalimab and pembrolizumab therapy have comparable efficacies in patients with AM and are both well tolerated. Adjuvant monotherapy with PD-1 inhibitors may not be appropriate for AM with NRAS mutations.

A PD-L1-targeting chimeric switch receptor enhances efficacy of CAR-T cell for pleural and peritoneal metastasis.

Pleural and peritoneal metastasis accompanied by malignant pleural effusion (MPE) or malignant ascites (MA) is frequent in patients with advanced solid tumors that originate from the lung, breast, gastrointestinal tract and ovary. Regional delivery of CAR-T cells represents a new strategy to control tumor dissemination in serous cavities. However, malignant effusions constitute an immune-suppressive environment that potentially induces CAR-T cell dysfunction. Here, we demonstrated that the anti-tumor cytotoxicity of conventional 2nd-generation CAR-T cells was significantly inhibited by both the cellular and non-cellular components of MPE/MA, which was primarily attributed to impaired CAR-T cell proliferation and cytokine production in MPE/MA environment. Interestingly, we found that PD-L1 was widely expressed on freshly-isolated MPE/MA cells. Based on this feature, a novel PD-L1-targeting chimeric switch receptor (PD-L1.BB CSR) was designed, which can bind to PD-L1, switching the inhibitory signal into an additional 4-1BB signal. When co-expressed with a 2nd-generation CAR, PD-L1.BB CSR-modified CAR-T cells displayed superior fitness and enhanced functions in both culture medium and MPE/MA environment, causing rapid and durable eradication of pleural and peritoneal metastatic tumors in xenograft models. Further investigations revealed elevated expressions of T-cell activation, proliferation, and cytotoxicity-related genes, and we confirmed that PD-L1 scFv and 4-1BB intracellular domain, the two important components of PD-L1.BB CSR, were both necessary for the functional improvements of CAR-T cells. Overall, our study shed light on the clinical application of PD-L1.BB CSR-modified dual-targeting CAR-T cells. Based on this study, a phase I clinical trial was initiated in patients with pleural or peritoneal metastasis (NCT04684459).

Low-Dose Radiation Therapy Promotes Radiation Pneumonitis by Activating NLRP3 Inflammasome.

PURPOSE: To determine the role of NLRP3 inflammasome activation in low-dose radiation-induced radiation pneumonitis (RP) and to assess whether inhibition or deletion of the NLRP3 inflammasome is critical for conferring protection against RP. METHODS AND MATERIALS: The human monocytic THP-1 cells were treated with increasing doses of radiation to assess the activation of NLRP3 by Western blot and enzyme-linked immunosorbent assay. Reactive oxygen species (ROS) production was measured by flow cytometry, with or without ROS inhibitor treatment. A mouse thoracic radiation model that received different doses of radiation was used, and the lung tissues of thoracic-irradiated nlrp3-/- and wild-type C57BL/6 mice were examined by hematoxylin and eosin and immunofluorescence staining. The concentrations of cytokines in the bronchoalveolar lavage fluid were measured by enzyme-linked immunosorbent assay and Luminex multiplex assays. Lipopolysaccharide (LPS) was administered intranasally 28 days after thoracic irradiation, and NLRP3 inhibitor, MCC950 was administered intraperitoneally after irradiation at 2 different doses. RESULTS: (1) The NLRP3 inflammasome was activated in 2 Gy irradiated THP-1 cells; NLRP3 and cleaved-caspase-1 levels were not associated with dose escalation of irradiation. (2) Activation of the NLRP3 inflammasome was mediated by ROS, and ROS inhibitor treatment decreased the production of IL-1ß and IL-18 in vitro. (3) NLRP3 was activated in mouse lungs by irradiation at 2 Gy, 4 Gy, and 16 Gy, and NLRP3 activation was continuous for 8 weeks. (4) NLRP3 deletion protects against LPS-mediated monocyte infiltration in the mouse lung. (5) The administration of MCC950 decreased the inflammation score of the mice irradiated with 2 Gy or 16 Gy in vivo. CONCLUSIONS: Our results indicate that the NLRP3 inflammasome is activated by low-dose irradiation both in vitro and in vivo. Inhibition or deletion of NLRP3 can specifically alleviate the mouse lung inflammation caused by radiation and LPS treatment. This study reveals the mechanism of low-dose radiation therapy-induced RP and offers a possible treatment strategy.

[The Construction of ROR1 Targeting Chimeric Antigen Receptor Modified T Cells and Its Killing Effect for ROR1-positive Tumor Cells].

OBJECTIVE: To test the killing effect of type Ⅰ receptor tyrosine kinase-like orphan receptor (ROR1) chimeric antigen receptor T cell (CAR-T) on several ROR1-expressing tumor cells in vitro. METHODS: The CAR gene was designed and synthesized by constructing the lentiviral vector plasmid, and BamHⅠ/EcoRⅠ was used to identify the plasmid. The expression levels of ROR1 among a variety of tumor cell lines were compared using flow cytometry (FCM). The killing effect of CAR-T on positive cells was detected by FCM, the LDH assay and ELISA. RESULTS: The double enzyme digestion identified CAR gene was successfully constructed to the lentivirus vector plasmid. FCM detection showed that the efficiency of CAR-T infection was about 47.23%. Multiple tumor cells expressed ROR1 in varying degrees. The FCM and the LDH assay indicated that CAR-T specifically killed ROR1-positive tumor cells. On positive target cells, more interferonI-γ (FN-γ) could be released during the CAR-T killing process than control T (P<0.05). CONCLUSION: We successfully constructed ROR1 CAR-T. CAR-T can specifically kill ROR1-positive tumor cells and cause the release of large amounts of IFN-γ, providing an experimental basis for clinical application.

The Multi-Purpose Tool of Tumor Immunotherapy: Gene-Engineered T Cells.

A detailed summary of the published clinical trials of chimeric antigen receptor T cells (CAR-T) and TCR-transduced T cells (TCR-T) was constructed to understand the development trend of adoptive T cell therapy (ACT). In contrast to TCR-T, the number of CAR-T clinical trials has increased dramatically in China in the last three years. The ACT seems to be very prosperous. But, the multidimensional interaction of tumor, tumor associated antigen (TAA) and normal tissue exacerbates the uncontrolled outcome of T cells gene therapy. It reminds us the importance that optimizing treatment security to prevent the fatal serious adverse events. How to balance the safety and effectiveness of the ACT? At least six measures can potentially optimize the safety of ACT. At the same time, with the application of gene editing techniques, more endogenous receptors are disrupted while more exogenous receptors are expressed on T cells. As a multi-purpose tool of tumor immunotherapy, gene-engineered T cells (GE-T) have been given different functional weapons. A network which is likely to link radiation therapy, tumor vaccines, CAR-T and TCR-T is being built. Moreover, more and more evidences indicated that the combination of the ACT and other therapies would further enhance the anti-tumor capacity of the GE-T.

Malignant Pleural Effusion and ascites Induce Epithelial-Mesenchymal Transition and Cancer Stem-like Cell Properties via the Vascular Endothelial Growth Factor (VEGF)/Phosphatidylinositol 3-Kinase (PI3K)/Akt/Mechanistic Target of Rapamycin (mTOR) Pathway.

Malignant pleural effusion (PE) and ascites, common clinical manifestations in advanced cancer patients, are associated with a poor prognosis. However, the biological characteristics of malignant PE and ascites are not clarified. Here we report that malignant PE and ascites can induce a frequent epithelial-mesenchymal transition program and endow tumor cells with stem cell properties with high efficiency, which promotes tumor growth, chemoresistance, and immune evasion. We determine that this epithelial-mesenchymal transition process is mainly dependent on VEGF, one initiator of the PI3K/Akt/mechanistic target of rapamycin (mTOR) pathway. From the clinical observation, we define a therapeutic option with VEGF antibody for malignant PE and ascites. Taken together, our findings clarify a novel biological characteristic of malignant PE and ascites in cancer progression and provide a promising and available strategy for cancer patients with recurrent/refractory malignant PE and ascites.

Hurdles of CAR-T cell-based cancer immunotherapy directed against solid tumors.

Recent reports on the impressive efficacy of chimeric antigen receptor (CAR)-modified T cells against hematologic malignancies have inspired oncologists to extend these efforts for the treatment of solid tumors. Clinical trials of CAR-T-based cancer immunotherapy for solid tumors showed that the efficacies are not as remarkable as in the case of hematologic malignancies. There are several challenges that researchers must face when treating solid cancers with CAR-T cells, these include choosing an ideal target, promoting efficient trafficking and infiltration, overcoming the immunosuppressive microenvironment, and avoiding associated toxicity. In this review, we discuss the obstacles imposed by solid tumors on CAR-T cell-based immunotherapy and strategies adopted to improve the therapeutic potential of this approach. Continued investigations are necessary to improve therapeutic outcomes and decrease the adverse effects of CAR-T cell therapy in patients with solid malignancies in the future.

Intensity-modulated radiation therapy versus 2D-RT or 3D-CRT for the treatment of nasopharyngeal carcinoma: A systematic review and meta-analysis.

OBJECTIVE: To compare clinical treatment outcomes and late toxicities of intensity-modulated radiation therapy (IMRT) with those obtained with two-dimensional radiation therapy (2D-RT) or three-dimensional conformal radiation therapy (3D-CRT) in nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS: We searched all the eligible studies from the Cochrane Library, PubMed, Medline, and Embase. The meta-analysis was performed to compare odds ratio (OR) for overall survival (OS), tumor local control (LC), and late toxicities. RESULTS: A total of eight studies met the criteria to perform a meta-analysis including 3570 participants, with 1541 patients in the IMRT group and 2029 in the 2D-RT or 3D-CRT group. The IMRT group was associated with a better 5-year overall survival (OR=1.51; 95% confidence interval (CI) 1.23-1.87; p=0.0001), and tumor local control (LC) (OR=1.94; 95% CI 1.53-2.46; p<0.00001). According to CTCAE v3.0 (Common Terminology Criteria for Adverse Events) and RTOG/EORTC (Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer), the incidence of late xerostomia in those who received IMRT was significantly lower than that of the control group (OR=0.18; 95% CI, 0.07-0.46; p=0.0004). In addition, the radiation-induced chronic toxicities rate of trismus and temporal lobe neuropathy (TLN) were also significantly lower in the IMRT group than in the control group (OR=0.18; 95% CI 0.04-0.83; p=0.03; OR=0.44; 95% CI 0.28-0.69; p=0.0003, respectively). CONCLUSIONS: This systematic review and meta-analysis demonstrated that IMRT mayobtain a better antitumor effect, and significantly decrease the incidence of radiation-induced late toxicities in patients with NPC.