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Purpose: Since 2020, Atezolizumab plus bevacizumab (Ate/Bev) has been the standard first-line therapy for unresectable hepatocellular carcinoma (HCC), but long-term treatment studies are limited. This study evaluated the clinical characteristics and effects of Ate/Bev for over 1 year. Materials and Methods: This study included patients with unresectable HCC treated with first-line Ate/Bev between May 2020 and April 2022. Those receiving Ate/Bev for 1 year or more were classified as the long-term treatment group. Results: Of 246 patients, 69 (28.0%) were in the long-term treatment group, which comprised more proportions of intrahepatic tumor burden <25%, ECOG 0, and a lower proportion of portal vein tumor thrombosis than the short-term treatment group. The long-term treatment group had a higher incidence of atezolizumab-related thyroid dysfunction (31.9% vs. 10.7%, p<0.001; median time to onset [mTTO]: 2.8 months), dermatologic toxicity (29.0% vs. 14.7%, p=0.017; mTTO: 3.3 months), bevacizumab-related hypertension (44.9% vs. 22.0%, p=0.001; mTTO: 4.2 months), and proteinuria (69.6% vs. 38.4%, p<0.001; mTTO: 6.8 months), compared to the short-term treatment group. Regarding liver function in the long-term treatment group, patients initially classified as Child-Pugh class A decreased from 87% to 75.4%, and albumin-bilirubin grade 1 decreased from 68.1% to 50.7% after 1 year of treatment. Conclusion: The Ate/Bev long-term treatment group had a lower intrahepatic tumor burden, less portal vein tumor thrombosis, and better performance status and liver function at baseline. Atezolizumab-related immunological adverse events emerged relatively early in treatment compared to the bevacizumab-related. Additionally, some patients demonstrated liver function deterioration during long-term Ate/Bev treatment.
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Immune checkpoint inhibitor (ICI) became a standard treatment for advanced renal cell carcinoma (RCC). However, clinically valid biomarkers of therapeutic outcome are lacking. We investigated the role of interleukin-10 (IL-10) as a predictive biomarker for first-line ICI therapy in patients with advanced RCC. Baseline serum samples were prospectively collected and analyzed using a cytometric bead assay. Patients were divided into two groups according to their serum IL-10 levels using maximally selected rank statistics. A fraction (13.0%) of patients had high levels of serum IL-10 at baseline. High serum IL-10 levels (> 4.3 ng/mL) were associated with a significantly shorter progression-free (median: 5.2 months vs. not reached, P = 0.007) and overall survival (median: 13.9 months vs. not reached, P < 0.001). Multivariate Cox regression analysis confirmed the independent association between high serum IL-10 levels and poor survival outcomes. Effector cytokine production and the proliferative response of CD8+ T cells were significantly lower in patients with high serum IL-10 levels, who also had a shorter duration of response to first-line ICI therapy (4.6 months vs. not reached, P < 0.001). In conclusion, elevated serum IL-10 levels at baseline were associated with reduced clinical benefit from first-line ICI therapy in patients with advanced RCC.
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BACKGROUND: The predictive value of immune monitoring with circulating CD8+ T lymphocytes for treatment response to programmed cell death protein 1 (PD-1) inhibitors has not been explored in non-small-cell lung cancer (NSCLC), prompting us to investigate whether dynamic changes in PD-1+CD8+ T lymphocytes have predictive value for durable clinical benefit (DCB) and survival after PD-1 blockade. METHODS: Patients with recurrent and/or metastatic NSCLC treated with PD-1 inhibitors were enrolled (discovery cohort; n = 94). Peripheral blood was obtained immediately before and after one cycle of treatment with PD-1 blockade. Phenotyping of circulating CD8+ T lymphocytes was conducted using multi-colour flow cytometry. Predictive values of dynamic changes in circulating PD-1+CD8+ T lymphocytes during the first cycle were validated in an independent cohort (validation cohort; n = 54) of a prospective trial with a PD-1 inhibitor (NCT03486119). RESULTS: Circulating PD-1+CD8+ T lymphocytes were enriched with effector/memory populations with elevated expression of activation- and exhaustion-related markers. Reduction in the frequency of PD-1+ cells among CD8+ T lymphocytes after one cycle of treatment was associated with a higher probability of DCB and superior survival outcomes in the discovery cohort. Similar results were obtained in the analysis of tumour antigen NY-ESO-1-specific CD8+ T lymphocytes and the validation cohort. Mechanistically, PD-1 molecule expression on CD8+ T lymphocytes suppresses the effector functions of tumour antigen-specific CD8+ T lymphocytes. CONCLUSIONS: Dynamic changes in circulating PD-1+CD8+ T lymphocytes predict clinical, and survival benefit from PD-1 blockade treatment in NSCLC, providing a useful tool to identify patient subgroups who will optimally benefit from PD-1 inhibitors.
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Linfocitos T CD8-positivos/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Masculino , Persona de Mediana EdadRESUMEN
PURPOSE: Immune-checkpoint inhibitors have shown therapeutic efficacy in various malignant diseases. However, anti-programmed death (PD)-1 therapy has not shown clinical efficacy in multiple myeloma. EXPERIMENTAL DESIGN: Bone marrow (BM) mononuclear cells were obtained from 77 newly diagnosed multiple myeloma patients. We examined the expression of immune-checkpoint receptors in BM CD8+ T cells and their functional restoration by ex vivo treatment with anti-PD-1 and TGFß inhibitors. RESULTS: We confirmed the upregulation of PD-1 and PD-L1 expression in CD8+ T cells and myeloma cells, respectively, from the BM of multiple myeloma patients. PD-1-expressing CD8+ T cells from the BM of multiple myeloma patients coexpressed other checkpoint inhibitory receptors and exhibited a terminally differentiated phenotype. These results were also observed in BM CD8+ T cells specific to myeloma antigens NY-ESO-1 and HM1.24. BM CD8+ T cells from multiple myeloma patients exhibited reduced proliferation and cytokine production upon T-cell receptor stimulation. However, anti-PD-1 did not increase the proliferation of BM CD8+ T cells from multiple myeloma patients, indicating that T-cell exhaustion in multiple myeloma is hardly reversed by PD-1 blockade alone. Intriguingly, anti-PD-1 significantly increased the proliferation of BM CD8+ T cells from multiple myeloma patients in the presence of inhibitors of TGFß, which was overexpressed by myeloma cells. CONCLUSIONS: Our findings indicate that combined blockade of PD-1 and TGFß may be useful for the treatment of multiple myeloma.
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Anticuerpos Monoclonales/farmacología , Médula Ósea/inmunología , Linfocitos T CD8-positivos/inmunología , Mieloma Múltiple/tratamiento farmacológico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptores de Antígenos de Linfocitos T/inmunología , Factor de Crecimiento Transformador beta/antagonistas & inhibidores , Adulto , Anciano , Anciano de 80 o más Años , Médula Ósea/efectos de los fármacos , Médula Ósea/patología , Células Cultivadas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/inmunología , Mieloma Múltiple/patología , Receptor de Muerte Celular Programada 1/inmunología , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Although immune checkpoint blockade therapies have demonstrated clinical efficacy in cancer treatment, harnessing this strategy is largely encumbered by resistance in multiple cancer settings. Here, we show that tumor-infiltrating T cells are severely exhausted in the microsatellite stable (MSS) colorectal cancer (CRC), a representative example of PD-1 blockade-resistant tumors. In MSS CRC, we found wound healing signature to be up-regulated and that T cell exhaustion is driven by vascular endothelial growth factor-A (VEGF-A). We report that VEGF-A induces the expression of transcription factor TOX in T cells to drive exhaustion-specific transcription program in T cells. Using a combination of in vitro, ex vivo, and in vivo mouse studies, we demonstrate that combined blockade of PD-1 and VEGF-A restores the antitumor functions of T cells, resulting in better control of MSS CRC tumors.