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BACKGROUND: Engineered arenavirus vectors have recently been developed to leverage the body's immune system in the fight against chronic viral infections and cancer. Vectors based on Pichinde virus (artPICV) and lymphocytic choriomeningitis virus (artLCMV) encoding a non-oncogenic fusion protein of human papillomavirus (HPV)16 E6 and E7 are currently being tested in patients with HPV16+ cancer, showing a favorable safety and tolerability profile and unprecedented expansion of tumor-specific CD8+ T cells. Although the strong antigen-specific immune response elicited by artLCMV vectors has been demonstrated in several preclinical models, PICV-based vectors are much less characterized. METHODS: To advance our understanding of the immunobiology of these two vectors, we analyzed and compared their individual properties in preclinical in vivo and in vitro systems. Immunogenicity and antitumor effect of intratumoral or intravenous administration of both vectors, as well as combination with NKG2A blockade, were evaluated in naïve or TC-1 mouse tumor models. Flow cytometry, Nanostring, and histology analysis were performed to characterize the tumor microenvironment (TME) and T-cell infiltrate following treatment. RESULTS: Despite being phylogenetically distant, both vectors shared many properties, including preferential infection and activation of professional antigen-presenting cells, and induction of potent tumor-specific CD8+ T-cell responses. Systemic as well as localized treatment induced a proinflammatory shift in the TME, promoting the infiltration of inducible T cell costimulator (ICOS)+CD8+ T cells capable of mediating tumor regression and prolonging survival in a TC-1 mouse tumor model. Still, there was evidence of immunosuppression built-up over time, and increased expression of H2-T23 (ligand for NKG2A T cell inhibitory receptor) following treatment was identified as a potential contributing factor. NKG2A blockade improved the antitumor efficacy of artARENA vectors, suggesting a promising new combination approach. This demonstrates how detailed characterization of arenavirus vector-induced immune responses and TME modulation can inform novel combination therapies. CONCLUSIONS: The artARENA platform represents a strong therapeutic vaccine approach for the treatment of cancer. The induced antitumor immune response builds the backbone for novel combination therapies, which warrant further investigation.
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Arenavirus , Neoplasias , Infecciones por Papillomavirus , Vacunas contra Papillomavirus , Humanos , Ratones , Animales , Linfocitos T CD8-positivos , Proteínas E7 de Papillomavirus , Arenavirus/metabolismo , Neoplasias/terapia , Modelos Animales de Enfermedad , Terapia de Inmunosupresión , Microambiente TumoralRESUMEN
BACKGROUND: Tigilanol tiglate (TT) is a protein kinase C (PKC)/C1 domain activator currently being developed as an intralesional agent for the treatment of various (sub)cutaneous malignancies. Previous work has shown that intratumoral (I.T.) injection of TT causes vascular disruption with concomitant tumor ablation in several preclinical models of cancer, in addition to various (sub)cutaneous tumors presenting in the veterinary clinic. TT has completed Phase I dose escalation trials, with some patients showing signs of abscopal effects. However, the exact molecular details underpinning its mechanism of action (MoA), together with its immunotherapeutic potential in oncology remain unclear. METHODS: A combination of microscopy, luciferase assays, immunofluorescence, immunoblotting, subcellular fractionation, intracellular ATP assays, phagocytosis assays and mixed lymphocyte reactions were used to probe the MoA of TT in vitro. In vivo studies with TT used MM649 xenograft, CT-26 and immune checkpoint inhibitor refractory B16-F10-OVA tumor bearing mice, the latter with or without anti-programmed cell death 1 (PD-1)/anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) mAb treatment. The effect of TT at injected and non-injected tumors was also assessed. RESULTS: Here, we show that TT induces the death of endothelial and cancer cells at therapeutically relevant concentrations via a caspase/gasdermin E-dependent pyroptopic pathway. At therapeutic doses, our data demonstrate that TT acts as a lipotoxin, binding to and promoting mitochondrial/endoplasmic reticulum (ER) dysfunction (leading to unfolded protein responsemt/ER upregulation) with subsequent ATP depletion, organelle swelling, caspase activation, gasdermin E cleavage and induction of terminal necrosis. Consistent with binding to ER membranes, we found that TT treatment promoted activation of the integrated stress response together with the release/externalization of damage-associated molecular patterns (HMGB1, ATP, calreticulin) from cancer cells in vitro and in vivo, characteristics indicative of immunogenic cell death (ICD). Confirmation of ICD in vivo was obtained through vaccination and rechallenge experiments using CT-26 colon carcinoma tumor bearing mice. Furthermore, TT also reduced tumor volume, induced immune cell infiltration, as well as improved survival in B16-F10-OVA tumor bearing mice when combined with immune checkpoint blockade. CONCLUSIONS: These data demonstrate that TT is an oncolytic small molecule with multiple targets and confirms that cell death induced by this compound has the potential to augment antitumor responses to immunotherapy.
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Inhibidores de Puntos de Control Inmunológico , Muerte Celular Inmunogénica , Animales , Ratones , Muerte Celular Inmunogénica/efectos de los fármacos , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Línea Celular Tumoral , Femenino , Ensayos Antitumor por Modelo de Xenoinjerto , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Neoplasias/terapiaRESUMEN
BACKGROUND: Despite recent advances in immunotherapy, a substantial population of late-stage melanoma patients still fail to achieve sustained clinical benefit. Lack of translational preclinical models continues to be a major challenge in the field of immunotherapy; thus, more optimized translational models could strongly influence clinical trial development. To address this unmet need, we designed a preclinical model reflecting the heterogeneity in melanoma patients' clinical responses that can be used to evaluate novel immunotherapies and synergistic combinatorial treatment strategies. Using our all-autologous humanized melanoma mouse model, we examined the efficacy of a novel engineered interleukin 2 (IL-2)-based cytokine variant immunotherapy. METHODS: To study immune responses and antitumor efficacy for human melanoma tumors, we developed an all-autologous humanized melanoma mouse model using clinically annotated, matched patient tumor cells and peripheral blood mononuclear cells (PBMCs). After inoculating immunodeficient NSG mice with patient tumors and an adoptive cell transfer of autologous PBMCs, mice were treated with anti-PD-1, a novel investigational engineered IL-2-based cytokine (nemvaleukin), or recombinant human IL-2 (rhIL-2). The pharmacodynamic effects and antitumor efficacy of these treatments were then evaluated. We used tumor cells and autologous PBMCs from patients with varying immunotherapy responses to both model the diversity of immunotherapy efficacy observed in the clinical setting and to recapitulate the heterogeneous nature of melanoma. RESULTS: Our model exhibited long-term survival of engrafted human PBMCs without developing graft-versus-host disease. Administration of an anti-PD-1 or nemvaleukin elicited antitumor responses in our model that were patient-specific and were found to parallel clinical responsiveness to checkpoint inhibitors. An evaluation of nemvaleukin-treated mice demonstrated increased tumor-infiltrating CD4+ and CD8+ T cells, preferential expansion of non-regulatory T cell subsets in the spleen, and significant delays in tumor growth compared with vehicle-treated controls or mice treated with rhIL-2. CONCLUSIONS: Our model reproduces differential effects of immunotherapy in melanoma patients, capturing the inherent heterogeneity in clinical responses. Taken together, these data demonstrate our model's translatability for novel immunotherapies in melanoma patients. The data are also supportive for the continued clinical investigation of nemvaleukin as a novel immunotherapeutic for the treatment of melanoma.
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Inhibidores de Puntos de Control Inmunológico , Inmunoterapia , Interleucina-2 , Melanoma , Neoplasias Cutáneas , Ensayos Antitumor por Modelo de Xenoinjerto , Humanos , Melanoma/terapia , Animales , Ratones , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Interleucina-2/administración & dosificación , Interleucina-2/uso terapéutico , Neoplasias Cutáneas/terapia , Inmunoterapia/métodos , Autoinjertos , Ratones Endogámicos NODRESUMEN
BACKGROUND: The redundant extracellular matrix (ECM) within tumor microenvironment (TME) such as hyaluronic acid (HA) often impairs intratumoral dissemination of antitumor drugs. Oncolytic viruses (OVs) are being studied extensively for cancer therapy either alone or in conjunction with chemotherapy and immunotherapy. Here, we designed a novel recombinant vaccinia virus encoding a soluble version of hyaluronidase Hyal1 (OVV-Hyal1) to degrade the HA and investigated its antitumor effects in combination with chemo drugs, polypeptide, immune cells, and antibodies. METHODS: We constructed a recombinant oncolytic vaccinia virus encoding the hyaluronidase, and investigated its function in remodeling the ECM of the TME, the antitumor efficacy both in vitro and in several murine solid tumors either alone, or in combination with chemo drugs including doxorubicin and gemcitabine, with polypeptide liraglutide, with immune therapeutics such as PD-L1/PD-1 blockade, CD47 antibody, and with CAR-T cells. RESULTS: Compared with control OVV, intratumoral injection of OVV-Hyal1 showed superior antitumor efficacies in a series of mouse subcutaneous tumor models. Moreover, HA degradation by OVV-Hyal1 resulted in increased intratumoral dissemination of chemo drugs, infiltration of T cells, NK cells, macrophages, and activation of CD8+ T cells. When OVV-Hyal1 was combined with some antitumor therapeutics, for example, doxorubicin, gemcitabine, liraglutide, anti-PD-1, anti-CD47 blockade, or CAR-T cells, more profound therapeutic outcomes were obtained. CONCLUSIONS: OVV-Hyal1 effectively degrades HA to reshape the TME, therefore overcoming some major hurdles in current cancer therapy, such as limited OVs spread, unfavored dissemination of chemo drugs, polypeptides, antibodies, and insufficient infiltration of effector immune cells. OVV-Hyal1 holds the promise to improve the antitumor outcomes of current cancer therapeutics.
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Neoplasias , Viroterapia Oncolítica , Virus Oncolíticos , Ratones , Animales , Virus Oncolíticos/genética , Virus Vaccinia/genética , Hialuronoglucosaminidasa/genética , Hialuronoglucosaminidasa/farmacología , Viroterapia Oncolítica/métodos , Gemcitabina , Linfocitos T CD8-positivos , Liraglutida/farmacología , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Inmunoterapia/métodos , Modelos Animales de Enfermedad , Péptidos/farmacología , Matriz Extracelular/patología , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Microambiente TumoralRESUMEN
BACKGROUND: Recombinant human interleukin (rhIL)-7-hyFc (efineptakin alfa; NT-I7) is a potent T-cell amplifier, with two IL-7 molecules fused to IgD/IgG4 elements. rhIL-7-hyFc promotes extensive infiltration of CD8+ T cells into the tumor, concurrently increasing the numbers of intratumoral PD-1+CD8+ T cells. The hIL-2/TCB2 complex (SLC-3010) inhibits tumor growth by preferential activation of CD122 (IL-2Rß)high CD8+ T cells and natural killer cells, over regulatory T cells (Tregs). We investigated the underlying mechanisms of rhIL-7-hyFc and hIL-2/TCB2c antitumor activity and the potential synergistic efficacy, specifically focusing on tumor-specific CD8+ cells within the tumor and the tumor-draining lymph nodes (tdLN). METHODS: MC38 and CT26 tumor-bearing mice were administered with 10 mg/kg rhIL-7-hyFc intramuscularly and 0.9 mg/kg hIL-2/TCB2c intravenously. Anti-PD-1 monoclonal antibody was administered intraperitoneally three times at 3-day intervals at a dose of 5 mg/kg. Tumor volume was measured to assess efficacy. To compare the composition of immune cells between each monotherapy and the combination therapy, we analyzed tumors and tdLNs by flow cytometry. RESULTS: Our data demonstrate that the combination of rhIL-7-hyFc and hIL-2/TCB2c increases efficacy and generates an immune-stimulatory tumor microenvironment (TME). The TME is characterized by an increased infiltration of tumor-specific CD8+ T cells, and a decreased frequency of CD39highTIM-3+ Treg cells. Most importantly, rhIL-7-hyFc increases infiltration of a CD62L+Ly108+ early progenitor population of exhausted CD8+ T cells (TPEX), which may retain long-term proliferation capacity and replenish functional effector CD8+ T cells. hIL-2/TCB2c induces differentiation of CD62L+Ly108+ TPEX rapidly into CD101+ terminally differentiated subsets (terminally exhausted T cell (TEX term)). Our study also demonstrates that rhIL-7-hyFc significantly enhances the proliferation rate of TPEX in the tdLNs, positively correlating with their abundance within the tumor. Moreover, rhIL-7-hyFc and hIL-2/TCB2c can overcome the limited therapeutic effectiveness of PD-1 blockade, culminating in the complete regression of tumors. CONCLUSIONS: rhIL-7-hyFc can expand and maintain the progenitor pool of exhausted CD8+ T cells, whereas hIL-2/TCB2c promotes their differentiation into TEX term. Together, this induces an immune-stimulatory TME that improves the efficacy of checkpoint blockade.
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Linfocitos T CD8-positivos , Interleucina-7 , Neoplasias , Proteínas Recombinantes de Fusión , Humanos , Animales , Ratones , Microambiente Tumoral , Receptor de Muerte Celular Programada 1 , Factores InmunológicosRESUMEN
BACKGROUND: Although immune checkpoint inhibitor (ICI)-based therapy is advantageous for patients with advanced melanoma, resistance and relapse are frequent. Thus, it is crucial to identify effective drug combinations and develop new therapies for the treatment of melanoma. SGN1, a genetically modified Salmonella typhimurium species that causes the targeted deprivation of methionine in tumor tissues, is currently under investigation in clinical trials. However, the inhibitory effect of SGN1 on melanoma and the benefits of SGN1 in combination with ICIs remain largely unexplored. Therefore, this study aims to investigate the antitumor potential of SGN1, and its ability to enhance the efficacy of antibody-based programmed cell death-ligand 1 (PD-L1) inhibitors in the treatment of murine melanoma. METHODS: The antitumor activity of SGN1 and the effect of SGN1 on the efficacy of PD-L1 inhibitors was studied through murine melanoma models. Further, The Cancer Genome Atlas-melanoma cohort was clustered using ConsensusClusterPlus based on the methionine deprivation-related genes, and immune characterization was performed using xCell, Microenvironment Cell Populations-counter, Estimation of Stromal and Immune cells in MAlignant Tumor tissues using Expression data, and immunophenoscore (IPS) analyses. The messenger RNA data on programmed death-1 (PD-1) immunotherapy response were obtained from the Gene Expression Omnibus database. Gene Set Enrichment Analysis of methionine deprivation-up gene set was performed to determine the differences between pretreatment responders and non-responders. RESULTS: This study showed that both, the intratumoral and the intravenous administration of SGN1 in subcutaneous B16-F10 melanomas, suppress tumor growth, which was associated with an activated CD8+T-cell response in the tumor microenvironment. Combination therapy of SGN1 with systemic anti-PD-L1 therapy resulted in better antitumor activity than the individual monotherapies, respectively, and the high therapeutic efficacy of the combination was associated with an increase in the systemic level of tumor-specific CD8+ T cells. Two clusters consisting of methionine deprivation-related genes were identified. Patients in cluster 2 had higher expression of methionine_deprivation_up genes, better clinical outcomes, and higher immune infiltration levels compared with patients in cluster 1. Western blot, IPS analysis, and immunotherapy cohort study revealed that methionine deficiency may show a better response to ICI therapy CONCLUSIONSï¼: This study reports Salmonella-based SGN1 as a potent anticancer agent against melanoma, and lays the groundwork for the potential synergistic effect of ICIs and SGN1 brought about by improving the immune microenvironment in melanomas.
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Inhibidores de Puntos de Control Inmunológico , Melanoma Experimental , Humanos , Ratones , Animales , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Linfocitos T CD8-positivos , Metionina , Estudios de Cohortes , Recurrencia Local de Neoplasia , Melanoma Experimental/tratamiento farmacológico , Salmonella , Microambiente TumoralRESUMEN
BACKGROUND: In CheckMate 9LA, nivolumab plus ipilimumab with chemotherapy prolonged overall survival (OS) versus chemotherapy regardless of tumor PD-L1 expression or histology. We report updated efficacy and safety in all randomized patients with a minimum 4-year follow-up and an exploratory treatment-switching adjustment analysis in all treated patients who received chemotherapy and subsequent immunotherapy. METHODS: Adults with stage IV/recurrent non-small cell lung cancer (NSCLC), no sensitizing EGFR/ALK alterations, and ECOG performance status ≤1 were randomized 1:1 to nivolumab 360 mg every 3 weeks plus ipilimumab 1 mg/kg every 6 weeks with chemotherapy (two cycles) or chemotherapy (four cycles, with optional maintenance pemetrexed for the nonsquamous population). Assessments included OS, progression-free survival, and objective response rate. Exploratory analyses included efficacy by tumor PD-L1 expression and histology and in patients who discontinued nivolumab plus ipilimumab with chemotherapy due to treatment-related adverse events (TRAEs), and a treatment-switching adjustment analysis using inverse probability of censoring weighting. RESULTS: With a 47.9-month minimum follow-up for OS, nivolumab plus ipilimumab with chemotherapy continued to prolong OS over chemotherapy in all randomized patients (HR 0.74, 95% CI 0.63 to 0.87; 4-year OS rate: 21% versus 16%), regardless of tumor PD-L1 expression (HR (95% CI): PD-L1<1%, 0.66 (0.50 to 0.86) and ≥1%, 0.74 (0.60 to 0.92)) or histology (squamous, 0.64 (0.48 to 0.84) and non-squamous, 0.80 (0.66 to 0.97)). In patients who discontinued all components of nivolumab plus ipilimumab with chemotherapy due to TRAEs (n=61), the 4-year OS rate was 41%. With treatment-switching adjustment for the 36% of patients receiving subsequent immunotherapy in the chemotherapy arm, the estimated HR of nivolumab plus ipilimumab with chemotherapy versus chemotherapy was 0.66 (95% CI 0.55 to 0.80). No new safety signals were observed. CONCLUSIONS: In this 4-year update, patients treated with nivolumab plus ipilimumab with chemotherapy continued to have long-term, durable efficacy benefit over chemotherapy regardless of tumor PD-L1 expression and/or histology. A greater estimated relative OS benefit was observed after adjustment for subsequent immunotherapy use in the chemotherapy arm. These results further support nivolumab plus ipilimumab with chemotherapy as a first-line treatment for patients with metastatic/recurrent NSCLC, including those with tumor PD-L1<1% or squamous histology, populations with high unmet needs.
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Carcinoma de Pulmón de Células no Pequeñas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Adulto , Humanos , Nivolumab/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/patología , Ipilimumab/farmacología , Ipilimumab/uso terapéutico , Antígeno B7-H1/metabolismo , Cambio de Tratamiento , Neoplasias Pulmonares/patología , Recurrencia Local de NeoplasiaRESUMEN
BACKGROUND: Immune checkpoint inhibitor (ICI) combinations represent an emerging treatment strategies in cancer. However, their efficacy in microsatellite stable (MSS) or mismatch repair-proficient (pMMR) colorectal cancer (CRC) is variable. Here, a multiomic characterization was performed to identify predictive biomarkers associated with patient response to ICI combinations in MSS/pMMR CRC for the further development of ICI combinations. METHODS: Whole-exome sequencing, RNA sequencing, and multiplex fluorescence immunohistochemistry of tumors from patients with MSS/pMMR CRC, who received regorafenib plus nivolumab (REGONIVO) or TAS-116 plus nivolumab (TASNIVO) in clinical trials were conducted. Twenty-two and 23 patients without prior ICI from the REGONIVO and TASNIVO trials were included in this study. A biomarker analysis was performed using samples from each of these studies. RESULTS: The epithelial-mesenchymal transition pathway and genes related to cancer-associated fibroblasts were upregulated in the REGONIVO responder group, and the G2M checkpoint pathway was upregulated in the TASNIVO responder group. The MYC pathway was upregulated in the REGONIVO non-responder group. Consensus molecular subtype 4 was significantly associated with response (p=0.035) and longer progression-free survival (p=0.006) in the REGONIVO trial. CD8+ T cells, regulatory T cells, and M2 macrophages density was significantly higher in the REGONIVO trial responders than in non-responders. Mutations in the POLE gene and patient response were significantly associated in the TASNIVO trial; however, the frequencies of other mutations or tumor mutational burden were not significantly different between responders and non-responders in either trial. CONCLUSIONS: We identified molecular features associated with the response to the REGONIVO and TASNIVO, particularly those related to tumor microenvironmental factors. These findings are likely to contribute to the development of biomarkers to predict treatment efficacy for MSS/pMMR CRC and future immunotherapy combinations for treatment.
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Neoplasias Colorrectales , Nivolumab , Humanos , Nivolumab/farmacología , Nivolumab/uso terapéutico , Linfocitos T CD8-positivos , Multiómica , Inmunoterapia , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , BiomarcadoresRESUMEN
BACKGROUND: The combination of immune-checkpoint inhibitors and antiangiogenic agents can synergistically modulate the tumor microenvironment and represents a promising treatment option. Here, we evaluated the efficacy and safety of camrelizumab plus famitinib (a receptor tyrosine kinase inhibitor) as a first-line treatment for advanced or metastatic NSCLC patients with a programmed death ligand-1 (PD-L1) tumor proportion score (TPS) of ≥1%, in an open-label, multicenter, phase 2 basket trial. METHODS: Eligible patients received camrelizumab (200 mg once every 3 weeks via intravenous infusion) plus oral famitinib at an initial dose of 20 mg once daily. The primary endpoint was the objective response rate (ORR), as assessed by the investigator per Response Evaluation Criteria in Solid Tumors V.1.1. Key secondary endpoints included disease control rate (DCR), duration of respons, progression-free survival (PFS), overall survival (OS), 12-month OS rate, and safety profile. RESULTS: Of the enrolled 41 patients, 21 (51.2%) had a PD-L1 TPS of 1-49%. As of the cut-off date on June 22, 2022, the combination regimen of camrelizumab and famitinib achieved an ORR of 53.7% (95% CI 37.4% to 69.3%) and a DCR of 92.7% (95% CI 80.1% to 98.5%). The median PFS was 16.6 months (95% CI 8.3 to not reached), and OS data were not yet mature, with an estimated 12-month OS rate of 76.8% (95% CI 60.0% to 87.3%). The most common treatment-related adverse events of grade 3 or higher included hypertension (22.0%), increased alanine aminotransferase (12.2%), decreased neutrophil count (9.8%), proteinuria (7.3%), decrease platelet count (7.3%), and hypokalemia (7.3%). One (2.4%) patient died from grade 5 hemoptysis, which was considered possibly related to the study treatment by the investigator. CONCLUSION: Camrelizumab plus famitinib demonstrated promising antitumor activity in advanced or metastatic NSCLC patients and had an acceptable safety profile. These findings suggest that this combination regimen could be an alternative therapeutic option and warrant further investigation. TRIAL REGISTRATION NUMBER: NCT04346381.
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Anticuerpos Monoclonales Humanizados , Carcinoma de Pulmón de Células no Pequeñas , Indoles , Neoplasias Pulmonares , Pirroles , Humanos , Antígeno B7-H1/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Microambiente TumoralRESUMEN
OBJECTIVE: In the global phase 3 Study 309/KEYNOTE-775 (NCT03517449) at the first interim analysis, lenvatinib+pembrolizumab significantly improved progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) versus treatment of physician's choice chemotherapy (TPC) in patients with previously treated advanced/recurrent endometrial cancer (EC). This exploratory analysis evaluated outcomes in patients enrolled in East Asia at the time of prespecified final analysis. METHODS: Women ≥18 years with histologically confirmed advanced, recurrent, or metastatic EC with progressive disease after 1 platinum-based chemotherapy (2 if 1 given in neoadjuvant/adjuvant setting) were enrolled. Patients were randomized 1:1 to lenvatinib 20 mg orally once daily plus pembrolizumab 200 mg intravenously every 3 weeks (≤35 cycles) or TPC (doxorubicin or paclitaxel). Primary endpoints were PFS per RECIST v1.1 by blinded independent central review and OS. No alpha was assigned for this subgroup analysis. RESULTS: Among 155 East Asian patients (lenvatinib+pembrolizumab, n=77; TPC, n=78), median follow-up time (data cutoff: March 1, 2022) was 34.3 (range, 25.1-43.0) months. Hazard ratios (HRs) with 95% confidence intervals (CIs) for PFS (lenvatinib+pembrolizumab vs. TPC) were 0.74 (0.49-1.10) and 0.64 (0.44-0.94) in the mismatch repair proficient (pMMR) and all-comer populations, respectively. HRs (95% CI) for OS were 0.68 (0.45-1.02) and 0.61 (0.41-0.90), respectively. ORRs were 36% with lenvatinib+pembrolizumab and 22% with TPC (pMMR) and 39% and 21%, respectively (all-comers). Treatment-related adverse events occurred in 97% and 96% (grade 3-5, 74% and 72%), respectively. CONCLUSION: Lenvatinib+pembrolizumab provided clinically meaningful benefit with manageable safety compared with TPC, supporting its use in East Asian patients with previously treated advanced/recurrent EC. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03517449.
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Anticuerpos Monoclonales Humanizados , Neoplasias Endometriales , Compuestos de Fenilurea , Médicos , Quinolinas , Humanos , Femenino , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/etiología , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/etiología , Asia Oriental/epidemiología , Protocolos de Quimioterapia Combinada AntineoplásicaRESUMEN
Aim: Investigate TKI sitravatinib plus anti-PD-1 antibody tislelizumab in patients with unresectable/advanced/metastatic melanoma with disease progression on/after prior first-line anti-PD-(L)1 monotherapy. Methods: Open-label, multicenter, multicohort study (NCT03666143). Patients in the melanoma cohort (N = 25) received sitravatinib once daily plus tislelizumab every 3 weeks. The primary end point was safety and tolerability. Results: Treatment-emergent adverse events (TEAEs) occurred in all patients, with ≥grade 3 TEAEs in 52.0%. Most TEAEs were mild-or-moderate in severity, none were fatal, and few patients discontinued treatment owing to TEAEs (12.0%). Objective response rate was 36.0% (95% CI: 18.0-57.5). Median progression-free survival was 6.7 months (95% CI: 4.1-not estimable). Conclusion: Sitravatinib plus tislelizumab had manageable safety/tolerability in patients with anti-PD-(L)1 refractory/resistant unresectable/advanced/metastatic melanoma, with promising antitumor activity. Clinical Trial Registration: NCT03666143 (ClinicalTrials.gov).
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Anilidas , Anticuerpos Monoclonales Humanizados , Crocus , Melanoma , Piridinas , Humanos , Melanoma/patología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
BACKGRUOUND: There is still a lack of research on which diabetic drugs are more effective in preventing stroke. Our network metaanalysis aimed to compare cerebrovascular benefits among glucose-lowering treatments. METHODS: We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and the ClinicalTrials.gov registry for clinical trials from inception through May 25, 2021. We included both prespecified cerebrovascular outcomes and cerebrovascular events reported as severe adverse events. Subgroup analyses were conducted by stroke subtype, publication type, age of patients, baseline glycosylated hemoglobin (HbA1c), duration of type 2 diabetes mellitus, and cardiovascular risks. RESULTS: Of 2,861 reports and 1,779 trials screened, 79 randomized controlled trials comprising 206,387 patients fulfilled the inclusion criteria. In the pairwise meta-analysis, the use of glucagon-like peptide-1 (GLP-1) agonist was associated with a lower risk of total stroke compared with placebo (relative risk [RR], -0.17; 95% confidence interval [CI], -0.27 to -0.07). In the network meta- analysis, only the use of sodium-glucose cotransporter-2 (SGLT-2) inhibitor was associated with a reduction of total stroke, compared with placebo (RR, 0.81; 95% CI, 0.67 to 0.98). In the subgroup analyses, the use of SGLT-2 inhibitor and GLP-1 agonist was associated with a lower risk of stroke in those with high HbA1c (≥8.0) and low-risk of cardiovascular disease, respectively. CONCLUSION: SGLT-2 inhibitors and GLP-1 agonists were shown to be beneficial for stroke prevention in patients with type 2 diabetes mellitus.
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Diabetes Mellitus Tipo 2 , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/inducido químicamente , Hipoglucemiantes/efectos adversos , Metaanálisis en Red , Glucosa , Hemoglobina Glucada , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Péptido 1 Similar al GlucagónRESUMEN
BACKGROUND: Among patients with advanced/metastatic triple-negative breast cancer (TNBC) with high/positive programmed death-ligand 1 (PD-L1) expression, a superior survival outcome has been demonstrated with immune checkpoint inhibitors (ICIs). However, it remains unclear whether ICIs are beneficial for patients with low PD-L1 levels. Here, we derived survival data for subgroups with low PD-L1-expressing and conducted a pooled analysis. METHODS: After a systematic search of Embase, PubMed, MEDLINE, and CENTRAL from inception until May 18, 2023, randomized controlled trials (RCTs) reporting progression-free survival (PFS), overall survival (OS), or duration of response (DOR) for metastatic TNBC treated with ICI-based regimens were included. Kaplan-Meier curves were extracted for the intention-to-treat population and high PD-L1 subgroups. KMSubtraction was used when survival curves were not provided for subgroups with low PD-L1 expression. A pooled analysis of survival data was then conducted. RESULTS: A total of 3022 patients were included in four RCTs: Impassion130, Impassion131, KEYNOTE-119, and KEYNOTE-355. Unreported low PD-L1-expressing subgroups were identified, including PD-L1 immune cell (IC)<1%, combined positive score (CPS)<1, and 1≤CPS<10. Compared with chemotherapy, ICI-chemotherapy combinations did not significantly differ in OS, PFS, or DOR in the Impassion PD-L1<1%, KEYNOTE-355 PD-L1 CPS<1, and KEYNOTE-355 1≤CPS<10 subgroups. In the KEYNOTE-119 CPS<1 subgroup, the risk of tumor progression was increased with pembrolizumab (HR, 2.23; 95% CI, 1.62 to 3.08; p<0.001), as well as in the 1≤CPS<10 subgroup (HR, 1.64; 95% CI, 1.22 to 2.20; p<0.001). A pooled analysis using a scoring system found no significant difference in OS and PFS among the subgroups with an IC of <1% between immunochemotherapy and chemotherapy. OS (HR, 1.07; 95% CI, 0.91 to 1.26), PFS (HR, 0.96; 95% CI, 0.84 to 1.10), and DOR were also not significantly different in pooled analysis of first-line trials for those with low PD-L1 expression. CONCLUSION: ICI-based regimens are not associated with a survival benefit versus chemotherapy in subgroups of advanced/metastatic TNBC that express low PD-L1 levels.
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Antígeno B7-H1 , Neoplasias de la Mama Triple Negativas , Humanos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Flujo de Trabajo , Quimioterapia Combinada , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéuticoRESUMEN
BACKGROUND: Tumor-infiltrating T cells enter an exhausted or dysfunctional state, which limits antitumor immunity. Among exhausted T cells, a subset of cells with features of progenitor or stem-like cells has been identified as TCF1+ CD8+ T cells that respond to immunotherapy. In contrast to the finding that TCF1 controls epigenetic and transcriptional reprogramming in tumor-infiltrating stem-like T cells, little is known about the regulation of TCF1. Emerging data show that elevated body mass index is associated with outcomes of immunotherapy. However, the mechanism has not been clarified. METHODS: We investigated the proliferation of splenic lymphocytes or CD8+ T cells induced by CD3/CD28 stimulation in vitro. We evaluated the effects of low-density lipoprotein (LDL) and LRP11 inhibitors, as well as MAPK13 inhibitors. Additionally, we used shRNA technology to validate the roles of LRP11 and MAPK13. In an in vivo setting, we employed male C57BL/6J injected with B16 cells or MC38 cells to build a tumor model to assess the effects of LDL and LRP11 inhibitors, LRP11 activators, MAPK13 inhibitors on tumor growth. Flow cytometry was used to measure cell proportions and activation status. Molecular interactions and TCF1 status were examined using Western blotting. Moreover, we employed RNA sequencing to investigate the effects of LDL stimulation and MAPK13 inhibition in CD8+ T cells. RESULTS: By using a tumor-bearing mouse model, we found that LDL-induced tumor-infiltrating TCF1+PD1+CD8+ T cells. Using a cell-based chimeric receptor screening system, we showed that LRP11 interacted with LDL and activated TCF1. LRP11 activation enhanced TCF1+PD1+CD8+ T-cell-mediated antitumor immunity, consistent with LRP11 blocking impaired T-cell function. Mechanistically, LRP11 activation induces MAPK13 activation. Then, MAPK13 phosphorylates TCF1, leading to increase of stem-like T cells. CONCLUSIONS: LRP11-MAPK13-TCF1 enhanced antitumor immunity and induced tumor-infiltrating stem-like T cells.
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Linfocitos T CD8-positivos , Melanoma Experimental , Masculino , Ratones , Animales , Fosforilación , Receptor de Muerte Celular Programada 1 , Ratones Endogámicos C57BL , InmunoterapiaRESUMEN
Type 2 diabetes (T2D) is a progressive disease in which it is challenging to achieve long-term durable glycemic control. However, intensive glycemic control is crucial for preventing diabetes-related complications. Previous studies showed that monotherapy with a stepwise add-on approach was seldom effective for long-term durable glycemic control. Combination therapy, which refers to the use of two or more drugs to control hyperglycemia, has multiple benefits, including the ability to target a variety of pathophysiological processes underlying hyperglycemia. In clinical trials, initial combination therapy showed better glycemic control than monotherapy or a stepwise approach. Emerging evidence indicates that initial combination therapy is associated with preserved ß-cell function and fewer complications in T2D. However, cost-effectiveness and adverse events with combination therapy are issues that should be considered. Therefore, initial combination therapy is an important option for patients with T2D that clinicians should consider with a view toward balancing benefits and potential harms. In this review, we summarize the literature addressing initial combination therapy in T2D, and we suggest optimal strategies based on clinical situations and patient characteristics.
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Complicaciones de la Diabetes , Diabetes Mellitus Tipo 2 , Hiperglucemia , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/complicaciones , Hipoglucemiantes/uso terapéutico , Complicaciones de la Diabetes/complicaciones , Terapia CombinadaRESUMEN
Objective:To investigate the clinical efficacy of ginkgo ketone ester dropping pills combined with agatroban injection in the treatment of acute cerebral infarction.Methods:This prospective case-control study was conducted on 120 patients with acute cerebral infarction who were treated at The Hospital of Shanxi University of Chinese Medicine between April 2020 and April 2022. These patients were randomly divided into a control group and a study group using the random number table method, with 60 patients in each group. The control group received intravenous injections of agatroban based on conventional treatment, while the study group received treatment with ginkgo ketone ester dropping pills combined with agatroban injection based on conventional treatment. The treatment duration was 2 weeks. Clinical efficacy was evaluated after continuous treatment for 2 weeks.Results:The overall response rate in the study group was 95.0% (57/60), which was significantly higher than 80.0% (48/60) in the control group ( χ2 = 6.17, P = 0.012). After treatment, the Barthel index in the study group was (65.3 ± 7.3) points, which was significantly higher than (59.8 ± 7.5) points in the control group ( t = -4.07, P < 0.001). The modified Rankin Scale score and the National Institutes of Health Stroke Scale score in the study group were (1.2 ± 0.4) points and (4.6 ± 0.7) points, which were significantly lower than (2.4 ± 0.6) points and (7.6 ± 1.1) points, respectively, in the control group ( t = 12.89, 17.82, both P < 0.001). Interleukin-6, hypersensitive C-reactive protein, and tumor necrosis factor-α levels in the study group were significantly lower than those in the control group ( t = 10.10, 18.25, 14.15, all P < 0.001). The nitric oxide levels in the study group were significantly higher than those in the control group, while endothelin 1 and thromboxane A2 levels in the study group were significantly lower than those in the control group ( t = -7.65, 10.77, 21.90, all P < 0.001). There was no significant difference in incidence of adverse reactions between the two groups ( P > 0.05). Conclusion:The combination of ginkgo ketone ester dropping pills and agatroban injection has a remarkable therapeutic effect on acute cerebral infarction. The combined therapy can reduce the severity of neurological deficits in patients, promote brain function recovery, improve quality of life, adjust serum inflammatory factors, and thereby be worthy of clinical application.
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Objective:To analyze the effect of donepezil hydrochloride combined with memantine on cognitive function in patients with Alzheimer's disease (AD).Methods:A randomized controlled trial was conducted among 90 patients with AD who were treated at the Zaozhuang Mental Health Center from January 2021 to March 2023. The patients were divided into a donepezil group and a combination group using a random number table grouping method, with 45 patients in each group. The donepezil hydrochloride group received only oral administration of donepezil hydrochloride tablets, while the combination group received oral administration of both donepezil hydrochloride tablets and memantine tablets. The two groups were continuously treated for 12 weeks. Before and after treatment, the Activities of Daily Living scale (ADL) score, the Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD) score, the Mini-Mental State Scale (MMSE) score, and biochemical indicators (homocysteine, neuron-specific enolase, and S100 β) were compared between the two groups. Adverse drug reactions were observed in each group.Results:After treatment, the ADL, BEHAVE-AD, and MMSE scores in the combination group were (78.9 ± 6.1) points, (5.2 ± 0.5) points, and (22.8 ± 2.2) points, respectively, and they were (65.2 ± 5.9) points, (9.6 ± 0.9) points, and (19.4 ± 2.4) points, respectively, in the donepezil hydrochloride group. The ADL and MMSE scores in the combination group were significantly higher than those in the donepezil hydrochloride group ( t = 10.83, 7.01, both P < 0.001). The BEHAVE-AD score in the combination group was significantly lower than that in the donepezil hydrochloride group ( t = -28.67, P < 0.001). After treatment, serum levels of homocysteine, neuron-specific enolase, and S100 β in the combination group were (17.8 ± 3.6) μmol/L, (16.8 ± 2.7) μg/L, and (17.4 ± 7.5) μg/L, respectively, which were significantly lower than (21.5 ± 3.3) μmol/L, (20.4 ± 3.7) μg/L, and (23.5 ± 5.1) μg/L in the donepezil hydrochloride group ( t = -5.08, -5.27, -4.51, all P < 0.001). The incidence of adverse drug reactions in the combination group was 13.3% (6/45), which was slightly, but not significantly, higher than 8.9% (4/45) in the donepezil group ( χ2 = 0.45, P = 0.502). Conclusion:The combination of donepezil hydrochloride and memantine can effectively improve the mental and behavioral symptoms and cognitive function of patients with AD, improve daily living ability, and do not increase adverse reactions. The combined therapy has high clinical application value.
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Objective:To investigate the efficacy of the combination of semaglutide, insulin degludec, and metformin in the treatment of type 2 diabetes mellitus and poor glycemic control accompanied by overweight or obesity.Methods:A total of 160 patients with type 2 diabetes mellitus and poor glycemic control accompanied by overweight or obesity were included in this case-control study after receiving treatment at Bayannur Hospital from April 2022 to March 2023. These patients were divided into a control group and an observation group based on different treatment regimens, with 80 patients in each group. The control group was treated with degludec insulin combined with metformin, while the observation group was treated with semaglutide, degludec insulin, and metformin. The treatment lasted for 12 weeks in both groups. The changes in fasting plasma glucose, 2-hour postprandial blood glucose (2 h PG), glycosylated hemoglobin, time in range for 2 h PG, fasting insulin, Homeostatic Model Assessment for Insulin Resistance index, body mass index, and visceral fat area and adverse reactions were monitored.Results:The overall response rate in the observation group was 100% (80/80), which was significantly higher than 97.5% (78/80) in the control group (χ 2 = 11.03, P < 0.05). After treatment, the levels of 2 h PG, glycosylated hemoglobin, fasting insulin, Homeostatic Model Assessment for Insulin Resistance index, body mass index, visceral fat area in the observation group were (7.35 ± 0.17) mmol/L, (6.08 ± 0.24)%, (10.30 ± 2.58) μU/mL,(2.69 ± 0.66), (24.40 ± 0.68) kg/m 2, (80.20 ± 8.94) cm 2, respectively, which were significantly lower than (7.92 ± 0.24) mmol/L, (6.34 ± 0.27)%,(13.71 ± 3.13) μU/mL,(3.57 ± 0.83), (26.77 ± 3.49) kg/m 2, (116.12 ± 34.09) cm 2 respectively in the control group ( t = -0.73, -3.74, -4.20, -4.15, -3.35, -5.10, all P < 0.05). The time in range for 2 h PG in the observation group was (72.68 ± 4.09)%, which was significantly higher than (50.16 ± 10.00)% in the control group ( t = -10.42, P < 0.05). The incidence of adverse reactions in the observation group was 3.8% (3/80), which was slightly, but not significantly, higher than 2.5% (2/80) in the control group ( P > 0.05). Conclusion:The combination of semaglutide, degludec insulin, and metformin demonstrates an ideal clinical effect in the treatment of type 2 diabetes mellitus and poor glycemic control accompanied by overweight or obesity. This combined approach can effectively regulate fasting and postprandial blood glucose levels, markedly decrease the body mass index and visceral fat levels, and improve insulin resistance while not significantly increasing the incidence of adverse reactions.
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Objective:To explore the effects of amlodipine combined with different doses of atorvastatin and simvastatin on hypertension complicated by atherosclerosis.Methods:A retrospective analysis was conducted on the clinical data of 100 patients with hypertension complicated by atherosclerosis who were diagnosed and treated at Jinan 2 nd People's Hospital from August 2019 to August 2020. These patients were divided into control group ( n = 32, amlodipine combined with simvastatin), study group 1 ( n = 34, amlodipine combined with 10 mg/day atorvastatin), and study group 2 ( n = 34, amlodipine combined with 20 mg/day atorvastatin) according to different treatment schemes. All three groups were treated for 6 months. The clinical efficacy, blood lipid level, blood pressure, oxidative stress level, carotid intima-media thickness and plaque area were compared among the three groups. Results:The overall response rates of the control group, study group 1, and study group 2 were 71.88% (23/32), 82.35% (28/34), and 91.18% (31/34), respectively. The difference in overall response rate among the three groups was statistically significant ( χ2 = 4.16, P < 0.05). After treatment, total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, 24-hour dynamic blood pressure, diurnal blood pressure, nighttime blood pressure, malondialdehyde, superoxide dismutase, glutathione peroxidase, carotid intima-media thickness and plaque area were statistically different among the three groups ( F = -19.54, -76.61, 11.15, -56.83, -147.35, -23.10, -11.47, -11.65, -128.36, -15.60, -24.52, 25.61, 118.99, -59.23, -81.64, all P < 0.05). The incidence rates of adverse reactions in the control group, study group 1, and study group 2 were 12.50% (4/32), 8.82% (3/34), and 11.76% (4/34), respectively. There was no statistically significant difference among the three groups ( χ2 = 0.25, P = 0.611). Conclusion:Amlodipine combined with atorvastatin is more effective in the treatment of hypertension complicated by atherosclerosis than the amlodipine combined with simvastatin. High-dose atorvastatin is more effective in reducing lipid, controlling blood pressure, improving the level of oxidative stress and clinical symptoms compared with low-dose atorvastatin.
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Objective:To explore the effect of bismuth containing triple therapy on serum gastrin (Gas), transforming growth factor-α (TGF-α), and high-sensitivity C-reactive protein (hs-CRP) levels in children with Helicobacter pylori (Hp) positive peptic ulcers.Methods:A total of 96 children with Hp positive peptic ulcers admitted to the Second Hospital of Jiaxing from January 2020 to December 2021 were selected as the study subjects. They were randomly divided into two groups using the remainder of a random number table. The control group (48 cases) received treatment with omeprazole, clarithromycin, and amoxicillin, while the observation group (48 cases) received treatment with bismuth containing triple therapy (amoxicillin+ metronidazole+ bismuth potassium citrate). After 10 days of treatment, the clinical efficacy of the two groups was evaluated The improvement time of clinical symptoms, Hp conversion rate, serum indicators (Gas, TGF-α, hs-CRP) before and after treatment, and incidence of adverse reactions were observed.Results:The total effective rate and Hp conversion rate of the observation group were significantly higher than those of the control group [95.83%(46/48) vs 81.25%(39/48), 97.92%(47/48) vs 83.33%(40/48), P<0.05]. The improvement time of upper abdominal pain, heartburn, and acid reflux symptoms was significantly shorter than that of the control group (all P<0.05). After 10 days of treatment, the serum Gas and hs-CRP levels in both groups significantly decreased compared to before treatment (all P<0.05), and the observation group was lower than the control group after treatment ( P<0.05); The levels of TGF-α in both groups increased compared to before treatment (all P<0.05), and the observation group was higher than the control group after treatment ( P<0.05). There was no statistically significant difference in the incidence of adverse reactions between the two groups [4.17%(2/48) vs 2.08%(1/48), P>0.05]. Conclusions:The triple therapy with bismuth containing agents has a better therapeutic effect on children with Hp positive peptic ulcers, and can promote ulcer mucosal repair by improving inflammatory response, with good safety.