Technological progress greatly contributes to the promotion of carbon productivity (CP). This study aims to identify an appropriate mode of technological progress that increases CP. A data ...envelopment analysis-based method was used to investigate the impacts of four forms of technological progress under two classifications of CP: the progress of neutral technology (NT) and capital-embodied technology (CET) under a technological source and the progress of energy technology (ET) and carbon technology (CT) under an abatement process. We applied dynamic panel data models to deeply analyze the different impacts of the four forms of technological progress on the CPs of Chinese manufacturing industries from 1995 to 2015. Results show that (1) a change in ET contributes more to the promotion of CP than a change in CT; (2) a change in CET promotes CP more than a change in NT; and (3) the indirect effect of a change in CET on CP through a change in ET and the indirect effect of a change in NT on CP through a change in CT are advantageous. These findings provide important policy implications in promoting technological progress and improving Chinese MIs’ CPs. Significant policy measures based on theoretical and empirical conclusions are proposed.
•Technological progresses promote China's MIs' carbon productivity (CP).•Energy technological change has a positive greater role on CP.•Capital bodied technological change has a positive greater role on CP.•Indirect effect of capital embodied technological change on CP is advantageous.•Indirect effect of neutral technological change on CP is advantageous.
The bottleneck of China's industrial carbon efficiency improvement is that the contribution of carbon emission technology is less than that of energy technology, and that of neutral technology is ...less than that of capital-based technology. The key to breaking through this bottleneck is to clarify how heterogeneous technological progress enhances carbon efficiency through industrial structural upgrading. The effects of four levels of technological progress on carbon efficiency under two technical classifications based on technology sources and carbon emission processes from energy consumption are studied by using the DEA method. The suitable choice of the path of technological progress to promoting China's industrial carbon efficiency is provided accordingly. The panel data model is used to deeply investigate the effects of these four levels of technological progress on industrial carbon efficiency in China's 30 provincial industries. The main results are as follows: First, in terms of direct effects, progress in energy technology is more conducive to improving carbon efficiency than progress in carbon emission technology, and progress in neutral technology is more effective in improving carbon efficiency than progress in capital-embodied technology. Second, in terms of indirect effects, progress in capital-embodied technology is effective in upgrading industrial structures and enhancing carbon efficiency; and, through green upgrading of industrial structures, progress in energy technology has a positive and significant impact on carbon efficiency. Third, the level of industrial development and government environmental governance have a positive impact on carbon efficiency, and the energy structure has a negative impact on carbon efficiency.
•Different technologies impact carbon efficiency through different paths.•NT and CET promote industrial structure grading and carbon efficiency.•Industrial structure grading promotes ET and CT progress.•Promoted by industrial structure grading promotes carbon efficiency.•ET and CT progress promotes carbon efficiency.
Abstract Background The PD-1 inhibitor pembrolizumab is approved as monotherapy for the adjuvant treatment of patients with renal cell carcinoma (RCC) who are at increased risk of recurrence ...following nephrectomy or nephrectomy and resection of metastatic lesions based on results from the phase 3 KEYNOTE-564 trial. Novel combination strategies could provide further clinical benefit in the adjuvant setting. V940 (mRNA-4157) is an individualized neoantigen therapy that is hypothesized to increase the antitumor activity of T cells and enhance the activity of pembrolizumab. V940 plus pembrolizumab showed improved clinical outcomes for stage III/IV melanoma compared with pembrolizumab alone in the phase 2b KEYNOTE-942 study. INTerpath-004 is a global, multicenter, randomized, double-blind, phase 2 trial (NCT06307431) designed to evaluate the efficacy and safety of adjuvant pembrolizumab with V940 or placebo in patients with RCC who have undergone nephrectomy. Methods Eligible patients are adults with histologically or cytologically confirmed RCC with clear cell or papillary histology (intermediate-high risk pT2 Gr4, N0, M0 or pT3 Gr3/4, N0, M0, high-risk pT4, N0, M0 or pT any stage, N1, M0, or M1 NED solid, isolated, soft tissue metastases that can be completely resected at the time of nephrectomy or ≤2 years from nephrectomy) with or without sarcomatoid features. Patients must have undergone nephrectomy and/or metastasectomy ≤12 weeks prior to randomization and be tumor-free as assessed by investigator. Patients must not have received prior systemic therapy ≤4 weeks or radiotherapy ≤2 weeks prior to randomization. Approximately 272 patients will be randomly assigned 1:1 to receive pembrolizumab 400 mg intravenously every 6 weeks for up to 9 cycles in combination with either V940 1 mg or placebo intramuscularly every 3 weeks for up to 9 doses or treatment discontinuation due to unacceptable toxicity, disease recurrence, patient withdrawal, or investigator decision. Randomization will be stratified by histology (clear cell vs papillary) and disease risk (intermediate-high vs high vs M1 NED). Imaging assessments (computed tomography or magnetic resonance imagery) will be performed every 12 weeks through year 2, every 16 weeks in years 3-5, and every 24 weeks in year 6 and beyond. The primary endpoint is disease-free survival by investigator assessment. Secondary endpoints include distant metastasis-free survival, overall survival, and safety parameters including adverse events (AEs), laboratory test results, and vital signs. AEs will be monitored throughout the study and for 30 days after the last dose of treatment (90 for serious AEs) and graded per National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. Efficacy will be assessed in all randomly assigned patients, and safety will be assessed in all patients who received ≥1 dose of study intervention. Recruitment is ongoing.
Abstract Background HC-7366 is a novel, orally administered, highly selective and potent activator of general control nonderepressible 2 (GCN2) kinase, a core regulator of metabolic stress through ...activation of the integrated stress response (ISR). Activation of GCN2 promotes cell survival, whereas prolonged activation induces apoptosis. GCN2 activation also suppresses general protein synthesis and induces cell cycle arrest, thereby preventing cell growth during nutrient scarcity. Additionally, HC-7366 decreases HIF expression and inhibits glycolysis, oxidative phosphorylation, and TCA cycle function. HC-7366 also inhibits HIF expression in immunosuppressive myeloid cells, including macrophages. These effects of HC-7366 on metabolism, HIF signaling, and immune suppression suggest therapeutic benefit in ccRCC with clear rationale for combinations with HIF2a antagonists and immune checkpoint inhibitors. HC-7366 (0.5-1 mg/kg), combined with belzutifan (1 mg/kg), exhibited combination benefit in HIF-2 dependent A-498 and 786-O RCC xenografts, yielding 90% tumor growth inhibition and a three-fold increase in complete responses, respectively. Additionally, HC-7366 drives significant monotherapy antitumor activity in PDX models that demonstrated belzutifan resistance. Mechanism of action studies have identified several pathway engagement and potential efficacy biomarkers (Stokes, et al., 2024). Trial design/schema This multicenter, open-label phase 1b study will identify the Maximum Tolerated Dose (MTD) and/or the Recommended Phase 2 Dose (RP2D) of HC-7366 in combination with fixed-dose belzutifan, 120 mg po qd, in patients with advanced or metastatic RCC with renal cell histology irrespective of VHL gene mutation. Monotherapy HC-7366 will be evaluated in parallel. The monotherapy arm, HC-7366, 60 mg p.o. qd, includes patients who have relapsed after 1 to 4 prior lines of standard of care that may include belzutifan or another HIF-2α inhibitor. The combination arm includes patients who have received 1 to 3 prior lines of standard of care and are belzutifan or HIF-2α naïve. HC-7366 dose escalation arm evaluates combination fixed dose belzutifan, 120 mg po qd plus HC-7366 at 20, 40, or 60 mg po qd. Enrollment will start with the HC-7366 monotherapy arm. Subsequently, patients will begin to enroll in the combination therapy HC-7366 dose escalation arm, while the monotherapy arm will continue to enroll. Expansion will evaluate the combination of fixed dose belzutifan with two doses of HC-7366 selected from escalation. Assessments include safety, PK, and anti-tumor activity. The study will enroll up to 80 patients at US study sites. Significance and vision Combination HC-7366 plus belzutifan, supported by preclinical evidence, is being studied to assess antitumor activity in the RCC relapsed setting. Determining safety and evaluation of dose are foundational to this study. Reference Stokes M, Tameire F, Wojnarowicz P, et al. HC-7366, a potent GCN2 activator, complements belzutifan, a HIF-2⍺ antagonist, by providing combination benefit in belzutifan-sensitive models and monotherapy activity in belzutifan-resistant models. Meeting of the American Association for Cancer Research; 2024 Apr 5-10; San Diego (CA); AACR; 2024. Abstract 4615. This study is in collaboration with Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA
Abstract Background First-line treatment for patients with metastatic clear cell renal cell carcinoma (mccRCC) often includes an anti-PD1 inhibitor in combination with either an anti-CTLA inhibitor ...(IO/IO) or a VEGF receptor tyrosine kinase inhibitor (TKI) (IO/TKI). Although some patients treated with nivolumab/ipilimumab (Nivo/Ipi) (IO/IO) experience durable responses leading to treatment free intervals, over two-thirds experience disease progression. Resistance to Nivo (anti-PD1) monotherapy has been associated with increased presence of a subpopulation of Tregs in the tumor microenvironment. Botensilimab (Bot) is an IO agent that leverages novel FcyR-associated mechanisms of action to enhance T cell priming, deplete intratumoral Tregs and enhance myeloid activation. Combination botensilimab/balstilimab (Bot/Bal) (anti-CTLA/anti-PD1) has shown impressive anti-tumor activity in diseases where Nivo/Ipi has shown little to no efficacy. Methods ARCITECT is a phase II, multicenter study evaluating the efficacy and safety of Bot/Bal relative to Nivo/Ipi. Patients with mccRCC (favorable, intermediate, or poor risk), no prior systemic therapy (including adjuvant or neoadjuvant), and at least one measurable lesion as defined by RECIST 1.1 are eligible for enrollment. 120 patients will be randomized in a 2:1 fashion to Arm A (Bot/Bal induction followed by Bal maintenance) or Arm B (Nivo/Ipi induction followed by Nivo maintenance) each for a maximum of 2 years. Stratification factors include IMDC risk groups and sarcomatoid histology. The primary endpoint is overall response rate (ORR) per RECIST 1.1. We hypothesize that Bot/Bal will lead to a superior ORR (55%) relative to Nivo/Ipi (40%). This trial has > 90% power to detect the alternative hypothesis while maintaining a one-sided significance level of not more than 0.10 using the exact binomial. The study will be monitored for early stopping in favor of the null hypothesis based on a Simon’s two stage design. In the first stage, 69 patients will be enrolled (Arm A:46 and Arm B:23). If at the end of the first stage, Arm A has either at least 18/42 (42.8%) of eligible patients responding or an ORR at least numerically equivalent to that for eligible patients in Arm B, then the trial will progress to the second stage. The primary endpoint will be met if there are 38/80 responders (ORR > 47.5%) in Arm A. Key secondary endpoints include landmark progression-free survival, treatment-free survival and rates of immune-related adverse events. Correlative studies will explore immune and molecular predictors of response and resistance to IO/IO in tumor and blood. Clinical trial information: NCT05928806. Results
Abstract Background Mucin 16 (MUC16) is a large integral membrane glycoprotein that is highly expressed in malignancies such as ovarian cancer but only at low abundance in epithelial cells of normal ...tissues. Proteolytic cleavage of cell surface MUC16 results in the shedding of its extracellular portion, known as cancer antigen 125 (CA-125), into the bloodstream and a short, membrane-associated C-terminal MUC16 domain that remains on the cell surface. Renal medullary carcinoma (RMC) and epithelioid sarcoma (ES) are aggressive SMARCB1-deficient malignancies found to have elevated serum CA-125 levels in 70-80% of cases. Our preclinical studies suggest that upregulation of MUC16 upon SMARCB1 loss is a viable and attractive tumor target for SMARCB1-deficient malignancies such as ES and RMC. Ubamatamab is a human IgG4-based anti-MUC16 x anti-CD3 bispecific antibody that specifically targets the cell surface bound C-terminal MUC16 domain and can thus induce T cell–redirected killing of tumor cells even in the presence of high concentrations of CA-125. It would thus be a rationale therapy to use in SMARCB1-deficient malignancies expressing MUC16, including those such as RMC known to downregulate MHC Class I as a resistance mechanism to conventional immunotherapy. This is because CD3-targeting bispecific antibodies such as ubamatamab replace conventional signal 1 by engaging T cells regardless of MHC class I expression. As proof of concept, a 20-year-old patient with metastatic SMARCB1-negative ES expressing high levels of serum CA-125 achieved a durable (12+ months) partial response to ubamatamab after progressing on multiple prior therapies, including EZH2 inhibition with tazemetostat as well as anti-PD1/CTLA4 immune checkpoint inhibition with nivolumab plus ipilimumab. The patient reported Grade 2 CRS, pleural effusion, and pericardial effusion, all of which resolved without intervention1. This serves as proof-of-concept for the ability of CD3-targeted bispecifics to overcome resistance to immune checkpoint inhibition. Given this strong preclinical and clinical evidence, we have developed a phase II clinical trial of ubamatamab alone or in combination with the anti-PD1 immune-checkpoint inhibitor cemiplimab in patients with MUC16-expressing RMC and ES who have progressed on at least one line of prior therapy. Up to 20 patients will be enrolled from each disease cohort (ES and RMC) for a total of up to 40 patients. Patients enrolled in Stage I of the trial will receive ubamatamab monotherapy. Patients with disease progression on ubamatamab monotherapy during Stage I can proceed to stage II, which will evaluate the combination of ubamatamab with cemiplimab combination. The co-primary endpoints will be objective response rate (ORR) at any time during the trial and disease control rate (DCR) through 18 weeks. Secondary endpoints will include overall survival, progression-free survival, duration of response, and safety. All endpoints will be analyzed and reported separately for each disease cohort (RMC and ES), and for each Stage (ubamatamab monotherapy and combination ubamatamab with cemiplimab). The trial will utilize the time-to-event Bayesian Optimal Phase II (TOP) design, which maximizes statistical power with well-controlled type I errors. For patients with ES, the joint null hypotheses are that the objective response rate (ORR) is 15% and the disease control rate (DCR) is 26%. The regimen will be promising if either ORR is greater than 15% or DCR is greater than 26% with 69.6% power to declare this an interesting regimen if ORR is 30% and the DCR is 43%. For patients with RMC, the joint null hypotheses are that the objective response rate (ORR) is 15% and the disease control rate (DCR) is 15%. The regimen will be promising if either ORR is greater than 15% or DCR is greater than 15% with 71.4% power to declare this an interesting regimen if ORR is 30% and the DCR is 30%. Pre- and post-treatment correlative analyses will be performed in blood and tumor biopsy tissues to identify changes in specific immune cell subsets and elucidate the dynamic evolution of tumor and immune cell compartments as well as their spatial relationships following ubamatamab alone or in combination with cemiplimab. References 1 Revon-Riviere G, Chami R, Mills D, et al. Mucin 16 (cancer antigen 125) Expression in Epithelioid Sarcoma leads to Single-Patient Study with Bispecific T-Cell Engager Ubamatamab (Mucin16xCD3): A Bench-To-Bedside Experience. Connective Tissue Oncology Society, Nov 16–19, 2022, Vancouver, Canada.
Abstract Background Despite the success of immunotherapy and VEGFR directed tyrosine kinase inhibitors (TKIs) for the treatment of renal cell carcinoma (RCC), a significant proportion of patients ...display primary or secondary resistance to systemic therapy. New treatment approaches are needed for these patients. Pre-surgical clinical trials allow us to study the effects of cancer treatment on the tumour microenvironment, comparing baseline biopsy with post-treatment nephrectomy in a ‘window of opportunity’ study. The results may give us insight into the mechanisms of new cancer therapies, that may be advanced into further clinical trials. Methods The WIRE trial (NCT03741426) is a phase II, multi-centre, multi-arm, non-randomised, neoadjuvant clinical trial platform. The overall aim of the trial is proof of mechanism for new RCC therapies. There are five investigational arms: 1. Cediranib (a VEGFR directed TKI), 2. Cediranib + Olaparib (a PARP inhibitor), 3. Olaparib, 4. Volrustomig (anti PD-1/CTLA-4 bispecific) and 5. Rilvegostomig (anti PD-1/TIGIT bispecific). The study uses a Bayesian adaptive design to optimise recruitment, with pre-specified criteria assessed at interim analyses to stop for futility, continue recruitment to that arm, or move to the next investigational arm. Eligible patients have cT1b+, cN0/1, cM0/1 clear cell RCC, planning to undergo surgery, without medical contraindication to trial therapy. Patients undergo baseline biopsy to confirm clear cell RCC and multiparametric dynamic contrast enhanced (DCE) MRI scan of the primary tumour. For tablet arms 1-3, patients receive at least 14 days of investigational medicinal product (IMP). For immunotherapy arms 4 & 5, patients receive one infusion of IMP. The tumour is re-evaluated by DCE-MRI immediately before surgery. At nephrectomy, multi-region tissue sampling from the tumour is performed both pre-arterial ligation and post resection. Serial translational blood and urine samples are collected before, during and after treatment. The primary endpoint for arms 1-3 is a ≥30% reduction in DCE-MRI assessed capillary permeability (Ktrans) compared to baseline. The primary endpoint for arms 4 & 5 is a ≥30% increase in IHC assessed CD8+ T cell density comparing the resected tumour to baseline biopsy. Secondary endpoints include RECIST v1.1 primary tumour response and adverse events. A comprehensive translational science programme accompanies the trial, which will assess the tumour microenvironment and peripheral blood response to therapy, using techniques including imaging mass cytometry and single cell RNA sequencing. This will allow us to gain a deep understanding of mechanisms of response in each investigational arm. To date, arms 1 & 2 have completed recruitment, and arm 3 is actively recruiting. Conclusions WIRE offers a unique opportunity to investigate the mechanisms of new therapies for RCC. Successful completion of these peri-surgical studies depends on co-ordination between many specialties, including surgery, oncology, radiology, and pathology. The adaptive design allows for efficient allocation of patients to treatment arms to generate optimal data for each IMP. WIRE may identify novel biomarkers of response and toxicity, to inform treatment selection for patients. The data generated will be a foundation for further trials of these IMPs in advanced disease.
Resulta necesario destacar que, tal y como viene repitiéndose a lo largo de la historia, el progreso de la humanidad y en general el tecnológico no es concebido de forma aritmética o lineal, sino que ...se produce de una manera exponencial. Es decir, cada alteración, cada cambio, cada avance, tarda menos en suceder que el producido con anterioridad, lo que nos avoca a un entorno extremadamente volátil e inestable, en el cual el legislador tendrá que irse adaptando a las nuevas problemáticas, casuísticas y particularidades tanto sociales como tecnológicas que emanan de la Cuarta Revolución Industrial en la que nos hallamos inmersos. Una buena muestra de ello la encontramos en el reto legislativo que supuso y aún supone, la regulación de las monedas virtuales. En este trabajo analizaremos su evolución legislativa en el panorama nacional, centrándonos en las recientes modificaciones normativas introducidas con la entrada en vigor del Real Decreto 249/2023.
