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.
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.
Abstract Background Complete response (CR) is still a rare event in patients with advanced clear cell renal cell carcinoma (ccRCC). The combination of nivolumab plus cabozantinib was recently ...approved for the first-line treatment of ccRCC based on the CheckMate 9ER phase 3 study demonstrating improved progression-free survival (PFS) and objective response rate (ORR) in comparison to sunitinib. However, the CR rate was only 9%. Since the anti-tumor effects of immune checkpoint inhibitors are dependent on the presence of activated tumor-infiltrating T cells, drugs that could synergize with T cells’ anti-tumor activity can allow us to improve CR rates. Activation of the cGAS-STING pathway, the master regulator of anti-tumor immunity which is induced by radiation-induced DNA damage, is one promising mechanism that has been investigated. Many studies have shown that radiation treatment augments immune checkpoint inhibition. However, it is not always possible to radiate all metastatic lesions. Therefore, targeted peptide receptor radionuclide therapies (PRRT), have been developed by conjugating radioisotopes to receptor binding analogs targeting specific cancer cell surface proteins, thereby delivering targeted radiation to cancer cells in the body with minimal damage to surrounding healthy cells. 177Lu girentuximab is the first antibody-radioisotope designed for ccRCC, targeting carbonic anhydrase IX-expressing cells, which includes >90% of ccRCC. It has been tested in metastatic ccRCC as a single agent and shown to be safe and effective in stabilizing disease in 57% of pts. In this study, we hypothesize that 177Lu girentuximab-induced DNA damage will potentiate the STING pathway, and this activation will synergize with nivolumab and cabozantinib to promote trafficking and infiltration of activated T cells to tumors and achieve higher CR rates. Methods Up to 100 patients with treatment naïve, biopsy-proven ccRCC with adequate organ/marrow function with ≥1 evaluable lesion by RECIST 1.1 will be enrolled. A 5-patient safety lead-in will evaluate myelosuppression. Ongoing safety, and futility monitoring will employ a Bayesian approach. The sample size was chosen for reasonable operating characteristics to distinguish a CR rate (primary endpoint) of 18% as better than 9% using a beta(0.09, 0.91) prior. Secondary endpoints are objective response, PFS by RECIST 1.1, and overall survival. 177Lu-girentuximab 1480 MBq/m2 (61% of single agent MTD) will be administered every 12 weeks for up to 3 treatment cycles. Starting with the second cycle, nivolumab and cabozantinib will be added at standard dose. To explore the effects of the combination therapy on inducing activated T cell infiltration, patients will undergo pre/post-treatment PET scan with 18FF-AraG radiotracer as well as biopsies for single cell, spatial transcriptomics and proteomics studies. This is an investigator initiated trial. Telix Pharmaceuticals provided drug and funding support. Also supported by DOD grant W81XWH-22-1-0456 CDMRP DOD Funding: yes
Abstract Background: Inactivation of the VHL gene leading to aberrant HIF2α activity is nearly universal in clear cell renal cell carcinoma (ccRCC). NKT2152 is a novel, potent, selective orally ...available HIF2α inhibitor optimized for enhanced PK exposure and sustained target inhibition which has demonstrated robust activity in both ccRCC cell line-derived and patient-derived xenograft RCC and other solid tumor models. This is a Phase 1/2 open label, multicenter, first in human study of NKT2152 in adults with advanced clear cell renal cell carcinoma (ccRCC) (NCT05119335). In Phase 1, up to ~60 patients will be enrolled according to a 3 + 3 design with backfill as permitted by the Safety Review Committee. The primary objective of phase 1 is to determine the recommended dose for expansion (RDE) based on the totality of clinical data. Phase 2 will enroll ~50 additional patients with the primary objective of determining investigator-assessed by RECIST v1.1. Key secondary objectives include safety, tolerability, PD effects, progression free survival, duration of response, and disease control rate. Exploratory objectives include evaluation of biomarkers predictive of tumor response. Adults who have advanced ccRCC without available standard therapy), ECOG PS 0-2, with measurable disease per RECIST 1.1 are eligible. Patients who have had prior HIF2a inhibitors, require supplemental oxygen, and with significant cardiac disease are excluded. Tumor assessments by CT or MRI are conducted every 8 weeks until 48 weeks, then every 12 weeks thereafter. Adverse events will be monitored and graded in severity using CTCAE v5.0. The Phase 1 study is currently actively accruing in the United States with Phase 2 dose expansion anticipated to start in Q3, 2023.
Abstract Background Ciforadenant is an investigational immunotherapeutic small molecule that selectively and reversibly binds adenosine2A receptors (A2ARs) on T lymphocytes and other cells of the ...immune system. RCC metabolism is known to be highly glycolytic with a need to export adenosine triphosphate (ATP) to allow for continued proliferation of cancer cells. In the tumor microenvironment (TME) ATP is hydrolyzed to adenosine by CD39/CD73. Adenosine has immune suppressive effects on the TME through the A2 adenosine receptor (A2AR) including decreased T cell activation and proliferation (Ohta et al., 2009). Blocking A2AR on tumor associated myeloid cells such as macrophages, dendritic cells, and myeloid derived suppressor cells in preclinical mouse models have shown enhanced tumor killing (Cekic et al 2014). Preclinical studies show that the addition of ciforadenant to CTLA4 and PD1 blockade shows enhanced efficacy and in some cases elimination of the established tumors (Willingham et al., 2018). Recently, in a first in human study, the A2AR antagonist ciforadenant was found to be safe and showed activity as monotherapy in RCC patients with refractory disease following multiple lines of therapy showing a median progression free survival (mPFS) of 4.1 months (Fong et al., 2019). In the same study, the addition of ciforadenant to PD-L1 blockade with atezolizumab was shown to be safe and demonstrate activity with mPFS of 5.8 months and OS probability at 25 months of 90%. We hypothesize that the addition of the A2aR antagonist, ciforadenant, to the combination of ipilimumab and nivolumab will favorably modulate metabolic adenosine signaling and the myeloid compartment to enhance patient response by reducing immunosuppression. Methods INC is a Phase 1b/2 single-arm, multicenter study to assess safety and efficacy of the combination of ipilimumab, nivolumab, and ciforadenant in the frontline treatment of patients with advance clear cell renal cell carcinoma. This study is being conducted through the Kidney Cancer Clinical Trial Consortium. Eligibility criteria include untreated advanced clear cell RCC, ECOG PS 0 or 1, measurable disease by RECIST 1.1 and adequate organ function and excludes patients who have previously received immunotherapy. The study will include a lead-in safety phase 1b portion with enrollment of four to eight patients treated with ciforadenant 100 mg BID, nivolumab 3 mg/kg and ipilimumab 1 mg/kg (IV) q3 weeks. If the rate of patients with a dose limiting toxicity is more than 45% another four patients will be enrolled at reduced dose of ciforadenant 50 mg BID, nivolumab 3 mg/kg and ipilimumab 1 mg/kg IV q3 weeks. If continuing on trial, patients will receive nivolumab 480 mg infusion and ciforadenant beginning Cycle 2, Day 1 q4 weeks. In the Phase 2 dose-expansion portion of the study, 42 additional patients (total 50) patients consisting of untreated advanced clear cell renal cell carcinoma will be treated at the RCD determined in the Phase 1b portion of the study. The primary objective is to determine the safety and tolerability and to assess the depth of response (>50% by RECIST 1.1 Eisenhaur, 2009) based on a Bayesian design in patients with advanced RCC treated with ipilimumab, nivolumab, and ciforadenant. Secondary objectives will estimate the objective response rate (ORR), duration of response (DOR) progression free survival (PFS), progressive disease (PD) rate, and irAE rate of ipilimumab, nivolumab, and ciforadenant combination in untreated advanced RCC. Exploratory objectives include assessing gene expression signatures and pharmacodynamic parameters with outcome. This study is open to enrollment with six patients on trial anticipating lead-in safety analysis to be completed shortly for identification of randomized phase 2 dosing and opening the expansion cohorts. The trial will be open through the Kidney Cancer Research Consortium at MD Anderson, Vanderbilt University Medical Center, Duke University, and University of Pennsylvania. CDMRP DOD Funding: yes
Abstract Background: Zanzalintinib (XL092) is a novel, potent, orally bioavailable small molecule inhibitor of several receptor tyrosine kinases, including VEGFR2, MET, and the TAM kinases AXL, and ...MER. These receptor tyrosine kinases are implicated in several oncogenic processes, including tumor angiogenesis, proliferation, invasion, and metastasis. MET and AXL are known to play important roles in the development of resistance to antiangiogenic therapies. In addition, drugs targeting the TAM kinases are thought to promote an immune-permissive environment, potentially enhancing responses to immune checkpoint inhibitors (ICIs). This hypothesis has been confirmed in preclinical murine tumor models in which zanzalintinib in combination with an anti–PD-1 agent showed significantly greater antitumor and immunomodulatory activity, as well as a greater survival benefit, when compared with either agent alone (Hsu J, et al. Mol Cancer Ther 2023). In a phase 1 first-in-human study, zanzalintinib alone or in combination with atezolizumab showed a manageable safety profile and a half-life of 16–22 hours for zanzalintinib supporting once-daily dosing. The combination also showed promising clinical activity in patients with advanced or metastatic solid tumors, including renal cell carcinoma (RCC; Sharma MR, et al. ESMO 2022:Abs 481P). The encouraging preclinical and clinical activity support the evaluation of zanzalintinib in combination with ICIs in clinical studies, including STELLAR-304 (NCT05678673), a randomized study that is exploring the efficacy and safety of zanzalintinib in combination with nivolumab in patients with non-clear cell RCC (nccRCC). STELLAR-002 (NCT05176483) is another ongoing study assessing the safety and preliminary efficacy of zanzalintinib in multiple ICI combinations in patients with advanced solid tumors. Presented here is the study design of the cohort-expansion stage for patients with RCC in STELLAR-002. Methods: STELLAR-002 is a multicenter, open-label, phase 1b trial consisting of a dose-escalation stage and a tumor-specific cohort-expansion stage. The study is enrolling adults who have a cytologically or histologically confirmed solid tumor that is unresectable, locally advanced, or metastatic. In addition, patients with RCC enrolled in the expansion phase must have measurable disease per RECIST v1.1 as assessed by the investigator. The recommended doses of zanzalintinib plus nivolumab, zanzalintinib plus nivolumab and ipilimumab, and zanzalintinib plus nivolumab and relatlimab are being established in the dose-escalation stage of the study. The study includes three dose-expansion cohorts for patients with RCC: first-line clear cell RCC (ccRCC; Cohort 1), second-line ccRCC after 1 prior ICI-based combination therapy (Cohort 2), and first-line nccRCC (Cohort 6). The following regimens are available options for randomization at the recommended dose depending on the cohort: single-agent zanzalintinib (Regimen A), zanzalintinib plus nivolumab (Regimen B), zanzalintinib plus nivolumab and ipilimumab (Regimen C), or zanzalintinib plus nivolumab and relatlimab (Regimen D). Patients in Cohort 1 may be randomized to Regimens B, C, or D, patients in Cohort 2 to Regimens A, B, or D, and patients in Cohort 6 to Regimens A or B. The primary objectives of the cohort-expansion stage are objective response rate per RECIST v1.1 (as assessed by the investigator) and incidence and severity of adverse events, including serious and immune-mediated events. The trial is ongoing and enrolling patients from 13 countries in North America, Europe, and the Asia-Pacific region.
