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
The first-line treatment for metastatic clear cell renal cell carcinoma (mccRCC) includes immune oncology (IO) based combination therapy. The current standard includes a PD-1 ...inhibitor plus either an anti-CTLA-4 inhibitor (IO/IO) or an anti-vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGF TKI) (IO/TKI). Currently, there is no evidence to guide a physician’s choice between an IO/IO versus an IO/TKI combination. The phase III IMmotion 151 trial performed RNA-seq from 823 ccRCC tumors and established seven biologically distinct gene expression clusters of ccRCC (Motzer and Rini et al., Cancer Cell 2020). The seven clusters showed differential responses to immune checkpoint inhibitor and may serve as a predictive biomarker to select clusters to assign patients with mccRCC to either an IO/IO (ipilimumab/ nivolumab) or an IO/TKI (nivolumab/cabozantinib) regimen.
Methods
Patients diagnosed with mccRCC without prior systemic therapy (including in the neoadjuvant or adjuvant setting) and at least one measurable lesion as defined by RECIST 1.1 are eligible for enrollment. RNA-seq will be performed on metastatic tumor specimens and used to assign tumor clusters. Patients with cluster 1/2 tumors will be assigned to the nivolumab/cabozantinib arm. Patients with cluster 4/5 tumors will be assigned to the ipilimumab/nivolumab arm. Cluster 3/6/7 will be excluded. The primary endpoint is overall response rate (ORR) per RECIST 1.1. Key secondary endpoints include progression-free survival, depth of response >80%, and rate of immune-related adverse events (irAEs).
The hypothesis is that use of tumor clusters to assign front-line therapy to either nivolumab/cabozantinib or ipilimumab/nivolumab will lead to a 20% greater ORR compared to unselected historical controls in CheckMate 9ER (ORR 55%) or CheckMate 214 (ORR: 40%). This trial adopts Simon’s MiniMax two-stage design (power: 80%, one-sided alpha: 0.1). For the nivolumab/cabozantinib arm, stage I will enroll 12 eligible patients. If there are 7 or more responders in the first 12 patients, stage II will enroll an additional 14 patients (n=26). For the ipilimumab/ nivolumab arm, stage I will enroll 16 eligible patients. If there are 7 or more responders in the first 16, stage II will enroll an additional 12 patients (n=28). The primary endpoint will be met if there are 15 or more responders (ORR>60%).
This trial is open and enrolling with 12 patients on study at Vanderbilt University Medical Center and additional sites to open including UT Southwestern, City of Hope, University Hospitals Seidman Cancer Center, and Cleveland Clinic.
This trial is funded by the Department of Defense Kidney Cancer Research Program Clinical Trial Award (W81XWH-22-1-1033) (NCT05361720).
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: PRO1160 is a novel antibody-drug conjugate (ADC) directed to CD70, an antigen mediating immuno-suppression that is overexpressed in multiple solid tumors and hematologic ...malignancies, with limited distribution in normal tissues. PRO1160 comprises (1) a human monoclonal antibody specific for CD70, (2) a protease-cleavable proprietary hydrophilic linker, and (3) exatecan, a topoisomerase 1 inhibitor. Comprehensive prior work demonstrated that the hydrophilic linker confers excellent physicochemical properties and pharmacokinetics (PK) across a range of payload mechanisms and is superior to conventional linkers on these critical parameters for ADCs. In addition, exatecan is broadly active in many tumor types, is membrane permeable, and is not a substrate of multidrug resistance pumps, thus likely lending strong bystander effects and durable treatment responses. PRO1160 is highly potent in cell-derived xenograft models of renal cell carcinoma (RCC), non-Hodgkin lymphoma (NHL), and nasopharyngeal carcinoma (NPC). PRO1160 also demonstrates marked antitumor activity in patient-derived xenograft models of diverse tumor sites, histologies, molecular subtypes, target expression levels, and Epstein Barr Virus status. PRO1160 is stable in circulation and displays PK characteristics indistinguishable from the parent antibody in rats. In a GLP toxicity study in cynomolgus monkeys, the primary PRO1160-related toxicity resided in the thymus and bone marrow, was consistent with exatecan toxicities, and was reversible.
PRO1160-001 is an ongoing, open-label Phase 1/2 study to evaluate the safety, tolerability, PK, and antitumor activity of PRO1160 in patients with metastatic RCC, metastatic or relapsed NPC, or advanced relapsed/refractory NHL.
Patients must have measurable disease per the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or the Lugano Classification for NHL. Patients must also have previously received therapies known to confer clinical benefit unless considered ineligible, refused by the patient, or not available in the region.
PRO1160 is given by intravenous infusion on Day 1 of a 21-day cycle and treatment may continue until disease progression, unacceptable toxicity, or other reason for discontinuation. The primary objectives are to evaluate the safety and tolerability of PRO1160 and to identify the maximum tolerated dose, if reached, and recommended phase 2 dose (RP2D).
This study consists of 2 parts, Part A: dose-escalation and dose-level expansion, and Part B: 3 tumor-specific expansion cohorts (metastatic RCC, metastatic or relapsed NPC, or advanced relapsed/refractory NHL) treated at the RP2D. PK, immunogenicity, and antitumor activity will also be evaluated. The study is currently enrolling at sites in the US, with future enrollment in China planned (Clinicaltrials.gov: NCT05721222).
