Background: GLS-010, a novel engineered fully human immunoglobin G4 monoclonal antibody, can specially block the PD-1/PD-L1/2 axis and reactivate the antitumor immunity. Aim: This phase Ia/Ib study was carried out to evaluate the safety, recommended phase II dose (R2PD), and primary antitumor effects of GLS-010 in patients with advanced, refractory lymphoma and solid tumors. Methods: In phase Ia study, patients with refractory solid tumors and lymphoma enrolled and received GLS-010 at a dose of 1, 4, or 10 mg/kg Q2W; 240 mg Q3W or Q2W. The primary objective was to assess the dose-limiting toxicity (DLT). In phase Ib study, doses were expanded in 9 specific tumors to ensure the R2PD and explore the efficacy. Tumor mutation burden level and PD-L1 expression were also assessed with whole-exome sequencing and immunohistochemistry (SP263), respectively. Results: Up to April 18, 2020, a total of 289 patients (n Z 24, phase Ia; n Z 265, phase Ib) were enrolled. DLT was not observed in phase Ia part. The T 1/2 , CL ss , and V d were similar among all dose groups and different tumors. The most common treatment-emergent adverse events (TEAEs) were anemia, leukopenia, elevated alanine aminotransaminase/asparate aminotransferase (ALT/AST), and elevated bilirubin. And hypothyroidism was the most common immune-related adverse event (irAE). The incidence of grade !3 TEAE was 39.8%, while grade !3 irAE was only 4.5%. Based on safety studies, pharmacokinetics/pharmacodynamics, and preclinical data, 240-mg Q2W was recommended as the expansion dose. The overall objective response rate was 23.6%, with 10 patients achieving complete response. Patients with a high PD-L1 expression level (31.3% Versus. 13.7%, p Z 0.012) or tissue tumor mutation burden level (31.3% Versus. 5.6%, p Z 0.009) showed a significantly better response. Conclusion: GLS-010 showed acceptable safety profile and favorable clinical response. The dose of 240 mg Q2W was an optimal recommended dose as monotherapy.

Carbon metabolism research has attracted worldwide attention as an important way to cope with climate change, promote carbon emission reduction, increase carbon sequestration, and support low-carbon city construction. Ecological network analysis (ENA) plays an important role in network analysis and simulation of carbon metabolism. However, current studies largely focus on single elements or local processes while rarely analyzing the spatial coupling between land use and carbon metabolism. Therefore, taking Tongzhou District as an example, based on the data of land use change and energy consumption, this study constructed an analysis framework based on ENA to explore the comprehensive impact of land use changes on carbon metabolism. The results show the following: (1) From 2014 to 2020, the total carbon emissions increased year by year. Carbon emissions of other construction land (OCL) were dominant, while the carbon sequestration capacity of forest land (FL) increased by 236%. The positive carbon metabolic density remained relatively stable, while the negative carbon metabolic density decreased year by year. (2) The negative carbon flow was concentrated in the transfer of other land to OCL, accounting for 40.2% of the total negative “carbon flow.” The positive carbon flow was primarily from the transfer of other land to FL. (3) From 2014 to 2016, the spatial ecological relationships of carbon flow were dominated by exploitation and control. From 2016 to 2018, competition relationships intensified due to the expansion of the field; from 2016 to 2018, exploitation and control relationships, competition relationships, and mutualism relationships increased significantly and were evenly distributed. This study provides decision-making guidance for the subsequent formulation of government carbon emission reduction policies.

7543 Background: B-cell malignancies evade apoptosis by overexpressing BCL-2 proteins. Approved BCL-2i venetoclax requires a slow dose ramp-up to limit risk of tumor lysis syndrome (TLS) and has been associated with severe neutropenia. Investigational single-agent lisaftoclax is a novel, oral BCL-2i active against hematologic malignancies (HMs), with potentially synergistic antitumor effects when combined with other agents in B-cell malignancies. Methods: The aim of this multicenter open-label study was to evaluate dose-limiting toxicity (DLT), maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), efficacy, pharmacokinetics (PK), and pharmacodynamics of lisaftoclax in pts with R/R CLL/SLL (per 2008 iwCLL NCI-WG guidelines). Lisaftoclax was administered orally once daily at 3 dose cohorts (400, 600, or 800 mg) every 28 days, with 15 pts in each cohort. Results: As of the data cutoff date of January 25, 2022, 45 pts had been enrolled, with a median (range) age of 58 (38-80) years. DLT and MTD were not observed. The preliminary PK profile showed that exposures increased with lisaftoclax doses from 400 to 800 mg (average half-life: 4.2-6.6 hours). A total of 42 pts experienced any-grade treatment-related adverse events (AEs), including neutropenia (55.6%); anemia (42.2%); decreased leukocyte count (40%); thrombocytopenia (37.8%); lowered lymphocyte count (17.8%); hyperuricemia (31.1%); hypokalemia (24.4%); increased blood bilirubin (22.2%); hypertriglyceridemia (20%); diarrhea (20%); hyperphosphatemia, hypocalcemia, and decreased weight (15.6% each); increased AST (15.6%) and blood LDH (13.3%); pyrexia; and increased ALT and blood creatinine (11.1% each). A total of 28 (62.2%) pts experienced grade ≥ 3 AEs and 13 (28.9%) serious AEs. Of these, 25 (55.6% of total) and 9 (20%) were related to lisaftoclax, and 14 (31.1%) led to treatment discontinuation. One clinical TLS was reported. With a median (range) treatment of 7 (1-17) cycles and median (range) time to response of 1 (1-13) cycles, 1 of 41 evaluable pts with CLL experienced complete response (CR) and 27 with CLL/SLL achieved partial response (PR), for an objective response rate (ORR) of 68.29%. The RP2D of lisaftoclax as monotherapy was determined as 600 mg. Conclusions: BCL-2i lisaftoclax was well tolerated up to 800 mg/day. There were no significant new or unmanageable safety findings, and the ORR was 68.29%. Lisaftoclax may offer a treatment alternative for pts with R/R HMs, with a daily ramp-up schedule that may be more convenient and “user friendly.” Clinical trial information: NCT04494503.

e20510 Background: Micropapillary is one of the most aggressive histologic subtypes of lung adenocarcinoma, which is considered a poor prognostic marker. Comprehensive analysis of tumor immune microenvironment (TIME) features of micropapillary of early invasive lung adenocarcinoma may provide better insight and facilitate the development of novel strategies for early detection and intervention. Methods: A total of 15 patients who underwent anatomical resection and were pathologically diagnosed with stage I micropapillary adenocarcinomas were included in this study. Gene expression profiles (GEPs) of tumor immune-related 289 genes were analyzed using NanoString nCounter. Differentially expressed genes(DEGs), estimation of TIME cell infiltration, and TIME signatures between micropapillary and non-micropapillary were assessed. Results: The number of micropapillary and non-micropapillary patients was 5 and 10. The comparison revealed CD69, IL6, CXCL8, CXCL2, POLR2A and so on were significantly upregulated in the micropapillary group compared with the non-micropapillary group, while HLA-DPA1, IFIT2, and other seven genes were down-regulated in the micropapillary group. These DEGs were mostly enriched in “positive regulation of cytokine production”， “T cell activation”， “receptor ligand activity，” and “signaling receptor activator activity” pathways according to GO enrichment analysis. The results of the KEGG analysis revealed that genes were significantly enriched in “IL-17 signaling pathway”, “TNF signaling pathway”, “cytokine-cytokine receptor interaction”, and so on. Meanwhile, different immune infiltration of the two groups was analyzed. Totally, there was a better TIME cell infiltration in the micropapillary group compared with the non-micropapillary group. Especially, the score of DCs and mast cells was significantly higher in micropapillary group. However, TIME signature scores were similar in both groups. Conclusions: Our study demonstrated that the TIME between micropapillary and non-micropapillary of stage I lung adenocarcinoma was different. Increased mast cells explained poor prognosis in lung adenocarcinoma with micropapillary pattern. A high level of DCs infiltration indicated that micropapillary adenocarcinoma might benefit from immunotherapy.

Background Treatment options for malignant and aggressive glioma are limited. Vascular endothelial growth factor (VEGF) antibodies are angiogenesis inhibitors that prevent the growth of neoplasms by inhibiting the expansion of the vascular tissue that supports them. We designed this phase I trial to assess the safety and establish the maximum tolerable dose (MTD) of GB222, a recombinant human anti-VEGF monoclonal, for patients with recurrent malignant glioma. Methods Eligible patients were those who were diagnosed with WHO grade III and IV glioma and progressed after initial treatment including surgery, radiotherapy, and temozolomide. GB222 was initiated at 3 mg/kg (Cohort 1) intravenously once every four weeks (Q4W), then escalated in a 3 + 3 design at 5 mg/kg (Cohort 2, Q4W), 5 mg/kg (Cohort 3, Q2W), 7.5 mg/kg (Cohort 4, Q2W), and 10 mg/kg (Cohort 5, Q2W). The initial 28 days of each dose level cohort was the observation period for dose-limiting toxicity (DLT). After that, patients continued the treatment with the same dose of GB222 in combination of temozolomide if patients were considered to have benefited from the treatment. Our study also evaluated anti-tumor efficacy including objective response rate (ORR), progress free survival (PFS), and overall survival (OS), as well as pharmacokinetic parameters of GB222. Findings Sixteen patients were enrolled: 4 in Cohort 1, 3 each in Cohort 2, 3, 4, and 5. In the 28 days with GB222 alone, no DLT events were observed in all dose cohorts, and MTD was not reached. Among 16 patients, 14 (87.5%) received the combined treatment of GB222 and temozolomide after the DLT observation period. Two patients stopped the treatment after the DLT observation period due to disease progression. All patients (100%) reported experiencing at least one adverse event (AE) among patients who either received GB222 alone or the combination therapy of both GB222 and temozolomide. Four patients experienced grade 3/4 AE (one in Cohort 1, one in Cohort 2, and two in Cohort 3), including status epilepticus, herpes zoster, bone marrow failure, and hematological laboratory abnormalities. None of them was determined to be GB222 related. No death and treatment termination occurred due to AEs. Among these 16 patients, 81.3% (13/16) had treatment-related adverse events (TRAE). The common TRAE included decreased neutrophil count, decreased leukocyte count, increased alanine aminotransferase, hypertension, and rash. Pharmacokinetics (PK) studies showed drug exposure of GB222 had a linear relationship with the dose administrated. The overall objective response rate among 16 patients was 31.3% (95% CI: 11.02%, 58.66%) with 0% in Cohort 1, 66.7% in Cohort 2 (1 CR and 1 PR), 33.3% in Cohort 3 (1PR), 0% in Cohort 4, and 66.7% in Cohort 4 (2 PR). The median PFS was 4.44 months [95% confidence interval (CL) 2.76–6.60 months]. The median OS was 8.38 months (95% Cl: 4.24-not reached). Interpretation GB222 alone or combined with temozolomide had manageable safety profiles and encouraging anti-tumour activity in treating patients with recurrent HGG.