Checkpoint inhibitors are integral to non-small-cell lung cancer treatment. Existing data suggests that nutritional status may play a role in antitumor immunity.This retrospective study of 106 non-small-cell lung cancer patients who started checkpoint inhibitors between 2014 and 2017 at our institution assessed relationship of nutritional parameters to overall survival (OS) and progression-free survival.Mean age was 68.7 ± 9.2 years and 59.4% patients were male. On multivariate analysis for OS, hypoalbuminemia and significant weight loss were prognostic at p-values of 0.0005 and 0.0052, respectively. We noted a parabolic association between age and OS (p = 0.026, 0.0025).In our study, some malnutrition parameters were associated with decreased OS. U-shape relationship between age and OS noted here warrants further evaluation.
DiakineTM DK210 (EGFR) couples wild-type IL-2 (wtIL2) to an IL-10 high affinity variant via a scFv scaffold that binds Epidermal Growth Factor Receptor (EGFR). Coupling the cytokines removes toxicity associated with IL-2 and improves potency of the molecule. Preclinical studies established tumor cell surface targeting improves potency. Utilizing an ex vivo response assay, we analyzed patient baseline samples and examined immune activation and safety biomarkers following DK210 (EGFR) dosing as part of an ongoing phase 1 study (NCT05704985) in patients with advanced/metastatic tumors known to express EGFR.
Methods
Patients (N=27) were administered DK210 (EGFR) at dose levels ranging from 2-16 mg thrice weekly subcutaneously. Plasma and PBMCs were collected at baseline and on treatment. An ex vivo pretreatment patient derived CD8+ T cell DiakineTM response assay (DRA), measuring culture supernatant cytokines, soluble immune checkpoints (sICP), and markers of enhanced cytotoxic function, was conducted. Immunophenotyping, proinflammatory cytokines, sICP, confirmatory markers of IL-2 and IL-10 function, and TCR sequencing were evaluated on treatment.
Results
DK210 (EGFR) dose-dependently (0-200 ng/ml) induced anti-tumor cytotoxic molecules (IFNg, Granzyme B [GzmB], and perforin) without marked increases in TNFα The magnitude of IFNg induced was higher than benchmarks observed from wtIL-2, without inducing TNFα. On treatment patient plasma showed IFNg increased 20-fold from cohort 1 to 3 but plateaued at the 8 mg dose. Additionally, GzmB and perforin increased in plasma, but not CRS-associated cytokines TNFα, IL-1β, and IL-6. GzmB and perforin increased in patient T and NK cells along with Ki-67. T cell proliferation was observed without increase in Tregs. Surface expression of ICP (PD-1, LAG3, TIM3, TIGIT) on T cells remained marginal throughout treatment. Plasma levels of sICP were induced in the DRA and increased in patient plasma during the first 21-day cycle, suggesting target engagement with tumor cell surface and shedding. Additionally, TCR sequencing showed immune activation correlated with at Day 5.
Conclusions
The immune response biomarker profile in patients in the DRA to DK210 (EGFR) and the on-treatment assessment demonstrated that coupling IL-2 with IL-10 and targeting the TME results in potent immune activation without induction of cytokine driven significant systemic toxicity or increase in Tregs. These data confirm the potent, balanced, and targeted hypothesized mechanism of action of DK210 (EGFR) in patients. This proof of mechanism supports further clinical evaluation of DK210 (EGFR) in RCC and NSCLC and validates the Diakine™ platform.
Trial Registration
NCT05704985.
Ethics Approval
The study was approved by University of Oklahoma/Castle IRB (approval number DEKA-1 (RM1017); City of Hope/WCG (approval number 20233898); NEXT Oncology/Salus IRB (approval number NXVIR22.60); UT Southwestern (approval number STU-2023-0521); Mary Crowley Cancer Research (approval number 23-08); Feinstein Institute for Medical Research (approval number 23-0724); MD Anderson Cancer Center (approval number 2023-0167). All participants gave informed consent before taking part in the study.
Abstract Background: After major liver resection, the volume status of patients is still undetermined. However, few concerns have been raised about postoperative fluid management. We aimed to compare gut function recovery and short-term prognosis of the patients after laparoscopic liver resection (LLR) with or without inferior vena cava (IVC) respiratory variability-directed fluid therapy in the anesthesia intensive care unit (AICU). Methods: This randomized controlled clinical trial enrolled 70 patients undergoing LLR. The IVC respiratory variability was used to optimize fluid management of the intervention group in AICU, while the standard practice of fluid management was used for the control group. The primary outcome was the time to flatus after surgery. The secondary outcomes included other indicators of gut function recovery after surgery, postoperative length of hospital stay (LOS), liver and kidney function, the severity of oxidative stress, and the incidence of severe complications associated with hepatectomy. Results: Compared with patients receiving standard fluid management, patients in the intervention group had a shorter time to anal exhaust after surgery (1.5 ± 0.6 days vs. 2.0 ± 0.8 days) and lower C-reactive protein activity (21.4 [95% confidence interval (CI): 11.9–36.7] mg/L vs. 44.8 [95%CI: 26.9–63.1] mg/L) 24 h after surgery. There were no significant differences in the time to defecation, serum concentrations of D -lactic acid, malondialdehyde, renal function, and frequency of severe postoperative complications as well as the LOS between the groups. Conclusion: Postoperative IVC respiratory variability-directed fluid therapy in AICU was facilitated in bowel movement but elicited a negligible beneficial effect on the short-term prognosis of patients undergoing LLR. Trial Registration: ChiCTR-INR-17013093.
Background : The efficacy and feeding‐related complications of a nasojejunal feeding tube and jejunostomy after pancreaticoduodenectomy (PD) was investigated with a randomized, controlled clinical trial at the Affiliated Drum Tower Hospital. Methods : Sixty‐eight patients who underwent PD in the Department of Hepatobiliary Surgery were randomly divided into 2 groups: 34 patients received enteral feeding via a nasojejunal tube (NJT group) and 34 patients received enteral feeding via a jejunostomy tube (JT group). The assessment of clinical outcome was based on postoperative investigation of complications. The second part of the assessment included tube related complications and an index on catheter efficiency. Results : There were 15 cases with infectious complications in the JT group and 13 cases in the NJT group, and there was no significant difference in the rate of infectious complications between the 2 groups. The rate of intestinal obstruction and delayed gastric emptying was significantly decreased in the NJT group ( P < .05). Catheter‐related complications were more common in the JT group as compared with the NJT group (35.3% vs 20.6%, P < .05). The time for removal of the feeding tube and nasogastric tube was significantly decreased in the NJT group. The postoperative hospital stay in the NJT group was significantly decreased ( P < .05), and there was no hospital mortality in this study. Conclusion : Nasojejunal feeding is safer than jejunostomy, and it is associated with only minor complications. Nasojejunal feeding can significantly decrease the incidence of delayed gastric emptying and shorten the postoperative hospital stay.
To investigate the impact of different time points of secondary warm ischemia on bile duct in a rat autologous liver transplantation model with external bile drainage.One hundred and thirty-six male inbred SD rats were randomly assigned to one of four groups (I-IV) according to the secondary warm ischemia time of 0, 10, 20 and 40 min. A rat model of autologous liver transplantation with continuous external biliary drainage under ether anesthesia was established. Ten rats in each group were used to evaluate the one-week survival rate. At 6 h, 24 h, 3 d and 7 d after reperfusion of the hepatic artery, 6 rats were killed in each group to collect the blood sample via the infrahepatic vena cava and the median lobe of liver for assay. Warm ischemia time of liver, cold perfusion time, anhepatic phase, operative duration for biliary external drainage and survival rates in the four groups were analyzed for the establishment of models.No significant difference was shown in warm ischemia time, anhepatic phase and operative duration for biliary external drainage among the four groups. Five of the 40 rats in this study evaluated for the one-week survival rate died, including three deaths of severe pulmonary infection in group IV. A significant decrease of one-week survival rate in group IV was noted compared with the other three groups. With the prolongation of the biliary warm ischemia time, the indexes of the liver function assessment were significantly elevated, and biliary epithelial cell apoptosis index also increased. Pathological examinations showed significantly aggravated inflammation in the portal area and bile duct epithelial cell injury with the prolonged secondary warm ischemia time. Microthrombi were found in the micrangium around the biliary tract in some sections from groups III and IV.The relationship between secondary warm ischemia time and the bile duct injury degree is time-dependent, and 20 min of secondary warm ischemia time is feasible for the study of bile duct injury.
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