133 Cs NMR was employed to study the structural characteristics and properties of perovskites at the atomic level. CsBi x Pb 1− x Br 3 perovskites doped with Bi at concentrations of 0.0059, 0.0072, and 0.0120 were studied. The importance of high-quality materials for applications in optics and photonics was noted. 133 Cs NMR showed high sensitivity for studying these concentrations of Bi, which affect the stability of perovskites and their dynamic parameters.

The principle of independent drug action proposes that responses to drug combinations result from responses to one or the other of two combining agents, but not both. Explorations of biological pathway interactions in signal transduction and immunobiology as synergy have not been connected to mathematical demonstrations of above–independent action activity, which would define pharmacologic synergy. We review independent action as the explanation for cancer drug combinations and find no evidence for pharmacologic synergy. Rather, a measure of correlation of response ( ρ) when positive can explain below–independent action results, and negative correlation can explain above–independent action results. Anticorrelated responses may be a mathematical demonstration of collateral sensitivity, which can achieve above–independent action activity. Inappropriate use of biological concepts of synergy may be contributing to high failure rates for immuno-oncology clinical trials, indicating a need for more rigorous applications of independent action to the development of cancer drug combination therapy.

Supplementary Figure Legends 1-2 from The Integrin αvβ3-5 Ligand MFG-E8 Is a p63/p73 Target Gene in Triple-Negative Breast Cancers but Exhibits Suppressive Functions in ER+ and erbB2+ Breast Cancers

Supplementary Figure 3 from Heat Shock Protein B8, a Cyclin-Dependent Kinase–Independent Cyclin D1 Target Gene, Contributes to Its Effects on Radiation Sensitivity

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The open-label phase Ib/II Study 111/KEYNOTE-146 of daily lenvatinib 20 mg plus pembrolizumab 200 mg once every 3 weeks showed promising efficacy and tolerable safety in patients with previously treated advanced endometrial carcinoma (EC; primary data cutoff date: January 10, 2019). This updated analysis reports long-term follow-up efficacy and safety data from 108 patients with previously treated EC included in the primary analysis. End points included objective response rate, duration of response, progression-free survival, overall survival, and safety. Investigators performed tumor assessments per immune-related RECIST. At the updated data cutoff date (August 18, 2020), the median study follow-up duration was 34.7 months (95% CI, 30.9 to 41.2), the objective response rate was 39.8% (95% CI, 30.5 to 49.7), and the median duration of response was 22.9 months (95% CI, 10.2 to not estimable). The median progression-free survival and overall survival were 7.4 months (95% CI, 5.2 to 8.7) and 17.7 months (95% CI, 15.5 to 25.8), respectively. Treatment-related treatment-emergent adverse events of any grade occurred in 104 (96.3%) patients. The most common grade ≥ 3 treatment-related treatment-emergent adverse events were hypertension (33.3%), elevated lipase (9.3%), fatigue (8.3%), and diarrhea (7.4%). The results demonstrate extended efficacy and tolerability of lenvatinib plus pembrolizumab in this cohort of patients with previously treated advanced EC.

Supplementary Materials and Methods, Figure Legends 1-3 from Heat Shock Protein B8, a Cyclin-Dependent Kinase–Independent Cyclin D1 Target Gene, Contributes to Its Effects on Radiation Sensitivity

PDF file - 493K, The MTAP-CDKN2A Locus Confers Susceptibility to Cancer in a Naturally Occurring Canine Model

Legends for Supplementary Figures 1-4 and Supplementary Tables 1 & 2

Supplementary Figure 1 from c-myc Repression of TSC2 Contributes to Control of Translation Initiation and Myc-Induced Transformation

Supplementary Methods from The Integrin αvβ3-5 Ligand MFG-E8 Is a p63/p73 Target Gene in Triple-Negative Breast Cancers but Exhibits Suppressive Functions in ER+ and erbB2+ Breast Cancers

Background Oncolytic virus V937 showed activity and safety with intratumoral administration. This phase 1 study evaluated intravenous V937±pembrolizumab in patients with advanced solid tumors.Methods Patients had advanced non-small cell lung cancer (NSCLC), urothelial cancer, metastatic castration-resistant prostate cancer, or melanoma in part A (V937 monotherapy), and metastatic NSCLC or urothelial cancer in part B (V937+pembrolizumab). Prior immunotherapy was permitted >28 days before study treatment. Patients received intravenous V937 on days 1, 3, and 5 (also on day 8 in part B) of the first 21-day cycle and on day 1 of subsequent cycles for eight cycles. Three ascending dose-escalation cohorts were studied. Dose-escalation proceeded if no dose-limiting toxicities (DLTs) occurred in cycle 1 of the previous cohort. In part B, patients also received pembrolizumab 200 mg every 3 weeks from day 8 for 2 years; dose-expansion occurred at the highest-dose cohort. Serial biopsies were performed.Results No DLTs occurred in parts A (n=18) or B (n=85). Grade 3–5 treatment-related adverse events (AEs) were not observed in part A and were experienced by 10 (12%) patients in part B. The most frequent treatment-related AEs (any grade) in part B were fatigue (36%), pruritus (18%), myalgia (14%), diarrhea (13%), pyrexia (13%), influenza-like illness (12%), and nausea (12%). At the highest tested dose, median intratumoral V937 concentrations were 117,631 copies/mL on day 8, cycle 1 in part A (n=6) and below the detection limit for most patients (86% (19/22)) on day 15, cycle 1 in part B. Objective response rates were 6% (part A), 9% in the NSCLC dose-expansion cohort (n=43), and 20% in the urothelial cancer dose-expansion cohort (n=35).Conclusions Intravenous V937+pembrolizumab had a manageable safety profile. Although V937 was detected in tumor tissue, in NSCLC and urothelial cancer, efficacy was not greater than that observed in previous studies with pembrolizumab monotherapy.Trial registration number NCT02043665.

Nanostring data from tumor biopsies.

2525 Background: LVGN6051 is a conditional 4-1BB agonistic monoclonal antibody with Fc γ-receptor IIB selective binding in the tumor microenvironment for optimal activity. Preclinical studies showed potent antitumor activity by LVGN6051 alone and in combination with anti-PD-1 antibody. Methods: We conducted this first in human (FIH) multicenter phase 1 dose escalation study in the US. Eligible pts with advanced solid tumor malignancies received escalating doses of LVGN6051 alone or in combination with pembrolizumab 200 mg IV Q3W until unacceptable toxicity, progressive disease, or withdrawal of consent. Results: As of Jan 23, 2023, 55 pts were enrolled and received LVGN6051 alone with the dose range of 0.003–7 mg/kg (n=18), or combination therapy of LVGN6051 2 mg/kg + pembrolizumab (n=22) or LVGN6051 4 mg/kg + pembrolizumab (n=15). The median age was 58 years (range 20-83) and number of prior therapies was 5; 46 pts (84%) had ECOG PS 1 and 21 pts (38%) had received prior immune checkpoint inhibitors (ICI). In pts who received LVGN6051 alone, the MTD was not reached up to 7 mg/kg and the RP2D was selected as 4 mg/kg IV Q3W for tolerance. The RP2D for combination therapy was established as LVGN6051 4 mg/kg and pembrolizumab 200 mg IV Q3W. Pts received a median of 2.8 months and a mean of 4.0 months (range 0.5 – 19.2) of study treatment. 33 pts (60%) experienced any grade treatment-related adverse events (TRAEs) with noteworthy (> 5%) AST increased (27%), ALT increased (26%), thrombocytopenia (16%), infusion related reaction (IRR) (9%), fatigue (7%), lipase increased (6%), nausea (6%) and chills (6%). 14 pts (25%), 1 mono- and 13 combination therapy, showed ≥ grade 3 TRAEs: AST increased (11%), ALT increased (9%), thrombocytopenia (7%), fatigue (4%), IRR (2%), lipase increased (2%) and nausea (2%). 6 drug-related serious adverse events and 1 DLT (grade 4 thrombocytopenia), all in combination therapy, were reported. In 42 evaluable pts, the disease control rate (DCR) was 50%. Combination therapy showed that target lesions were reduced by 57%, 42% and 48% in melanoma (n=2) and pancreatic cancer (n=1), respectively. Among 11 melanoma pts (10 had progressed on anti-CTLA4 and anti-PD-1 therapy), 2 PR and 5 SD were observed per RECIST 1.1, including one being treated for 19+ months (26+ cycles). Pts with HNSqCC (n=1) and CRPC (n=1) also showed remarkable tumor shrinkage. Paired tumor biopsies for single cell RNAseq biomarker exploration confirmed activation of effector T cells following LVGN6051 treatment. Conclusions: We established the RP2Ds of LVGN6051 alone and in combination with pembrolizumab in this FIH phase 1a study. These regimens were well tolerated. Preliminary efficacy data showed encouraging anti-tumor activity in heavily pretreated pts who had progressed on ICI. Phase 1b dose expansion for the combination therapy is ongoing in pts with melanoma, GI malignancies and NSCLC. Clinical trial information: NCT04130542 .

Supplementary Tables 1-2, Figure Legends 1-2 from Identification of Cyclin D1– and Estrogen-Regulated Genes Contributing to Breast Carcinogenesis and Progression

Supplementary Table S1. Anti-PD-1/L1 treatment experience by SD-101 dose group. Supplementary Table S2. Overview of safety. Supplementary Table S3. Treatment-related events in 20% or more of patients in the total treatment cohort are presented. Supplementary Figure S1.Percent change from baseline over time in tumors in patients who were naïve to anti-PD-1/L1 therapy. Supplementary Figure S2. IFN gene signature in Blood Cells. Supplementary Figure S3. RNA gene expression profiling. Supplementary Figure S4. A subset of patient biopsies that were assessed by RNA expression profiling, were assessed by fluorescent immunohistochemistry for infiltration of CD4 (A) and CD8 (B) T cells. Supplementary Figure S5. Correlation between fluorescent immunohistochemistry (IHC) and RNA expression profiling by Nanostring.

Supplementary Figures 1-5, Table 1 from The Connectivity Map Links Iron Regulatory Protein-1–Mediated Inhibition of Hypoxia-Inducible Factor-2a Translation to the Anti-inflammatory 15-deoxy-Δ12,14-Prostaglandin J2

Table S1. Patient flow by dose group Table S2. PK parameters of utomilumab following multiple dosing Figure S1. Partial response in a patient with anaplastic thyroid carcinoma (utomilumab 3.6 mg/kg + pembrolizumab 2 mg/kg) at cycle 4 versus baseline. Figure S2. Mean concentration-time profile for pembrolizumab

Supplementary Figure 1 from Identification of Cyclin D1– and Estrogen-Regulated Genes Contributing to Breast Carcinogenesis and Progression

Supplementary Methods and Materials, Tables 1-3 from c-myc Repression of TSC2 Contributes to Control of Translation Initiation and Myc-Induced Transformation

Background The phase I first-in-human study ENGAGE-1 evaluated the humanized IgG1 OX40 agonistic monoclonal antibody GSK3174998 alone (Part 1 (P1)) or in combination with pembrolizumab (Part 2 (P2)) in patients with advanced solid tumors. Methods GSK3174998 (0.003–10 mg/kg) ± pembrolizumab (200 mg) was administered intravenously every 3 weeks using a continuous reassessment method for dose escalation. Primary objectives were safety and tolerability; secondary objectives included pharmacokinetics, immunogenicity, pharmacodynamics, and clinical activity. Results 138 patients were enrolled (45 (P1) and 96 (P2, including 3 crossovers)). Treatment-related adverse events occurred in 51% (P1) and 64% (P2) of patients, fatigue being the most common (11% and 24%, respectively). No dose-toxicity relationship was observed, and maximum-tolerated dose was not reached. Dose-limiting toxicities (P2) included Grade 3 (G3) pleural effusion and G1 myocarditis with G3 increased troponin. GSK3174998 ≥0.3 mg/kg demonstrated pharmacokinetic linearity and >80% receptor occupancy on circulating T cells; 0.3 mg/kg was selected for further evaluation. Limited clinical activity was observed for GSK3174998 (P1: disease control rate (DCR) ≥24 weeks 9%) and was not greater than that expected for pembrolizumab alone (P2: overall response rate 8%, DCR ≥24 weeks 28%). Multiplexed immunofluorescence data from paired biopsies suggested that increased infiltration of natural killer (NK)/natural killer T (NKT) cells and decreased regulatory T cells (Tregs) in the tumor microenvironment may contribute to clinical responses: CD16+CD56–CD134+ NK /NKT cells and CD3+CD4+FOXP3+CD134+ Tregs exhibited the largest magnitude of change on treatment, whereas CD3+CD8+granzyme B+PD-1+CD134+ cytotoxic T cells were the least variable. Tumor gene expression profiling revealed an upregulation of inflammatory responses, T-cell proliferation, and NK cell function on treatment with some inflammatory cytokines upregulated in peripheral blood. However, target engagement, evidenced by pharmacologic activity in peripheral blood and tumor tissue, did not correlate with clinical efficacy. The low number of responses precluded identifying a robust biomarker signature predictive of response. Conclusions GSK3174998±pembrolizumab was well tolerated over the dose range tested and demonstrated target engagement. Limited clinical activity does not support further development of GSK3174998±pembrolizumab in advanced cancers. Trial registration number NCT02528357 .