bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase 2 study of alrizomadlin, a novel MDM2/p53 inhibitor, in combination with pembrolizumab for treatment of patients with malignant peripheral nerve sheath tumor (MPNST).
Authors: Somaiah Neeta , Van Tine Brian Andrew , Chmielowski Bartosz , Drabick Joseph J. , Chawla Sant P. , McKean Meredith , Spira Alexander I. , O'Byrne Kenneth John , Foresto Steven A. , Movva Sujana , Kim AeRang , Gastman Brian , Pressey Joseph Gerald , Paudyal Ben , De Asit , Winkler Robert E. , Li Mingyu , Ahmad Mohammad , Yang Dajun , Zhai Yifan 
Published: June 2023

e14627 Background: MPNST is a rare and aggressive soft tissue malignancy accounting for 10% of all soft tissue sarcomas. This disease is characterized by high risk of local recurrence and distant metastasis, and there is no current effective standard of care treatment option for patients with MPNST, with the only curative option of complete resection. Therefore, further treatment options are warranted. Investigational mouse double minute 2 (MDM2) inhibitor alrizomadlin restores TP53 function, activating p53-mediated apoptosis in tumor cells. Alrizomadlin also functions as a host immunomodulator and may restore antitumor activity in patients with MPNST that progressed on PD-1/PD-L1 inhibitors. Methods: This US/Australian multicenter trial evaluated alrizomadlin combined with PD-1 inhibitor pembrolizumab in patients with MPNST that progressed on available therapy or in those for whom therapy was unavailable. ECOG performance status was between 0-2 for eligible patients. Alrizomadlin 150 mg was administered orally every other day for 2 consecutive weeks, with 1 week off, and pembrolizumab 200 mg intravenously for 30 minutes on Day 1 of a 21-day cycle. Results: As of December 12, 2022, preliminary clinical results are reported for 24 patients with MPNST, of whom 16 were male, with a median (range) age of 35 (14-73) years. Treatment (alrizomadlin or pembrolizumab)-related adverse events of any grade (>10%) were reported in 18 patients. They included nausea (41.7%), vomiting and anemia (37.5% each), fatigue and diarrhea (33.3% each), thrombocytopenia (25.0%), and decreased leukocyte and lymphocyte counts (12.5% each). A total of 12.5% of patients reported treatment-related serious adverse events, including colitis, abdominal pain, diarrhea, and pericardial effusion. Among17 efficacy evaluable patients, the clinical benefit rate, as defined by the combination of overall response rate and stable disease for ≥ 4 cycles, was 53% per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v.1.1) and iRECIST. The median (range) treatment duration was 10 (4-20) cycles. Conclusions: Alrizomadlin combined with pembrolizumab is well tolerated and demonstrates meaningful clinical benefit in patients with MPNST for whom standard of care therapy is unavailable. Internal study identifiers: APG-115-US-002. Clinical trial information: NCT03611868 .
Prognostic value of human leukocyte antigen G (HLA-G) expression in solid tumors: A systematic review and meta-analysis.
Authors: Bartolome Jorge , Molto Consolacion , Benitez Fuentes Javier David , Fernández-Hinojal Gonzalo , Manzano Aránzazu , Perez Segura Pedro , Mittal Abhenil , Tamimi Faris , Amir Eitan , Ocana Alberto 
Published: June 2023

e14639 Background: Identification of modulators of the immune response with inhibitory properties that could be susceptible for therapeutic intervention is a key goal in cancer research. An example is the human leukocyte antigen G (HLA-G), a nonclassical major histocompatibility complex (MHC) class I molecule, involved in cancer progression. Methods: We performed a systematic review and meta-analysis on the role of HLA-G expression and outcome in solid tumors. A total of 25 studies met the inclusion criteria comprising data from 4871 patients reporting overall survival (OS) outcomes, and 961 patients, in 5 studies, for disease free survival (DFS). This study was performed in accordance with PRISMA guidelines and registered in PROSPERO. Results: HLA-G expression was associated with worse OS (HR 2.09, 95% CI = 1.67 to 2.63; P < .001), that was higher in gastric (HR = 3.40; 95% CI = 1.64 to 7.03), pancreatic (HR = 1.72; 95% CI = 0.79 to 3.74) and colorectal (HR = 1.55; 95% CI = 1.16 to 2.07) cancer. No significant differences were observed between the most commonly utilized antibody (4H84) and other methods of detection. HLA-G expression was associated with DFS which approached but did not meet statistical significance. Conclusions: We describe the first meta-analysis associating HLA-G expression and worse survival in a variety of solid tumors.
Precision immuno-oncology (IO) ISH/IF multiplex panel: Spatial detection of cytokines and IO biomarkers.
Authors: Patel Bhavika , Dennison Brenna , Allen Stephanie , Stapleton Jacob , Archuleta Roni , Rath Mary Lou , Mehra Navi , Talwalkar Sameer S. 
Published: June 2023

e14654 Background: Cytokines have a large impact on the tumor microenvironment by affecting cell growth, survival, inflammation, and differentiation. Understanding the spatial biology within the tumor microenvironment, including the cytokine organization within specific cell types, can lead to better treatment plans for patients. Methods: We developed a hybrid multiplex panel, using RNA in-situ hybridization (ISH) and immunofluorescence (IF) to investigate the spatial biology of the tumor microenvironment. This panel also enabled us to simultaneously detect the RNA of cytokines and protein of specific immuno-oncology (IO) biomarkers. This allows us to visualize spatially, not only the organization of cell types but also to identify the cellular sources of specific cytokines. In this study, we analyzed the tumor microenvironment of samples from non-small cell lung cancer (NSCLC) and breast cancer in two panels for cytokine RNAs and IO protein biomarkers. Panel 1 included TNFa and IL-2 cytokines combined with CD68 and CD163 IO protein biomarkers. Panel 2 consisted of IL-6 and IL-2 cytokines with PAX5 and CD3 IO protein biomarkers. Staining was completed on the Leica Bond RX autostainer, and slides were scanned using the PhenoImager Fusion. Visiopharm software wasused to analyze the tumor microenvironment of tissue samples and localize cytokines in specific cell types. Results: CD163 positive macrophages (M2 phenotype) were seen predominantly within the tumors (NSCLC and breast cancer) whereas CD68 positive macrophages were identified towards the periphery in the non-tumor microenvironment. NSCLC tumor cells showed higher expression levels of IL-2, IL-6 and TNFa compared to breast cancer tumor cells. Predominance of CD3 positive T cells was noted with relative lack of PAX5 positive B cells within both NSCLC and breast cancer tumors. Multiplexing enabled assessment of relative expression levels of IL-2, IL-6 and TNFa in T lymphocytes and macrophages and TNFa in dendritic cells. Conclusions: Our hybrid multiplex panel can provide insights into the visualization of spatial organization of tumor microenvironment. It also enables semi-quantitative assessments for the expression levels of cytokines and their relative expression within tumor and immune cells, thereby helping to correlate response to treatment, especially with checkpoint inhibitors.
Safety and tolerability of immune checkpoint inhibitor (CPI) use in advanced hepatocellular carcinoma (aHCC) with Child-Pugh (CP) class B and C.
Authors: Valerin Jennifer Brooke , Kaakour Dalia , Mar Nataliya , Vosoughi Elham 
Published: June 2023

e14676 Background: The vast majority of HCC cases occur in the setting of liver cirrhosis. Patients with decompensated cirrhosis CHILD-Pugh Class B and C (CPB and CPC) are usually excluded from clinical trials. Here we report the safety and tolerability of CPI in patients with CPB/CPC. Methods: A retrospective chart review was performed of all patients with aHCC who received therapy with CPI from 1/2019 to 12/2022 at our institution. Patients with CP class B and C were included in this study. Safety endpoints included rates of immune-related adverse events (irAEs), grade ≥3 adverse events (graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 5.0]), duration of treatment with CPI and overall survival (OS) were reported. Results: We performed this retrospective chart review of 60 patients with aHCC who were treated with CPI at our institution. A total of 22 patients with CPB and CPC at the time of CPI initiation were included, 86.4% with CPB (n=19) and 13.6% with CPC (n=3). Median age was 68 (range 40-82). Amongst patients with CPB, 10 patients (45.4%) had CP score 7 (CP7) and 9 patients (40.9%) had CP score 8 or 9. Single agent nivolumab was the most common CPI used, followed by pembrolizumab and combination of ipilimumab and nivolumab, 38.4%, 27.3% and 13.6% respectively. Any grade irAEs were reported in 54.5% of patients (n=12).9% of patients (n=2) had grade ≥3 irAEs. In the CP7 subgroup, the rate of irAEs reported was 40% and no grade ≥3 irAEs were observed. In contrast, 55.5% of patients with CP 8 and 9 experienced irAEs and of those, 11.1% had grade ≥3 irAEs (n=1). In the CPC subgroup, 2 out of 3 patients reported irAEs (75%), one with a grade 4 irAE. GI complications(n=5) were the most common irAEs reported, followed by endocrine (n=4) and dermatologic complications (n=3). The median time on treatment was 1.63 months (95% CI,1.08-2.99). The median overall survival from the time of CPI initiation was 3.7 months (95% CI, 1.97-9.79). Conclusions: Immunotherapy has an acceptable safety and toxicity profile in aHCC patients with CP7. Higher rate of irAEs were observed in patients with CP ≥8. Further studies are warranted to evaluate the safety of CPI in patients with CP ≥8. We reported shorter duration of treatment with CPI and shorter OS in real world practice compared with those reported in the CheckMate 040 trial.[Table: see text]
Tumor immunity portrait: An AI-driven molecular predictor combining tumor microenvironment and tumor mutational burden for immune checkpoint inhibitor response prediction.
Authors: Shilo Polina , Tarasov Artem , Filatova Anna , Danilov Konstantin , Valiev Ivan , Kotlov Nikita , Brown Jessica H. , Ogloblina Anna , Bagaev Alexander , Fowler Nathan 
Published: June 2023

e14691 Background: Low response rates and toxicities from immune checkpoint inhibitors (ICI) highlight the need for improved ICI response prediction tools. Increasing evidence shows the tumor microenvironment (TME) plays a critical role in therapy response; however, current ICI response prediction methods often use a single tumor characteristic (i.e., tumor mutational burden [TMB]). Here, we present the BostonGene Tumor Immunity Portrait, an AI-driven molecular predictor based on the TME subtype combined with TMB status to identify ICI responders in non-small cell lung cancer (NSCLC), melanoma, and gastric cancer (GC). Methods: We collected a meta cohort from 26 publicly available datasets (n = 2,077) composed of NSCLC, melanoma, and GC patients that received ICI therapy. A transcriptomic-based TME subtyping approach was used to classify the TME as fibrotic (F), immune-enriched, fibrotic (IE/F), immune-enriched (IE), or desert (D) (Bagaev, Cancer Cell, 2021). TMB status (low < 10; high > 10) was determined by whole exome sequencing. A logistic regression model was used to generate a score of 0, 1, 2, or 3 based on the sum of points assigned to the TME subtype (F = 0 points, IE/F and D = 1 point, IE = 2 points) and to the TMB status (high = 1 point and low = 0 points). Each score corresponded to one of four Tumor Immunity Portrait types: 0 - Immunosuppressive; 1 - Resistant; 2 - Neutral; 3 - Immune Primed. Results: Tumor Immunity Portrait types were associated with increasing ICI response rates in each cancer type. Immune Primed type (IE + TMB-High) response rates in melanoma and GC were 76.2% and 100%, respectively. Immunosuppressive type (F + TMB-Low) was associated with ICI non-response in melanoma (p = 0.003) and NSCLC (p < 0.001). The Tumor Immunity Portrait accurately predicted ICI non-response, shown by the negative predictive value (NPV) of the Immunosuppressive type (F + TMB-Low) for NSCLC (100%), melanoma (92.3%), and GC (96.1%). Conclusions: Using an integrated approach combining the tumor’s characteristics and TME, the BostonGene Tumor Immunity Portrait provides accurate prediction of ICI non-response in 3 cancer types, warranting further validation for use in personalized treatment decision making. [Table: see text]
Microbiome, socioeconomic status (SES), fiber intake, and response to checkpoint inhibitor therapy in patients with non-small cell lung cancer (NSCLC): A pilot study.
Authors: Patel Monaliben , Bebek Gurkan , Vu Brandon , Ghannoum Mahmoud , Berger Nathan A. , Bruno Debora S. 
Published: June 2023

e14710 Background: Lung cancer affects a disproportional number of socioeconomically disadvantaged patients (pts). Responses to checkpoint inhibitor therapy (CIT) vary. Microbiome diversity may correlate with benefit from CIT. High fiber diets lead to microbiome diversity. We hypothesize that unexplained lung cancer disparities may be in part due to differences in microbiome diversity determined by unhealthy dietary patterns dictated by lower SES. Methods: Following IRB review, 25 pts with metastatic NSCLC starting CIT-based treatment were enrolled. Pre-treatment oral and fecal samples were collected. 24-hour dietary recalls were obtained. SES index was calculated based on education, employment, housing and annual income. High fiber intake was defined as > 20 g/day. Best treatment response per RECIST 1.1 was assessed. Microbial 16s rRNA were sequenced with Illumina MiSeq platform. Sequence analyses utilized QIIME 2 with DADA2 plugin. Taxonomic assignments used the Greengenes database. Microbiome composition was analyzed by calculating alpha diversity (Chao1, Shannon diversity and Simpson index), beta diversity and differential abundance of microbial compositions. Hierarchical linear model was constructed for each SES variable with and without biological covariates. Results: Pts with samples >1000 operational taxonomic unit (OTU) levels were included (N = 22) in the analysis. 50% were male, median age was 71, 36% (8/22) were of Black race and 23% (5/22) were of low SES. Median fiber intake was 11.9 grams. Males had higher alpha diversity than females (p=.038). Pts with high fiber intake had greater fecal Proteobacteria compared to low fiber intake pts (p<0.05). Bacteroides and Firmicutes fecal levels were significantly different for all pts compared to Human Microbiome Project (HMP) reported normal levels (p<0.01). Actinobacteria and Proteobacteria levels for low-fiber intake pts were also significantly elevated compared to HMP normal levels (p<0.05). There were no differences observed in microbiome when comparing SES index. However, high SES index patients had elevated fecal levels of Actinobacteria, Firmicutes and Proteobacteria and lower levels of Bacteroides compared to HMP levels. There was a trend towards higher alpha diversity of oral samples in partial responders pts compared to those with stable or progression of the disease (p=0.08). Conclusions: Pts with metastatic NSCLC exhibited different microbial composition compared to HMP normal levels. Associations between SES and microbial distribution in such pts warrant further investigation. Increased sample size is needed to better determine differences in oral microbiome in responders to immunotherapy and better evaluate the role of sex in this setting.
Retrospective analysis of digital biomarker predictability of immune checkpoint inhibitor therapy outcomes in patients with NSCLC.
Authors: Abousaud Marin , Frame David , Harvey R. Donald , Kaddoura Layan , Ekpenyong Asari , Abousaud Aseala , Steuer Conor Ernst , Derstine Brian , Wang Nicholas C. , Mackler Emily R. 
Published: June 2023

e14713 Background: Immune checkpoint inhibitor (ICI) therapy (pembrolizumab monotherapy and pembrolizumab combined with platinum-based chemotherapy) is recommended as first line for patients with PD-L1 positive advanced or metastatic non-small cell lung cancer (NSCLC) without actionable biomarkers due to incredible improvements in overall survival (OS). Despite this, 15-20% of patients do not respond to ICI therapy in NSCLC. This study examines the effect of body composition features, via analytic morphomics, in conjunction with current clinical and laboratory data to predict ICI response. Methods: This retrospective analysis included 35 patients from the University of Michigan (UM) with newly diagnosed advanced or metastatic NSCLC (adenocarcinoma) receiving single-agent pembrolizumab or in combination with chemotherapy between January 2018 – December 2020. Clinical/ laboratory data included patient gender, age, BMI, neutrophil to lymphocyte ratio (NLR), PDL1 %, and albumin. Analytic Morphomics was performed using proprietary, semi-automated high-throughput CT image processing (mBIOHEALTH, Inc.). Multivariable Cox regression analysis identified clinical and morphomic characteristics predictive of OS at 6 months. Risk models were developed on the UM cohort and tested on an external validation dataset of 24 adenocarcinoma patients from Emory Healthcare who received similar treatment between January 2018 to December 2021. Results: Among the evaluable patients at both sites, 15 (43%) at UM and 19 (79%) at Emory were female, mean age was 66 years at UM and 70 years at Emory, and 6-month OS (95% CI) was 89% (80%, 100%) at UM and 71% (55%, 92%) at Emory. Five regression models with risk scores were assessed with the UM data and then tested with the Emory dataset. Of the five models, 2 matched in their predictability of 6-month OS at both sites. The first, a model of clinical and laboratory features only (age, BMI, PDL1 > = 50%, NLR, and albumin) which had an AUC of 0.79 at UM and 0.66 at Emory. The other utilized an L3 skeletal muscle z-score threshold ( < = -1) alone (previously studied as a measurement of sarcopenia) with an AUC of 0.741 at UM and 0.57 at Emory. Conclusions: Our analysis indicates that the measurement of muscle z-score prior to initiating treatment with ICIs in patients with NSCLC could serve as an indicator for those patients who are unlikely to benefit from therapy. This may be especially important for ICI therapy as skeletal muscle effects the immune function through myokines. Sarcopenia has been associated with immune senescence and thus may play a significant role in decreasing response to ICI therapy. More analysis is warranted with a larger patient population.
Analysis of systemic immune changes in patients with advanced cancer treated with immunotoxin LMB-100 and tofacitinib.
Authors: Skorupan Nebojsa , Peer Cody J. , Yu Yunkai , Lee Min-Jung , Lee Sunmin , Rastogi Shraddha , Sato Nahoko , Choo-Wosoba Hyoyoung , Hassan Raffit , Figg William Douglas , Cao Liang , Trepel Jane B. , Pastan Ira , FitzGerald David J.P. , Alewine Christine 
Published: June 2023

e15017 Background: LMB-100 recombinant immunotoxin delivers a modified Pseudomonas exotoxin A payload to mesothelin-expressing tumors. Almost all patients receiving LMB-100 develop anti-drug antibodies (ADAs) after 2 cycles/ 6 doses of the drug, therefore reducing peak serum drug concentrations to near the lower limit of detection. Tofacitinib is an oral JAK inhibitor that had been shown to prevent ADA formation in pre-clinical studies. Apart from assessing safety and tolerability, this trial sought to determine whether co-administration of tofacitinib with LMB-100 delays the formation of neutralizing ADAs so more patients could achieve the peak LMB-100 concentration of > 600 ng/mL during treatment cycle 2. Correlative data examining circulating immune cell subsets and cytokines pre- and on-treatment are presented here. Methods: Patients with pancreatic adenocarcinoma (n = 13) and other mesothelin-expressing solid tumors (n = 3; cholangiocarcinoma, appendix, cystadenocarcinoma) were treated for up to 3 cycles (21 days) with LMB-100 given on days 4, 6, and 8 at 2 dose levels (100 and 140 mcg/kg), accompanied by oral tofacitinib for the first 10 days of the cycle (10 mg BID). Adverse events were assessed as per CTCAE 5.0. Analysis of the cytokine data was performed using a Wilcoxon signed-rank test. Results: DLTs of grade 3 cardiac toxicity (n = 1) and grade 4 hyponatremia (n = 1) were seen at the 140mcg/kg dose of LMB-100. One patient treated at 100 mcg/kg developed a grade 4 pericardial effusion, resulting in early closure of the study for safety. The two patients who experienced cardiac toxicity had lower baseline CD4+ cells and increased CD19+ cells post-LMB-100 treatment. Four out of 8 evaluable patients achieved LMB-100 concentration above the threshold during cycle 2, and 2 out of 3 did so during cycle 3. Analysis of peripheral blood cytokine levels showed sustained increases in TNF-α, IL-8, and IL-10 following LMB-100 administration through to the start of cycle 2. Percentage of Tregs increased through cycle 1 in patients who developed drug-neutralizing ADAs and was significantly higher than in patients with LMB-100 levels above threshold at the start of cycle 2. Conclusions: Combination of LMB-100 with tofacitinib is not safe. An insufficient number of patients was treated to conclusively assess the ability of tofacitinib to stop or delay ADA formation. Increases in circulating Tregs were observed in patients with early neutralizing ADA formation. Clinical trial information: NCT04034238 .