bluuebunny/crossref_metadata_2025_split huggingface dataset:
A pilot study of Bruton’s tyrosine kinase inhibitor ibrutinib alone and in combination with PD-1 inhibitor nivolumab in patients with metastatic solid tumors.
Authors: Benner Brooke , Quiroga Dionisia Marie , Good Logan , Sun Steven , Savardekar Himanshu , Duggan Megan Christina , Konda Bhavana , Verschraegen Claire F. , Kendra Kari Lynn , Shah Manisha H. , Rupert Robert , Monk Paul , Shah Hiral A. , Noonan Anne M. , Bixel Kristin Leigh , Hays John L. , Behbehani Gregory , Pietrzak Maciej , Carson William Edgar , Wesolowski Robert ,   ASCO Authors Group
Published: May 2020

3111 Background: Myeloid-derived suppressor cells (MDSC) are expanded in cancer and promote immune suppression. We have shown that ibrutinib inhibits migration and immunosuppressive function of MDSC. Moreover, the combination of ibrutinib and a PD-L1 inhibitor has been found to have synergistic anti-tumor effects in a multiple solid tumor mouse models. Therefore, we conducted a pilot study testing the combination of ibrutinib and nivolumab in patients with metastatic solid tumors. Methods: Sixteen patients with advanced solid tumors were recruited to this trial. Ibrutinib was dosed as an oral single agent, starting 7 days prior to cycle 1 of nivolumab and given until cycle 1, day 8 of nivolumab. Nivolumab was administered intravenously on days 1 and 15 on 28-day cycles. Patients had blood samples collected prior to initiation of ibrutinib, day 1 of cycle 1, day 8 of cycle 1, day 1 of cycle 2, and at the time of disease progression. From these specimens, we measured circulating MDSC levels, other circulating immune subsets, T cell proliferation, and cytokines/chemokines levels. Circulating MDSC levels were measured by mass spectrometry. T cell function was evaluated by CFSE to monitor proliferating cells by dye dilution and cytokine/chemokine levels were measured with a U-PLEX assay. Data were analyzed using two-tailed, paired Student's t-tests to assess statistical significance. Results: An increase in circulating MDSC (22% to 28%; SD 9.158) levels was observed following 7 days of single-agent ibrutinib compared to baseline. However, in combination therapy, MDSC levels decreased (19%; SD 13.17) prior to cycle 2. Despite increasing levels of circulating MDSC, T cell function improved throughout the study. Furthermore, plasma levels of chemokines associated with MDSC recruitment and migration significantly decreased with ibrutinib treatment (IL-12, CCL2, CCL3, and CCL4). Of the 16 patients, four achieved a partial response and four achieved stable disease. Median progression free survival was 3.5 months and median overall survival was 11.5 months. Conclusions: The combination of ibrutinib and nivolumab was well tolerated, demonstrated early signs of immune modulation, and showed preliminary signs of promising clinical activity in patients with metastatic solid tumors. Clinical trial information: NCT03525925 .
Gene signature of antigen processing and presentation machinery (APM) as highly predictive of response to checkpoint blockade in lung cancer and melanoma.
Authors: Thompson Jeffrey C. , Davis Christiana , Hwang Wei-Ting , Deshpande Charuhas , Jeffries Seth , Langer Corey J. , Albelda Steven M. 
Published: May 2020

3121 Background: Treatment of non-small cell lung cancer (NSCLC) with immune checkpoint blockade (ICB) has resulted in striking clinical responses, but only in a subset of patients (pts), underscoring the need to identify genomic and molecular determinants of immune evasion. Limited data exist on the potential role of alterations in HLA Class I antigen processing and presentation machinery (APM) in mediating response to ICB. Methods: We conducted a retrospective cohort study analyzing transcriptional profiles from pre-treatment tumor samples of chemotherapy-refractory advanced NSCLC pts treated with ICB. RNA was analyzed using the AmpliSeq transcriptomic platform. An APM signature was generated utilizing 8 genes associated with antigen processing ( B2M, CALR, NLRC5, PSMB9, PSME1, PSME3, RFX5, HSP90AB1) and was examined for its association with response to therapy and progression-free and overall survival (PFS, OS). The APM signature was then evaluated in two independent melanoma cohorts treated with ICB. Results: We analyzed pre-treatment tumor samples from 51 advanced NSCLC pts treated with ICB, median age 64 (range 31-92), smokers (n = 43), adenocarcinoma (n = 31). There were 23 responders and 28 non-responders. The APM signature was significantly higher in responders compared to non-responders (average z-score 2.69 vs. -2.49, p = 0.0001). An APM score above the median value for the entire cohort was significantly associated with improved PFS (HR 0.24, 95% CI, 0.12-0.47, log-rank = 0.001) and OS (HR 0.34, 95% CI, 0.18-0.67, log-rank = 0.005). The APM score was significantly correlated with the well-validated T-cell-inflamed resistance gene expression profile (GEP) score (R2 = 0.32, p < 0.0001). However, the APM score demonstrated improved ability to predict response to ICB relative to the GEP score with AUCs of 0.83 and 0.69, respectively. In an independent cohort of 14 high-risk resectable stage III/IV melanoma pts treated with neoadjuvant anti-PD1 therapy, upregulation of genes involved in antigen processing was associated with improved disease free survival (HR: 0.08, 95% CI, 0.01-0.50, p = 0.0065). In an additional independent melanoma cohort of 28 metastatic pts treated with ICB, a higher APM score was associated with improved overall survival (HR 0.31, 95% CI, 0.09-0.89, log-rank = 0.044). Conclusions: Our data demonstrate that defects in antigen presentation may be an important feature in predicting outcomes to ICB in both lung cancer and melanoma.
A machine learning-based approach for the inference of immunotherapy biomarker status in lung adenocarcinoma from hematoxylin and eosin (H&E) histopathology images.
Authors: Batenchuk Cory , Chang Huan-Wei , Cimermancic Peter , Yi Eunhee S. , Sadhwani Apaar , Velez Vanessa , Patel Hardik L. , Behrooz Ali , Tekiela Kamilla , Findlater Robert , Hanks Debra , Kulig Kimary 
Published: May 2020

3122 Background: The current standard work-up for both diagnosis and predictive biomarker testing in metastatic non-small cell lung cancer (NSCLC), can exhaust an entire tumor specimen. Notably, gene mutation panels or tumor mutation burden (TMB) testing currently requires 10 tissue slides and ranges from 10 days to 3 weeks from sample acquisition to test result. As more companion diagnostic (CDx)-restricted drugs are developed for NSCLC, rapid, tissue-sparing tests are sorely needed. We investigated whether TMB, T-effector (TEFF) gene signatures and PD-L1 status can be inferred from H&E images alone using a machine learning approach. Methods: Algorithm development included two steps: First, a neural network was trained to segment hand-annotated, pathologist-confirmed biological features from H&E images, such as tumor architecture and cell types. Second, these feature maps were fed into a classification model to predict the biomarker status. Ground truth biomarker status of the H&E-associated tumor samples came from whole exome sequencing (WES) for TMB, RNAseq for the TEFF gene signatures or reverse-phase protein array for PD-L1. Digital H&E images of NSCLC adenocarcinoma for model development were obtained from the cancer genome atlas (TCGA) and commercial sources. Results: This approach achieves > 75% accuracy in predicting TMB, TEFF and PD-L1 status, offers a way to interpret the model, and provides biological insights into the tumor-host microenvironment. Conclusions: These findings suggest that biomarker inference from H&E images is feasible, and may be sufficiently accurate to supplement or replace current tissue-based tests in a clinical setting. Our approach utilizes biological features for inference, and is thus robust, interpretable, and readily verifiable by pathologists. Finally, biomarker status inference from a single H&E image may enable testing in patients whose tumor tissue has been exhausted, spare further tissue use, and return test results within hours to enable rapid treatment decision-making to maximize patient benefit.
The HLA Ligand Atlas: A novel immuno-oncology resource for T-cell antigen discovery.
Authors: Marcu Ana , Bichmann Leon , Kuchenbecker Leon , Backert Linus , Kowalewski Daniel J , Freudenmann Lena-Katharina , Löffler Markus W. , Lübke Maren , Walz Juliane , Velz Julia , Moch Holger , Regli Luca , Silginer Manuela , Weller Michael , Schlosser Andreas , Kohlbacher Oliver , Stevanovic Stefan , Rammensee Hans-Georg , Neidert Marian Christoph 
Published: May 2020

3128 Background: The human leukocyte antigen (HLA) complex regulates the adaptive immune response by showcasing the intracellular and extracellular protein content to the immune system, which is the basis for T cell-dependent tumor rejection. Therefore, a comprehensive map of the entirety of both HLA class I- and class II-presented peptides from various benign tissues is a highly sought after resource, as it enables the definition of tumor-association on the immunologically pivotal level of the HLA ligandome. Methods: Human tissue samples were snap frozen post mortem during autopsy. The study was approved by the local IRB. HLA ligands were immunopurified and characterized using an Orbitrap Fusion Lumos mass spectrometer coupled to an Ultimate 3000 RSLC Nano UHPLC System. Data acquisition was performed as technical triplicates in data-dependent mode, and data were analyzed using the containerized, computational pipeline MHCquant. Results: In this work, we describe the HLA Ligand Atlas, a comprehensive collection of matched HLA class I and class II ligandomes from 29 non-malignant tissues and 13 human subjects (208 samples in total), covering 38 HLA class I, and 17 HLA*DRB alleles and comprising 48,381 HLA class I and 16,146 HLA class II peptides. Nearly 50% of HLA ligands have not been previously described. The HLA Ligand Atlas is publicly available as a raw data resource, but also in the form of a user-friendly web interface that allows users to quickly formulate complex queries against the data set. Both downloadable data and the query interface are available at www.hla-ligand-atlas.org. Conclusions: This data set provides a valuable tool for research in diverse fields such as systems biology, general immunology, autoimmune disease and organ transplantation. Most importantly, the HLA Ligand Atlas provides essential information for translational applications in immuno-oncology. The knowledge of HLA ligands from benign tissues strongly supports the informed design of proteogenomic HLA-dependent target discovery approaches.
Effect of chemokine signaling signatures on resolving discrepancy between TMB and checkpoint expression.
Authors: Szeto Christopher , Veerapaneni Saihitha , Parulkar Rahul , Reddy Sandeep K. , Rabizadeh Shahrooz , Benz Stephen Charles 
Published: May 2020

3131 Background: Tumor mutation burden (TMB) and PD1/L1 expression are independent biomarkers for immune checkpoint blockade therapy, as seen in the Checkmate227 trial. Here we explore whether chemokine activity, an intermediate step between neoantigen presentation and immune-infiltration, can resolve this lack of association between existing biomarkers. We further use this novel biomarker to corroborate recent findings from Crowther et al. for a role of MHC class 1-related gene ( MR1) downregulation in immune evasion. Methods: 1,395 clinical samples from the NantHealth database with matched tumor:normal whole exomes and deep whole-transcriptomic sequencing (> 200M reads) were available for analysis. The most common indications in the cohort were Breast (18%), Colon (9.8%), Lung (7.8%), Soft-tissue/Sarcomas (7.7%), and Pancreatic (6.1%). TMB was calculated by counting non-synonymous exonic mutations as per Rizvi, 2015. Immune-infiltration and chemokine signaling were inferred from RNAseq expression of published immune-cell-specific genesets (Bindea, 2013) and chemokine ligands (Nagarsheth, 2017) respectively. Significant associations between TMB, chemokine activity, immune-infiltration, and checkpoint expression were analyzed by ranksums test and corrected for multiple-hypothesis testing using Benjamini-Hochberg adjustment. Results: As expected, TMB and PD1/L1 mRNA expression were not correlated in this cohort (r = 0.08 and r = 0.07 respectively). 36.3% of patients classified as highly immune-infiltrated by unsupervised clustering of immune-cell scores, and this subgroup significantly overexpressed all 11 targetable checkpoint genes analyzed including PD1, PDL1, CTLA4, IDO1, and VISTA (adj. p 9.7e-68 to 4e-168). There was no association between immune-infiltrated samples and TMB (t = 0.9, p = 0.35). Twice as many patients classified as chemokine-active (70.0%) and there was significant agreement between immune-infiltrated and chemokine-active patients (OR = 34.8, p = 6.5e-81). Interestingly, there was a weak but significant association between high chemokine-activity and increased TMB (t = 3.3, p = 0.001). Within patients that were chemokine-active but lacked immune-infiltration, MR1 expression was significantly depleted (t = -10.7, p = 1e-26). Conclusions: Chemokine signatures can help resolve discordance between TMB and checkpoint expression. Analysis of discordance between chemokine-active but immune-depleted tumors may aid in identifying targets for converting from cold to hot tumor microenvironments.
A shared tumor-antigen RNA-lipoplex vaccine with/without anti-PD1 in patients with checkpoint-inhibition experienced melanoma.
Authors: Loquai Carmen , Hassel Jessica Cecile , Oehm Petra , Derhovanessian Evelyna , Jabulowsky Robert Alexander , Gold Maike , Schwarck-Kokarakis Doreen , Attig Sebastian , Cuk Katarina , Vogler Isabel , Sikorski Julian , Leierer Melanie , Mitzel-Rink Heidrun , Miederer Matthias , Grabbe Stephan , Utikal Jochen , Pinter Andreas , Kaufmann Roland , Sahin Ugur , Tureci Oezlem 
Published: May 2020

3136 Background: Cancer vaccines are considered unsuitable for patients with advanced tumours and have not been clinically successful. Methods: Lipo-MERIT is an ongoing phase 1/2 trial (NCT02410733) with melanoma FixVac, a liposomal RNA vaccine targeting four non-mutant shared tumour-associated antigens (TAAs) (MAGE-A3, NY-ESO-1, tyrosinase, TPTE). Patients with stage IIIB-C and IV melanoma are eligible. The trial comprises 7 dose escalation and 3 dose expansion cohorts, the latter with FixVac alone or combined with anti-PD1. Eight doses of FixVac are administered i.v. weekly/bi-weekly followed by optional continued monthly treatment. This abstract summarizes the findings of an exploratory interim analysis (cut-off JUL2019) of 89 patients. Results: 42 of 89 patients had measurable disease at baseline and were eligible for assessment of best objective overall response. All but one patient were stage IV and had undergone previous lines of treatment, 41 patients were checkpoint-inhibitor (CPI)-experienced, and 35 had been exposed to both anti-CTLA4 and anti-PD1 therapy. In the vaccine monotherapy group (n = 25) three patients experienced a partial response (PR) and 7 patients had stable disease (SD). An additional patient showed a complete metabolic remission of metastatic lesions based on [18F]-FDG PET/CT imaging. In the group of patients treated with melanoma FixVac and PD1 blockade, 6 of 17 patients developed a PR. Patients with PR showed induction of poly-epitopic and strong CD4+ and CD8+ T cell immunity against the vaccine antigens. The number of antigen-specific cytotoxic T cells in some responders reached up to low 2-digit percentages of circulating CD8+ T cells and was maintained at high levels by continued vaccination. Overall, 75% of the 50 patients tested by ex vivo IFNg ELISpot analysis and all 20 patients tested by IFNg ELISpot after in vitro stimulation showed vaccine-induced immune responses against at least one vaccine antigen. Typically, antigen-specific T cells ramped up within the first 4-8 weeks to single-digit and low double-digit percent fractions of circulating CD8+ T cells. Immune responses were of effector memory phenotype and their strength and frequency did not depend on disease status at baseline (measurable versus non-measurable disease), on vaccine dose or on treatment (FixVac alone versus in combination with anti-PD1). Conclusions: FixVac alone and in combination with anti-PD1 mediates durable objective responses in pre-treated, CPI experienced patients with advanced progressing melanoma. Clinical trial information: NCT02410733 .
Inhaled corticosteroid use and risk of pneumonitis in patients treated with immune checkpoint inhibitors.
Authors: Li Mingjia , Spakowicz Daniel , Zhao Songzhu , Patel Sandip H. , Johns Andrew , Grogan Madison , Miah Abdul , Husain Marium , He Kai , Bertino Erin Marie , Shields Peter G. , Wei Lai , Carbone David Paul , Otterson Gregory Alan , Presley Carolyn J , Owen Dwight Hall 
Published: May 2020

3140 Background: The identification of risk factors for immune-related adverse events (irAEs) is an important area of research. Among irAEs, pneumonitis carries one of the highest morbidities. There is a lack of strong predictors for pneumonitis in patients (pts) treated with ICI. We sought to identify predictors for the development of pneumonitis, and whether the use of inhaled corticosteroids (ICS) at time of ICI could be protective. Methods: Pts with advanced cancer treated with ICI from 2011 and 2018 were included in this retrospective study. Pneumonitis attribution to ICI was determined by treating physician at time of diagnosis. Time to pneumonitis was defined as days from the start of ICI to pneumonitis diagnosis. Pts who never had pneumonitis were censored at the time of last follow up or death. Predictors of pneumonitis were assessed by univariate Cox proportional hazard models at a significance threshold of alpha = 0.05. Results: A total of 837 pts were identified, and 30 (3.6%) pts developed any grade pneumonitis (12 grade 2, 14 grade 3, 1 grade 4, 3 grade 5) after receiving ICI (Table). Pts with age ≥65 years (y) had increased risk of developing pneumonitis over pts with age < 65y (HR 2.1, 95 CI: 1.02-4.4, p=0.041). 82 (9.7%) of the total cohort were on inhaled corticosteroid (ICS) at time of ICI, and 9 (11%) developed pneumonitis. Rather than being protective, pts on ICS had higher risk of pneumonitis (HR 4.2, 95 CI: 1.9-9.2, p=0.001). Pts with lung cancer had an increased risk for pneumonitis compared to pts with other cancers (HR 3.2, 95 CI: 1.5-6.4, p =0.003). Other risk factors included performance status, smoking history, line of therapy, or prior treatment including radiation were not statistically significant. Conclusions: Rather than a protective effect of ICS, our analysis found a higher risk of pneumonitis in pts treated with ICS. We confirmed an increased risk of pneumonitis for lung cancer pts compared to pts with other cancers, and higher risk of pneumonitis in pts age >65y. We hypothesize that the increased inflammatory status in chronic lung inflammation may predispose pts to pneumonitis that was not ameliorated by ICS. Future study is needed in prospective cohorts to further clarify the underlying inflammatory mechanism. [Table: see text]
Response criteria for intratumoral immunotherapy in solid tumors: ItRECIST.
Authors: Goldmacher Gregory V. , Khilnani Anuradha D. , Andtbacka Robert H. I. , Luke Jason J. , Hodi F. Stephen , Marabelle Aurelien , Harrington Kevin Joseph , Perrone Andrea Marie , Tse Archie N. , Madoff David C. , Schwartz Lawrence Howard 
Published: May 2020

3141 Background: The approval of intratumoral (IT) immunotherapy for metastatic melanoma and the active development of numerous novel IT drugs have created a need for standardized evaluation of response to this unique treatment strategy. The Response Evaluation Criteria in Solid Tumors (RECIST) is not suitable for assessing responses separately for injected and noninjected tumors. Building on RECIST concepts, we propose an IT immunotherapy RECIST (itRECIST) to capture data and assess local and systemic responses in a standardized fashion for clinical trials involving IT immunotherapies. Methods: itRECIST will address the unique needs of IT immunotherapy trials but, where possible, aligns with RECIST 1.1 and iRECIST. It does not dictate which lesions to inject but provides guidelines for collecting data and assessing response as treatment evolves. Results: itRECIST enables overall response assessment, separate response assessments in injected and noninjected lesions, and continued assessment following modifications of therapy at initial progression. At baseline, lesions are classified into 4 categories: target injected, target noninjected, nontarget injected, and nontarget noninjected. After baseline, lesions can be reclassified from noninjected to injected if the investigator decides to change the lesions to inject, but target and nontarget designations never change. Overall response at each assessment is based on target lesion response (injected and noninjected), nontarget lesion response, and absence/appearance of new lesions. Noninjected lesion response is determined by comparing tumor burden with baseline and nadir values. Injected lesion assessment is based on visit-to-visit changes in the lesions injected during treatment and on a combined assessment once the patient is off treatment. A new response category is defined to capture progression that would be “confirmed” per iRECIST even though injected lesions are responding and therapy continues. Multiple examples have been created to aid in training and adoption. Conclusions: itRECIST is an important step toward a standardized method of response assessment for this promising and evolving therapeutic modality. The proposed guidelines can be adopted into trial protocols and routine clinical practice without the need for complex additional assessments by treating physicians. Until there is evidence to support wider use, itRECIST is intended only to support standardized collection of data and to facilitate exploratory analysis. Authors G.V.G. and A.D.K. contributed equally to this work.