tbuckley/cabot-search huggingface dataset:
Abstract 1582: A pre-existing inflammatory immune microenvironment predicts the clinical and immunological response of vulvar high-grade squamous intraepithelial lesions to therapeutic HPV16 peptide vaccination
Authors: Ziena Abdulrahman, Noel F. de Miranda, Mariette I. van Poelgeest, Sjoerd H. van der Burg
Journal: Cancer Research (2020)

Abstract Background: Vulvar High-grade Squamous Intraepithelial Lesion (vHSIL) is predominantly induced by high-risk Human Papilloma Virus type 16 (HPV16). In two independent trials, therapeutic vaccination against the oncoproteins of HPV16 with synthetic long peptides (SLP) resulted in vHSIL regression in about half of the patients after 12 months. Several studies have shown that the immune microenvironment influences therapy outcome. Therefore, a thorough investigation of the vHSIL immune microenvironment before and after SLP vaccination was performed, and its impact on clinical response was studied. Methods: Two novel multiplex immunofluorescence panels were designed and fully optimized for formalin-fixed paraffin-embedded tissue, one for T cells (CD3, CD8, Foxp3, Tim3, Tbet, PD-1, DAPI) and one for myeloid cells (CD14, CD33, CD68, CD163, CD11c, PD-L1, DAPI). Pre- and post-vaccination biopsies of 29 vHSIL patients, as well as 27 healthy vulva excisions, were stained, scanned with the Vectra multispectral imaging system, and automatically phenotyped and counted with inForm advanced image analysis software. Results: A pre-existing pro-inflammatory tumor microenvironment, marked by high numbers of CD4+ and CD8+ T cells expressing Tbet and/or PD-1 as well as CD14+ inflammatory macrophages, is a strong predictor for good clinical response to therapeutic HPV16 SLP vaccination. A clear stepwise increase in pre-vaccination infiltrating Tbet+, CD4+, CD8+ T cells and CD14+ macrophages, and decrease in Foxp3+ regulatory T cells was observed as response increased from non to partial to complete response. Moreover, the pre-vaccination immune microenvironment of complete responders resembled healthy vulva. Vaccination further increased infiltrating CD4+ and Tbet+ T cells and CD14+ macrophages, and decreased Foxp3+ regulatory T cells and CD68+CD163+ M2 macrophages in the complete and partial responders, but not in the non responders. Conclusion: Clinical responsiveness to therapeutic HPV16 SLP vaccination requires a pre-existing inflamed type 1 immune contexture in vHSIL. Hence, only patients with an inflamed microenvironment should be selected for monotherapy by therapeutic peptide vaccination, since this strategy is incapable of overcoming an immunologically cold tumor microenvironment. Citation Format: Ziena Abdulrahman, Noel F. de Miranda, Mariette I. van Poelgeest, Sjoerd H. van der Burg. A pre-existing inflammatory immune microenvironment predicts the clinical and immunological response of vulvar high-grade squamous intraepithelial lesions to therapeutic HPV16 peptide vaccination [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1582.
Abstract 3311: B cell like neutrophil found in peripheral blood of melanoma patients
Authors: Melissa A. Meyer, Huy Q. Dinh, Yanfang Zhu, Shu Liang, Gregory Seumois, Pandurangan Vijayanand, Sergio D. Catz, Catherine C. Hedrick
Journal: Cancer Research (2020)

Abstract An expansion of neutrophils often marks cancer. To date, neutrophils are assumed to be a relatively homogenous population, but recent studies describe both pro- and anti-tumor functions in neutrophils. This suggests there is more heterogeneity in neutrophils than previously appreciated. To better understand and target neutrophil functions in cancer, we must dissect neutrophil heterogeneity and how it changes from health to disease. To this end, we employed single-cell transcriptome technology to profile immature neutrophils from bone marrow of healthy individuals. Intriguingly, we identified a new neutrophil subset that expresses several B cell markers, including CD79a/b, components of the B cell receptors and PAX5, a lineage-specific transcriptional factor. We termed this population the BNeut. Using flow cytometry, we found that BNeuts are confined to the bone marrow of healthy individuals but expand into the blood of melanoma patients at an early stage, suggesting BNeuts might be a biomarker for disease. Additionally, we find BNeuts in the mouse models of different cancer types, including breast and lung carcinoma. The BNeut appears and functions more similar to a neutrophil than a B cell. BNeuts possess a neutrophil-like transcriptional profile, large cytoplasm with segmented nucleus, and produce ROS and NETs. Using imaging, we show that the BNeuts are single cells co-expressing both CD66b and CD79b, and lack the B cell surface marker CD19. To understand why neutrophils might use a B cell program, we explored different B cell functions including antigen presentation, a function that is usually absent from neutrophils. We show BNeuts are excellent at phagocytosis, including uptake of tumor cells. Further, BNeuts have increased expression of antigen presentation-related genes compared to other neutrophils and can modulate CD4+ T cell responses. Together, we have identified a novel neutrophil subset expressing B cell markers that is preferentially expanded in the blood of melanoma patients and poised to control T cell responses during disease. Citation Format: Melissa A. Meyer, Huy Q. Dinh, Yanfang Zhu, Shu Liang, Gregory Seumois, Pandurangan Vijayanand, Sergio D. Catz, Catherine C. Hedrick. B cell like neutrophil found in peripheral blood of melanoma patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3311.
Abstract 1442: Identifying the molecular basis by which βIII-tubulin promotes tumor cell survival and drug resistance in non-small cell lung cancer
Authors: Simon Brayford, Wee Siang Teo, Amelia Parker, Laura McVeigh, Joshua A. McCarroll, Maria Kavallaris
Journal: Cancer Research (2020)

Abstract Lung cancer is the leading cause of cancer-related mortality worldwide with the most common sub-type, non-small cell lung carcinoma (NSCLC), accounting for &amp;gt;80% of cases. Despite advances in treatments, 5-year survival rates for this disease remain dismal. Advanced NSCLC responds poorly to current therapy and the mechanisms underlying its resistance and aggressive nature are not well defined. Microtubules form a component of the cell cytoskeleton and alterations in the expression of microtubule proteins are increasingly correlated with more aggressive and treatment-refractory cancers. βIII-tubulin is a neuronal-specific isotype that is aberrantly expressed in a range of cancers including NSCLC, and has been found to be correlated with reduced patient survival. Our group has recently demonstrated that βIII-tubulin contributes to activation of the PI3K/AKT cell-survival pathway in NSCLC cells[1]. One of the key negative regulators of this pathway is the tumor suppressor PTEN. PTEN can inhibit cell growth, migration and invasion, and a loss of PTEN function is often associated with cancer progression through AKT hyperactivation. Here, using forced-genetics cell models, we show that AKT activation is reduced by βIII-tubulin knockdown, and that re-expression of βIII-tubulin restores these levels in NSCLC cells. Interestingly, we also found that βIII-tubulin knockdown resulted in increased PTEN mRNA along with altered levels of Snail-1/β-catenin, suggesting a possible role for βIII-tubulin in regulating the transcriptional pathway of the PTEN tumor suppressor. Building on these findings, we also identified, through a high-throughput cell-based drug screen, several receptor tyrosine kinase inhibitors that synergize with βIII-tubulin knockdown to reduce NSCLC cell proliferation and tumoroid growth. Together, our data demonstrate an important role for βIII-tubulin in modulating the activation and/or expression levels of signaling proteins which form part of a major pro-survival pathway in NSCLC. In addition, our results suggest that inhibition of βIII-tubulin in combination with drugs that target multiple kinases may offer a novel therapeutic strategy for the treatment of NSCLC to improve patient outcomes. [1] McCarroll et al., TUBB3/betaIII-tubulin acts through the PTEN/AKT signaling axis to promote tumorigenesis and anoikis resistance in non-small cell lung cancer. Cancer Research. 2015;75:415-425. Citation Format: Simon Brayford, Wee Siang Teo, Amelia Parker, Laura McVeigh, Joshua A. McCarroll, Maria Kavallaris. Identifying the molecular basis by which βIII-tubulin promotes tumor cell survival and drug resistance in non-small cell lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1442.
Abstract LB-354: Immune phenotyping of diverse syngeneic brain tumors identifies critical tumor micro-environmental differences
Authors: Jasneet K. Khalsa, Joshua W. Keegan, Nina Cheng, Joseph Driver, Ameen Chaudry, Wenya Linda Bi, James A. Lederer, Khalid Shah
Journal: Cancer Research (2020)

Abstract Immunotherapy has emerged as a promising approach to treat cancer, however, its efficacy in highly malignant brain-tumors, glioblastomas (GBM), is limited. Pre-clinical syngeneic mouse models are at the forefront of testing and understanding emerging novel immune based therapies prior to their translation in patients. We generated distinct imageable syngeneic GBM-tumor models and assessed tumor infiltrating immune cells from end-stage tumors by utilizing RNA sequencing, CyTOF (mass Cytometry by Time of Flight) and correlative immunohistochemistry. CyTOF facilitates multiparametric analysis of up to 40 different markers which is useful especially in the case of GBM where number of TILs is limiting. We identified immunologically-inert and active syngeneic tumor types and show that inert tumors have an immune-suppressive phenotype with numerous MDSCs (Ly6C+ CD11b+), exhausted CD8 T cells and fewer eosinophils. To mimic the clinical settings of first line of GBM treatment, we performed tumor resection in an immunologically inert tumor model. We show that tumor-resection invigorates an anti-tumor response via significant increase in CD8+ T cells, monocyte/macrophages and decrease in Ly6G+ myeloid cells. A comparative CyTOF analysis of resected-tumor samples from GBM patients and mouse GBM tumors showed stark similarities in one of the mouse GBM tumors tested. These findings guide informed choices for use of GBM models for immunotherapeutic interventions and offer a potential to facilitate immune-therapies in GBM patients. Citation Format: Jasneet K. Khalsa, Joshua W. Keegan, Nina Cheng, Joseph Driver, Ameen Chaudry, Wenya Linda Bi, James A. Lederer, Khalid Shah. Immune phenotyping of diverse syngeneic brain tumors identifies critical tumor micro-environmental differences [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-354.
Abstract 2251: Analysis of cancer survival using peripheral blood immunological parameters
Authors: R. Michael Williams, Joaquin Zuniga, Julio Granados, Edmond Tato Feris, Edmond J. Yunis
Journal: Cancer Research (2020)

Abstract The purpose of this study is to use Immunological Evaluation of Peripheral Blood NK cell number to predict survival in the War of the Immune System against cancer. Comparison of the two survival curves starts with the null hypothesis: there is no difference between the top 50% NK vs bottom 50% NK survival curves. P value is derived from Test Statistic found using log rank test. Breast cancer patients and colon cancer patients were evaluated. Both showed statistically significant differences in survival based on NK Cell number. Eight breast cancer patients had local radiation which showed in every one that the peripheral blood NK cell number decreased during radiation and returned to baseline values after radiation ended. In colon cancer patients the level of quantitative IgM and IgA defined a difference in overall survival. This was not the case for breast cancer patients. Survival was evaluated over a 9+ year period in a single California practice. Citation Format: R. Michael Williams, Joaquin Zuniga, Julio Granados, Edmond Tato Feris, Edmond J. Yunis. Analysis of cancer survival using peripheral blood immunological parameters [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2251.
Abstract 3042: Anti-cancer efficacy of an anti-ErbB3 antibody, ISU104, against the cancers with NRG1-overexpression, NRG1-fusion, or oncogenic ErbB3 mutations
Authors: Seung-Beom Hong, Mirim Hong, Tae-Eun Kim, Ju Yeon Kim, Jung Won Kim, Jeongin Cho, Bongseok Shin, Donggoo Bae
Journal: Cancer Research (2020)

Abstract ErbB3, a heterodimeric partner of EGFR or ErbB2, plays important roles in the survival and growth of cancer cells through activation of PI3K/AKT pathway. ErbB3 can be activated by NRG1 expressed either by cancer cells or adjacent mesenchymal cells, or NRG1-fusion proteins produced by genetic alterations in cancer cells. Oncogenic driver mutations in ErbB3 also induce its activation. Previously, we have demonstrated preclinical anti-cancer efficacy of a monoclonal anti-ErbB3 antibody, ISU104 as a monotherapy or in combination with anti-EGFR antibody in various preclinical models. Biomarker analysis of the models demonstrated that there is a significant positive correlation between tumor growth inhibition by ISU104 and NRG1 mRNA/pERBB3 protein expression levels. Based on this analysis, anti-cancer efficacy of ISU104 was further explored in cancer cells and cell line- or patient-derived xenograft cancer models with high NRG1 expression, NRG1-fusion or oncogenic ErbB3 mutations. ISU104 potently inhibited phosphorylation of ERBB3 and AKT, cell proliferation and tumor growth of such models. Potential impacts of other genetic alterations on the anti-cancer efficacy of ISU104 were also investigated. Overall, the presented data suggest that ISU104, an anti-ErbB3 agent in the early stage of clinical development, can be applied for the treatment of the solid tumors expressing high level of NRG1 or harboring genetic alterations such as NRG1-fusion or oncogenic ErbB3 mutations. Citation Format: Seung-Beom Hong, Mirim Hong, Tae-Eun Kim, Ju Yeon Kim, Jung Won Kim, Jeongin Cho, Bongseok Shin, Donggoo Bae. Anti-cancer efficacy of an anti-ErbB3 antibody, ISU104, against the cancers with NRG1-overexpression, NRG1-fusion, or oncogenic ErbB3 mutations [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3042.
Abstract 2008: Pan-cancer profiling of the effect of biopsied site on tumor mutational burden measurements in a real-world data cohort
Authors: Simon Papillon-Cavanagh, Chuan Gao, G. Celine Han, Alice M. Walsh
Journal: Cancer Research (2020)

Abstract Background: Tumor mutational burden (TMB) has been associated with efficacy of immune checkpoint therapy and is being investigated as a potential biomarker in several tumor types. The foundational studies evaluating TMB in clinical trials have not examined factors that may affect TMB estimates in real-world practice, such as the site of biopsy relative to the tumor tissue of origin. Methods: We used the Flatiron Health/Foundation Medicine Clinico-Genomic Database (Presley CJ, et al. JAMA 2018; Singal G, et al. JAMA 2019), which contains deidentified patient-level clinical records from Flatiron Health (New York, NY), combined with genomic sequencing test results of tissue TMB from Foundation Medicine (Cambridge, MA). We examined patient records from 7 advanced cancer types: non-small cell lung cancer (NSCLC), breast cancer (BC), gastric/esophageal cancer (G/EC), melanoma (MEL), metastatic castration-resistant prostate cancer (CRPC), head and neck cancer (H&amp;N), and small cell lung cancer (SCLC). We performed a multivariate mixed-model linear regression to test for associations between the site of tissue biopsy and TMB measurement. We used a cutoff of 10 mutations per megabase (mut/Mb) to classify specimens as high TMB. Results: TMB data were available for 11,928 biopsy specimens from 11,567 patients: NSCLC, n = 5556; BC, n = 3381; G/EC, n = 1335; MEL, n = 528; CRPC, n = 506; H&amp;N, n = 342; SCLC, n = 280. In multiple cancer types, we found that TMB estimates were significantly associated with the biopsied site. For example, brain metastasis specimens from patients with NSCLC had higher TMB (median 11.3 mut/Mb) than specimens collected from primary lung tissue (median 7.0 mut/Mb) or from pleura or pleural fluid (median 3.5 mut/Mb). TMB measurements were higher in brain metastases than in samples from the primary tissue across multiple cancer types. In contrast, biopsies from lymph nodes showed different TMB patterns depending on the cancer type. Consistent with those results, the proportion of patients with high TMB differed significantly by biopsied site. Conclusion: We used a real-world database of clinical data linked with genomic tests to evaluate TMB values across tissue biopsy sites for multiple cancer types. Our results highlight the biopsied site as a potential source of variation for TMB results measurements in a cancer type–specific manner. This will be important to consider when performing research in heterogenous data sets. Citation Format: Simon Papillon-Cavanagh, Chuan Gao, G. Celine Han, Alice M. Walsh. Pan-cancer profiling of the effect of biopsied site on tumor mutational burden measurements in a real-world data cohort [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2008.
Abstract 565: A single institutional experience with droplet digital polymerase chain reaction (ddPCR) liquid biopsy for therapeutic decision in avanced solid tumors
Authors: Andre Marcio Murad
Journal: Cancer Research (2021)

Abstract Droplet digital polymerase chain reaction (ddPCR) is a promising method for analyzing minor amounts of cell-free circulating free nucleic acid (DNA and RNA) due to its high sensitivity, low cost, and fast reading, since it dispenses bioinformatics, making it an appropriate alternative to new generation sequencing (NGS) for the detection of biomarkers to guide molecularly targeted cancer therapy. The assay covers main actionable hotspot alterations across many actionable genes: EGFR(mutations), ALK (fusion, mutations), ROS1(fusion), BRAF(mutations), KRAS (mutations), NRAS(mutations), PIK3CA (mutations), ERBB2(CNV- copy number variation), ESR1(mutations), KIT(CNV) and PDGFRA(CNV). Therefore, our genes can be used in panels, both in therapeutically applied genotyping and in detecting molecular responses as well as in secondary resistance to tumors such as NSCLC, breast, cervix. rectal, GIST, melanoma and pancreas. METHODS: dd-PCR was performed using the QX200 system (BIO-RAD®, Hercules). The extraction of DNA and RNA was done using the magnetic beads technique of Thermofisher's MagMAX Kit. All samples were tested in duplicate. Up to now, 108 metastatic cancer patients were tested: NSCLC - 28 (26%), breast - 22 (20%), colorectal - 22(20%), melanoma - 18(17%), pancreas - 8(7%), ovarian - 6(6%), salivary glands - 2 (4%) and GIST 2(4%). RESULTS: Significant genomic alterations were detected in 38(35%) patients: 10 (9%) mutations in the KRAS G12V gene (all in colorectal cancer), 10 (9%) ERBB2 amplification (breast cancer), 4 (3.65%) EGFR L858R mutations (NSCLC), 4 (3.5%) EGFR del19 mutations (NSLC), 4 (3.5%) EGFR T790M mutations (NSCLC), 4 (3.5%) BRAF-V600E mutations (colon and melanoma), 2 (1.8%) ALK-EML4 fusion (NSCLC). The MAF (Mutant Allele Fraction) ranged from 0.9% to 24%. In all cases, the results were decisive for the indication or change of a targeted therapy. Median turnaround time was 36 hours and the average cost of the panels was around 500 USD (median of 4 genes per panel). CONCLUSION: Our results suggest that dd-PCR is a highly sensitive method and could be used for a routine laboratory detection of the important genomic variations to determine the targeted therapy in patients with varied advanced solid tumors. Citation Format: Andre Marcio Murad. A single institutional experience with droplet digital polymerase chain reaction (ddPCR) liquid biopsy for therapeutic decision in avanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 565.
Abstract 5764: Descriptive epidemiology and clinicopathology of latent versus active JAK2-myeloproliferative neoplasms (MPN)
Authors: Philip A. Haddad, Kevin Gallagher, Dalia Hammoud
Journal: Cancer Research (2020)

Abstract Splanchnic vein thromboses (SVT) encompass portal, mesenteric, splenic, and hepatic veins thromboses, and often cause Budd-Chiari syndrome (BCS). JAK2-MPNs were found to be the most common cause of SVT and BCS, accounting for up to 50% of all cases. Moreover, endothelial cells harboring JAK2 mutations have been demonstrated in patients with BCS which may contribute to the overall prothrombotic propensity. The aim of this study is to describe the epidemiology and clinicopathology of latent JAK2-MPN (LMPN), where JAK2 mutation is detected without clinical evidence of MPN, versus active JAK2-MPN (AMPN) where JAK2+ MPN is present, in a pooled cohort with SVT and/or BCS. In order to study the demographic characteristics, survival, and prognostic factors, we compiled a pooled database of 90 cases. Kaplan-Meier survival curves were constructed. Cox proportional-hazards model and Log-rank tests were used to assess the influence of demographic and clinical factors on survival. The cohort consisted of 65% LMPN and 35% AMPN. The median age for patients with SVT/BCS with LMPN and AMPN was 39(15-85) years and 42(24-80) years respectively. The peak incidence of SVT/BCS seems to occur between ages 36 and 48 for LMPN and 24-36 for AMPN. In both groups, females were twice more predominant than males. The AMPN group consisted of 41% Polycythemia Vera (PV), 22% Essential Thrombocythemia (ET), 28% Myelofibrosis (MF), and 3% others. There was no difference in the frequency of particular splanchnic veins' involvement or the number of coexisting acquired or inherited conditions between the two groups. Survival of patients with BCS did not differ by their MPN status or sex. Twenty-four percent of LMPN progressed to AMPN (57% ET, 21.5% PV, and 21.5% MF). The median time to progression was 55 (12-96) months among those that progressed. While the median time to progression was longer for males (63 vs 39 months) this difference did not reach statistical significance. This study describes for the first time the epidemiologic and clinical characteristics of patients with SVT/BSC and LMPN and compares them to those of AMPN. It also reveals that while some SVT/BCS with LMPN progress to active MPN diseases, a sizable proportion of these patients remain latent indicating that its prothrombotic propensity is independent of AMPN phenotype expression. Citation Format: Philip A. Haddad, Kevin Gallagher, Dalia Hammoud. Descriptive epidemiology and clinicopathology of latent versus active JAK2-myeloproliferative neoplasms (MPN) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5764.