tbuckley/cabot-search huggingface dataset:
Abstract 4976: Combining measures of immune infiltration uncovers predictors of survival in high-grade serous ovarian cancer
Authors: Anne Montfort, Steph J. Owen, Anna M. Piskorz, Anna Supernat, Luiza Moore, Sarwah Al-Khalidi, Steffen Boehm, Paul Pharoah, Jacqueline McDermott, Frances R. Balkwill, James D. Brenton
Journal: Cancer Research (2020)

Abstract Background: In colorectal and breast cancer, the density and localization of immune infiltrates provides strong prognostic information. We asked whether similar automated quantitation and combined analysis of immune infiltrates could refine prognostic information in high-grade serous ovarian carcinoma (HGSOC) and tested associations between patterns of immune response and genomic driver alterations. Methods and Findings: Epithelium and stroma were semi-automatically segmented and the infiltration of CD45RO+, CD8+ and CD68+ cells was automatically quantified from images of 332 HGSOC patient tissue microarray cores. Epithelial CD8 (p=0.027, HR=0.83), stromal CD68 (p=3 × 10-4, HR=0.44) and stromal CD45RO (p=7 × 10-4, HR=0.76) were positively associated with survival and remained so when averaged across the tumor and stromal compartments.Using principal component analysis (PCA), we identified optimized multiparameter survival models that combined information from all immune markers (p=0.016, HR=0.88). There was no significant association between PTEN expression, type of TP53 mutation or presence of BRCA1/BRCA2 mutations and immune infiltrate densities or principal components. Conclusions: Combining measures of immune infiltration provided improved survival modeling and evidence for the multiple effects of different immune factors on survival. The presence of stromal CD68+ and CD45RO+ populations was strongly associated with survival, underscoring the benefits that evaluating stromal immune populations may bring for prognostic immunoscores in HGSOC. Citation Format: Anne Montfort, Steph J. Owen, Anna M. Piskorz, Anna Supernat, Luiza Moore, Sarwah Al-Khalidi, Steffen Boehm, Paul Pharoah, Jacqueline McDermott, Frances R. Balkwill, James D. Brenton. Combining measures of immune infiltration uncovers predictors of survival in high-grade serous ovarian 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 4976.
Incidence, Clinical Features, and Outcomes of Late‐Onset Neutropenia From Rituximab for Autoimmune Disease
Authors: Reza Zonozi, Zachary S. Wallace, Karen Laliberte, Noah R. Huizenga, Jillian M. Rosenthal, Eugene P. Rhee, Frank B. Cortazar, John L. Niles
Journal: Arthritis & Rheumatology (2020)

Late-onset neutropenia (LON) is an underrecognized complication of rituximab treatment. We undertook this study to describe its incidence, risk factors, clinical features, management, and recurrence.We conducted a single-center retrospective cohort study of 738 adult patients with autoimmune disease who were treated with rituximab to induce continuous B cell depletion. The primary outcome measure was LON, defined as an unexplained absolute neutrophil count of <1,000 cells/µl during B cell depletion. Secondary outcome measures included incidental diagnosis, fever, sepsis, filgrastim use, and recurrent LON. We assessed predictors of LON using Cox proportional hazards regression models. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were calculated.We identified 107 episodes of LON in 71 patients. The cumulative incidence at 1 year of B cell depletion therapy was 6.6% (95% CI 5.0-8.7). The incidence rate during the first year was higher compared to thereafter (7.2 cases per 100 person-years [95% CI 5.4-9.6] versus 1.5 cases per 100 person-years [95% CI 1.0-2.3]). Systemic lupus erythematosus and combination therapy with cyclophosphamide were each independently associated with an increased risk of LON (adjusted HR 2.96 [95% CI 1.10-8.01] and 1.98 [95% CI 1.06-3.71], respectively). LON was not observed in minimal change disease or focal segmental glomerulosclerosis. The majority of episodes (59.4%) were asymptomatic. Fever and sepsis complicated 31.3% and 8.5% of episodes, respectively. Most patients (69%) were treated with filgrastim. Rituximab rechallenge occurred in 87% of patients, of whom 21% developed recurrent LON.LON is common and often incidental. Most cases are reversible and respond well to filgrastim. However, LON can be associated with serious infections and thus warrants vigilant monitoring.
Abstract 3171: Biomarkers of responses to immunotherapy in advanced hepatocellular carcinoma
Authors: Vox Z. Ting, Valerie Chew, Carmen C. Wong, Thomas C. Yau
Journal: Cancer Research (2020)

Abstract Biomarkers from the peripheral blood may serve as a useful tool to identify who will likely benefit from immunotherapy in patients with advanced hepatocellular carcinoma; hence, oncologists might be able to monitor treatment responses regularly via blood tests in addition to routine radiological assessment. To investigate immune profiles of patients with advanced HCC after exposure to immunotherapy by analysing circulating T cells from peripheral blood, our study included stage IV HCC patients (n = 14) seen at the Department of Medical Oncology, Queen Mary Hospitals. Nine patients received PD-1/PD-L1 inhibitor immunotherapy at the discretion of their clinicians, and five treatment-naïve patients were included as a control group. A control group of healthy subjects was also included in the study. Samples from patients who received PD-1/PD-L1 inhibitor therapy were collected after the treatment response was confirmed by radiological assessment. T cell profiles and exhaustion markers were compared along with treatment response as determined by radiological assessment. A total of 14 HCC patients were enrolled in the study: 4 patients showed a partial response to PD-1/PD-L1 inhibitor treatment, 5 patients progressed during PD-1/PD-L1 inhibitor treatment, and 5 patients were not treated with PD-1/PD-L1 inhibitors. Five buffy coat samples from healthy subjects were included as controls. Decreases in the percentage of regulatory T cells (0.8% of T cells in responders, p&amp;lt;0.0001) and in the ratio of effector memory T cells to regulatory T cells (EMT/Treg) were noted in patients who responded to PD-1/PD-L1 inhibitor therapy compared to those who did not, and thus may serve as biomarkers for immunotherapy responses in HCC. Similarly, we observed decreases in Tim-3 (2.09%, p&amp;lt;0.0001) and OX-40 (6.12%, p&amp;lt;0.0001) expression between responders and non-responders, and thus expression levels of these factors could potentially serve as response predictors. An increase in the proportion of CD4 CD8 double-positive (DP) T cells in peripheral blood was observed in immunotherapy responders (16.63%) versus non-responders (4.03%, p&amp;lt;0.05). Biomarkers in circulating T cells allow the investigation of immune profiles after treatment with immunotherapy using non-invasive approach from peripheral blood. Coupled with conventional surveillance strategies, we have identified biomarkers may serve as predictors for HCC patients who will likely benefit from immunotherapy. Citation Format: Vox Z. Ting, Valerie Chew, Carmen C. Wong, Thomas C. Yau. Biomarkers of responses to immunotherapy in advanced hepatocellular carcinoma [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 3171.
Abstract 1074: Programmable bacteria induce durable tumor regression and systemic antitumor immunity
Authors: Sreyan Chowdhury, Kelly Pu, Clare Nimura, Samuel Castro, Courtney Coker, Taylor Hinchliffe, Nicholas Arpaia, Tal Danino
Journal: Cancer Research (2020)

Abstract Synthetic biology is driving a new era of medicine through the engineering of living cells. This transformative approach allows for the creation of systems that intelligently sense and respond to diverse environments, adding specificity and efficacy beyond the capabilities of molecular-based therapeutics. One particular area of focus has been the engineering of bacteria as therapeutic delivery systems to selectively release therapeutic payloads in vivo. We recently engineered a non-pathogenic Escherichia coli strain to specifically lyse within the tumor microenvironment and release an encoded nanobody antagonist of CD47 (CD47nb), an anti-phagocytic receptor that is commonly overexpressed in several human cancer types. We show that delivery of CD47nb by tumor-colonizing bacteria increases activation of tumor-infiltrating T cells, stimulates rapid tumor regression, prevents metastasis and leads to long-term survival in a syngeneic tumor model in mice. Moreover, we report that local injection of CD47nb-expressing bacteria stimulates systemic tumor-antigen-specific immune responses that reduce the growth of untreated tumors, providing proof-of-concept for an abscopal effect induced by an engineered bacterial immunotherapy. We have expanded this approach to include additional human and murine specific immunotherapeutic payloads and evaluate efficacy in multiple tumor model systems. Citation Format: Sreyan Chowdhury, Kelly Pu, Clare Nimura, Samuel Castro, Courtney Coker, Taylor Hinchliffe, Nicholas Arpaia, Tal Danino. Programmable bacteria induce durable tumor regression and systemic antitumor immunity [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 1074.
Abstract 1523: Novel role of TBK1 in breast cancer EMT
Authors: Meenu Maan, Mainak Dutta, Neha Jaiswal, Harold Saavedra, Srikumar Chellappan
Journal: Cancer Research (2020)

Abstract TANK Binding Kinase 1 (TBK1) regulates interferon signaling and NFκB function by acting as a non-canonical IκB kinase. TBK1 also participates in RalB-mediated inflammatory responses and is essential for the survival of non-small cell lung cancers (NSCLC) driven by oncogenic KRAS. Recent evidence suggests a role for TBK1 as a driver of cancer progression and it is overexpressed in breast, colon, lung and pancreatic cancers. Our published results demonstrate that TBK1 is essential for proper microtubule dynamics and regulation of mitosis. Here we show that knockdown of TBK1 results in a decreased expression of mesenchymal genes involved in EMT and a re-distribution of β-catenin in breast cancer cells. Similarly, expression of matrix metalloproteinases 2 and 9 was altered. This led us to hypothesize that TBK1 acts as an EMT driver in cancer. Inhibition of TBK1 resulted in decreased adherence dependent as well as independent colony formation and stem cell self-renewal, while inducing senescence like phenotypes. We propose that TBK1 mediated EMT is mediated through its interaction with the transcription factor E2F1; the interaction was detected in breast cancer cell lines as well as breast cancer Tissue Micro Arrays. To get a holistic view of the changes that take place in the cell after TBK1 knockdown, we performed a global metabolomics and RNAseq analysis of breast cancer cell lines. An integrated analysis of this data suggested significant alterations in glucose, galactose and nucleotide metabolism upon TBK1 knockdown. Two of the genes that were markedly altered were aldoketoreductase1 B10 (AKR1B10) and thymidine phosphorylase (TP); attention was focused on these genes, as both have been reported to be cancer drivers and their over-expression results in poor prognosis. We observed a downregulation of AKR1B10 and TP in response to the TBK1 knockdown. Experiments are under way to investigate whether the pro-cancer role of TBK1 is dependent on AKR1B10 and TP, especially in breast cancer cells. These results suggest that TBK1 mediated EMT might be a function of the altered expression of mesenchymal proteins and the metabolic profile of the cell brought about by TBK1. Citation Format: Meenu Maan, Mainak Dutta, Neha Jaiswal, Harold Saavedra, Srikumar Chellappan. Novel role of TBK1 in breast cancer EMT [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 1523.
Abstract 1188: The effect of insurance status on diagnosis stage and overall survival among children and adolescents with cancer: A propensity score weighting analysis
Authors: Xiaoyan Wang, Kimberly Johnson
Journal: Cancer Research (2020)

Abstract Background. Differences in access, delivery or utilization of health care may impact childhood and adolescent cancer survival. In this study, we evaluated the impact of insurance coverage on diagnosis stage, treatment received, and overall survival among children and adolescents diagnosed with cancer based on a counterfactual framework. Methods. We identified 58,421 individuals diagnosed with any cancer type at ≤ 19 years old from 2004-2010 from the National Cancer Database. We applied the inverse probability of treatment weighting (IPTW) estimator to correct for observed selection biases generated by insurance enrollment at diagnosis or initial treatment and examined associations between insurance status and diagnosis stage, treatment received (any vs. none), and all-cause mortality using weighted logistic and weighted Cox proportional hazard regressions. Results. Compared to privately insured individuals, there was a higher percentage of younger individuals in the Medicaid category for all cancers, whereas the uninsured category had a higher percentage of older individuals. Children and adolescents with Medicaid and no insurance were more likely to be non-White and from lower income counties. Applying the IPTW estimator, all the imbalances on the above covariates were removed. Results from weighted analysis showed a 15% (95 confidence interval (CI): 0.78-0.93) lower odds of being diagnosed at metastatic stage had children and adolescents with Medicaid been enrolled on private insurance but comparable odds for uninsured individuals (odds ratio: 0.98, 95%CI: 0.79-1.22), vs. those with private insurance. The odds of receiving any treatment were 17% (95%CI: 1.08-1.28) and 68% (95%CI: 1.39-2.04) higher had those with Medicaid and no insurance been enrolled on private insurance at diagnosis or initial treatment. Medicaid and uninsured individuals would have a 24% (95%CI: 0.72-0.80) and 24% (95%CI: 0.66-0.87) lower hazard of death during 5 years of follow-up if they were enrolled on private insurance at diagnosis or initial treatment. Conclusion. Children and adolescents without private insurance would have a lower risk of being diagnosed at metastatic stage, higher odds of receiving any treatment, and lower hazard of death within five years following cancer diagnosis had they been enrolled on private insurance at diagnosis or initial treatment. Additional research is needed to further understand underlying mechanisms. Citation Format: Xiaoyan Wang, Kimberly Johnson. The effect of insurance status on diagnosis stage and overall survival among children and adolescents with cancer: A propensity score weighting analysis [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 1188.
Abstract 944: Quantitative cell-based reporter bioassays for functional characterization of immunotherapeutic biologics targeting co-stimulatory and co-inhibitory immune checkpoint receptors
Authors: Jamison Grailer, Julia Gilden, Pete Stecha, Denise Garvin, Jun Wang, Michael Beck, Jim Hartnett, Gopal Krishnan, Frank Fan, Mei Cong, Zhi-jie Jey Cheng
Journal: Cancer Research (2020)

Abstract The human immune system is regulated by a complex network of inhibitory and stimulatory immune checkpoint receptors that regulate T Cell function. These receptors are promising new immunotherapy targets for the treatment of a variety of cancers and autoimmune disorders. Novel therapies employing a variety of strategies have been developed that rely on releasing the brakes on the immune system, with the aim of eliminating tumor cells even more efficiently. Immunotherapies designed to block co-inhibitory receptors (e.g. PD-1, CTLA-4) are showing unprecedented efficacy in the treatment of cancer. However, not all patients and tumor types respond to this approach. This has resulted in broadening of immunotherapy research programs to target additional co-inhibitory (e.g. LAG-3, TIM-3, TIGIT) and co-stimulatory (e.g. 4-1BB, GITR, OX40, ICOS) receptors, individually and in combination. A major challenge in the development of antibody-based biologics is access to quantitative and reproducible functional bioassays. Existing methods rely on primary cells and measurement of complex functional endpoints. These assays are cumbersome, highly variable and fail to yield data required for drug development in a quality-controlled environment. To address this need, we have developed a suite of cell-based functional bioassays to interrogate modulation of immune checkpoint receptors individually (e.g. PD-1, LAG-3, TIM-3, GITR, 4-1BB) and in combination (e.g. PD-1+CTLA-4, PD-1+LAG-3). These bioassays consist of stable cell lines that express luciferase reporters driven by response elements under the precise control of mechanistically relevant intracellular signals from TCR and immune checkpoint receptors. Thus, these bioassays reflect mechanisms of action for drug candidates designed for each immune checkpoint receptor and demonstrate high specificity, sensitivity and reproducibility. The bioassays are prequalified according to ICH guidelines and show the precision, accuracy and linearity required for routine use in potency and stability studies. Here we describe the application of MoA-based immune checkpoint receptor bioassays as tools for biologics drug discovery, development, potency and stability studies. Citation Format: Jamison Grailer, Julia Gilden, Pete Stecha, Denise Garvin, Jun Wang, Michael Beck, Jim Hartnett, Gopal Krishnan, Frank Fan, Mei Cong, Zhi-jie Jey Cheng. Quantitative cell-based reporter bioassays for functional characterization of immunotherapeutic biologics targeting co-stimulatory and co-inhibitory immune checkpoint receptors [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 944.
Abstract 1702: Cancer stem cell marker DCLK1 correlates with tumorigenic immune infiltrates in the colon and gastric adenocarcinoma microenvironments
Authors: Dongfeng Qu, Xiangyan Wu, Nathaniel Weygant, Jun Peng, Courtney Houchen
Journal: Cancer Research (2020)

Abstract Immunotherapy that has proved efficacy in several solid cancers plays a partial role in improving clinical outcomes of advanced gastrointestinal (GI) cancers. There is an unmet need to find new immune-related therapeutic targets. Doublecortin-like kinase 1 (DCLK1) marks tuft cells which are recognized as cancer initiating cells and regulators of the type II immune response, and has been studied for its role in many cancers including colon and gastric cancers, but its role in tumor immunity remains unexplored. In the current study, we analyzed colon and gastric cancer RNA sequencing data from 283 and 415 patients respectively from The Cancer Genome Atlas (TCGA). High DCLK1 expression predicted the worse clinical outcomes in colon and gastric cancer patients and correlated with increased immune and stromal components. Further analysis indicated that DCLK1was strongly linked to infiltration of multiple immune cell types, especially TAMs and Tregs, and strongly correlated with increased CD8+ T cell inhibitors TGFB1 and CXCL12 and their receptors, suggesting it may contribute to TAM-mediated inhibition of CD8+ T cells. Interestingly, we found that DCLK1 was a prognostic biomarker in left-sided colon cancer which has worse outcomes and demonstrates a reduced response to existing immunotherapies. In conclusion, our results demonstrate that DCLK1 is linked with functional regulation of the tumor microenvironment and may have potential as a prognostic biomarker and adjuvant target to promote immunotherapy sensitivity in colon and gastric cancer patients. Citation Format: Dongfeng Qu, Xiangyan Wu, Nathaniel Weygant, Jun Peng, Courtney Houchen. Cancer stem cell marker DCLK1 correlates with tumorigenic immune infiltrates in the colon and gastric adenocarcinoma microenvironments [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 1702.
Inhaled RNA Therapy: From Promise to Reality
Authors: Michael Y.T. Chow, Yingshan Qiu, Jenny K.W. Lam
Journal: Trends in Pharmacological Sciences (2020)

RNA-based medicine is receiving growing attention for its diverse roles and potential therapeutic capacity. The largest obstacle in its clinical translation remains identifying a safe and effective delivery system. Studies investigating RNA therapeutics in pulmonary diseases have rapidly expanded and drug administration by inhalation allows the direct delivery of RNA therapeutics to the target site of action while minimizing systemic exposure. In this review, we highlight recent developments in pulmonary RNA delivery systems with the use of nonviral vectors. We also discuss the major knowledge gaps that require thorough investigation and provide insights that will help advance this exciting field towards the bedside.
Abstract 5455: Identifying somatic variants with defined confidence level in targeted sequencing of tumor DNA without a matched normal sample
Authors: Yanmei Huang, Amanda G. Young, Jason D. Hughes
Journal: Cancer Research (2020)

Abstract Sequencing tumor DNA without a matched normal sample is currently routine practice for many clinical diagnostic services that use NGS to identify somatic mutations in a panel of cancer-relevant genes, due to cost constraints. Various computational algorithms have been developed to distinguish somatic mutations from germline variations in this “single sample” setting. However, the sensitivity and specificity of these methods have not been rigorously investigated, and factors affecting accuracy of the somatic classification have not been thoroughly mapped out. We seek to address these inadequacies and identify avenues towards better somatic variant identification in “single sample” setting. We use tumor/matched normal pairs to establish true somatic/germline status of variants and analyze how adjustments in the algorithms for variant calling and somatic/germline classification affect the ability to identify true somatic variants. We show that somatic variants can be identified with varying degrees of certainty under different circumstances and demonstrate that our algorithmic methods can effectively identify a substantial subset of calls that have a very high likelihood of being truly somatic. Tunable filtering methods and confidence scoring for somatic likelihood has utility in the development of complex biomarkers such as tumor mutational burden and ctDNA measurements. Citation Format: Yanmei Huang, Amanda G. Young, Jason D. Hughes. Identifying somatic variants with defined confidence level in targeted sequencing of tumor DNA without a matched normal sample [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 5455.