bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1177: The chronology of immune-related adverse events (irAEs)-mechanistic implications
Authors: Mazahreh Farah , Safar Haya , Mazahreh Liyan , Safar A. Mazin 
Published: March 2024

Abstract
Immune Oncology (IO) is a novel component of the oncology armamentarium given its distinct mechanism of action, and by extension, unique mechanisms of toxicity (Tx). To recognize these unusual Txs, the term irAEs was popularized in clinical trials. Most organs have been involved by irAEs and autoimmunity has been implicated commonly by practicing oncologists. The onset of irAEs has not been studied well, however. We reasoned that autoimmune phenomena would be expected early after IO, since this is the timeframe within which T-cells expand to exert their effects on tumor and other ‘self’ tissues. It follows that if autoimmunity is the sole mechanism of irAEs, such toxicities should be reported early. Mechanism(s) of irARs may prove important for IO duration discussions. In some cases, tumor antigenic epitopes may mimic self-tissues, and in such cases irAEs develop early after initiation of IO. We hypothesized that irAEs have distinct chronology: earlier events representing autoimmunity (unavoidable); later events reflecting an intercurrent exposure to an antigen (e.g., virus) and therefore are avoidable by limiting duration of IO. Methods: We reviewed published IO monotherapy trials if individual patient data (swimmers’ plot) were reported. We derived the timing and frequency of Tx. We used therapy discontinuation without progressive disease as a surrogate for Tx if reported before the planned 24 months IO therapy.Results: Table depicts the data on included clinical trialsConclusion: The emergence of irAEs after IO extends over a protracted periods with 86% of events occurring beyond 4 months of IO. Though responses occasionally develop late after IO, for Tx consideration, T-cell expansion starts within days of IO initiation, and if autoimmunity is the mediator of Tx, irAEs would emerge only early. Our results suggest dual mechanisms and provide one more impetus to consider shortening IO duration.
Tumor Author Discontinued IO (n) Months of IO Discontinuation 0-2 3-4 5-6 7-8 9-10 11-12 13-14 15-16 17-18 19-20 21-22 NSCLC Topalian 12 1 1 4 1 1 3 1 Dart 11 3 4 3 1 Warburton 56 2 2 7 8 7 22 1 3 1 2 1 Melanoma Topalian 13 4 1 2 1 2 2 1 Weber 2 1 1 Demetriou 66 8 4 6 5 6 10 6 10 6 5 RCC Topalian 3 1 2 Total 163 14 10 15 25 14 38 9 15 10 11 2 8% 6% 9% 15% 8% 23% 5% 9% 6% 7% 1%
Citation Format: Farah Mazahreh, Haya Safar, Liyan Mazahreh, A. Mazin Safar. The chronology of immune-related adverse events (irAEs)-mechanistic implications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1177.
Abstract 1203: Mushroom: a tool for identification of 3D cellular neighborhoods in multi-modal spatial datasets
Authors: Storrs Erik , Chen Siqi , Mo Chia-Kuei , Houston Andrew , Shinkle Andrew , Southard-Smith Austin , Simin Faria , Targino Andre , Li Xiang , Abedin Ateih , Jayasinghe Reyka , Karpova Alla , Liu Jingxian , Herndon John , Fenyo David , Chen Feng , Fields Ryan , Ju Tao , Raphael Ben , Ding Li 
Published: March 2024

Abstract
A comprehensive understanding of the spatial localization of cellular processes is necessary to fully describe tissue biology. Numerous techniques exist to identify cellular neighborhoods in spatial datasets, however, these techniques are limited in that they either only capture two-dimensional phenomena - and can't describe the full, 3-dimensional tumor volume, or they are restricted to one spatial technology (i.e. IF, 10X Visium, Xenium, MERFISH, etc.). To address this, we developed Mushroom, a tool for identification of three-dimensional cellular neighborhoods in serial-sectioned multi-modal datasets. Mushroom’s methodology consists of two main steps: 1) registration of multi-modal technologies taken in serial sections (such as multiplex imaging, H&E, or spatial transcriptomics), and 2) identification of 3-dimensional cellular neighborhoods comprising the tissue volume that has been serially sectioned. Keypoint registration is performed with BigWarp, after which the resulting dense displacement field (DDF) is used to register neighboring serial sections - including those from different data modalities. We then implement a neural network to identify three dimensional cellular neighborhoods. The network is a variational autoencoder (VAE) with a vision transformer (VIT) backbone that has been adapted to work with multiple spatial data modalities. Features extracted from the VIT backbone are then clustered to identify cellular neighborhoods unique to each input data type. With 3D neighborhoods in hand, biological questions not answerable in traditional 2D approaches can be investigated, such as z-dimensional changes in morphology and cellular interactions. Further, seamless characterization of cellular neighborhoods by simultaneous technologies at multiple levels of spatial and genomic resolution becomes possible.
Citation Format: Erik Storrs, Siqi Chen, Chia-Kuei Mo, Andrew Houston, Andrew Shinkle, Austin Southard-Smith, Faria Simin, Andre Targino, Xiang Li, Ateih Abedin, Reyka Jayasinghe, Alla Karpova, Jingxian Liu, John Herndon, David Fenyo, Feng Chen, Ryan Fields, Tao Ju, Ben Raphael, Li Ding. Mushroom: a tool for identification of 3D cellular neighborhoods in multi-modal spatial datasets [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1203.
Abstract 1229: BDTX-1535: A MasterKey EGFR inhibitor targeting classical and non-classical oncogenic driver mutations and the C797S acquired resistance mutation to address the evolving molecular landscape of EGFR mutant NSCLC
Authors: Dardenne Etienne , O'Connor Matthew , Nilsson Monique , He Junqin , Yu Xiaoxing , Heymach John V. , Le Xiuning , Buck Elizabeth 
Published: March 2024

Abstract
The molecular landscape of EGFR mutated NSCLC has evolved over time in response to changing treatment practices with EGFR inhibitors and through the expanding use of NGS. With the replacement of first-generation reversible EGFR tyrosine kinase inhibitors (TKIs) by the third generation covalent TKI osimertinib as front-line therapy for patients with NSCLC expressing classical EGFR mutations, acquired resistance mutations have shifted with the near disappearance of EGFR-T790M and the emergence and growing incidence of EGFR-C797S. Our understanding of the EGFR mutation landscape has also continued to mature with comprehensive sequencing across all EGFR exons and with the vast majority of patients now undergoing sequencing. We now see how classical oncogenic drivers represent only a subset of oncogenic EGFR driver mutations and where other non-classical driver mutations are numerous and represent a major unmet medical need. Furthermore, there is a growing appreciation of the differences between the classical EGFR-L858R and EGFR-Ex19 deletion (Ex19del) mutations. For patients expressing L858R, many co-express non-classical drivers and this may explain the weaker relative activity for osimertinib in patients expressing L858R versus Ex19del. For patients expressing Ex19del, the co-expression of non-classical mutations is less common. In contrast, patients with Ex19del more often gain C797S as an acquired resistance mutation. Using the Foundation Medicine’s FoundationInsights™ web-based platform, we present real world evidence (RWE) to define the molecular landscape of classical, non-classical, and acquired resistance mutations from a survey of &gt;80,000 sequenced cases of NSCLC, including &gt;12000 EGFR altered cases. We further present the profile for BDTX-1535 as a MasterKey EGFR inhibitor designed to address this evolved EGFR mutational landscape and tested against over &gt;50 EGFR mutations. We also show how BDTX-1535 can address classical EGFR mutations in addition to on target mechanisms of resistance post osimertinib with potency against C797S as well as non-classical mutations affecting both the intracellular and extracellular domains, including L718X, E709X, S784F, V834L and A289V.
Citation Format: Etienne Dardenne, Matthew O'Connor, Monique Nilsson, Junqin He, Xiaoxing Yu, John V. Heymach, Xiuning Le, Elizabeth Buck. BDTX-1535: A MasterKey EGFR inhibitor targeting classical and non-classical oncogenic driver mutations and the C797S acquired resistance mutation to address the evolving molecular landscape of EGFR mutant NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1229.
Abstract 125: Development of humanized VEGFA models to assess preclinical efficacy of novel therapeutics in vivo
Authors: Zhang Shujin , Liu Chonghui , Guo Jin , Shen Zhiyuan , Jin James , Huwatibieke Bahetiyaer , Shen Yang 
Published: March 2024

Abstract
VEGFA is an essential growth factor required for angiogenesis in the context of normal wound healing as well as malignant tissue growth, ultimately facilitating the delivery of oxygen and nutrients to fuel cellular survival, expansion, and repair. VEGFA signaling has also been reported to exert effects on cancer cells and immune cells directly, with evidence suggesting that the pathway can both support tumor growth and inhibit immune surveillance. Thus, targeting VEGFA has been intensely explored as a therapeutic strategy for several cancer indications. Here, we generated a novel humanized VEGFA model (B-hVEGFA mice) to explore the ability of novel VEGFA-targeting therapeutics to curb cancer cell growth and angiogenesis in vivo. This was achieved by replacing the murine Vegfa gene with the corresponding human VEGFA coding region. We confirmed exclusive expression of human VEGF in lung homogenates of the humanized model at levels comparable to murine VEGF quantified in wild-type C57BL/6 mice. Immunohistochemical analysis at 8 weeks of age demonstrates no significant difference in the CD31+ area in several organs of the humanized mice when compared to wild-type C57BL/6 mice, including kidney, heart, liver, and eye. To assess the functional utility of this model in evaluating VEGFA modulators, tumor studies were conducted: murine colon cancer MC38 cells that were also engineered to express VEGFA in a similar manner (B-hVEGFA MC38 cells) were subcutaneously implanted into homozygous B-hVEGFA mice. Treatment with bevacizumab analog essentially abolished tumor growth in the humanized mice, while control tumors continued to expand over the 3 week study. To further evaluate the role of novel combination therapies or bispecific antibodies targeting VEGFA and PD-1, we also generated a triple humanized model expressing human VEGF, PD-1, and PD-L1 (B-hPD-1/hPD-L1/hVEGFA mice) by crossing B-hVEGFA mice with our B-hPD-1/hPD-L1 mice model, which expresses the extracellular domains of human PD-1 and PD-L1. Flow cytometric analysis of this model is currently underway to validate the model for further efficacy testing. Together, these humanized VEGF models provide robust in vivo platforms to evaluate novel VEGFA therapeutic candidates.
Citation Format: Shujin Zhang, Chonghui Liu, Jin Guo, Zhiyuan Shen, James Jin, Bahetiyaer Huwatibieke, Yang Shen. Development of humanized VEGFA models to assess preclinical efficacy of novel therapeutics in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 125.
Abstract 1298: Assessing the impact of Medicaid expansion on colorectal cancer preventative services utilization
Authors: Omeaku Paulette 
Published: March 2024

Abstract
Introduction: Colorectal cancer (CRC) is the second leading cause of cancer mortality. CRC screening rates have steadily risen and incidence rates around the nation have declined. To date, forty-one states have expanded Medicaid across the United States, with 9 states remaining that have not expanded. Although, access through insurance has increased, colorectal disparities in screening and mortality persist. Other studies have shown that screening guideline concordance can be inconsistent based on insurance type. Data suggests Medicaid enrollees are more likely to present advanced-stage cancers than those privately enrolled. The screening differences throughout the United States emphasize how complex colorectal cancer disparities are and how insurance may play a role.
Aims: Our study aims to investigate the impact of Medicaid expansion on timely CRC screenings, specifically examining whether these effects differ by African Americans, Hispanics, and White Americans.
Methods: Data was utilized from the Behavioral Risk Factor Surveillance System (BRFSS) to analyze timely CRC screening data of adults below 138% of the federal poverty level (FPL) of states with different Medicaid expansion statuses. Most recently available data was used in our analysis spanning the years 2014-2022 in all 50 states. States were stratified by dummy variables for Medicaid expansion and non-expansion status. Timely CRC screenings were determined by eligible respondent responses. Difference-in-difference analyses were used to study the effect of Medicaid expansion on timely CRC screenings in states with different Medicaid expansion statuses.
Results: Our sample included 60.52% White Americans, 12.22% African Americans, and 16.41% Hispanics in both Medicaid expanded and non-expanded states. Sex and race had significant associations to Medicaid expansion status and timely CRC screenings, particularly when analyzing race for Hispanics and White Americans. Between 2014 and 2022, timely CRC screening for low-income adults in Medicaid expansion states was at 33.15% compared to 23.17% from non-expansion status states. Notably, adults aged 45-64 demonstrated the highest differences in timely CRC screenings for Medicaid-expanded states (12.26% and 18.98%) compared to non-expanded states (9.27% and 13.96%, respectively).
Citation Format: Paulette Omeaku. Assessing the impact of Medicaid expansion on colorectal cancer preventative services utilization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1298.
Abstract 1356: The VISTA blocking antibody HMBD-002 promotes type-I interferon signaling and drives anti-tumor responses through macrophage reprograming and cytotoxic CD8+ T cell activation
Authors: Dharmadhikari Bhushan , Zharkova Olga , Thakkar Dipti , Tirado-Magallanes Roberto , Paszkiewicz Konrad , Ingram Piers J. , Boyd-Kirkup Jerome D. 
Published: March 2024

Abstract
VISTA, a predominantly myeloid immune checkpoint, promotes an immunosuppressive tumor microenvironment and has been associated with resistance to approved checkpoint therapies. While blockade of VISTA with antibodies has shown anti-tumor efficacy in preclinical models, the biological mechanisms that underlie this effect remain poorly understood. To investigate the mechanistic basis of anti-tumor responses, we performed single-cell RNA sequencing of tumor infiltrating leukocytes from the cell-derived murine colon carcinoma xenograft model, CT26, which is known to be sensitive to VISTA blockade. We used HMBD-002, a uniquely blocking but non-depleting clinical-stage IgG4 anti-VISTA antibody, to identify the key immune cells and pathways impacted by VISTA blockade in the absence of Fc-mediated cell depletion. The translatability of these findings was validated in a human PBMC mixed leukocyte reaction assay. Subsequently, targeted depletion or inhibition of the identified immune populations and pathways was performed to confirm their contribution to the anti-tumor efficacy of HMBD-002.The blockade of VISTA by HMBD-002 significantly increased CD8+ T cells in the CT26 tumors, promoting an activated cytotoxic Tc1 program without inducing exhaustion. Concurrently, a substantial increase in proinflammatory M1 tumor-associated macrophages (TAMs) was noted within treated tumors, while other immune cell populations remained unaffected. Among the signaling pathways, the type-I interferon (IFN) response exhibited a significant upregulation, particularly in TAMs, indicating a type-I IFN-driven M1 reprogramming by HMBD-002. Validation experiments further demonstrated that the depletion of TAMs or CD8+ T cells, but not CD4+ T cells, abrogated the efficacy of HMBD-002. Moreover, blocking the type-I IFN signaling effectively impeded HMBD-002-induced TAM reprogramming and subsequent anti-tumor efficacy, thus confirming the pivotal roles of CD8+ T cells, TAMs, and type-I IFN signaling in driving the anti-tumor response to VISTA blockade. In conclusion, VISTA blockade with HMBD-002 promotes an anti-tumor response by type-I IFN mediated reprogramming of TAMs and activation of cytotoxic CD8+ T cells.
Citation Format: Bhushan Dharmadhikari, Olga Zharkova, Dipti Thakkar, Roberto Tirado-Magallanes, Konrad Paszkiewicz, Piers J. Ingram, Jerome D. Boyd-Kirkup. The VISTA blocking antibody HMBD-002 promotes type-I interferon signaling and drives anti-tumor responses through macrophage reprograming and cytotoxic CD8+ T cell activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1356.
Abstract 1371: SLAMF9 promotes tumor progression and immunotherapy resistance by reshaping the tumor microenvironment
Authors: Fan Tao , Xiao Chu , Deng Ziqin , Cai Wenpeng , Tian He , Wang Liyu , Li Chunxiang , He Jie 
Published: March 2024

Abstract
Tumor prognosis and immunotherapy efficacy coincides with the infiltration ratio and functional status of immune cells in the tumor microenvironment (TME). Signaling lymphocytes activating molecule factors (SLAMFs) has been reported to play a key role in regulating tumor immunity. Herein, using multi cohorts, in vitro and in vivo experiments, we showed that SLAMF9 worsens tumor and suppresses immune therapy responses by remodeling TME. A pan-cancer analysis showed that SLAMF9 had relatively high transcriptional levels within tumor tissues compared with normal tissues across most cancer types. High SLAMF9 expression is associated with poor prognosis and anti-PD-L1 therapy resistance in advanced clear cell renal cell carcinoma cohorts and metastatic urothelial cancer cohorts. SLAMF9 expression was markedly upregulated in anti-CTLA-4-resistant murine B16 melanoma compared with parental tumors. In particular, SLAMF9 expression was generally negatively correlated with CD8+T cell infiltration score in 12159 patients of 40 cancer types even using different immune cell infiltrating algorithms. Although in vitro experiments have shown that SLAMF9 knockdown has almost no effect on the malignant phenotype of tumor cells, subcutaneous melanoma and lung adenocarcinoma with SLAMF9 deficiency grew slowly, which featured with increased infiltration of CD8+T and PD-1+cells. More importantly, SLAMF9-knockdown significantly increases the sensitivity of subcutaneous melanoma to anti-CTLA-4 inhibitor or anti-PD-L1 antibodies and improved the survival benefits of tumor-bearing mice. This work highlights SLAMF9 as a new target in reshaping the tumor immune microenvironment by controlling the functional status of CD+8 T cells and to improve the efficacy of immunotherapy.
Citation Format: Tao Fan, Chu Xiao, Ziqin Deng, Wenpeng Cai, He Tian, Liyu Wang, Chunxiang Li, Jie He. SLAMF9 promotes tumor progression and immunotherapy resistance by reshaping the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1371.
Abstract 1391: Therapeutic salmonella induces long-term protective trained immunity in NK cells against metastasis
Authors: Rong Li , Huang Jiandong 
Published: March 2024

Abstract
Immune memory is a trait commonly associated with adaptive immunity. Nevertheless, it has been observed that activation of the innate immune system can also result in enhanced responsiveness to subsequent triggers, a form of innate immune memory known as trained immunity. This phenomenon has been primarily explored in the context of host defense against infectious disease, where myeloid cells, including monocytes, macrophages, and their precursor cells, are conditioned by specific stimuli such as β-glucan, LPS, or the bacillus Calmette-Guιrin (BCG) to boost protection against microbial pathogens. However, the induction of trained immunity in innate lymphocytes, particularly through these known or yet-to-be-discovered stimuli and its explicit contribution to tumor immunity, remain insufficiently characterized. Metastasis accounts for 90% of cancer-related deaths, and no effective clinical therapies are currently available to halt the metastatic cascade. Based on multiple cancer metastasis mouse models and immunological analysis, we found that a single dose of therapeutic Salmonella YB1, an engineered oxygen-sensitive strain, provides extensive and persistent protection against metastasis by inducing protective trained immunity in NK cells, consistently observed irrespective of the mouse genetic background or cancer cell lines. Following inflammatory resolution, salmonella YB1-trained NK cells exhibit an enhanced capacity to release IFN-γ upon secondary stimulation and increased cytotoxicity towards cancer cells, which is associated with epigenetic changes. Further investigation using single-cell transcriptomic profiling indicates that the formation of long-term anti-metastatic trained immunity in NK cells by Salmonella YB1 is dependent on IL12 and IL18. Additionally, Salmonella YB1-trained NK cells outperform common immune checkpoint therapies like PD1 blockade and TIGIT blockade in suppressing metastasis. In summary, our results revealed a novel anti-metastatic function of trained NK cells induced by therapeutic Salmonella, suggesting the induction of trained immunity in NK cells as a potential anti-tumor strategy.
Citation Format: Li Rong, Jiandong Huang. Therapeutic salmonella induces long-term protective trained immunity in NK cells against metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1391.