bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2567: An analysis of proviral insertion site of Moloney murine leukemia virus, PIM1, kinase expression and clinical outcomes in renal cell carcinoma
Authors: Holder Sheldon L. , Lagos Galina , Carneiro Benedito A. , Mega Anthony , De Souza Andre , McKay Rana R. , Elliott Andrew , Nabhan Chadi , Graff Stephanie L. 
Published: March 2024

Abstract
Background: Wild-type Proviral Insertion Site of Moloney Murine Leukemia Virus 1 Kinase (PIM1) is a constitutively active serine/threonine kinase that inhibits apoptosis and promotes cell cycle progression, proliferation, angiogenesis, invasion, and migration. Due to constitutive activation, PIM1 is regulated at transcription and degradation. We have previously shown PIM1 protein levels are elevated in clear cell renal cell carcinoma (ccRCC) compared to normal kidney and that PIM1 inhibition induces tumor regression in pre-clinical models. Current approved therapies for ccRCC do not inhibit PIM1. We hypothesized that high PIM1 expression will adversely affect clinical outcomes in ccRCC.
Methods: Whole transcriptome sequencing (WTS) data in the Caris Life Sciences database were examined for PIM1expression and overall survival (OS; defined as time from diagnosis to last contact or death). We assessed PIM1 in primary and metastatic ccRCC, and the impact on survival in ccRCC and papillary RCC. Differentially expressed genes (DEGs) associated with high PIM1 were also determined.
Results: PIM1, in the highest quintile, was associated with a shorter OS (869 vs 1738 days; HR 2.629; CI 1.495 - 4.611; p&lt;0.001; N=147) in ccRCC. PIM1 is enriched in metastatic (median 7.62 transcripts per million (TPM), CI 6.35 - 9.26) vs primary (median 5.07 TPM; CI 4.28 - 6.45; p=0.0025) RCC. Upregulated DEGs associated with high PIM1 are involved in the extracellular matrix. IL-6 expression, known to correlate with worse outcomes, was 6.5-fold higher in PIM1 high vs PIM1 low (13.2 vs 2.1 TPM, p&lt;0.0001) RCC. High PIM1 was associated with poor survival following checkpoint inhibition (HR 3.714, 95% CI 1.339 - 10.303, p=0.007) and a trend towards poorer survival following mTOR inhibition and VEGF inhibition. PIM1 did not affect survival in papillary RCC.
Conclusions: Real-word data show that high PIM1 correlates with poorer survival in ccRCC but not in papillary RCC. This effect likely persists independent of treatment received. PIM1 enrichment in metastatic ccRCC, and associated DEGs, suggest that PIM1 influences the extracellular matrix to promote metastases. The correlation between IL-6expression and PIM1 supports our prior data that an IL-6/JAK/STAT/PIM1 pathway is involved in ccRCC.
Citation Format: Sheldon L. Holder, Galina Lagos, Benedito A. Carneiro, Anthony Mega, Andre De Souza, Rana R. McKay, Andrew Elliott, Chadi Nabhan, Stephanie L. Graff. An analysis of proviral insertion site of Moloney murine leukemia virus, PIM1, kinase expression and clinical outcomes in renal cell carcinoma [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 2567.
Abstract 2607: Dual payload immunochemotherapy to treat CD276 positive cancers
Authors: Zhou Zhuoxin Zora , Zhang Jiashuai , Zhou Lufang , Liu Xiaoguang Margaret 
Published: March 2024

Abstract
The Cancer Genome Atlas (TCGA) dataset showed higher level of CD276 (B7-H3) transcript in multiple cancers, including triple-negative breast cancers (TNBCs), non-small cell lung cancers (NSCLCs) and other cancers, than normal tissues. Our immunohistochemistry staining of hundreds of patient tissue microarrays confirmed the high expression of CD276 surface receptor in &gt;60% of TNBC and &gt;70% of NSCLC while minimal or low expression in 33 normal organs or tissues. This study aims to develop and evaluate a novel treatment strategy, i.e. anti-CD276 mAb-dual payloads conjugate (DualADC), as immune-chemotherapy to treat CD276-positive TNBCs and NSCLCs. First, a new CD276-targeting monoclonal antibody (mAb) capable of delivering payloads and upregulating tumoral immunity was developed and engineered. Then, a new platform to concurrently conjugate both traditional cytotoxic payload and immunoregulating regent with one CD276 mAb (DualADC) was established. Our evaluations showed that this targeted therapy effectively killed multiple subtypes of TNBC and NSCLC, significantly upregulated immune functions in tumor microenvironment, and reduced tumor burden by up to 90-100% in seven animal models (including patient-derived xenograft). The post-treatment analysis using single-cell RNA sequencing, Luminex multiplex cytokine assay, whole blood, histology and histopathology analysis demonstrated an integrated anti-cancer mechanisms and minimal systematic toxicity. Altogether, our study suggested that the 276-DualADC could provide a promising targeted chemo-immunotherapy for CD276-postive cancer patients. In future, translational investigations will be performed to determine the toxicology, optimal dose, and treatment strategy, and the combination with other therapy will also be evaluated.
Citation Format: Zhuoxin Zora Zhou, Jiashuai Zhang, Lufang Zhou, Xiaoguang Margaret Liu. Dual payload immunochemotherapy to treat CD276 positive cancers [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 2607.
Abstract 2616: BCG033, a novel bispecific antibody-drug conjugate targeting PTK7 and TROP2, demonstrates preclinical efficacy against triple-negative breast cancer and other solid tumor xenografts
Authors: Yao Sufei , Shang Chengzhang , An Gao , Guo Chaoshe , an W. Frk , Yang Yi 
Published: March 2024

Abstract
Metastatic triple-negative breast cancer (TNBC) patients have poor overall survival, highlighting the need for novel treatments. Although the TROP2-targeting ADC sacituzumab govitecan recently received accelerated approval from the FDA for the treatment of patients with metastatic TNBC, the on-target toxicity of this single-target agent has limited clinical efficacy. We sought to improve the specificity and efficacy of future TNBC-targeted therapies by generating a bispecific antibody-drug conjugate (bsADC) targeting TROP2 and PTK7, another tumor-associated antigen (TAA) that is highly expressed in TNBC and correlates with poor prognosis and metastatic disease.
We previously generated fully human antibodies targeting PTK7 and TROP2 from Biocytogen’s fully human, common light chain antibody transgenic RenLite® mice, which were selected such that their monovalent antibodies exhibited reduced internalization profiles for improved tumor selectivity. These antibodies were then constructed into a bispecific antibody targeting PTK7 × TROP2, which demonstrated reactivity to human and cynomolgus monkey antigens and binding to multiple cancer cell lines, including TNBC, with high affinity. PTK7 × TROP2 bsAb also showed enhanced internalization in vitro compared with parental monovalent antibodies. Next, the PTK7 x TROP2 bsAb was conjugated to vcMMAE with a drug-to-antibody ratio (DAR) of 4 to generate a bsADC (BCG033). BCG033-vcMMAE demonstrated superior activity to benchmark and parental ADCs in a cell line-derived xenograft (CDX) TNBC model with low PTK7 expression. Here, we demonstrate that BCG033-vcMMAE ADCs also exhibited superior efficacy to benchmark ADCs in PDX models, including TNBC xenografts and NSCLC xenografts. We next tested the efficacy of the PTK7 x TROP2 bsAb conjugated to BLD1102, Biocytogen’s novel, proprietary linker/payload composed of a DNA Topo I inhibitor payload and a highly hydrophilic protease-cleavable linker, with a DAR of 8. BCG033-BLD1102 showed potent activity in a colorectal cancer PDX model in which benchmark ADCs were inactive, even at high doses.
In summary, BCG033 conjugates demonstrate promising preclinical efficacy in vivo, which ultimately could provide a new treatment option for TNBC and other solid tumors expressing PTK7 and TROP2.
Citation Format: Sufei Yao, Chengzhang Shang, Gao An, Chaoshe Guo, W. Frk an, Yi Yang. BCG033, a novel bispecific antibody-drug conjugate targeting PTK7 and TROP2, demonstrates preclinical efficacy against triple-negative breast cancer and other solid tumor xenografts [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 2616.
Abstract 2627: PanCancer epigenetic regulators of lymphocyte activation states
Authors: Karpova Alla , Terekhanova Nadezhda V. , Chen Siqi , Jayasinghe Reyka G. , Houston Andrew , Caravan Wagma , Fields Ryan C. , Ding Li 
Published: March 2024

Abstract
Several immune cell types have been successfully targeted for immunomodulatory therapy; however, the efficacies of such therapies are hindered by incompatible immune cell activation states. CD8+ T-cell exhaustion is one of the most studied T-cell states in the context of cancer and was shown to limit checkpoint blockade efficacy. Although CD8+ T-cell exhaustion studies in mice showed this state is tightly regulated by chromatin accessibility of cis-regulatory elements (CREs) and transcription factor activation, the exploration of these mechanisms, their prevalence, and their specificity in human cancers remains limited. In addition, chromatin accessibility signatures of other lymphocyte (CD4+ and NK) states frequently found in solid tumors have not been carefully characterized in a pan-cancer setting. Here we introduce the first single-nuclei atlas of pan-cancer and disease-specific cis- and trans-regulatory elements in tumor infiltrating lymphocytes. We profiled ~140K T-cell and NK cell nuclei with snATAC-seq and snRNA-seq from 227 tumor and normal samples from eleven cancer types. We distinguished two major subpopulations among exhausted CD8+ T-cells: GZMK expressing (CD8+ GZMK+ Tex) and ITGAE+ tissue-resident (CD8+ Trm ex). CD8+ GZMK+ Tex was enriched in clear cell renal cell carcinoma, while CD8+ Trm ex was found in all other cancers. Both exhausted groups featured high motif accessibility and expression of NR4A1, NFATC2, and NFKB2 transcription factors (previously reported to regulate exhaustion), but differed in EOMES motif accessibility and gene expression. We have identified other lymphocyte subpopulations showing exhaustion signatures, including CD4+ follicular helpers (CD4+ Tfh), CD4+ regulatory cells (CD4+ Tregs), and weakly cytotoxic tissue-resident NK cells (trNK weak). All these subpopulations showed increased expression and motif accessibility of the NR4A1 transcription factor, highlighting its role in regulating dysfunctional states not only in CD8+ T-cells, but also in CD4+ and NK cells. Additionally, CD4+ Tfh and Tregs showed enhanced activity of NFKB1, NFKB2, and POU2F2, and trNK weak cells had increased activity of NR4A2 and NR2F2. To put our results into clinical perspective, we have collected cohorts of renal cancer, melanoma and triple-negative breast tumors treated with immunotherapy in clinical trial settings, and showed elevated GZMK expression in exhausted T-cells in responders compared to non-responders.
Citation Format: Alla Karpova, Nadezhda V. Terekhanova, Siqi Chen, Reyka G. Jayasinghe, Andrew Houston, Wagma Caravan, Ryan C. Fields, Li Ding. PanCancer epigenetic regulators of lymphocyte activation states [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 2627.
Abstract 2642: KEAP1 mutation in lung cancer cells leads to increased immunosuppressive capability
Authors: Occhiuto Christopher John , Liby Karen T. 
Published: March 2024

Abstract
Considerable advances have been made in lung cancer therapies, but there is still an unmet clinical need to improve survival for lung cancer patients. Immunotherapies have improved survival, although only 20-30% of patients respond to these treatments. Interestingly, cancers with mutations in KEAP1, the negative regulator of the NRF2 cytoprotective pathway, are resistant to immune checkpoint inhibition and correlate with decreased immune cell infiltration. NRF2 is known for promoting an anti-inflammatory phenotype when activated in immune cells, but the study of NRF2 activation in cancer cells has not been adequately assessed. The overall objective of this study is to determine how lung cancer cells with constitutive NRF2 activity interact with the immune microenvironment to promote cancer progression and metastasis. To assess this, we generated CRISPR-edited mouse lung cancer cell lines (Lewis Lung Carcinoma/LL2) with knockouts (KO) of the KEAP1 and NFE2L2 genes. The transcriptomic profiles of 3 KEAP1 KO and 1 NRF2 KO cell lines were compared to the parental wildtype (WT) line using RNA-sequencing. On unsupervised hierarchical clustering of differentially expressed genes, the 3 KEAP1 KO cell lines clustered together and the NRF2 KO clustered with WT cells. Importantly, canonical NRF2 pathway-related genes were significantly increased in KEAP1 KO clones, but the same genes were either decreased or similar to WT in the NRF2 KO clone. We then used flow cytometry to evaluate immunosuppressive surface markers known to suppress T cell function when expressed on cancer cells. Importantly, PD-L1, CD155, CD80, and CD86 were increased in the KEAP1 KO lines compared to WT, but not in the NRF2 KO clone. In addition, the cytokine release profile was differentially regulated in the KEAP1 KO clones in a manner that could alter T cell recruitment and function. These results were also consistent with gene expression in the sequencing dataset. Finally, using an orthotopic allograft model, we completed a preliminary immunophenotyping study of lung tumors for WT, KEAP1 KO, and NRF2 KO cell lines. The activation status of CD8+ T cells and the ratio of CD8+/CD4+CD25+ T cells (a prognostic marker) were decreased in KEAP1 KO tumors. Taken together, these data suggest cancers with KEAP1 mutations may increase tumor growth through suppression of T cells.
Citation Format: Christopher John Occhiuto, Karen T. Liby. KEAP1 mutation in lung cancer cells leads to increased immunosuppressive capability [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 2642.
Abstract 2648: CD155 regulates cell growth and immune evasion in diffuse midline glioma
Authors: Tzaridis Theophilos , Eisemann Tanja , Andrade Augusto Faria , Hope Jennifer L. , Becher Oren , Jabado Nada , Bradley Linda M. , Adams Peter , Wechsler-Reya Robert 
Published: March 2024

Abstract
There is an unmet need for effective treatment strategies for diffuse midline glioma (DMG), a devastating brain tumour arising in children and young adults. While immunotherapy is emerging as a powerful approach for treatment of other cancers, clinical trials with immune checkpoint inhibitors have failed to show a survival benefit for DMG patients. In this study, we analysed the expression of known immune checkpoint molecules on the surface of human and murine DMG cells by flow cytometry and identified CD155 and B7-H3 as the most highly expressed checkpoint molecules, with minimal expression of others, including PD-L1 and PD-L2. These findings were confirmed in primary patient samples from pediatric brain tumours (gliomas, medulloblastomas and ependymomas). To test whether CD155 regulates susceptibility to CD8+ T cell killing, we cultured murine DMG cells expressing ovalbumin (OVA) with CD8+ T cells from OT-I mice, which express T cell receptors specific for OVA. shRNA mediated silencing of CD155 led to a strong increase in T cell-mediated killing. In vivo, adoptive transfer of OT-I T cells into OVA-positive DMG-bearing immuno-compromised mice resulted in delayed tumour growth, and this effect was enhanced when tumours lacked CD155. Strikingly, CD155-deficient DMG cells failed to grow at all in immuno-competent mice, and depletion of CD8 T cells allowed these tumours to grow, highlighting a role for CD8 T cells in rejection of CD155-deficient cells. In addition to its effects on susceptibility to T cells, CD155 also exerted cell-autonomous effects on tumour cells: silencing of CD155 led to induction of apoptosis of DMG cells in vitro and to delayed tumour growth in vivo, even in immune-compromised mice. These studies demonstrate that CD155 functions as an immune checkpoint and as a regulator of tumour cell survival in DMG, and suggest that targeting CD155 could be a valuable double-pronged therapeutic strategy for this devastating disease.
Citation Format: Theophilos Tzaridis, Tanja Eisemann, Augusto Faria Andrade, Jennifer L. Hope, Oren Becher, Nada Jabado, Linda M. Bradley, Peter Adams, Robert Wechsler-Reya. CD155 regulates cell growth and immune evasion in diffuse midline glioma [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 2648.
Abstract 2711: A novel bispecific antibody to reprogram the immune suppressive GBM TME
Authors: Wong Thomas , Leu Jia-Shiun , Fan Xuejun , Kang Reece , Abdelfattah Nourhan , Leonard Fransisca , Zhang Ningyan , Yun Kyuson 
Published: March 2024

Abstract
GBM (glioblastoma) is the most common and aggressive primary brain tumor in adults. Immunotherapy is an emerging and promising treatment modality for GBM. Unfortunately, most immunotherapy trials have provided only modest benefit to GBM patients thus far. A significant barrier that limits efficacy of immunotherapy in GBM is the paucity of tumor infiltrating lymphocytes and abundance of immune suppressive myeloid cells. A critical step in enhancing the efficacy of immunotherapy for GBM requires approaches that enhance T cell infiltration and reprogram the myeloid cells to a more pro-inflammatory state.
S100A4 is a major regulator of stemness, epithelial-mesenchymal transition, and immunosuppression in glioma stem cells and a critical regulator of immune suppressive myeloid and T cell phenotypes in GBM. Targeting S100A4 in either glioma cells or stromal cells is sufficient to reprogram the tumor immune landscape and extend survival of glioma bearing mice, indicating that S100A4 is a promising immunotherapy target. Since S100A4 has both intracellular and extracellular function as well as cytokine-like function, we developed a S100A4 blocking antibody. While the anti-S100A4 antibody blocks breast cancer metastasis efficiently, it did not cross the BBB. Hence, we generated a bispecific S100A4-TfR antibody (BsA) that allows robust BBB penetration. Using ELISA, confocal immunofluorescent microscopy, and multiplexed flow cytometry, our preliminary results suggest that systemic administration of the S100A4-TfR BsA results in accumulation of BsA in the brain and glioma tissue, increased T cell infiltration and immune remodeling. Furthermore, the BsA is taken up by glioma cells and accumulates intracellularly, which is correlated with decreased nuclear SOX2 expression. These results suggest that S100A4-TfR BsA is a promising agent to treat GBM to reprogram the GBM immune landscape and reduce stemness. We are currently performing single cell RNA-sequencing to elucidate molecular and cellular changes induced by the bispecific antibody treatment in different cell types and performing long term survival analyses to evaluate its therapeutic potential.
Citation Format: Thomas Wong, Jia-Shiun Leu, Xuejun Fan, Reece Kang, Nourhan Abdelfattah, Fransisca Leonard, Ningyan Zhang, Kyuson Yun. A novel bispecific antibody to reprogram the immune suppressive GBM TME [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 2711.
Abstract 2718: A novel TROP2-targeted immune stimulating antibody conjugate (ISAC) with potent anti-tumoral activtiy and accpetable safety
Authors: Chen Ye , You Fei , Zhu Chenchen , Xiong Yao , Li Li , Luo Nana , Zhou Shuaixiang , Wang Fushuai , Xu Chenyang , Fei Fan , Li Chang , Wang Jianglu , Xu Jinling , Xiong Huizhong 
Published: March 2024

Abstract
Immune stimulating antibody conjugates (ISACs) are a unique class of ADC in which antibodies recognizing tumor antigens are conjugated with immune agonists. ISACs target tumor tissue and specifically activate intra-tumoral myeloid cells, unleashing downstream immune response. Like the other immune agonists, balance between efficacy and safety remains a challenge for ISACs.
Here we describe a potential first-in-class TROP2 ISAC with rationally selected antibody and TLR7/8 agonist linker-payload. The anti-TROP2 antibody elicited robust ADCP of TROP2+ tumor cells by macrophages. In-vitro, TROP2 ISAC mildly activated myeloid cells only in the presence of TROP2+ tumor cells. In-vivo, the molecule potently suppressed tumor growth in different TROP2+ xenograft tumors, and effectively enhanced killing of an ADC. In terms of safety, the ISAC was tolerated in both WT and hTROP2KI mice, and, importantly, in monkeys. Taken together, our data demonstrate a novel TROP2 ISAC with outstanding efficacy and manageable safety profile, which may benefit patients with TROP2+ tumors.
Citation Format: Ye Chen, Fei You, Chenchen Zhu, Yao Xiong, Li Li, Nana Luo, Shuaixiang Zhou, Fushuai Wang, Chenyang Xu, Fan Fei, Chang Li, Jianglu Wang, Jinling Xu, Huizhong Xiong. A novel TROP2-targeted immune stimulating antibody conjugate (ISAC) with potent anti-tumoral activtiy and accpetable safety [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 2718.