bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 6298: A novel topoisomerase I inhibitor based anti-ICAM-1 antibody drug conjugate for the treatment of hematologic malignancies and solid tumors
Authors: Wong Oi Kwan , Jackson David , Shi Lei , Fei Qi , Chen Xiaocheng , Post Leonard 
Published: June 2023

Abstract
Intercellular Cell Adhesion Molecule 1 (ICAM-1, CD54) is a type I transmembrane protein and a member of the immunoglobulin superfamily. ICAM-1 is involved in many key processes such as cell-cell interactions, signal transduction and leukocytes trans-endothelial migration. ICAM-1 is constitutively present at low levels on healthy tissues but highly expressed in some lymphoma, myeloma and some types of solid tumors including melanoma, non-small cell lung cancers and liver cancers. Previous attempt to target ICAM-1 with a monoclonal antibody bersanlimab (BI505, BioInvent) showed that it was well-tolerated but with limited clinical efficacy. To improve the effectiveness of targeting ICAM-1, we developed a novel ICAM-1 antibody drug conjugate (ADC). The ICAM-1 ADC is comprised of a humanized anti-ICAM-1 hIgG1 antibody conjugated to a novel topoisomerase I inhibitor through a cleavable linker at a drug-to-antibody ratio (DAR) of about 8. The antibody moiety of the ADC targets a unique epitope on ICAM-1 which is far from its ligand binding domain. Potent in vitro cytotoxicity of ICAM-1 ADC, with nanomolar to sub-nanomolar EC50, was observed on a panel of hematologic and solid tumor cell lines. In preclinical studies, one or two doses of ICAM-1 ADC at 5-6 mg/kg were generally sufficient to induce tumor regression in multiple cell line-derived xenograft models, including those of lung and liver cancers. In all models tested so far, the novel topoisomerase I inhibitor conjugated ICAM-1 ADC is at least as efficacious as the same ICAM-1 antibody conjugated to the benchmark topoisomerase I inhibitor linker payload deruxtecan (ICAM-1-DXd). Furthermore, in a repeat dose exploratory non-human primate safety study, the benchmark conjugate ICAM-1-DXd (DAR 8) was well-tolerated at 41 mg/kg, the highest dose tested. In conclusion, ICAM-1 is an attractive target for topoisomerase I inhibitor based ADC and warrants further investigation.
Citation Format: Oi Kwan Wong, David Jackson, Lei Shi, Qi Fei, Xiaocheng Chen, Leonard Post. A novel topoisomerase I inhibitor based anti-ICAM-1 antibody drug conjugate for the treatment of hematologic malignancies and solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6298.
Abstract 63: Machine learning identifies experimental brain metastasis subtypes based on their influence on neural circuits
Authors: Masmudi-Martín Mariam , Sanchez-Aguilera A , Navas-Olive A , Baena P , Hernández-Oliver C , Martínez S , Lafarga M , Cerebral Renacer Red Nacional de Metástasis , Lin MZ , de la Prida L Menendez , Valiente M 
Published: June 2023

Abstract
A high percentage of patients with brain metastases frequently develop neurocognitive symptoms, however understanding how brain metastasis co-opt the function of neuronal circuits beyond a mass effect remains unknown. We report a comprehensive multidimensional modelling of brain functional analysis in the context of brain metastasis. By testing different pre-clinical models of brain metastasis from various primary sources and oncogenic profiles we dissociated the heterogeneous impact on brain function that we detected from the homogeneous inter-model tumor size or glial response. In contrast we report a potential underlying molecular program responsible for impairing neuronal crosstalk in a model-specific manner. Additionally, measurement of various brain activity readouts matched with machine learning strategies confirmed model-specific alterations that could help to predict the presence and subtype of metastasis.
Citation Format: Mariam Masmudi-Martín, A Sanchez-Aguilera, A Navas-Olive, P Baena, C Hernández-Oliver, S Martínez, M Lafarga, Renacer Red Nacional de Metástasis Cerebral, MZ Lin, L Menendez de la Prida, M Valiente. Machine learning identifies experimental brain metastasis subtypes based on their influence on neural circuits [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 63.
Abstract 6302: Identification of OASEP1 as a biomarker and therapeutic target for oral cancer
Authors: Takano Atsushi , Yoshitake Yoshihiro , Shinohara Masahiro , Daigo Yataro 
Published: June 2023

Abstract
This study aims to identify new biomarkers and therapeutic targets for oral cancer. Our strategies are as follows: i) Identification of overexpressed genes in oral cancers by gene expression array analysis, ii) Validation of clinicopathologic significance of their protein expression by tissue microarray, iii) Examination of their growth effect on cancer cell by siRNAs. We identified a secreted protein, OASEP1 (oral cancer-associated serum protein 1) as a candidate. Immunohistochemical staining showed that OASEP1 protein expression was observed in 120 (75.4%) of 159 oral cancers that had undergone curative surgery. High level of OASEP1 expression was associated with poor prognosis for oral cancer patients (P = 0.0054, by log-rank test). Multivariate analysis revealed that strong OASEP1 expression was an independent prognostic factor. Suppression of OASEP1 expression by siRNA significantly inhibited the growth of oral cancer cell lines through apoptosis as detected by apoptosis assays and time lapse imaging. Transient OASEP1 overexpression significantly enhanced the growth of oral cancer cells. In addition, knock down of OASEP1 receptor by siRNAs also significantly inhibited the growth of oral cancer cells. Addition of OASEP1 protein significantly increased the growth of oral cancer cells in a dose dependent manner, suggesting that the interaction between OASEP1 and its receptor regulated the growth of oral cancer cells. Microarray analysis coupled with siRNAs for OASEP1 demonstrated various OASEP1-related oncogenic pathways in oral cancer cells. Our data suggest that OASEP1 is a possible prognostic biomarker and therapeutic target for oral cancer.
Citation Format: Atsushi Takano, Yoshihiro Yoshitake, Masahiro Shinohara, Yataro Daigo. Identification of OASEP1 as a biomarker and therapeutic target for oral cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6302.
Abstract 6316: In vitro and in vivo studies of human granzyme B fusion constructs targeting mesothelin
Authors: Mohamedali Khalid A. , Cheung Lawrence H. , DePalatis Louis R. , Thuning-Roberson Claire , Rosenblum Michael G. 
Published: June 2023

Abstract
Mesothelin is highly expressed on tumor cells and promotes tumor growth and drug resistance. Pancreatic, ovarian, mesothelioma, and lung cancers highly express mesothelin and are cancers of unmet needs with ≤16% relative 5-year survival using standard of care. When delivered to tumor cells by immune effector cells, granzyme B (GrB) is a highly cytotoxic serine protease which induces apoptosis through both caspase-dependent and -independent mechanisms. We developed a fusion protein (GrB-Fc-SD1) composed of human GrB and containing SD1, a novel human single-domain antibody that uniquely targets Region III of the glycoprotein, mesothelin. The SD1 and GrB domains are connected by a human IgG heavy chain fragment which enables dimerization. Thus, the increase in total construct molecular weight leads to an increased in vivo circulation time and anti-tumor efficacy. GrB-Fc-SD1 was transiently expressed in HEK-293E cells under serum-free conditions and purified to homogeneity to a final yield of approximately 5 mg/L. Anti-GrB western blot analysis confirmed the expression of GrB-Fc-SD1 exclusively as a dimer. Comparison of GrB-Fc-SD1 with its expected molecular weight suggests significant glycosylation when produced in HEK-293E cells. The enzymatic activity of granzyme B in GrB-Fc-SD1 was comparable to that of commercially available human granzyme B. In vitro cytotoxicity against a limited panel of lung, pancreatic and ovarian cancer cell lines expressing surface mesothelin indicate cytotoxicity in the nanomolar range, while cytotoxicity against mesothelin-negative cells was at micromolar levels. GrB-Fc-SD1 bound specifically to mesothelin extra-cellular domain compared to a non-specific control, as determined by ELISA. Biacore analysis confirmed binding with a dissociation constant between 10−7 to 10−8 M. These data warrant continued investigation of the protein as a therapeutic candidate. Accordingly, ex vivo serum stability studies are underway. In addition, screening of an expanded panel of tumor cell lines for in vitro cytotoxicity is currently in progress and will be reported. In vivo efficacy studies against nude mice bearing Capan-2 xenograft models are currently underway and will also be reported. Research supported by H2Biologics. Research conducted, in part, by the Clayton Foundation for Research.
Citation Format: Khalid A. Mohamedali, Lawrence H. Cheung, Louis R. DePalatis, Claire Thuning-Roberson, Michael G. Rosenblum. In vitro and in vivo studies of human granzyme B fusion constructs targeting mesothelin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6316.
Abstract 6325: A novel EGFR x MUC1 bispecific antibody-drug conjugate, BSA01, targets MUC1 transmembrane cleavage products and improves tumor selectivity
Authors: Zhang Yifu , Shang Chenzhang , Wang Anqi , Zhang Jia , Liu Yuji , Li Hao , Li Xiaopeng , An Gao , Hui Li , An Frank , Yang Yi 
Published: June 2023

Abstract
Epidermal growth factor receptor (EGFR) and mucin 1 (MUC1) are tumor-associated antigens that are highly co-expressed in esophageal squamous cell carcinomas, non-small cell lung cancers (NSCLC), and triple negative breast cancers, among others. MUC1, a glycoprotein essential for the formation of the epithelial mucous barrier, is hypoglycosylated and dimerizes with EGFR, a potent oncoprotein, in transformed cells. Dual-targeting of both tumor-associated antigens (TAAs) represents a promising therapeutic strategy to treat common malignancies. We generated a fully human anti-EGFR/MUC1 bispecific antibody-drug conjugate (BSA01) from RenLite® humanized, common light chain mice. BSA01 is conjugated with Monomethyl auristatin E (MMAE). BSA01 targets the extracellular domain of MUC1-C (C-terminal domain of MUC1), which is the membrane-bound MUC1 cleavage product that remains after MUC1 is cleaved, providing more access to the tumor antigen in situ. In addition, we generated affinity and internalization optimized binders targeting EGFR that increases the tumor selectivity, to avoid potential skin toxicity due to ubiquitous basal EGFR expression. Internalization assays demonstrate that the anti-EGFR/MUC1 bispecific antibody used to generate BSA01 was endocytosed in tumor cells co-expressing EGFR/MUC1 more efficiently than mono- or bivalent antibodies targeting EGFR or MUC1 alone. When conjugated with payload, BSA01 also exhibited strong anti-tumor efficacy in vitro against gastric, NSCLC and pancreatic cancer cell lines. Moreover, BSA01 showed similar activity in vivo, effectively inhibiting tumor growth in multiple cell-derived xenograft and patient-derived xenograft models. These results suggest that BSA01 has great clinical potential for treating tumors co-expressing EGFR and MUC1.
Citation Format: Yifu Zhang, Chenzhang Shang, Anqi Wang, Jia Zhang, Yuji Liu, Hao Li, Xiaopeng Li, Gao An, Li Hui, Frank An, Yi Yang. A novel EGFR x MUC1 bispecific antibody-drug conjugate, BSA01, targets MUC1 transmembrane cleavage products and improves tumor selectivity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6325.
Abstract 6336: Heterodimeric Fc-fused IL12 shows potent antitumor activity and low toxicity
Authors: Huang Yang , Liu Wenting , Zhang Dayan , Zhou Pengfei , Zhou Weiming , Zeng Xiaoli , Zhao Qun , Li Liangwei , Shen Guodong , Cheng Liansheng 
Published: June 2023

Abstract
Background: Interleukin-12 (IL12) is a heterodimeric pro-inflammatory cytokine (70 kDa) composed of two different polypeptide chains: an α-chain (p35 subunit) and a β-chain (p40 subunit). IL12 could induce the proliferation and cytotoxicity of T and NK cell and production of interferon-γ (IFN-γ), promote the differentiation of T helper 1 (TH1) cells and regulate innate resistance and adaptive immunity. However, the clinical efficacy of IL12 has been hindered for its high dose-related toxicities and short serum half-life. Here we have developed a heterodimeric Fc-fused IL12, HK054-V, with reduced potency to improve tolerability and prolong half-life.
Methods: We assessed the binding, bioactivity, anti-tumor efficacy and safety of HK054-V. The binding ability of IL12-Fc lead variants to activated PBMCs was analyzed by flow cytometry. The bioactivity of HK054-V was determined by assessing the activated T-cell proliferation and IFN-γ production in human PBMCs, and STAT-4 phosphorylation in a reporter gene assay. A murine surrogate, mHK054-V, was engineered to mimic HK054-V to evaluate the antitumor efficacy in MC38 and CT26 syngeneic tumor mouse models. Cytokine release assay was conducted by incubating HK054-V with peripheral blood mononuclear cells (PBMCs) from healthy donors. The safety profiles and pharmacokinetic (PK) behavior of HK054-V were characterized in non-tumor-bearing Balb/c mice.
Results: HK054-V is a heterodimeric Fc-fused IL12, which was designed with reduced potency. HK054-V was observed to stimulate the proliferation of activated T cells and NK cells and induce production of IFN-γ in a dose-dependent manner. HK054-V could activate pSTAT4 signal in luciferase reporter gene assay and showed up to 100-fold reduction of potency compared to wild-type IL12-Fc. Human IL12 is inactive in mice, so in vivo anti-tumor activity was assessed by a murine surrogate, mHK054-V. mHK054-V demonstrated anti-tumor efficacy in syngeneic mouse models and was better tolerated than WT mIL12-Fc. Furthermore, mHK054-V has improved PK and therapeutic index in mice.
Conclusion: These data demonstrate that HK054-V, a heterodimeric Fc-fused IL12 with reduced potency, retain strong anti-tumor efficacy with a favorable tolerability profile, which may provide a practical alternative to the systemic administration of IL12 for antitumor therapy.
Citation Format: Yang Huang, Wenting Liu, Dayan Zhang, Pengfei Zhou, Weiming Zhou, Xiaoli Zeng, Qun Zhao, Liangwei Li, Guodong Shen, Liansheng Cheng. Heterodimeric Fc-fused IL12 shows potent antitumor activity and low toxicity. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6336.
Abstract 634: The impact of IL-4 on migration in triple negative breast cancer cell lines
Authors: Andrews Portia , Kimbro Kevin S. 
Published: June 2023

Abstract
In the United States, triple-negative breast cancer (TNBC), an aggressive form of breast cancer (BCa), disproportionately affects women of African descent and contributes to racial disparities in BCa mortality. Various risk factors are thought to drive this disparity, including socioeconomic status, tumor characteristics, comorbidities, and quality of treatment. Complex diseases and environmental insults all invoke and/or disrupt host inflammation, with individual immune and variable responses to therapeutic agents being dictated in part by genetic variants. This latter has seldom been studied with regards to precision diagnosis and prognosis of individual patient responses, in the frame of geographical ancestry and TNBC. Interleukin-4 receptors (IL4R) have been shown to be upregulated in many epithelial cancers and could be a promising target for metastatic tumor therapy. Yet, IL4R overexpression and/or IL4R variants have not been evaluated in TNBC cell lines of varying genetic ancestry. In view of this, we investigated the effects of IL-4 treatment in four TNBC cell lines varying in proportions of West African Ancestry (WAA) in each cell line: MDA-MB-231 (0.019), HCC-1143 (0.012), HCC-1806 (0.807), MDA-MB-468 (0.803). The frequency of IL4R variants also differed in each cell line. We used high content live cell imaging to evaluate the effect of IL-4 treatment on cellular migration by measuring wound healing. We show that IL-4 treatment on TNBC cells enhances migration as indicated by increased wound healing when compared to non-treated cells. High glucose, at a concentration of 10 g/L, delays cell migration in IL4-treated TNBC cells. This data suggests that comorbidities, such as high glucose levels (i.e., uncontrolled diabetes) could impact tumor behavior and mortality disparities between populations.
Citation Format: Portia Andrews, Kevin S. Kimbro. The impact of IL-4 on migration in triple negative breast cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 634.
Abstract 6353: Combination of poly-γ-glutamic acid with anti PD-L1 blockade leads to improved anti-tumor activity in murine models
Authors: Jang Jae-Pyung , Choi Jae Chul , Hahm Kyung-Soo , Lee Do Young , Park Young-Chul 
Published: June 2023

Abstract
Immune checkpoint inhibitors(ICIs) have been shown to be key role in cancer therapy. Especially, antibodies targeting programmed cell death ligand1(PD-L1) promoted T cells to activate immune response against cancer cells. However, the current ICIs still have insignificant to motivate effective antitumor immunity by blocking PD-1/PD-L1 pathway and the regulatory network of PD-L1 by cytokines in the tumor microenvironment remains to be uncovered. Previously, we have reported the anti-cancer effects of combination treatment with a natural product, poly-γ-glutamic acid(γ-PGA), and PD-1 blockade. Now, we showed that combination therapy with anti PD-L1 and γ-PGA overcome the limits of ICIs and enhance anticancer effect in murine melanoma(B16F10). In vivo efficacy studies were performed by intraperitoneal injection of antibody targeting PD-L1 and oral administration of γ-PGA in C57BL/6 model transplanted with B16F10 melanoma cell. Systemic changes in immunophenotype were measured by tumor volume size and survival rate. The splenocytes were isolated from mice and the populations of myeloid-driven suppressor cells(MDSCs) and CD4/CD8 T cells were analyzed by FACS. Combination therapy with γ-PGA and anti PD-L1 blockade showed dramatically more suppressive tumor growth and enhanced long-term survival rate than other monotherapic treatment. In addition, γ-PGA was shown to play a role in the immune modulation of tumor microenvironment by activation of T cells and inhibition of MDSCs so as to prevent tumors from immune escape. Therefore, we suggest that γ-PGA can promote ICI-mediated antitumor responses by the transformation of "cold tumors" into “hot tumors”
Citation Format: Jae-Pyung Jang, Jae Chul Choi, Kyung-Soo Hahm, Do Young Lee, Young-Chul Park. Combination of poly-γ-glutamic acid with anti PD-L1 blockade leads to improved anti-tumor activity in murine models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6353.
Abstract 6362: Overcoming resistance to immunotherapy due to loss of antigen presentation
Authors: Miller Brian C. , Choutri Yacine , Abosy Rose Al , Huang Amy , Cox Emily K. , Zimmerman Matthew P. , Chong Wan Lin , Vietor Katherine J. , Collier Jenna , Weiss Sarah A. , Sen Debattama , Haining W. Nicholas , Sharpe Arlene H. 
Published: June 2023

Abstract
Resistance to immune checkpoint inhibitors represents a major therapeutic challenge, as only 40% of patients with melanoma (and less with other tumor types) have a long-term response to anti-PD-1 therapy. Resistance can arise because of somatic mutations in cancer cells that allow evasion of T cell-mediated killing. One commonly acquired resistance mutation in melanoma, loss of beta-2 microglobulin (B2m), prevents T cell killing by hiding cancer cells from CD8+ T cell recognition. To understand the failed immune response against resistant tumors, we used single-cell RNA-seq to characterize tumor-infiltrating immune cells in antigen presentation-deficient human melanoma biopsies and CRISPR-modified mouse melanoma tumors. Our data demonstrate an increase in immunosuppressive M2-like macrophages and absence of CD8+ T cells in B2m-null tumors. To overcome this resistance, we treated tumor-bearing mice with CD40 agonist antibody, which promotes differentiation of macrophages towards a pro-inflammatory phenotype and increases dendritic cell priming of CD8+ T cells. Treatment with CD40 agonist reduced tumor growth and improved tumor clearance in B2m-null melanoma and colorectal cancer models. To determine how CD40 agonist treatment works, we depleted different immune populations from the tumor microenvironment. We hypothesized that by depleting M2 macrophages, CD40 agonist treatment would remove an immunosuppressive brake to allow natural killer (NK) cells to kill tumor cells lacking MHC expression. To our surprise, NK cells were not required for the efficacy of CD40 agonist. Instead CD8+ T cells were required, even though the CD8+ T cells cannot directly recognize the tumor cells. scRNA-seq identified a transcriptionally unique state of CD8+ T cells that is recruited to the tumor microenvironment after CD40 agonist treatment. These CD8+ T cells produce IFNγ, which is required for the efficacy of CD40 agonist treatment. These data demonstrate that CD8+ T cells, a key mediator of anti-tumor immunity, can still be recruited to control tumors deficient in antigen presentation. More broadly, they suggest that strategies to activate CD8+ T cells may be effective even in the context of acquired resistance to checkpoint inhibitor therapy.
Citation Format: Brian C. Miller, Yacine Choutri, Rose Al Abosy, Amy Huang, Emily K. Cox, Matthew P. Zimmerman, Wan Lin Chong, Katherine J. Vietor, Jenna Collier, Sarah A. Weiss, Debattama Sen, W. Nicholas Haining, Arlene H. Sharpe. Overcoming resistance to immunotherapy due to loss of antigen presentation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6362.