bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4008: DASH CAR-T: accelerating CD276-targeted immunotherapy for pancreatic cancer
Authors: Wang Haiying , Deng Tian , Li Hao , Yao Yue , Tian Yuan , Wang Hongwei , Jiang Pengfei 
Published: March 2024

Abstract
B7 homolog 3 protein (B7-H3), recognized as CD276, is a pivotal immune checkpoint molecule extensively expressed in cancer cells, presenting a limited presence in normal tissues. Immunohistochemical analysis of 150 pancreatic cancer patients revealed positive CD276 staining in 66% of cases, with elevated expression correlating to diminished disease-free survival. Additional findings from an independent study on 59 patients highlighted significantly elevated CD276 levels, particularly in lymph node metastasis and advanced pathology. This study introduces an innovative Chimeric Antigen Receptor T (CAR-T) therapy targeting CD276, leveraging our DASH CAR-T manufacturing platform. Significantly, our approach reduces the ex vivo cell expansion time from 10 days to 1-2 days. T cells were enriched, activated, and transduced with a CD276 CAR-encoding retroviral vector, achieving the final product in 2-3 days. In preclinical models, our shorten-time CAR-T against CD276 exhibited superior expansion and heightened tumor-killing efficacy. Remarkably, DASH CAR-T demonstrated superior tumor control compared to conventional CAR-T, requiring only one-tenth of the dosage. This research advances our understanding of CD276 in pancreatic cancer and presents a transformative approach in CAR-T therapy manufacturing. The shortened production timeline and enhanced therapeutic outcomes underscore the potential clinical impact of our novel CAR-T strategy, offering a more efficient and potent treatment option for pancreatic cancer.
Citation Format: Haiying Wang, Tian Deng, Hao Li, Yue Yao, Yuan Tian, Hongwei Wang, Pengfei Jiang. DASH CAR-T: accelerating CD276-targeted immunotherapy for pancreatic cancer [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 4008.
Abstract 4029: HPK1 inhibitor reinvigorates exhausted tumor-infiltrating CD8 T cells and synergizes with anti-PD-1 blockade in gynecologic malignancies
Authors: Park Junsik , Lee Yong Jae , Kim Sunghoon , Lim Seungmook , Park A Yeong , Kim Jamie Jae Eun , Lee Jinhwa , Kim Sang Wun , Park Su-Hyung , Lee Jung-Yun 
Published: March 2024

Abstract
HPK1 (Hematopoietic Progenitor Kinase 1) is a negative intracellular immune checkpoint that interferes with the priming and activation of T cells. In recent years, several HPK1 inhibitors have been discovered as novel immune-oncology drugs with promising potential to improve anti-tumor immune responses. However, there has been no study showing the effects and potential application of HPK1 in gynecologic malignancies. Therefore, we investigated the expression and role of HPK1 in tumor-infiltrating CD8 T cells (CD8 TILs) and how the selective small molecule kinase inhibitor, FB849, affected the reinvigoration of exhausted CD8 TILs in gynecologic cancers. We isolated TILs from patients with newly diagnosed endometrial (n=53) and ovarian cancer (n=46). The immunological properties and HPK1 signaling pathway of CD8 TILs were explored using flow cytometry. TILs were in vitro stimulated with anti-CD3 in the presence of FB849 and/or anti-PD-1, and their proliferation was assessed. We observed that HPK1 marked severely exhausted PD-1+CD8 TILs, and high HPK1 expressers had more exhausted PD-1+CD8 TILs compared to low HPK1 expressers. In addition, FB849 could successfully restore the effector function of exhausted CD8 TILs. In particular, the reinvigorating capacity of FB849 was negatively correlated with phosphorylated SLP76+PD-1+CD8 TILs in endometrial cancer. In addition, FB849 further enhanced anti-PD-1-mediated reinvigoration of CD8 TILs in endometrial cancer. However, there was no synergistic effect of FB849 + anti-PD-1 in terms of proliferative capacity in ovarian cancer. Overall, the results of our present study provide a rationale for clinical trials investigating the anti-tumor efficacy of FB849 ± anti-PD-1 tailored to the respective properties of gynecologic malignancies.
Citation Format: Junsik Park, Yong Jae Lee, Sunghoon Kim, Seungmook Lim, A Yeong Park, Jamie Jae Eun Kim, Jinhwa Lee, Sang Wun Kim, Su-Hyung Park, Jung-Yun Lee. HPK1 inhibitor reinvigorates exhausted tumor-infiltrating CD8 T cells and synergizes with anti-PD-1 blockade in gynecologic malignancies [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 4029.
Abstract 4046: Orally active PD-L1 inhibitor MAX-10181 in combination with temozolomide effectively prolonged survival in GBM animal model study
Authors: Wang Yuguang , Feng Zhenhua , Zhao Qiang , Zhang Wu , Jiang Yiwei , Huang Yingqi , Qi Chenxing , Zhang Cheng 
Published: March 2024

Abstract
Treatment of glioblastoma (GBM) with PD-1/PD-L1 immuno therapy is highly challenging due to the limited brain blood barrier (BBB) penetration of the marketed antibody drugs. During the past several years, we have successfully developed orally active, BBB penetrating, small molecule PD-L1 inhibitor MAX-10181 which is in the phase II clinical development. To demonstrate the utility of PD-1/L1 immuno therapy for the treatment of GBM, we completed the study of MAX-10181 in combination with Temozolomide (TMZ) in GL-261 animal model study. In this study, the combination of MAX-10181 with TMZ effectively prolonged the survival by 50% in comparison with TMZ single therapy. Details of this study will be reported in this meeting.
Citation Format: Yuguang Wang, Zhenhua Feng, Qiang Zhao, Wu Zhang, Yiwei Jiang, Yingqi Huang, Chenxing Qi, Cheng Zhang. Orally active PD-L1 inhibitor MAX-10181 in combination with temozolomide effectively prolonged survival in GBM animal model study [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 4046.
Abstract 4098: A citrullinated-ENO1 peptide vaccine delayed tumor growth and markedly improved overall survival in a mouse model of triple-negative breast cancer
Authors: Letelier Ricardo A. Leon , Katayama Hiroyuki , Chen Yihui , Cai Yinning , Hsiao Fuchung , Arun Banu , Hanash Samir 
Published: March 2024

Abstract
Purpose: To evaluate the impact of a novel citrullinated-enolase 1 (cit-ENO1) peptide-based vaccine on the immune response, tumor growth and overall survival in a mouse model of triple-negative breast cancer (TNBC).
Background: Cancer vaccines have consisted primarily of mutated or overexpressed proteins in cancer. We have uncovered dysregulated protein citrullination by peptidyl arginine deiminases (PADI) as a feature of triple negative breast cancer inducing immunogenicity to citrullinated proteins. On the basis of these findings, we investigated a novel vaccine based on cancer-selective cit-ENO1 peptides that we identified from mass spectrometry analysis of the surfaceome and immunopeptidome in TNBC. We assessed the extent to which the vaccine elicited an immune response and delayed tumor growth and improved overall survival in a syngeneic mouse model of TNBC.
Experimental Design: We immunized female B6129SF1/J mice with cit-ENO1 peptides or corresponding unmodified ENO1 (unm-ENO1) peptides as antigens, together with the TLR3 agonist poly I:C as an adjuvant, once a week, for three weeks. PBS or poly I:C alone were used as controls. One week post the last round of immunization, draining lymph nodes (LN) and immunized skin were harvested, and T cell phenotypes evaluated using flow cytometry. To assess anti-cancer efficacy, mice were immunized with cit-ENO1 or unm-ENO1 peptides, followed by orthotopic implantation with murine BRCA1co/co; MMTV-Cre; p53+/- TNBC cells. Tumor growth and overall survival were assessed.
Results: Cit-ENO1 peptide vaccination induced a statistically significantly greater percentage of activated CD8+ PD-1+ effector T cells as well as CD8+ CD44+ CD62L- effector memory T cells in the LNs compared with either the control groups or the unm-ENO1 peptide. CD8+ PD-1+ T-cells were also significantly elevated in immunized skin of cit-ENO1 vaccinated mice. Both cit-ENO1 and unm-ENO1 vaccine increased CD4+ PD-1+ T cells from the LNs and immunized skin. Remarkably, the cit-ENO1 vaccine but not the um-ENO1 vaccine significantly delayed tumor growth and markedly improved overall survival compared to respective controls.
Conclusion: Cancer-selective cit-ENO1 peptides induced a potent anti-cancer immune response and significantly delayed tumor initiation and progression in a preclinical, immune competent mouse model of TNBC.
Citation Format: Ricardo A. Leon Letelier, Hiroyuki Katayama, Yihui Chen, Yinning Cai, Fuchung Hsiao, Banu Arun, Samir Hanash. A citrullinated-ENO1 peptide vaccine delayed tumor growth and markedly improved overall survival in a mouse model of triple-negative breast cancer [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 4098.
Abstract 4104: Randomized phase II trial of imiquimod with or without 9vHPV vs observation in patients with CIN 2 and 3
Authors: Sheth Sangini S. , Oh Ji Eun , Bellone Stefania , Siegel Eric R. , Buza Natalia , Iwasaki Akiko , Santin Alessandro D. 
Published: March 2024

Abstract
Introduction: We report the results of a randomized phase II trial of imiquimod, a topical immune-response modulator, vs imiquimod plus a 9-valent human papillomavirus vaccine (9vHPV) vs surveillance in cervical intraepithelial neoplasia (CIN) 2 and 3 patients.
Methods: We randomly allocated 133 patients with untreated CIN 2/3 in equal proportions to a 4-month treatment with self-applied vaginal suppositories containing imiquimod (arm B) or imiquimod plus 9vHPV (arm C) vs clinical surveillance (arm A). The main outcome was efficacy, defined as histologic regression to CIN 1 or less. Secondary outcomes were HPV clearance and treatment tolerability. Exploratory objectives included the comparison of cervical CD4/CD8 T-cell infiltration at baseline, mid-study, and post-treatment by flow-cytometry.
Results: Of the 114 evaluable patients 77% and 23% had CIN2 and CIN3, respectively. Histologic regression to CIN1 or less was observed in 95% of patients in the Arm B: imiquimod group and 84% in the Arm C: imiquimod+9vHPV compared with 79% in Arm A: surveillance (p=0.043 and 0.384, respectively). The difference between either treatment arm compared with control did not reach the prespecified α=0.025. No significant differences were noted in HPV clearance. The number of tissue-resident memory CD4/CD8 T-cells in cytobrush samples demonstrated a &gt;5-fold increase in Arm-B: imiquimod when compared to Arm-A: surveillance (p&lt;0.01). Imiquimod treatment was well tolerated. In contrast, there was no significant difference in T-cell responses among participants in Arm-C compared to Arm-A. Imiquimod treatment was well-tolerated.
Conclusions: Although imiquimod induced a higher percentage of regression to CIN1 or less and significant increases in CD4/CD8 T-cells infiltrating the cervix, it did not meet its prespecified statistical outcome for efficacy. A higher regression rate than expected was observed in the surveillance arm of this prospective trial. Future clinical trial with imiquimod targeting CIN3 patients are warranted.
Citation Format: Sangini S. Sheth, Ji Eun Oh, Stefania Bellone, Eric R. Siegel, Natalia Buza, Akiko Iwasaki, Alessandro D. Santin. Randomized phase II trial of imiquimod with or without 9vHPV vs observation in patients with CIN 2 and 3 [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 4104.
Abstract 4106: A novel synthetic long peptide vaccine composition targeting multiple PD-L1 T-cell epitopes exhibits anti-tumor efficacy in a syngeneic mouse colorectal cancer model
Authors: Lin Kenneth Nansheng , Toh Melvin 
Published: March 2024

Abstract
Background Cancer immunotherapy targeting immune checkpoints has shown promising clinical anti-tumor efficacy over the past decades. Monoclonal antibodies against PD-1 or PD-L1 have demonstrated clinical efficacy in a wide spectrum of cancer types. Despite the clinical success of therapies using immune checkpoint inhibitors (ICI), only a subset of patients shows long-lasting tumor remission, while resistance and toxicities to these agents remain to be addressed. This supports the need to explore alternative immunotherapeutic approaches or additional therapies for synergistic combinations to augment the anti-tumor efficacy for cancer patients receiving ICI therapies.
Methods As an active immunotherapy approach, we developed a blend of four novel synthetic peptide vaccines each containing one PD-L1 T-cell epitope with individual covalent conjugation of the carrier protein, keyhole limpet haemocyanin (KLH), which is to break immune tolerance towards self-molecules. The four PD-L1 epitopes range from 30 to 40 amino acids in length, which target different domains of mouse PD-L1 protein. The PD-L1 peptides were synthesized using the technique of solid-phase peptide synthesis and purified by high performance liquid chromatography. All naked peptides were conjugated to KLH protein by thiol-maleimide reaction, followed by dialysis for purification. The peptide vaccines were formulated with a Toll-like receptor 9 agonist CpG ODN 1826 and aluminum hydroxide gel for animal immunization.
Results These synthetic long PD-L1 peptide vaccines are highly immunogenic in a syngeneic BALB/c mouse model for a cell-mediated immune response when admixed and formulated with adjuvants. The vaccine composition is well tolerated by the mice with no evidence of toxicity and autoimmunity. In vivo administration of the vaccine formulation can elicit a positive PD-L1-specific T cell response in splenocytes with an IFN-γ ELISPOT assay. Moreover, in vivo vaccination of these PD-L1 peptide vaccines in a CT26 syngeneic mouse preventive colorectal cancer model exhibits a potent anti-tumor activity, with a 54% tumor growth inhibition (p&lt;0.001) in tumor volume compared to that of the adjuvant-control group at the end of the study.
Conclusions Taken together, our data demonstrate a proof-of-concept that T cell-based PD-L1 peptide vaccines are a promising therapeutic strategy for inducing anti-tumor immunity to combat cancers.
Citation Format: Kenneth Nansheng Lin, Melvin Toh. A novel synthetic long peptide vaccine composition targeting multiple PD-L1 T-cell epitopes exhibits anti-tumor efficacy in a syngeneic mouse colorectal cancer model [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 4106.
Abstract 4115: Unleashing the power of MHC associated peptide proteomics: Immunogenicity assessment of oncology drugs
Authors: Pattyn Sofie 
Published: March 2024

Abstract
Bispecifics targeting multiple antigens or epitopes have been showing great promise for treatment of cancer. However, managing unwanted immunogenicity has become a challenge in the development cycle of these promising therapeutics as there is a trend towards higher unwanted immune responses compared with classical monoclonal antibodies. A thorough assessment of their immunogenic potential leads to safe biotherapeutics with high treatment efficacy. MAPPS assays (MHC associated peptide proteomics) enable the precise identification of all the regions of a protein that may evoke an immune response. This information is key for correct risk assessment and for modulating biotherapeutics. High-sensitive MAPPS workflow leads to higher numbers of identified peptides (self + non-self peptides) and gives the deepness of analysis required for confident immunogenicity derisking and modulation. We show the importance of peptides presented by HLA-DP and HLA-DQ (next to the standard HLA-DR presented peptides). Next, we also show the first ever comparison of presented peptides in true immune cells: dendritic cells (as compared to monocyte derived dendritic cells) and B cells.
Citation Format: Sofie Pattyn. Unleashing the power of MHC associated peptide proteomics: Immunogenicity assessment of oncology drugs [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 4115.
Abstract 4148: Extracellular matrix biophysical properties change during nevus to melanoma progression
Authors: Kavuturu Aditya , Constantino Maira A. , Sassano Antonella , Merlino Glenn 
Published: March 2024

Abstract
Cutaneous malignant melanoma is one of the most aggressive forms of skin cancer and its major etiological risk factor is ultraviolet (UV) solar radiation. The extracellular matrix (ECM) has been shown to influence many of the hallmark characteristics of tumor development, survival, and progression across several types of cancer, including melanoma. Interactions between the tumor and the ECM often results in rearrangement, cross-linking, and deposit of specific ECM proteins, which can contribute to stiffening of the tissue and tumorigenesis. To simulate tumorigenesis, we have previously used a hepatocyte growth factor (HGF) transgenic mouse model, which develops melanoma nevii when exposed to UVB radiation. This model is highly representative of human melanoma lesions in terms of biological, genetic, and etiologic criteria. In general, microrheology involves injecting beads into a medium, tracking movement of the beads using two-photon microscopy, and using the movement to calculate the viscosity and elasticity of the medium. The physical properties of the ECM during tumorigenesis have not been well studied at the cellular level, and microrheology has rarely been used in vivo. In our in vivo microrheology study, we injected fluorescent beads into the skin of these transgenic mice. Then, we used intra-vital microscopy with particle tracking to image the beads and measure changes in ECM elasticity as nevii grow into melanoma tumors. These results, combined with transcriptomic analysis of ECM regulation and proteomic analysis of ECM signaling, could provide unique insights into components of the extracellular matrix that are involved in melanoma tumor development and offer opportunities for therapeutics to target oncogenesis. &lt;!–EndFragment–&gt;
Citation Format: Aditya Kavuturu, Maira A. Constantino, Antonella Sassano, Glenn Merlino. Extracellular matrix biophysical properties change during nevus to melanoma progression [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 4148.
Abstract 415: Keratin-fusion mutation promotes tumor aggressiveness via genomic instability induction
Authors: Chuang Hsiang-Hao , Kuo Brian Yu-Ting , Sriramadasu Kalpana , Chen Yi-Che , Sheu Jim Jinn-Chyuan 
Published: March 2024

Abstract
Keratin intermediate filament is one critical component of cellular architectures, which provides necessary mechanical support to vanquish environmental stresses. Our previous study shows that keratin fusion mutation promotes tumor aggressiveness via enhancing cancer stemness in oral squamous cell carcinoma. It implies proper functions of keratins play a critical role in maintain cell integrity and fate determination. In the present study, keratin fusion mutation functions as a driver to promote genomic instability via centrosome overduplication and trigger the formation of polyaneuploid cancer cell (PACC). Interestingly, genes involved in DNA damage repair were found upregulated in keratin fusion expressing cells, an important feature for mitotic slippage during cancer progression. In addition, PACCs caused by keratin fusion render cancer cells insensitive to cisplatin treatment, which coupled with lower levels of γH2AX induction and higher survival rates. Transcriptome analyses revealed enhanced activity for Regulation_of_Actin_Cytoskeleton in the PACCs, leading to increased actin filament network and higher invasiveness. In summary, keratin fusion mutation promote cancer aggressiveness through genomic instability-mediated PACC formation and cytoskeleton remodeling, which lead to enhanced drug resistance and metastasis.
Citation Format: Hsiang-Hao Chuang, Brian Yu-Ting Kuo, Kalpana Sriramadasu, Yi-Che Chen, Jim Jinn-Chyuan Sheu. Keratin-fusion mutation promotes tumor aggressiveness via genomic instability induction [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 415.
Abstract 4162: Peptide-targeted probe identifies pancreatic cancer using optoacoustic imaging
Authors: Sanderson Emma , Husarova Tereza , McNally Lacey 
Published: March 2024

Abstract
Introduction: Advanced pancreatic ductal adenocarcinoma (PDAC) suffers from inadequate early detection, inoperability, and poor outcomes. While tumor identication in an intraoperative setting largely utilize ultrasound, ultrasound suffers from insufficient resolution and lacks the ability to identify molecular features to differentiate tumor from non-tumor. To overcome these limitations, we utilized optoacoustic imaging combined with a pH-sensitive peptide-based probe, V3, to identify pancreatic cancer in orthotopic mouse models.
Methods: The V3 peptide was synthesized using microwave chemistry which resulted in a peptide of &gt;90% purity. The V3 peptide was conjugated to a fluorescent dye and dialyzed to make the V3-750 probe. S2VP10 cancer cell line was plated in a 6-well plate and acclimated to 7.4, 6.8, and 6.6 pH media to mimic a healthy microenvironment and the acidic tumor microenvironment found in pancreas cancer. Cells were treated with 1 micromolar of V3-750 probe for 1 hour, then imaged on the near-infrared fluorescence imager. Treated cells were loaded into tissue mimicking phantoms and imaged using multispectral optoacoustic tomography. Athymic mice were orthotopically implanted with S2VP10 cells and tumor grew to 3 mm. V3-750 was intraveneously injected and mice were imaged 3h after injection with MSOT.
Results: Signal values for the samples displayed a trend that the V3-750 probe has higher signal values in the 6.8 and 6.6 pH as compared to the 7.4 pH. MSOT data supported this trend, with the signal values from the 6.8 and 6.6 pH being greater than the 7.4 pH by 10-fold (p&lt;0.05). Biodistribution demonstrates peak tumor-specific uptake at 3h post injection (3.1 a.u., 0.003 a.u. liver, 0.002 a.u. kidney).
Conclusion: The heightened signal values for the acidic pH’s from the fluorescence imaging and the MSOT suggest that the V3-750 probe can contrast acidic cancer cells from healthy cells because it targets the acidic cancer microenvironment.
Citation Format: Emma Sanderson, Tereza Husarova, Lacey McNally. Peptide-targeted probe identifies pancreatic cancer using optoacoustic imaging [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 4162.