bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4131: Long-term anti-tumor immunity induced by of HPN328, a DLL3-targeting trispecific, half-life extended T cell engager, in a preclinical immunocompetent mouse model
Authors: Molloy Mary Ellen , Valenzuela Laura B. , Wu Chi-Heng , Wesche Holger , Anand Banmeet S. 
Published: June 2023

Abstract
Tri-specific T Cell-Activating Constructs (TriTACs) are T-cell engagers that have been developed to redirect T cells to kill tumor cells. HPN328 is a Delta-like ligand 3 (DLL3)-targeting TriTAC currently being evaluated in a Phase 1/2 clinical trial enrolling patients with advanced cancers associated with DLL3 expression, including small cell lung cancer (SCLC) and other neuroendocrine malignancies (NCT04471727). HPN328 consists of three binding domains: a CD3 binder for T cell engagement, an albumin binder for half-life extension, and a DLL3 binder for tumor cell engagement. We have previously reported that HPN328 induces potent dose-dependent killing of DLL3 expressing SCLC cell lines together with dose-dependent T cell activation and cytokine release in T cell co-cultures in vitro. Based on these data and the proposed mechanism of TriTAC induced tumor cell killing we hypothesized that HPN328 could induce epitope spreading and long-term immunogenic effects. To test this hypothesis, we generated an immunocompetent mouse model in which six amino acid residues corresponding to the portion of human CD3ε which TriTAC molecules bind were added to the N terminus of the mouse CD3ε subunit. Homozygous knock-in mice (hCD3ε) were implanted subcutaneously with MC38 murine colon cancer cell line expressing human DLL3 and treated with HPN328 following tumor establishment. HPN328 treatment led to eradication of established tumors in mice. In addition, tumor infiltrating lymphocyte (TIL) analysis was performed on tumors harvested on day 4 post HPN328 treatment. Activation markers CD69 and CD25 were induced on both CD4+ and CD8+ TILs in this model. To evaluate if HPN328 can induce long-term immunity, mice whose tumors were cured by HPN328 were rechallenged on the opposite flank. As expected, tumors grew in treatment naïve mice, but no tumors were detected in mice previously treated with HPN328, demonstrating sustained and durable anti-tumor immunity induced by HPN328 treatment. Anti-tumor immunity is an indicator of T cell memory against tumor antigens. Concomitant with anti-tumor immune response, we detected increases in memory T cells in the spleens of mice previously treated with HPN328. Together these results indicate that HPN328 can induce epitope spreading and prolonged anti-tumor immunity, suggest a novel mechanism for its activity and efficacy in vivo.
Citation Format: Mary Ellen Molloy, Laura B. Valenzuela, Chi-Heng Wu, Holger Wesche, Banmeet S. Anand. Long-term anti-tumor immunity induced by of HPN328, a DLL3-targeting trispecific, half-life extended T cell engager, in a preclinical immunocompetent mouse model. [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 4131.
Abstract 4405: Tumor mutational burden, as a potential predictive marker for the efficacy of immunotherapy in advanced gastric cancer
Authors: Jang Jaeyeon , Jeon Youngkyung , Jeong Sun Young , Jung Ye Ji , Choi Daeho , Hong Joohyun , Lee Jeeyun , Kang Won Ki , Kim Seung Tae 
Published: June 2023

Abstract
Background: The optimal value of tumor mutational burden (TMB) for predicting treatment response of immunotherapy in advanced gastric cancer (AGC) is still unclear. We aimed to establish the optimal cut-off value of TMB, and evaluate the efficacy of immunotherapy in AGC according to TMB and other markers.
Method: From October 1, 2020, to July 27, 2021, at Samsung medical center in Korea, patients with AGC, who received pembrolizumab or nivolumab were included. TMB was measured by next-generation sequencing (NGS)-based assays, and PD-L1 is tested using immune-histochemical assay 22C3 pharmDx. Based on receiver operating characteristic analysis, the cut-point value of TMB was determined as the point where the Youden’s index is maximum.
Result: A total of 53 patients were analyzed. The cut-off value of TMB for predicting the overall response of immune checkpoint inhibitors was defined as 13.31 mutations/megabase (mt/mb), with 56% of sensitivity and 95% of specificity. Under this definition of TMB, 7 patients were TMB-high group (≥13.31 mt/mb), while 46 patients were TMB-low group (&lt;13.31 mt/mb). The overall response rate (ORR) had a statistically significant difference between TMB-low (8.7%, n=4/46) and TMB-high patients (71.4%, n=5/7; p=0.001). The progression-free survival (PFS) and overall survival (OS) for 53 patients were 1.93 months (95% CI, 1.600-2.268) and 4.26 months (95% CI, 2.992-5.532). The OS was longer in the TMB-high group with the median of 20.8 months (95% CI, 2.292-39.281) compared to the TMB-low group with the median of 3.31 months (95% CI, 1.604-5.019; p=0.049). The ORR of the patients whose PD-L1 CPS was 1 or above was not different from the patients whose PD-L1 CPS was lower than 1.
Conclusion: In this study, the optimal value of TMB for predicting the objective response rate of immunotherapy in AGC was determined as 13.31 mt/mb. TMB-high (≥13.31 mt/mb) was associated with a better objective response rate, and TMB-high patients exhibited better overall survival. TMB has the potential for predicting therapeutic response to immunotherapy in advanced gastric cancer.
Citation Format: Jaeyeon Jang, Youngkyung Jeon, Sun Young Jeong, Ye Ji Jung, Daeho Choi, Joohyun Hong, Jeeyun Lee, Won Ki Kang, Seung Tae Kim. Tumor mutational burden, as a potential predictive marker for the efficacy of immunotherapy in advanced gastric 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 4405.
Abstract 4585: Tumor lymphangiogenesis sensitizes melanomas to the immunological effects of radiotherapy but also disrupts the local lymphatic vasculature
Authors: Mukherjee Anish , Mitrousis Nikolaos , Sasso Mari Stella , MacDonald Margo , Arina Ainhoa , Ang Phillip , Baginski Ariana , Medellin J. Emiliano G. , Weichselbaum Ralph R. , Swartz Melody A. 
Published: June 2023

Abstract
Tumor lymphangiogenesis is typically associated with cancer progression and metastasis. However, recent studies from our group have demonstrated that tumor lymphangiogenesis promotes intratumor T cell infiltration and potentiates the efficacy of a wide range of immunotherapies in melanoma-bearing mice as well as patients undergoing checkpoint blockade. Radiotherapy (RT) can also induce immunogenic tumor cell death, so we investigated whether lymphangiogenic tumors would yield more immunogenic responses to RT than non-lymphangiogenic tumors. Here, we compared effects of RT in mice bearing B16-F10 melanomas expressing either a control vector (B16-Ctrl) or overexpression the lymphangiogenic factor VEGF-C (B16-VC), where lymphatic vessels were significantly increased in number and size compared to B16-Ctrl tumors. First, we find that B16-VC regress faster than B16-CT after RT (either a single 20 Gy dose or two 15 Gy doses), and that this regression was correlated with enhanced CD8+ T cell activity. On the other hand, lymphatic endothelial cells (LECs) can be more sensitive to damage from RT if they are undergoing lymphangiogenesis. We found that irradiated B16-VC tumors showed higher levels of intra-lymphatic fibrin. Consistent with this, LECs in the irradiated B16-VC tumors expressed higher levels of tissue factor and caspase-3, which correlated with the degree of lymphatic clotting. Fibrin clotting was also observed in the subcapsular sinus of the draining lymph nodes of irradiated B16-VC tumors. These findings highlight the complex role of tumor lymphangiogenesis in radiotherapy responses, where they may potentiate acute anti-tumor immune responses but may also cause localized damage of the vasculature, potentially leading to increased metastasis. Further studies are needed to investigate therapeutic targets to inhibit lymphatic coagulation and look at its effects on cancer immunotherapy and metastasis.
Citation Format: Anish Mukherjee, Nikolaos Mitrousis, Mari Stella Sasso, Margo MacDonald, Ainhoa Arina, Phillip Ang, Ariana Baginski, J. Emiliano G. Medellin, Ralph R. Weichselbaum, Melody A. Swartz. Tumor lymphangiogenesis sensitizes melanomas to the immunological effects of radiotherapy but also disrupts the local lymphatic vasculature. [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 4585.
Abstract 4656: Targeting macrophage PI3KGamma in aggressive prostate cancer
Authors: Adusei Kenneth M. , Nirschl Thomas R. , Lee Alex J.-E. , Shen Fan , Wang Xiaoxu , Alvarez Jade , Lotan Tamara L. , Varner Judith , Zarif Jelani 
Published: June 2023

Abstract
The phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) family of lipid kinases play key roles in cancer biology by promoting cell motility, growth, and survival. Of the four class I PI3K isoforms, PI3Kα,β,δ,γ, the PI3Kγ isoform is primarily expressed by myeloid cells. Studies from the Varner lab have established that the macrophage lipid kinase, PI3Kγ, selectively promotes myeloid cell trafficking and immune suppressive transcription in tumor associated monocytes and macrophages, thereby inhibiting T cell recruitment, activation, and tumor eradication. We hypothesized that antagonism or deletion of PI3Kγ would induce tumor growth inhibition in vivo in prostate cancer (PCa) models. To test our hypothesis, we implanted syngeneic murine prostate cancer tumors (B6CaP) into global PI3Kγ knock out mice and preliminary studies show severe tumor growth inhibition. Using a publicly available single cell RNA sequencing database of metastatic PCa (mPCa) tumors from bone, we calculated regulon scores for transcription factors C/EBPβ and NFκB which are up and down-regulated by PI3Kγ signaling in myeloid cells respectively. This analysis indicated that a notable proportion of monocytes in mPCa have active PI3Kγ signaling based on C/EBPβ activity and a lack of NFκB activity. Finally, we tested the significance of eganelisib treatment on monocytes and found that this pathway was essential for monocyte survival during macrophage differentiation and adhesion. Altogether, our proposed research delineates the mechanistic roles of PI3Kγ in the regulation of prostate cancer tumor growth and support PI3Kγ as a target to sensitize PCa to immune checkpoint inhibitors.
Citation Format: Kenneth M. Adusei, Thomas R. Nirschl, Alex J.-E. Lee, Fan Shen, Xiaoxu Wang, Jade Alvarez, Tamara L. Lotan, Judith Varner, Jelani Zarif. Targeting macrophage PI3KGamma in aggressive prostate 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 4656.
Abstract 4832: Copy number amplification of OXPHOS genes drives tumor hypoxia in NSCLC
Authors: Benej Martin , Benejova Katarina , Kreamer McKenzie , Wu Jinghai , Ashraf Syed , Wheeler Caroline , Hoyd Rebecca , Spakowicz Daniel , Denko Nicholas C. 
Published: June 2023

Abstract
Non-small cell lung cancer (NSCLC) is a highly aggressive disease with a dismal prognosis associated with high rates of treatment resistance and disease recurrence. High-dose stereotactic body radiation therapy (SBRT) is the standard of care for locally advanced non-resectable NSCLC. However, as discovered more than six decades ago, tumor hypoxia is a significant barrier to effective radiation therapy. In the last decade, immunotherapy targeting immune checkpoints such as programmed cell death 1 (PD-1) has been introduced as first-line NSCLC treatment, yet long-term disease control occurs in less than 25% of patients. Therefore, understanding the mechanisms of the treatment resistance is essential to address the need for novel synergistic therapies to sensitize refractory NSCLC tumors to anti-cancer treatment. Tumor hypoxia has been associated with treatment resistance for decades, yet its role in the clinical management of NSCLC remains largely unexplored. The basis of tumor hypoxia has traditionally been attributed to the oxygen supply deficit as malformed tumor vasculature fails to meet the high demand of the rapidly proliferating tumor mass. However, our preliminary analysis of NSCLC patient datasets in the Cancer Genome Atlas (TCGA) revealed a significant correlation between high-level expression of nuclear genes encoding mitochondrial subunits essential for oxidative phosphorylation (OXPHOS) and the expression of validated hypoxia-regulated genes (Buffa hypoxia score). The oxygen-consumption expression signature was implemented in software that enables the calculation of numerous tumor microenvironment expression signatures, called tmesig. Furthermore, we have observed a direct positive correlation between the hypoxia expression signatures levels in NSCLC patient samples and the copy number amplification (CNA) of essential OXPHOS genes. Because mitochondrial function consumes up to 90% of available cellular oxygen, its activity may indirectly regulate oxygen availability in the tumor microenvironment by rapidly consuming oxygen upon its delivery to the tumor. Mechanistically, this leads to the hypothesis that OXPHOS gene amplification drives mitochondrial function, which may, in turn, promote tumor hypoxia and treatment resistance in NSCLC.
Citation Format: Martin Benej, Katarina Benejova, McKenzie Kreamer, Jinghai Wu, Syed Ashraf, Caroline Wheeler, Rebecca Hoyd, Daniel Spakowicz, Nicholas C. Denko. Copy number amplification of OXPHOS genes drives tumor hypoxia in NSCLC. [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 4832.
Abstract 529: Novel inhibitors of the NRF2 pathway also arrest lung cancer cells in G2/M
Authors: Occhiuto Christopher John , Lockwood Lizbeth , Hou Zhilin , Odom Aaron , Liby Karen 
Published: June 2023

Abstract
Background: Non-small cell lung (NSCLC) constitutes approximately 80% of all diagnosed cases of lung cancer. Up to 30% of NSCLC acquire mutations that result in constitutive NRF2 pathway activity, which correlates with worse patient prognosis. NRF2 regulates antioxidant genes that confer cytoprotection and chemoresistance. Inhibiting NRF2 activity increases tumor susceptibility to chemotherapy in preclinical lung cancer models; however, there are no FDA-approved NRF2 inhibitors available. Because current inhibitors have low potency and specificity, we developed novel compounds that target the NRF2 pathway. Previously, a high throughput screen identified MSU-38225, which was efficacious in sensitizing chemoresistant lung cancer to chemotherapy in a mouse xenograft model. We sought to improve the poor pharmacokinetics of this compound and developed and characterized a series of novel derivatives with increased solubility.
Hypothesis: Derivatives of MSU-38225 inhibit the NRF2 pathway and decrease cancer cell viability.
Methods: The efficacy of our NRF2 pathway inhibitors was assessed in A549 and H460 human lung cancer cells with constitutive NRF2 pathway activity using western blotting, RT-PCR, and MTT or Cell Titer Glow viability assays. Cell death and cell cycle analysis were evaluated using flow cytometry. Data were evaluated with one or two-way ANOVA and the Dunnett post-hoc test.
Results: The NRF2 pathway inhibitors decreased NRF2 protein level in A549 and H460 cells by approximately 60%, as measured by western blotting. As a result, NRF2-mediated transcription of cytoprotective genes NQO1, GCLC, GCLM, and AKR1C2 were decreased by 30-60% (p&lt;0.05) by qPCR. Further, these compounds decreased lung cancer cell viability, as measured in an MTT assay, by 50% in A549 cells and by 90% in H460 (p&lt;0.05). We then evaluated a specific inhibitor, MSU-71, to determine the cause of decreased viability and found it did not induce annexin-V positive apoptosis. However, subsequent analysis of the cell cycle with propidium iodide univariate analysis showed MSU-71 arrests lung cancer cells. 50% of H460 and 75% of A549 cells were arrested in G2/M (p&lt;0.05). Finally, we developed several “click” chemistry tool compounds that have equitable NRF2 pathway inhibition, which will aid in target identification of the new inhibitors.
Conclusion: Taken together, the new NRF2 pathway inhibitors are efficacious in blocking NRF2 activation. Optimization of these inhibitors could lead to a new therapy to treat lung cancer.
Citation Format: Christopher John Occhiuto, Lizbeth Lockwood, Zhilin Hou, Aaron Odom, Karen Liby. Novel inhibitors of the NRF2 pathway also arrest lung cancer cells in G2/M [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 529.
Abstract 5304: Development of a plasma biomarker panel for gastric cancer detection based on an autoimmune response signature
Authors: Dou Rongzhang , Irajizad Ehsan , Cai Yining , Fahrmann Johannes F. , Vykoukal Jody V. , Chen Yihui , Katayama Hiroyuki , Sater Ali H. Abdel , Pizzi Melissa , Yamashita Kohei , Da Silva Matheus Sewastjanow , Ostrin Edwin J. , Ajani Jaffer , Hanash Samir M. 
Published: June 2023

Abstract
Background: Gastric cancer is frequently diagnosed at an advanced stage and is associated with poor outcomes. Harnessing the immune response to tumor antigens which occurs early during tumor development has potential for the early detection of gastric cancer.
Methods: Plasma samples from gastric cancer patients were collected before and after treatment and from healthy controls for identification of immunoglobin (Ig)-bound antigens using mass spectrometry. Ingenuity pathway analysis(IPA) was utilized to investigate networks and pathways associated with Ig bound proteins identified in plasmas from cases. A combined biomarker panel was established based on a logistic-regression model and ROC analysis was used to assess panel performance.
Results: A total of 65 Ig bound proteins were identified that were upregulated in gastric cancer patients’ plasma compared with healthy control. Canonical pathways involving these immunogenic proteins included HIF-1α, VEGF, actin cytoskeleton, and immunogenic cell death signaling which play important roles in both gastric cancer development and progression. Four of the top ten performing proteins exhibited high mRNA levels in gastric cancer tissue. The association of these four Ig bound proteins in gastric cancer plasmas was further validated using as controls a cohort of MEN1 patients plasmas. A blood-biomarker panel based on these four biomarkers was established using a logistic-regression model which yielded an area under the curve (AUC) of 0.963 (95% confidential interval [CI] =0.89-1.00) for gastric cancer discrimination with a sensitivity of 0.889 at 95% specificity.
Conclusion: Our data reveal a panel of plasma Ig-bound antigens associated with the development of gastric cancer with potential application for early detection and monitoring.
Citation Format: Rongzhang Dou, Ehsan Irajizad, Yining Cai, Johannes F. Fahrmann, Jody V. Vykoukal, Yihui Chen, Hiroyuki Katayama, Ali H. Abdel Sater, Melissa Pizzi, Kohei Yamashita, Matheus Sewastjanow Da Silva, Edwin J. Ostrin, Jaffer Ajani, Samir M. Hanash. Development of a plasma biomarker panel for gastric cancer detection based on an autoimmune response signature. [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 5304.
Abstract 5477: An investigation to study differential gene expression of lung cancer cells, tumor associated macrophages, and bone marrow derived mesenchymal stems cells in the tumor microenvironment
Authors: Banerjee Hirendra N. , Hedley Joseph , Aurelus Cheslsey , Banerjee Narendra , Rawat Kuldeep , Reaves Quentin , Brown Shennel , Gilmartin Darla , Liverman Makieyah , Cuffee Jazmine , Cagle Elizabeth , Armstrong Erik , Lake Brent , Mandal Santosh , Ghosh Somiranjan , Beebe Stephen , Asadipour Kamal , Krauss Christopher , Bhattacharya Santanu , Kulkarni Tanmay , Abedin Zahidur 
Published: June 2023

Abstract
Cancer is a public health crisis affecting approximately 19.3 million globally, annually. Lung cancer has the highest percentage of incidence and is responsible for 27% of cancer-related deaths. The prevalence of lung cancer worldwide led us to investigate differential gene expression in lung adenocarcinoma and small cell lung cancer cell lines in comparison to a healthy lung cell line. We also investigated the effect of lung tumor microenvironment to bone marrow derived pluripotent mesenchymal stem cells (PMSC) and tumor associated macrophages. This research involved cancer and healthy cell line culture with appropriate medium. Whole transcriptomic and small non-coding RNA sequencing and analysis by Ingenuity Pathway Analysis (Qiagen, USA), Quantitative RT-PCR and ELISA assays. We further studied morphological changes and differential gene expression in extracellular vesicles(exosomes) isolated from the TAM and TME exposed PMCs by atomic force microscopy and RNA sequencing techniques. The results of our investigation showed differential gene expression and novel core canonical pathways in the lung cancer cells, TME exposed TAM, and PMSC. We also observed morphological changes in TME derived exosomes from TAM and PMSC. RNA sequencing results showed differential gene expression of both coding and non-coding RNAs including tRNA fragments. Thus, our findings of this investigation led to identification of multiple cancer related genes and small non-coding microRNA, long non-coding RNA, and tRNA fragments which will have potential diagnostic and therapeutic target value that demands further future research. Acknowledgement: This research is supported by a grant from US NIH-NIGMS- 5T34GM100831-08 and US-NIH Grant# U 54 MD007597-31-5959.
Citation Format: Hirendra N. Banerjee, Joseph Hedley, Cheslsey Aurelus, Narendra Banerjee, Kuldeep Rawat, Quentin Reaves, Shennel Brown, Darla Gilmartin, Makieyah Liverman, Jazmine Cuffee, Elizabeth Cagle, Erik Armstrong, Brent Lake, Santosh Mandal, Somiranjan Ghosh, Stephen Beebe, Kamal Asadipour, Christopher Krauss, Santanu Bhattacharya, Tanmay Kulkarni, Zahidur Abedin. An investigation to study differential gene expression of lung cancer cells, tumor associated macrophages, and bone marrow derived mesenchymal stems cells in the tumor microenvironment. [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 5477.