bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4028: Inhibition of IL25 IL17RA improves immune related adverse events of checkpoint inhibitors and reveals antitumor activity
Authors: Hu Xizi , Bukhari Shoiab , Tymm Carly , Adam Kieran , Lerrer Shalom , Henick Brian , Winchester Robert , Mor Adam 
Published: March 2024

Abstract
Immune checkpoint inhibitors (ICI) have improved outcomes and extended patient survival in several tumor types. However, ICI often induces immune-related adverse events (irAEs) that warrant therapy cessation, thereby limiting the overall effectiveness of this class of therapeutic agents. Currently, available therapies used to treat irAEs might also blunt the antitumor activity of the ICI themselves. Therefore, there is an urgent need to identify treatments that have the potential to be administered alongside ICI to optimize their use. Using a translationally relevant murine model of anti-PD-1 and anti-CTLA-4 antibodies-induced irAEs, we compared the safety and efficacy of prednisolone, anti-IL-6, anti-TNFɑ, anti-IL-25 (IL-17E), and anti-IL-17RA (the receptor for IL-25) administration to prevent irAEs and to reduce tumor size. While all interventions were adequate to inhibit the onset of irAEs pneumonitis and hepatitis, treatment with anti-IL-25 or anti-IL-17RA antibodies also exerted significant additional antitumor activity. Mechanistically, IL-25/IL-17RA blockade reduced the number of organ-infiltrating lymphocytes. These findings suggest that IL-25/IL-17RA may serve as an additional target when treating ICI-responsive tumors, allowing for better tumor control while suppressing immune-related toxicities.
Citation Format: Xizi Hu, Shoiab Bukhari, Carly Tymm, Kieran Adam, Shalom Lerrer, Brian Henick, Robert Winchester, Adam Mor. Inhibition of IL25 IL17RA improves immune related adverse events of checkpoint inhibitors and reveals antitumor activity [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 4028.
Abstract 404: LINE-1 retrotransposition promotes chromosomal translocations through RNA-templated DNA repair in human cancers
Authors: Tao Jianli , Alessandri Luca , Mendez-Dorantes Carlos , Burns Kathleen H. , Wang Qi , Chiarle Roberto 
Published: March 2024

Abstract
Introduction: Approximately 50% of human cancers have somatic integrations of long interspersed element-1 (LINE-1; also known as L1). L1 is a retrotransposon that copies itself through RNA and integrates into new genomic loci. Although L1 sequences comprise approximately 17% of the human genome, only 100-150 L1 loci have retained the ability to retrotranspose. These full-length, retrotransposition-competent L1s are typically repressed in human somatic cells, but there is evidence of their significant reactivation in human cancers. Therefore, L1 overexpression is a hallmark of many human cancers, particularly in highly malignant tumor types such as breast, ovarian, pancreatic, esophageal, lung, head-and-neck, colon, prostate, and liver cancers.
Results: In many cancers, chromosomal translocations are fundamental pathogenetic events initiated by the generation of DNA double-strand breaks (DSBs). Although LINE-1 (L1) retrotransposition events have been implicated in chromosomal rearrangements associated with most human cancers, the frequency and mechanisms by which L1 is involved in these rearrangements, including chromosomal translocations, remain poorly characterized. By combining high-throughput genome-wide translocation sequencing (HTGTS) and two sequencing techniques to detect L1 insertion sites (PolyA-seq and CELTICS-seq), we demonstrated that the presence of an active human L1 retrotransposition significantly increases the frequency of chromosomal translocations. By identifying L1-dependent translocation hotspots in HEK293T cells we highlight the requirement for the L1 reverse transcriptase (RT) activity and the crucial role of pre-existing DNA DSBs in promoting L1-mediated chromosomal translocations. L1-dependent translocation hotspots showed a marked preference for transcription end sites (TES) of active genes, early replication timing regions, and accessible chromatin regions. Therefore, while cancer genome analysis provides a static view of chromosomal rearrangements based on canonical L1 integrations, our functional studies reveal an unanticipated predominance of chromosomal translocations facilitated by non-canonical L1 retrotransposition via RNA-templated repair of existing DSBs, largely expanding our knowledge on the mechanism by which L1 retrotransposition induces genomic instability in human cancers.
Citation Format: Jianli Tao, Luca Alessandri, Carlos Mendez-Dorantes, Kathleen H. Burns, Qi Wang, Roberto Chiarle. LINE-1 retrotransposition promotes chromosomal translocations through RNA-templated DNA repair in human 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 404.
Abstract 4069: IL12-expressing genetically engineered myeloid cells remodel the stromal dense and T cell poor tumor microenvironment and premetastatic niche of F42010 murine osteosarcoma
Authors: Jackett Kailey , Browne Alice , Kaczanowska Sabina , Clements Miranda , Kaplan Rosandra , Wessel Kristin , Ball Brendan , Cronk James 
Published: March 2024

Abstract
Treatment options for patients with metastatic and recurrent osteosarcoma are poor. The development of immunotherapies for osteosarcoma has been hindered by the lack of immunocompetent preclinical models that recapitulate the stromal dense, myeloid-rich, T cell poor, and overall immunosuppressive microenvironment of human osteosarcoma. We hypothesized that the syngeneic murine osteosarcoma model F42010 may serve as a useful immunocompetent preclinical model of osteosarcoma suitable for developing novel immunotherapies for osteosarcoma. To test this, we used flow cytommetry, bulk RNA sequencing, and immunohistochemistry to characterize the stromal and immune compartments of this model. We found that the F42010 osteosarcoma model recapitulates the ECM-rich and immunosuppressive nature of human osteosarcoma primary tumor and pre-metastatic microenvironments, characterized by increased myeloid infiltrate expressing suppressive markers and lymphocyte exhaustion. Finally, we used this model to test the utility of a myeloid immunotherapy for osteosarcoma, IL-12 secreting genetically engineered myeloid cells (IL12-GEMys) that can reverse immune suppression in the pre-metastatic niche and tumor microenvironment. IL12-GEMy treatment augmented immune activation and significantly extended survival by delaying tumor growth. Our findings highlight that the F42010 osteosarcoma model effectively replicates key features of the osteosarcoma tumor microenvironment and is a valuable model for developing novel tumor microenvironment and pre-metastatic niche modulating immunotherapies for osteosarcoma.
Citation Format: Kailey Jackett, Alice Browne, Sabina Kaczanowska, Miranda Clements, Rosandra Kaplan, Kristin Wessel, Brendan Ball, James Cronk. IL12-expressing genetically engineered myeloid cells remodel the stromal dense and T cell poor tumor microenvironment and premetastatic niche of F42010 murine osteosarcoma [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 4069.
Abstract 4081: rhIL-7-hyFc (efineptakin-alfa, NT-I7) increases tumor-specific CD8+ T cells despite FOLFOX cytotoxicity effect
Authors: Lee Soung-Min , Kim Miyoung , Ferrando-Martínez Sara , Im Sun-Kyoung , Ji Mankyu , Choi Donghoon 
Published: March 2024

Abstract
rhIL-7-hyFc (efineptakin-alfa; NT-I7) is a potent T cell amplifier, comprised of two molecules of interleukin-7 (IL-7) fused to the hybrid Fc domain of IgD/IgG4 immunoglobulin. NT-I7 safely, significantly, and persistently increases the absolute lymphocyte counts (ALC) in humans in a dose-proportional manner. Importantly, this increase is primarily due to an increase in T cells (1). Previous studies have shown that NT-I7 not only significantly increases the number of CD8+ T cells in peripheral blood but also dramatically boosts the presence of tumor-infiltrating CD8+ T cells, including both tumor-specific (p15E+PD-1+) and tumor non-specific (PD-1-) CD8+ T cells in mice (2). FOLFOX is a chemotherapy regimen composed of 5-fluorouracil, leucovorin, and oxaliplatin that inhibits DNA duplication and eradicates rapidly dividing cells (3). Although the mechanism of FOLFOX results in direct tumor killing, it also has the potential to kill newly dividing lymphocytes during NT-I7 treatment (4-6). Therefore, in this study, we aimed to evaluate the feasibility of combining FOLFOX with NT-I7 in a syngeneic MC38 mouse tumor model. Our results show that NT-I7 improves the efficacy of FOLFOX, irrespective of the timing of NT-I7 administration: simultaneous administration or delayed 3 hours, or 2 days after FOLFOX administration. This improvement persists despite a significant decrease in ALC for the first 6 days, which was significantly lower than the ALC observed with FOLFOX alone. FOLFOX decreases the absolute numbers of tumor non-specific CD8+ T cells. However, adding FOLFOX does not affect the NT-I7-driven increase of tumor-specific CD8+ T cells within the tumor. Taken together, our data demonstrate that FOLFOX does not compromise NT-I7’s ability to increase tumor-specific T cells within the tumor and the combination enhances the anti-tumor response irrespective of the timing of NT-I7 administration.
Citation Format: Soung-Min Lee, Miyoung Kim, Sara Ferrando-Martínez, Sun-Kyoung Im, Mankyu Ji, Donghoon Choi. rhIL-7-hyFc (efineptakin-alfa, NT-I7) increases tumor-specific CD8+ T cells despite FOLFOX cytotoxicity effect [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 4081.
Abstract 4084: Potent anti-tumor activity of ABN202 (anti-EGFR antibody-interferon-beta mutein) through direct cytotoxicity and indirect immune activation against non-small cell lung cancer, regardless of EGFR mutation status
Authors: Park Hee Geon , Cho Sung Hun , Park Ha Yeon , Jo Mi Gyoung , Park Ji Hyun , Seo Myeung Ryun , Kim Ji Hyun , Hong Sung Youl , Song Kyoung , Lee Chan Gyu , Jeong Hae Min , Lee Sae Hyung , Kim Na Young , Choi Jun Young , Shin Young Kee 
Published: March 2024

Abstract
Epidermal growth factor receptor (EGFR) is overexpressed or mutated in many patients with non-small cell lung cancer (NSCLC). Targeting EGFR mutation by tyrosine kinase inhibitors (TKIs) has significantly improved overall survival (OS) in patients with EGFR mutations. However, many patients experience tumor recurrence due to various resistance mechanisms. Therefore, there is an unmet medical need for new treatment strategies for patients with EGFR-positive NSCLC, regardless of EGFR mutation status. ABN202 is an antibody-cytokine fusion protein (ACFP) that serves as a platform technology compromising the IFN-β mutein (ABN102) fused to various antibodies for specific tumor targeting. In a previous study, we designed ABN202 (αEGFR) to comprise an EGFR targeting antibody (Cetuximab) and IFN-β mutein (ABN102) and we confirmed anti-cancer activities of ABN202 against EGFR-positive NSCLC. In this study, the direct cytotoxicity of ABN202 (αEGFR) was evaluated in human NSCLC cell lines with various driving mutations and EGFR expression levels. The indirect immune activation was tested in human peripheral blood mononuclear cells (PBMCs) and human IFNAR1/2 knock-in (KI) mice. The in vivo efficacy was evaluated in human NSCLC xenograft mouse models and human IFNAR1/2 KI mouse models. ABN202 (αEGFR) demonstrates potent anti-tumor activity through direct cytotoxicity and indirect immune activation in NSCLC, regardless of EGFR mutation status. Taken together, we suggest that ABN202 (αEGFR) is a promising drug candidate against NSCLC, regardless of EGFR mutation status.
Citation Format: Hee Geon Park, Sung Hun Cho, Ha Yeon Park, Mi Gyoung Jo, Ji Hyun Park, Myeung Ryun Seo, Ji Hyun Kim, Sung Youl Hong, Kyoung Song, Chan Gyu Lee, Hae Min Jeong, Sae Hyung Lee, Na Young Kim, Jun Young Choi, Young Kee Shin. Potent anti-tumor activity of ABN202 (anti-EGFR antibody-interferon-beta mutein) through direct cytotoxicity and indirect immune activation against non-small cell lung cancer, regardless of EGFR mutation status [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 4084.
Abstract 4120: Adherent-to suspension transition by hematopoietic factors in metastatic dissemination of circulating tumor cells
Authors: Park Hyun Woo 
Published: March 2024

Abstract
Although metastasis is the foremost cause of cancer-related death, a specialized mechanism that reprograms anchorage dependency of solid tumor cells into circulating tumor cells (CTCs) during the metastatic cascade remains elusive. We discovered a biological phenomenon referred to as Adherent-to-Suspension Transition (AST) that reprograms adherent cells into suspension cells via aberrant induction of hematopoietic transcriptional regulators, which are hijacked by solid tumor cells to disseminate into CTCs. During dissemination, tumor microenvironment triggers epigenetic alteration of AST factors in the invasive front of solid tumors to evoke spontaneous cell-matrix dissociation, acquire anoikis resistance, and bypass immune surveillance of CTCs, however, in the absence of lineage differentiation and EMT. Using mouse models and de novo metastatic patient specimens, we uncovered how Adherent-Suspension Plasticity (ASP) dictates anchorage plasticity during the dissemination and colonization process within the metastatic cascade. Finally, we demonstrate therapeutic strategies that target AST factors to specifically abrogate CTC formation and suppress distant metastases. Together, these findings underscore an important early mechanism of how cancer cells spread and highlight novel targets for the development of anti-metastatic therapy. Furthermore, AST opens unexplored scenarios how reprogramming anchorage dependency orchestrates physiological events such as development, organ morphogenesis and immune cell activation.
Citation Format: Hyun Woo Park. Adherent-to suspension transition by hematopoietic factors in metastatic dissemination of circulating tumor cells [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 4120.
Abstract 4129: Mitochondria-targeted antioxidant MitoQ inhibits human breast cancer metastasis in mice
Authors: Capeloa Tania , Sonveaux Pierre 
Published: March 2024

Abstract
In oncology, the occurrence of distant metastases often marks the transition from curative to palliative care. Such outcome is highly predictable for triple-negative and HER2-positive breast cancer patients, even if tumors are detected early, and there is no treatment to prevent metastasis. Here, considering that mitochondria are bioenergetic sensors of the tumor microenvironment, we report in preclinical mouse models that human breast cancer relapse is not a fatality: local recurrence and metastatic dissemination can be prevented by MitoQ, a mitochondria-targeted antioxidant that already underwent Phase I safety and Phase II efficacy trials in humans for pathologies other than cancer. Metastatic prevention was confirmed in the MMTV-PyMT model of spontaneously metastatic mouse breast cancer. After oral delivery, MitoQ was effective at nanomolar concentrations at which nonmalignant cells were spared. In anticipation of future clinical trials, a robust signature of the response to MitoQ was defined, applicable to bulk primary tumor biopsies.
Citation Format: Tania Capeloa, Pierre Sonveaux. Mitochondria-targeted antioxidant MitoQ inhibits human breast cancer metastasis in mice [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 4129.
Abstract 4134: The abscopal effect of combination IRE with αPD-1 treatment against PDACs
Authors: Cao Qizhen , Egan Nicholas A. , Peng Weiyi , Li Chun 
Published: March 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is associated with a high capacity of metastatic dissemination, which results in a dismal 5-year relative survival rate. Irreversible electroporation (IRE) represents an innovative intervention utilizing short high-voltage electric pulses to induce cell death through either permanent membrane lysis or disruption of cellular homeostasis. Previous studies from our lab have demonstrated that the combination of IRE and immune checkpoint blockade using anti-PD-1 antibody (αPD-1) enhances the infiltration of CD8+ cytotoxic T cells, significantly prolonging survival in an orthotopic murine PDAC model. However, the impact of IRE/αPD-1 on metastatic PDAC tumors, known as the abscopal effect, remains unclear. In this investigation, we bilaterally implanted C57BL/6J mice with subcutaneous KRAS* PDAC tumors, treating the right flank tumors with or without IRE, in conjunction with or without αPD-1 administered intraperitoneally. Tumor growth in both the treated (with or without IRE) and untreated (abscopal) left flank tumors was closely monitored until humane euthanasia or long-term survival. In a separate study, mice serum and tumor tissues were collection on the 5th day post-IRE/αPD-1 treatment. Luminex cytokine assays were conducted on the collected serum, and immunostaining was performed on tumor tissue. Results demonstrated significantly enhanced antitumor activity in both IRE-treated and untreated tumors on mice treated with combined IRE and αPD-1, leading to a marked extension of overall survival. Luminex cytokine assays revealed a substantial increase in crucial cytokines, including IL-2, IFN-gamma, IL-18, IL-19, and IL-3, known for their pivotal roles in fostering cytotoxic T lymphocyte development, promoting T cell differentiation into effector T cells, and facilitating the recruitment of effector CD8+ T cells to the tumor microenvironment. Moreover, immunofluorescence staining of tumor tissue illustrated a notable accumulation of CD169+ macrophages in IRE-treated tumors compared to untreated tumors. Tumors from the combined IRE with αPD-1 group exhibited increased CD8+ T cell accumulation compared to other groups. These data suggest IRE combined with PD-1 blockade promotes robust antitumor immune, leading to systemic antitumor activity and robust abscopal effect.
Citation Format: Qizhen Cao, Nicholas A. Egan, Weiyi Peng, Chun Li. The abscopal effect of combination IRE with αPD-1 treatment against PDACs [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 4134.
Abstract 4146: Brain permeable bioluminescent substrates for NanoLuc based reporters
Authors: Gao Chao , Su Yichi , Wu Yan , Fitzgerald Connor , Uyeda Tetsuo H. , Wang Hui , Kirkland Thomas A. , Lin Michael Z. , Zhou Wenhui 
Published: March 2024

Abstract
Non-invasive imaging methods for tracking gene expression, cell growth and migration and other biological events in vivo are indispensable tools for biomedical studies. Bioluminescence imaging (BLI) can achieve sensitive detection with low background in vivo, which is desirable for body imaging of small animals. Yet, BLI in the central nervous system (CNS) is challenging because many luciferase substrates show limited permeability of the blood-brain-barrier (BBB). To address this issue, we developed a family of new brain-permeant NanoLuc (NLuc) substrates, cephalofurimazine (CFz). CFz family paired with Antares, a fusion of CyOFP and NLuc that emits orange light instead of blue, produces an order of magnitude more signal from the brain than the standard combination of D-luciferin with firefly luciferase and matches the peak output of AkaLumine with AkaLuc but without the need of ATP. One of the substrates in the family, CFz-9, not only produces outstanding signal as other CFz substrates when paired with Antares, but also is able to be formulated into lyophilized cake that can be reconstituted in aqueous buffers for i.p. injections. Toxicity studies demonstrate that CFz-9 and its reconstituted solutions are non-toxic to mice and thus multiple injections are allowed.
Citation Format: Chao Gao, Yichi Su, Yan Wu, Connor Fitzgerald, Tetsuo H. Uyeda, Hui Wang, Thomas A. Kirkland, Michael Z. Lin, Wenhui Zhou. Brain permeable bioluminescent substrates for NanoLuc based reporters [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 4146.