bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5532: An ‘anti-PD1-IL2 beta-only super-agonist’ displays potent anti-tumor efficacy
Authors: To Minh D. , Munegowda Manjunatha Ankathatti , Merchant Rosemina , Sharma Aanchal 
Published: June 2022

Abstract
Introduction: Combination studies with engineered IL-2 variants and immune-checkpoint blockade have demonstrated synergy in both pre-clinical models and the clinic. Co-administration of those 2 agents can potentially face challenges related to overlapping toxicities in obtaining optimal doses for synergistic effects. We propose to potentiate the synergy by enabling cis activation of IL-2 agonism and blockade of PD-1/PDL-2 binding with a single anti-PD1-IL2 to generate Bifunctional SuperKines for ImmunoTherapy (BiSKIT). Both human (h) and mouse (m) versions of anti-PD1 are fused with MDNA109FEAA, an IL-2 superkine with enhanced affinity for IL-2Rβ (CD122) and no binding to IL-2Rα (CD25).
Experimental Procedure: Studies included binding analyses with Biacore/SPR, signaling analyses in an IL-2 cell reporter assay, cell proliferation assay, in vitro pSTAT5 signaling in human PBMCs, PD1/PDL-1 cell reporter assay and efficacy in syngeneic tumor models.
Summary of Data: Anti-hPD1-MDNA109FEAA and surrogate anti-mPD1-MDNA109FEAA were tested in both in vitro and in vivo assays. Both constructs demonstrated selective binding to either hPD1 or mPD1 as expected, and the MDNA109FEAA motif retained its receptor selectivity (enhanced affinity to CD122 and no binding to CD25). In both HEK-Blue IL-2 reporter and CTLL-2 proliferation bioassays, anti-PD1-MDNA109FEAA exhibited similar agonistic effect as MDNA109FEAA-Fc, demonstrating that potency towards the IL-2 axis was not diminished. This was further confirmed with pSTAT5 signaling in primary human PBMCs where anti-PD1-MDNA109FEAA showed enhanced activation of CD8 T-cells and NK cells with reduced activity on Treg when compared to rhIL-2. Both constructs were also effective at inhibiting PD1/PDL-1 pathway in respective human and mouse specific cell-based reporter assays. In a CT26 syngeneic colon tumor model, anti-mPD1-MDNA109FEAA exhibited superior efficacy over monotherapy and combination with anti-mPD1 and MDNA109FEAA-Fc when administered at equal molar dosage and same schedule.
Conclusion: We have engineered anti-PD1-MDNA109FEAA to enable cis engagement with IL-2 receptor and PD1 as an approach to activate immune cells while reducing their exhaustion. Anti-mPD1-MDNA109FEAA achieved potent efficacy in a CT26 colon tumor model and is currently being evaluated in additional syngeneic tumor models with varying responsiveness to immune checkpoint blockade.
Citation Format: Minh D. To, Manjunatha Ankathatti Munegowda, Rosemina Merchant, Aanchal Sharma. An ‘anti-PD1-IL2 beta-only super-agonist’ displays potent anti-tumor efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5532.
Abstract 5550: QLS31904: An anti-DLL3/CD3 bispecific antibody for T cell immunotherapy of small cell lung cancer
Authors: Yang Liuqing , Li Ruimei , Jiang Jiahua , Qian Hongliang , Ge Hongxiu , Lu Ting , Fang Yan , Liu Jun , Zhao Shuyong 
Published: June 2022

Abstract
Background: More than 150,000 patients are diagnosed with small cell lung cancer (SCLC) each year in the world. Standard of care for patients at different stages of SCLC includes radiation, etoposide, cisplatin/carboplatin, and atezolizumab. However, relapse is quite common. Therefore, there is a strong need to develop a more effective treatment. Delta-like ligand 3 (DLL3) is a target selectively expressed in SCLC rather than normal tissue. We have developed an anti-DLL3/CD3 bispecific antibody QLS31904 that is engineered to direct and activate T cells through CD3 to kill SCLC cells expressing DLL3.
Methods: Tumor cell killing, T cell activation, and cytokine production of QLS31904 in a concentration range were assessed in the presence of SCLC cells and human T cells in vitro. Antitumor activity of QLS31904 was evaluated in SCLC xenograft models, in which NCG mice were co-implanted with SHP-77 and human T cells first, then treated with intraperitoneal QLS31904 or control IgG1AA isotype. The in vivo tumor growth inhibition was assessed. Pharmacokinetic analyses were performed in non-human primates (NHP). The cross-reactivity of QLS31904 with NHP DLL3 and CD3 were established, and the tolerability was also evaluated in NHP model.
Results: QLS31904 displayed the anticipated bispecific binding properties and mediated potent and selective lysis of DLL3-positive cancer cell lines through recruitment and activation of human T cells. No cytokine activation was observed with human peripheral blood mononuclear cell alone. In xenograft models, QLS31904 induced significant tumor growth inhibition at doses as low as 20 µg/kg, including complete regression of established tumors. QLS31904 exhibits about 100 hours of T1/2 in NHP, supporting feasibility of weekly dosing. QLS31904 was well tolerated with no related adverse findings up to the highest tested dose (five weekly doses of 10mg/kg) in NHP.
Conclusions: QLS31904 has an impressive efficacy and safety profile in the preclinical studies, making it a potentially viable option for DLL3-expressing SCLC in the clinical setting.
Citation Format: Liuqing Yang, Ruimei Li, Jiahua Jiang, Hongliang Qian, Hongxiu Ge, Ting Lu, Yan Fang, Jun Liu, Shuyong Zhao. QLS31904: An anti-DLL3/CD3 bispecific antibody for T cell immunotherapy of small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5550.
Abstract 5559: Development of a novel PD-L1xCD40 bispecific antibody with excellent efficacy and safety profile for cancer therapy
Authors: luo Haishan , Meng Zihong , Rong Jimmy , Wang Yuandong , Yang Yunxing , Chen Fei , Wang Youhong , Chen Victor , Deng Gang , He Yebo , Gan Xin , Rong Yiping 
Published: June 2022

Abstract
CD40 agonistic antibody is emerging as a front-line immunotherapy for patients with cancer. However, despite its remarkable curative effects, serious immune-related adverse reactions limit the clinical application of CD40 agonists. Crosslinking-dependent activation is one of the promising approaches to diminish the adverse effects of CD40 agonists. Agonistic CD40 stimulation on antigen presenting cells (APCs) not only promotes activation of T cells, but also results in PD-L1 upregulation on APCs, thus creating a negative feedback loop to dampen the anti-tumor immune response. Therefore, we hypothesized that the combination of CD40 agonist and blockade of PD-1/PD-L1 interaction may further induce a synergistic effect on T cell activation and anti-tumor activity. Here, we report a novel PD-L1xCD40 Bispecific Antibody (BsAb) designed to have synergistic curative effects as well as improved safety profiles. The PD-L1/CD40 BsAb was generated using the Harbour HBICE࣪® platform. It exhibited superior binding activities to both PD-L1 and CD40, respectively. CD40 activation was fully relied on the PD-L1 crosslinking. The PD-L1xCD40 BsAb showed potent tumor growth inhibition in preclinical efficacy models. Meanwhile, it showed much improved safety profile compared to a reference anti-CD40 agonistic antibody in the preclinical tox models. Overall, the PD-L1xCD40 BsAb demonstrated remarkable in vivo anti-tumor efficacy and improved safety profiles in preclinical models, which presents it as a promising candidate for the development of next-generation cancer immune therapeutics.
Citation Format: Haishan luo, Zihong Meng, Jimmy Rong, Yuandong Wang, Yunxing Yang, Fei Chen, Youhong Wang, Victor Chen, Gang Deng, Yebo He, Xin Gan, Yiping Rong. Development of a novel PD-L1xCD40 bispecific antibody with excellent efficacy and safety profile for cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5559.
Abstract 5697: Targeting PARP inhibitor resistance with Polθ inhibitors
Authors: Zatreanu Diana , Robinson Helen , Alkhatib Omar , Boursier Marie , Finch Harry , Geo Lerin , Grande Diego , Grinkevich Vera , Heald Robert , Langdon Sophie , Majithiya Jayesh , McWhirter Claire , Martin Niall , Moore Shaun , Neves Joana , Rajendra Eeson , Ranzani Marco , Schaedler Theresia , Stockley Martin , Wiggins Kimberley , Brough Rachel , Sridhar Sandhya , Gulati Aditi , Shao Nan , Badder Luted , Novo Daniela , Knight Eleanor , Marlow Rebecca , Haider Syed , Callen Elsa , Hewitt Graeme , Schimmel Joost , Prevo Remko , Alli Christina , Ferdinand Amanda , Bell Cameron , Blencowe Peter , Bot Chris , Calder Mathew , Charles Mark , Curry Jayne , Ekwuru Tennyson , Nussenzweig Andre , Tijsterman Marcel , Tutt Andrew N. , Boulton Simon , Higgins Geoff , Pettitt Stephen J. , Smith Graeme C. , Lord Christopher J. 
Published: June 2022

Abstract
To target DNA repair vulnerabilities in cancer, we discovered nanomolar potent, selective, low molecular weight (MW), allosteric inhibitors of the polymerase function of DNA polymerase Polθ, including ART558. ART558 inhibits the major Polθ-mediated DNA repair process, Theta-Mediated End Joining (TMEJ), without targeting Non-Homologous End Joining. Moreover, we show that exposure to ART558 can elicit DNA damage and synthetic lethality in BRCA1- or BRCA2-mutant tumor cells and enhances the effects of a PARP inhibitor. Genetic perturbation screening revealed that defects in the 53BP1/Shieldin complex, which are a cause of PARP inhibitor resistance, result in in vitro and in vivo sensitivity to Polθ polymerase inhibitors. Mechanistically, ART558 increases biomarkers of single-stranded DNA and synthetic lethality in 53BP1-defective cells. The inhibition of DNA nucleases that promote end-resection, such as Exo1 or Blm-Dna2 reversed these effects, implicating these in the synthetic lethal mechanism-of-action. Taken together, these observations describe a drug class that elicits BRCA-gene synthetic lethality and PARP inhibitor synergy, as well as targeting a biomarker-defined mechanism of PARPi-resistance.
Citation Format: Diana Zatreanu, Helen Robinson, Omar Alkhatib, Marie Boursier, Harry Finch, Lerin Geo, Diego Grande, Vera Grinkevich, Robert Heald, Sophie Langdon, Jayesh Majithiya, Claire McWhirter, Niall Martin, Shaun Moore, Joana Neves, Eeson Rajendra, Marco Ranzani, Theresia Schaedler, Martin Stockley, Kimberley Wiggins, Rachel Brough, Sandhya Sridhar, Aditi Gulati, Nan Shao, Luted Badder, Daniela Novo, Eleanor Knight, Rebecca Marlow, Syed Haider, Elsa Callen, Graeme Hewitt, Joost Schimmel, Remko Prevo, Christina Alli, Amanda Ferdinand, Cameron Bell, Peter Blencowe, Chris Bot, Mathew Calder, Mark Charles, Jayne Curry, Tennyson Ekwuru, Andre Nussenzweig, Marcel Tijsterman, Andrew N. Tutt, Simon Boulton, Geoff Higgins, Stephen J. Pettitt, Graeme C. Smith, Christopher J. Lord. Targeting PARP inhibitor resistance with Polθ inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5697.
Abstract 5881: The efficacy of a technology-based support program on survivorship experience: Asian American breast cancer survivors
Authors: Im Eun-Ok , Chee Wonshik , Paul Sudeshna ,   TICAA Research Team
Published: June 2022

Abstract
Purpose: A technology-based intervention without face-to-face interactions could work better for many women from cultures where breast cancer is still a stigmatizing experience. Also, a technology-based intervention could meet the necessity of information and support without time and/or geographical restrictions. The purpose of this study was to test the efficacy of a technology-based support program for Asian American breast cancer survivors (TICAA) in enhancing the women’s breast cancer survivorship experience.
Methods: This was a randomized controlled intervention with repeated measures (pretest [Time Point 0; T0], post 1-month [T1], and post 3-months [T2]). A total of 199 Asian American breast cancer survivors were recruited/retained through online and offline settings and included in the data analysis. While the intervention group was requested to use the TICAA and the American Cancer Society (ACS) website on breast cancer for 3 months, the control group was requested to use the ACS website for 3 months. Multiple instruments were used: the Cancer Behavior Inventory (CBI), the Personal Resource Questionnaire (PRQ), the Perceived Isolation Scale (PIS), the Support Care Needs Survey-34 Short Form (SCNS), the Memorial Symptom Assessment Scale-Short Form (MSAS), and the Functional Assessment of Cancer Therapy Scale-Breast Cancer (FACT-B). The data were analyzed using growth curve models, fitted within the framework of mixed effects modeling, and mediation analyses.
Results: Within the mixed-effect model, there were significant decreases in the needs for help scores (SCNS scores) from T0 to T2 (β = -3.0236, p = .005) and the symptom distress scores (MSAS scores) from T0 to T1 and T2 (β = -2.8131, p &lt; .001; β = -3.0356, p &lt; .001). Yet, the change over time in the quality-of-life scores (FACT-B scores) was not statistically significant although the fixed effect of time was significant (β = -1.0476, p = .004). All the theory-based mediators (attitudes, self-efficacy, perceived barriers, and social influences) had statistically significant mediating impact on all outcome variables (needs for help, symptom distress, and quality-of-life; all p &lt; .001), but there were differences in the mediating effects among different individual outcome variables.
Conclusions: The findings supported the efficacy of the technology-based program in reducing the need for help and symptoms of Asian American breast cancer survivors. Further studies are needed on the differences in the effects of theory-based mediators on different outcome variables.
Citation Format: Eun-Ok Im, Wonshik Chee, Sudeshna Paul, TICAA Research Team. The efficacy of a technology-based support program on survivorship experience: Asian American breast cancer survivors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5881.
Abstract 5979: Evaluating therapeutic strategies against lung cancer using multispectral optoacoustic tomography
Authors: Wang Tianyuan , Wanniarachchi Hashini , Arango Lorena , Zhang Li , Liu Li 
Published: June 2022

Abstract
Tumor hypoxia is an important feature of the microenvironment in various types of tumors. The leaky and compressed vessels in the tumor lead to impaired blood flow and oxygen delivery and cause hypoxia. Significant tumor hypoxia exists in non-small cell lung cancer (NSCLC) and is closely associated with radiation-resistant and poor survival. Recently, we have identified a new class of antitumor drugs, cyclopamine tartrate (CycT) and heme-sequestering peptide 2 (HeSP2). They are heme-targeting agents that effectively inhibit NSCLC oxidative metabolism, oxygen consumption, and ATP generation, which lead to the suppression of tumor progression. By using multispectral optoacoustic tomography (MSOT), an advanced noninvasive imaging modality that monitors the changes in blood oxygen saturation and vascular function in real-time, we observed the effect of heme-targeting agents in normalizing tumor vasculature and alleviating tumor hypoxia. To investigate the impact of heme-targeting agent on mediating the lung cancer radiotherapy response, we characterized the vasculature and antigenic profile of NSCLC growth during the treatment of CycT in combination with radiotherapy by performing MSOT, together with other imaging approaches including bioluminescence imaging (BLI) and immunohistochemistry (IHC). We demonstrated that the heme-targeting agents increased tumor radiation sensitivity by regulating tumor vasculature and oxygenation. Our novel combination therapy can be a powerful strategy in improving the treatment of lung cancer and potentially other radiation-resistant cancers.
Citation Format: Tianyuan Wang, Hashini Wanniarachchi, Lorena Arango, Li Zhang, Li Liu. Evaluating therapeutic strategies against lung cancer using multispectral optoacoustic tomography [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5979.
Abstract 5988: Intra-carotid artery brain metastasis models for evaluation of lung and breast cancer drugs
Authors: Wang Fuyang , Yang Yuying , Zhao Haoxia , Dai Chunlei , Han Bingrui , Zhang Mengyao , Xiong Xia , Zhang Chao , Tang Xuzhen , Ji Qunsheng 
Published: June 2022

Abstract
Non-CNS metastatic brain cancer is about 10 times more common than CNS cancer. Lung cancer and breast cancer account for most brain metastasis. KRAS-mutant NSCLC compose a third lung adenocarcinoma, among which 17% to 55% will develop brain metastases. Likewise, more than a third HER2-positive breast cancer will develop brain metastasis. Among existing animal models, the ectopic injection in brain cannot reflect the mechanism of tumor invasion and metastasis, while tail vein and intra-cardiac injection usually produces extra-cerebral metastatic disease and the animals have to be sacrificed before brain metastases appeared. Here we developed several metastasis models injected by intra-carotid artery (ICA) to address these problems. Two KRAS-mutant lung cancer cells and two HER2-positive breast cancer cells selected by their metastasize potential were luciferase labeled for in vivo imaging and drug evaluation. The tumor pathology in brain was evaluated by H&E staining. Compared to ectopic models, these ICA models have natural dissemination and progression in the brain, which recapitulate the different pattern of metastatic lesions in the clinic. With synchronized growth rate and little variation compared to tail vein and intra-cardiac models, these tumor growth kinetics allow for more appropriate animal efficacy study. Both KRAS-sensitive and insensitive models have been developed and validated for the next generation drug development; HER-2 positive breast models with ICA method also showed a good discriminative power on anti-HER2 modalities including antibodies, small molecules and ADC. Meanwhile, ICA models with human immune cell reconstitution were also developed to support immune therapies in pre-clinical stage. In summary, we have developed a panel of intra-carotid artery brain metastatic models for drug evaluation, and demonstrated their superiority in growth kinetics, brain microenvironment, drug selectivity and immune component. These models can be a promising predictive tool for novel drug/modality discovery to target brain metastasis.
Citation Format: Fuyang Wang, Yuying Yang, Haoxia Zhao, Chunlei Dai, Bingrui Han, Mengyao Zhang, Xia Xiong, Chao Zhang, Xuzhen Tang, Qunsheng Ji. Intra-carotid artery brain metastasis models for evaluation of lung and breast cancer drugs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5988.
Abstract 6051: Longitudinal single-cell sequencing of high-risk neuroblastoma tumors reveals intrinsic and extrinsic mechanisms of therapy resistance
Authors: Uzun Yasin , Grossmann Liron D. , Chen Chia-Hui , Thadi Anusha , Wu Chi-Yun , Gao Peng , Diep Dinh , Surrey Lea , Martinez Daniel , Patel Tasleema , Qiu Qi , Johnson Sarah , Yu Wenbao , Drabings Shane , Chen Changya , Hu Yuxuan , Chen Gregory , Oldridge Derek A. , Zhang Kun , Wu Hao , Bernt Kathrin , Zhang Nancy , Maris John M. , Tan Kai 
Published: June 2022

Abstract
Neuroblastoma is a childhood cancer originating from embryonic neuronal progenitor cells and is the most common cancer diagnosed in infants. Although the majority of patients respond to initial chemotherapy, most high-risk patients suffer relapse due to therapy resistance.
Here, we generated single-cell transcriptome and bulk whole-genome sequencing data of diagnosis and post-therapy samples from 23 patients diagnosed with high-risk neuroblastoma. We found two distinct adrenergic populations in the patient samples. Most tumor cells showed a mature sympathoblast phenotype whereas a small fraction was in an undifferentiated state with activation of protein translation, unfolded protein, and oxidative phosphorylation pathways. We found that therapy-resistant tumor cells in these two subpopulations had distinct characteristics. The more mature resistant subpopulation upregulated genes associated with epithelial-to-mesenchymal transition, including TWIST1, PLCB1 and CD276. The undifferentiated resistant subpopulation upregulated Ras signal transduction and TP53 pathway genes.
Analysis of the immune microenvironment revealed that most tumor-associated macrophages became more immunosuppressive post-therapy via multiple newly gained signaling interactions including the complement signaling pathway. We discovered a limited infiltration of T lymphocytes in the tumor microenvironment, and chemotherapy induced an effector state with upregulated mTOR signaling and metabolism. Overall, our study revealed subpopulations of tumor cells in neuroblastoma that responded differently to induction chemotherapy. Our findings uncovered distinct molecular signatures of the resistant cells and their interactions with the immune microenvironment, paving the way for developing novel therapies for high-risk neuroblastoma.
Citation Format: Yasin Uzun, Liron D. Grossmann, Chia-Hui Chen, Anusha Thadi, Chi-Yun Wu, Peng Gao, Dinh Diep, Lea Surrey, Daniel Martinez, Tasleema Patel, Qi Qiu, Sarah Johnson, Wenbao Yu, Shane Drabings, Changya Chen, Yuxuan Hu, Gregory Chen, Derek A. Oldridge, Kun Zhang, Hao Wu, Kathrin Bernt, Nancy Zhang, John M. Maris, Kai Tan. Longitudinal single-cell sequencing of high-risk neuroblastoma tumors reveals intrinsic and extrinsic mechanisms of therapy resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6051.