bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 6244: A T cell engaging bispecific antibody utilizing a bivalent tumor-selective folate receptor alpha binding arm for the treatment of ovarian cancer
Authors: Avanzino Brian C. , Prabhakar Kirthana , Dalvi Pranjali , Hartstein Sharon , Kehm Hannes , Balasubramani Aarti , Boudreau Andrew A. , Buelow Ben , Chang Karen , Davison Laura M. , Iyer Suhasini , Kalwit Vidyut , Malik-Chaudhry Harbani , Pierson Will , Pineda Geovanni , Rangaswamy Udaya S. , Saiganesh Sowmya , Schellenberger Ute , Ugamraj Harshad S. , Buelow Roland , Chapman Jocelyn , Trinklein Nathan D. , Harris Katherine E. 
Published: June 2022

Abstract
The use of T cell engagers (TCEs) to treat solid tumors in humans is challenging, and several have been limited by narrow therapeutic windows due to substantial toxicity. Dose-limiting toxicities of TCEs include cytokine release syndrome (CRS) and on-target, off-tumor toxicities since many solid tumor target antigens are also expressed in healthy tissues, albeit at lower levels. While there have been improvements in the clinical management of immune-mediated toxicities such as CRS, on-target, off-tumor effects remain one of the primary challenges of using TCEs for treatment of solid tumors. Here, we describe TNB-928B, a novel fully human TCE that is bivalent for folate receptor alpha (FRα) that selectively targets FRα overexpressing tumor cells yet avoids targeting cells that express low levels of FRα found in normal human cells. Selectivity is conferred by an avidity effect of the FRα targeting arm in combination with a unique low-affinity CD3 arm and is anticipated to reduce the risk of adverse events in normal cells expressing low levels of FRα. TNB-928B induces preferential effector T cell activation, proliferation, and cytotoxic activity with minimal cytokine release, compared to a positive control containing OKT3, thereby improving the therapeutic index. Moreover, TNB-928B exhibits substantial ex vivo tumor cell lysis using endogenous T cells and is effective in vivo promoting T cell infiltration and tumor regression in mouse models of ovarian cancer. Together, these results demonstrate TNB-928B represents a novel next generation immunotherapy modality with enhanced safety and specificity for the treatment of ovarian cancer.
Citation Format: Brian C. Avanzino, Kirthana Prabhakar, Pranjali Dalvi, Sharon Hartstein, Hannes Kehm, Aarti Balasubramani, Andrew A. Boudreau, Ben Buelow, Karen Chang, Laura M. Davison, Suhasini Iyer, Vidyut Kalwit, Harbani Malik-Chaudhry, Will Pierson, Geovanni Pineda, Udaya S. Rangaswamy, Sowmya Saiganesh, Ute Schellenberger, Harshad S. Ugamraj, Roland Buelow, Jocelyn Chapman, Nathan D. Trinklein, Katherine E. Harris. A T cell engaging bispecific antibody utilizing a bivalent tumor-selective folate receptor alpha binding arm for the treatment of ovarian 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 6244.
Abstract 6248: Modulation of CD22 protein expression in childhood leukemia by pervasive splicing aberrations: Implications for CD22-directed immunotherapies
Authors: Zheng Sisi , Gillespie Elisabeth , Naqvi Ammar S. , Hayer Katharina E. , Ang Zhiwei , Torres-Diz Manuel , Quesnel-Vallières Mathieu , Hottman David A. , Bagashev Asen , Chukinas John A. , Schmidt Carolin , Asnani Mukta Mukta , Shraim Rawan , Taylor Deanne M. , Rheingold Susan R. , M. O’Brien Maureen , Singh Nathan , Lynch Kristen W. , Ruella Marco , Barash Yoseph , Tasian Sarah K. , Thomas-Tikhonenko Andrei 
Published: June 2022

Abstract
Downregulation of surface epitopes causes post-immunotherapy relapses in B-lymphoblastic leukemia (B-ALL). Here we demonstrate that mRNA encoding CD22 undergoes aberrant splicing in B-ALL. We describe the plasma-membrane-bound CD22 Δex5-6 splice isoform resistant to CAR-T cells targeting the third immunoglobulin-like domain of CD22. We also describe splice variants skipping the AUG-containing exon 2 and failing to produce any identifiable protein; therefore, this event is rate-limiting for epitope presentation. Indeed, forcing exon 2 skipping with Morpholino oligonucleotides reduced CD22 protein expression and conferred resistance to the CD22-directed antibody-drug conjugate inotuzumab in vitro. Furthermore, among inotuzumab-treated pediatric B-ALL patients, we identified one non-responder in whose blasts Δex2 isoforms comprised the majority of CD22 transcripts. In a second patient, a sharp reduction in CD22 protein levels during relapse was driven entirely by increased CD22 exon 2 skipping. Thus, dysregulated CD22 splicing is a major mechanism of epitope downregulation and ensuing resistance to immunotherapy.
Citation Format: Sisi Zheng, Elisabeth Gillespie, Ammar S. Naqvi, Katharina E. Hayer, Zhiwei Ang, Manuel Torres-Diz, Mathieu Quesnel-Vallières, David A. Hottman, Asen Bagashev, John A. Chukinas, Carolin Schmidt, Mukta Mukta Asnani, Rawan Shraim, Deanne M. Taylor, Susan R. Rheingold, Maureen M. O’Brien, Nathan Singh, Kristen W. Lynch, Marco Ruella, Yoseph Barash, Sarah K. Tasian, Andrei Thomas-Tikhonenko. Modulation of CD22 protein expression in childhood leukemia by pervasive splicing aberrations: Implications for CD22-directed immunotherapies [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 6248.
Abstract 6262: Emergence of tumor mismatch repair deficiency and increased mutational burden in blood and tissue of metastatic colorectal cancer patients treated with temozolomide
Authors: Crisafulli Giovanni , Sartore-Bianchi Andrea , Lazzari Luca , Pietrantonio Filippo , Amatu Alessio , Macagno Marco , Barault Ludovic , Cassingena Andrea , Bartolini Alice , Luraghi Paolo , Mauri Gianluca , Battuello Paolo , Personemi Nicola , Pessei Valeria , Vitiello Pietro Paolo , Tosi Federica , Idotta Laura , Valtorta Emanuele , Bonoldi Emanuela , Germano Giovanni , Nicolantonio Federica Di , Marsoni Silvia , Siena Salvatore , Bardelli Alberto 
Published: June 2022

Abstract
The majority of metastatic colorectal cancers (mCRC) are mismatch repair (MMR) proficient (MMRp) and unresponsive to immunotherapy, while MMR deficient (MMRd) tumors often respond to immune checkpoint blockade (ICB). We previously reported that treatment of CRC preclinical models with temozolomide (TMZ) leads to MMR deficiency, increased tumor mutational burden (TMB) and, sensitization to immunotherapy. To clinically translate these findings, we designed the ARETHUSA clinical trial whereby O6-Methylguanine-DNA-methyltransferase (MGMT) deficient, MMR proficient and KRAS mutant mCRC patients receive priming therapy with TMZ. Analysis of solid tissue biopsies and circulating tumor DNA (ctDNA) obtained after TMZ treatment revealed the emergence of TMZ mutational signature, alterations in MMR genes and increased TMB in 14 out of 16 patients. Genetic mutations induced by TMZ were dose-dependent and multiple alterations in the nucleotide context favored by the TMZ signature emerged in MMR genes such as the MSH6 T1219I variant which was detected in ctDNA and tissue of 13/14 (93%) of the cases. A subset of the patients whose tumors after TMZ priming displayed the MSH6 mutation, the TMZ mutational signature and increased TMB, achieved disease stabilization upon pembrolizumab treatment. Overall, we provide proof-of-concept that treatment of MGMT deficient/MMR proficient KRAS mutant mCRCs with TMZ can be tracked by mutational signature analysis and lead to inactivation of the MMR pathway, emergence of the TMZ mutational signature, TMB increase, and, in some cases, to disease stabilization during ICB.
Citation Format: Giovanni Crisafulli, Andrea Sartore-Bianchi, Luca Lazzari, Filippo Pietrantonio, Alessio Amatu, Marco Macagno, Ludovic Barault, Andrea Cassingena, Alice Bartolini, Paolo Luraghi, Gianluca Mauri, Paolo Battuello, Nicola Personemi, Valeria Pessei, Pietro Paolo Vitiello, Federica Tosi, Laura Idotta, Emanuele Valtorta, Emanuela Bonoldi, Giovanni Germano, Federica Di Nicolantonio, Silvia Marsoni, Salvatore Siena, Alberto Bardelli. Emergence of tumor mismatch repair deficiency and increased mutational burden in blood and tissue of metastatic colorectal cancer patients treated with temozolomide [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 6262.
Abstract 6270: Integrating spatial transcriptomics and single-cell RNA-seq reveal the tumorigenesis and heterogeneity of esophageal squamous cell carcinoma
Authors: Yin Xiaoyang , Li Baosheng 
Published: June 2022

Abstract
Background: Esophageal cancer is the sixth leading cause of cancer death globally and esophageal squamous cell carcinoma (ESCC) is the major histological type in China. The heterogeneity of ESCC resulted in poor therapeutic effect and tumor recurrence. To investigate the heterogeneity of ESCC at the single-cell level and the oncogenic evolution, we performed single-cell RNA-seq and spatial transcrtiptomics analysis in ESCC samples from different patients and position.
Methods: We performed single-cell RNA-seq of tumor, adjacent normal tissue and the junction of cancer and normal tissues from 4 ESCC patients. We also performed spatial transcriptomics of paired cancer, normal and junction of ESCC patients. Unsupervised clustering was performed to find different cell clusters of ESCC and marker genes of different clusters were determined. Inferred copy number variation was performed to identify malignant cells and pseudotime analysis to investigate the development of different cell clusters. Combined analysis of single-cell and spatial data was performed to reveal the spatial characteristics of different cell types.
Results: We successfully determined different cell types including epithelial cells, immune cells, fibroblasts, myeloid cells and so on. And we also reclustered epithelial, myeloid and T/NK cells to investigate different subtypes and their marker genes. We also distinguished malignant cells from heterogeneous cellular populations using inferred copy number variation analysis. Pseudotime analysis revealed the evolution of different cell types of ESCC. We identified key signatures associated with oncogenic evolution of ESCC and the spatial characteristics of key cell clusters.
Conclusion: These findings reveal the heterogenesis of ESCC and key signatures in ESCC tumorigenesis.
Keywords: ESCC, single cell sequencing, spatial transcriptomics, heterogeneity, tumorigenesis
Citation Format: Xiaoyang Yin, Baosheng Li. Integrating spatial transcriptomics and single-cell RNA-seq reveal the tumorigenesis and heterogeneity of esophageal squamous cell carcinoma [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 6270.
Abstract 6280: Preclinical development of a bispecific antibody-trap selectively targeting CD47 and HER2 for the treatment of breast as well as gastric cancer
Authors: Tian Wenzhi , Li Song , Chen Dianze , Liu Dandan , Guo Huiqin , Yang Chunmei , Zhang Li , Zhang Wei , Tu Xiaoping , Peng Liang , Zhao Gui , Zhang Ruliang , Zhang Fan 
Published: June 2022

Abstract
Trastuzumab executes anti-tumor efficacy mainly via antibody-dependent cell cytotoxicity (ADCC). However due to the fact that majority of the populations including patients with cancers carry a CD16A-158F allele which has low binding affinity to the Fc fragment of trastuzumab, response to trastuzumab treatment is hindered. Furthermore, overexpression of CD47 on cancer cells prevent macrophages from activation via Fc-FcγRIIa interaction due to the so called “Don’t eat me” signal. We therefore designed a bispecific mAb-trap designated as IMM2902. Extensive in vitro as well as in vivo characterization demonstrated that IMM2902 binds to both CD47 and HER2 with high affinity (KD = 5.8x10-10M for HER2; KD = 8.9x10-9M for CD47) and has stronger ADCC activity against NCI-N87 (EC50 = 0.054nM for IMM2902, v.s. 0.868nM for trastuzumab). In vivo efficacy studies in several xenograft tumor models revealed a robust anti-tumor activity as reflected by the complete elimination of established tumors in BT-474 breast cancer and NCI-N87 gastric xenograft models even at the dose as low as 3.5mg/kg. Interestingly, even in Herceptin-resistant breast tumor model, when administered at a dose of 10mg/kg, the established HCC-1954 tumors were also eliminated. Immunohistochemistry staining of the tumor tissues demonstrated an accelerated HER2 degradation which is highly correlated with tumor volume. IMM2902 has no impact on hemagglutination, nor does it have significant hemotoxicity following single as well as multiple administrations in non-human primate animals at different dosage. Our study suggests that IMM2902 has the potential to be an alternative promising treatment option for patients with her2-positive cancers refractory to trastuzumab treatment.
Citation Format: Wenzhi Tian, Song Li, Dianze Chen, Dandan Liu, Huiqin Guo, Chunmei Yang, Li Zhang, Wei Zhang, Xiaoping Tu, Liang Peng, Gui Zhao, Ruliang Zhang, Fan Zhang. Preclinical development of a bispecific antibody-trap selectively targeting CD47 and HER2 for the treatment of breast as well as gastric 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 6280.
Abstract 6281: Preclinical development of a bispecific antibody-trap selectively targeting CD47 and CD24 for cancer immunotherapy
Authors: Tian Wenzhi , Li Song , Chen Dianze , Liu Dandan , Guo Huiqin , Yang Chunmei , Zhang Li , Zhang Wei , Tu Xiaoping , Peng Liang , Zhao Gui , Zhang Ruliang , Zhang Fan 
Published: June 2022

Abstract
Limited treatment beneficial rate and market saturation of the first generation of immune checkpoint inhibitors (Such as PD-(L)1 inhibitors) have turned the attention of pharmaceutical industry to the next generation of innate immune checkpoints such as CD47/SIRPα and CD24/Siglec-10. Various cancers of lung, breast, colon, prostate, ovarian, stomach, pancreas, myeloid and lymphoid tissues are known to highly express CD47 and/or CD24, which confer cancer cells means of immune-evasion via induction of “Don’t eat me” signals. Precisely and simultaneously neutralizing CD47 and CD24 signaling on tumors, when coupled with an IgG1 antibody’s potent phagocytosis and cytotoxicity activity, may serve as potent immunotherapy for multiple cancer types. We have developed a humanized CD24 neutralizing antibody which has been revealed to neutralize CD24-Siglec-10 interaction and completely eliminate established colon cancer in syngeneic mouse models via proposed mechanisms of antibody-dependent cell cytotoxicity (ADCC), antibody-dependent cell phagocytosis (ADCP), and subsequent tumor-specific immunity as a result of macrophage activation. Using this mAb as backbone, we developed an CD24 mAb-CD47 trap by conjugating the SIRPα decoy receptor to the N-terminal of the antibody heavy chain. Initial in vitro studies indicated that this mAb-trap has simultaneous two-target binding as well as blocking activities. More promisingly, eight administrations of the mAb-trap at 3mg/kg dose in mice bearing triple-negative breast cancer resulted in a complete tumor growth inhibition. Furthermore, in a Herceptin-resistant xenograft tumor model, the mAb-trap is also efficacious and resulted in over 60% of tumor growth inhibition when administrated at 7.2mg/kg. Taken together, our data show that precise neutralization of CD47 and CD24 signaling on tumors using IgG1 antibody may serve as potent monotherapy for cancers.
Citation Format: Wenzhi Tian, Song Li, Dianze Chen, Dandan Liu, Huiqin Guo, Chunmei Yang, Li Zhang, Wei Zhang, Xiaoping Tu, Liang Peng, Gui Zhao, Ruliang Zhang, Fan Zhang. Preclinical development of a bispecific antibody-trap selectively targeting CD47 and CD24 for cancer immunotherapy [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 6281.
Abstract 6310: Designing genomic test reports using a user-centered approach for clinicians in Pakistan
Authors: Agha Momal , Khan Faisal 
Published: June 2022

Abstract
In the developed world, precision medicine and genomics are transforming traditional healthcare approaches. In spite of rapid technological progress being made in genomics, a 'genomic divide' is emerging between developed and developing countries. This is partly because of the limited genomic literacy of healthcare professionals and a scarcity of available genomics workforce that reportedly deters them from proposing genomic testing. We aim to help reduce this 'genomic divide' by proposing a genomic test report design for clinicians in Pakistan, that incorporates user-centered design principles. We tested two commonly used genomic reportswiththat varied in language, content and layout. Report A was a one-page genomic report from the Laboratory for Molecular Medicine, of a patient with suspected hypertrophic cardiomyopathy. Report B was a report from FoundationOneCDx, of a breast carcinoma specimen with confirmed findings mentioned. We employed a qualitative descriptive study design, including a survey for trainees, non-specialists, and specialists. The parameters recorded were: subject comprehension, overall visual impression, level of difficulty of the language, and ease of understanding, along with, actionability and degree of trust. A total of 49 medical professionals across 11 institutes in Pakistan participated in the survey, of which 11 were specialists and 38 were non-specialists. We extracted 19 recommendations from the survey and broadly grouped them into three categories: communication style, report content, and layout. About 25% of the respondents commented that they would prefer a short and concise report, 20.8% wanted the language to be ‘doctor-friendly’ and 8.3% preferred data to be presented in tables. All recommendations were incorporated into our proposed genomic test report template. The template displays the results and what they mean for the patient (in layman's terms for ease of access to non-specialists), what possible action is to be taken by the doctor, and details of further information and support regarding the results. We propose the addition of a box on technical methodology at the end of the report template that may help in assisting with refreshing the genomic knowledge of non-specialists. Our findings have shown that in order to design impactful genomic reports for clinicians in Pakistan, we will have to start with a user-centered design approach. This can be instrumental in helping us improve the adoption of genomic testing in clinics around Pakistan.
Citation Format: Momal Agha, Faisal Khan. Designing genomic test reports using a user-centered approach for clinicians in Pakistan [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 6310.
Abstract 6314: TME subtype impacts response to combined thermal ablation and immunotherapy
Authors: Wang James , Fite Brett Z. , Kare Aris , Wu Bo , Raie Marina N. , Tumbale Spencer , Davis Ryan R. , Tepper Clifford G. , Ferrara Katherine 
Published: June 2022

Abstract
The tumor microenvironment (TME) subtype is a critical factor when combining immunotherapy with tumor debulking strategies such as ultrasound ablation. To understand the effects of the TME subtype, we studied two multi-site murine cancer models, an immune-suppressed KPC (Kras+/LSL-G12D; Trp53+/LSL-R172H; Pdx1-Cre) pancreatic adenocarcinoma (MT4) model and a neu deletion HER2+ (NDL) mammary adenocarcinoma model with a larger naïve lymphocyte population. After profiling the two models with histology and single-cell sequencing, we designed immunotherapy combinations with Magnetic Resonance-guided Focused Ultrasound (MRgFUS) thermal ablation that were specific to each TME subtype. To understand the impact of the molecular and cellular differences upon each model, we characterized the treatment effect with transcriptomic analysis and digital cytometry. We found that combining MRgFUS ablation with immunotherapy reduced tumor growth and extended survival by at least 2-fold in the MT4 pancreatic cancer model. Gene set enrichment analysis (GSEA) of bulk RNA sequencing data indicated that the combination of ablation with immunotherapy preferentially enriched functional annotations for leukocyte migration in the MT4 model and wound healing and inflammatory cytokines in the NDL model (e.g. for IL6: 1.6 fold increase in MT4 vs 10.3 fold in NDL tumors). We then particularly focused on whether dendritic cell (DC) activation and CD4 T cell populations could be enhanced when ablating pancreatic tumors. By CIBERSORTx digital cytometry, aCD40 + aPD-1 combinations increased the presence of activated DCs in MT4 tumors by 2.4-fold. Activated DCs were also increased by CP4 (aCD40 + aPD-1 + CTLA-4) alone 1.7 fold or in combination with ablation in both treated (2.4 fold) and distant (2.2 fold) lesions. Ablation combined with aPD-1 alone did not significantly impact DCs in the MT4 model. In addition, CD4 lymphocytes increased 5 and 8 fold in treated and distant tumors by ablation combined with CP4 in the MT4 model. Taken together, inflammatory cytokines were preferentially elevated by ablation in a dense epithelial breast cancer as compared with a pancreatic tumor model. Further, the results suggest that aCD40 immunotherapy retains efficacy when combined with thermal ablation in pancreatic tumors. This work can inform clinical translation of ablative and immunotherapy combination protocols.
Citation Format: James Wang, Brett Z. Fite, Aris Kare, Bo Wu, Marina N. Raie, Spencer Tumbale, Ryan R. Davis, Clifford G. Tepper, Katherine Ferrara. TME subtype impacts response to combined thermal ablation and immunotherapy [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 6314.