bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 55: A genome-wide atlas of recurrent repeat expansions in human cancer genomes
Authors: Erwin Graham S. , Gursoy Gamze , Al-Abri Rashid , Hoerner Christian , Dolzhenko Egor , Eberle Michael , Fan Alice , Leppert John , Gerstein Mark , Snyder Michael P. 
Published: June 2022

Abstract
Expansion of a single repetitive DNA sequence, termed a tandem repeat (TR), is known to cause more than 40 neurodegenerative diseases. However, repeat expansions have not been systematically examined in contexts beyond neurological disorders. In a specific form of cancer, termed microsatellite instability (MSI), mutations accumulate in short (&lt;50 bp) tracts of TRs, suggesting that cancer genomes may also harbor larger repeat expansions. Here, we developed a new method to systematically identify TR alterations and applied it to the analysis of 2,622 cancer genomes spanning 29 cancer types. We identified 160 recurrent repeat expansions (rREs) in 7 cancers; most (155/160) rREs were cancer-subtype specific. Surprisingly, rREs were not correlated with MSI status, demonstrating that they arise by a distinct process. We also found that rREs are situated closer to candidate cis-regulatory elements than expected by chance, suggesting a role in gene regulation. Interestingly, an rRE in the intron of UGT2B7, detected in 34% of renal cell carcinoma samples, is associated with a decrease in gene expression. Our results demonstrate that rREs are an important and unexplored source of genetic variation in human cancer and provide a large catalog for further study.
Citation Format: Graham S. Erwin, Gamze Gursoy, Rashid Al-Abri, Christian Hoerner, Egor Dolzhenko, Michael Eberle, Alice Fan, John Leppert, Mark Gerstein, Michael P. Snyder. A genome-wide atlas of recurrent repeat expansions in human cancer genomes [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 55.
Abstract 5504: Adoptive cell therapy with tumor-specific Th9 cells induces viral mimicry to restrain acquired resistance from antigen-loss-variant tumor cells
Authors: Lu Yong 
Published: June 2022

Abstract
Adoptive cell therapy (ACT) with tumor-specific T cells expressing T-cell-receptors (TCR) or chimeric antigen receptors (CAR) has not mediated sustained responses in solid tumors. Several factors limit the efficacy of ACT in solid tumors and lead to primary resistance and acquired resistance (refers to recurrence after the initial response). These include but not limited to the insufficient proliferation of T cells, the low capacity of T cells to penetrate stroma-rich solid tumors, and heterogeneity of antigen expression in solid tumors, which allows the escape of T cell attack by tumor cells when becoming antigen-loss-variant cancer cell (ALV). Hence, it is urgent to develop novel ACT strategies to eradicate solid tumors and prevent acquired resistance.
We have previously reported (Yong Lu, Cancer Cell, 2018) that tumor-specific IL-9-producing CD4+ Th9 cells represent a novel T cell paradigm for ACT - they are less exhausted, fully cytolytic, and hyperproliferative. This hyperproliferation of Th9 cells is driven by a unique Th9 master transcriptional factor Pu.1 mediated Pu.1-Traf6-NFκB signaling to ensure Th9 cells persist as long as “stem cell-like” T cells, which is not presented in other known CD4+ T cells subsets. In our most recent study, we demonstrate that murine and human Th9 cells, but not Th1/Tc1 or Th17 cells, expressing tumor-specific T-cell-receptors (TCR) or chimeric antigen receptors (CAR), eradicate advanced tumors that contain ALVs. This unprecedented antitumor capacity of Th9 cells is attributed to both enhanced direct tumor cell killing and bystander antitumor effects promoted by intratumor release of IFNα/β. Mechanistically, tumor-specific Th9 cells increase the intratumor accumulation of extracellular ATP (eATP, released from dying tumor cells), because of a unique feature of Th9 cells that lack the expression of ATP degrading ectoenzyme CD39. Intratumor enrichment of eATP promotes the monocyte infiltration and stimulates their production of IFNα/β by inducing eATP-endogenous retrovirus-TLR3/MAVS pathway activation. These results identify tumor-specific Th9 cells as a unique T cell subset endowed with the unprecedented capacity to eliminate ALVs for curative responses.
Citation Format: Yong Lu. Adoptive cell therapy with tumor-specific Th9 cells induces viral mimicry to restrain acquired resistance from antigen-loss-variant tumor cells [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 5504.
Abstract 5545: Intestinal toxicity to CTLA-4 blockade driven by IL-6 and myeloid infiltration
Authors: Zhou Yifan , Medik Yusra B. , Patel Bhakti , Zamler Daniel B. , Chen Sijie , Chapman Thomas , Schneider Sarah , Babcock Rachel L. , Chrisikos Taylor T. , Kahn Laura M. , Dyevoich Allison M. , Park Elizabeth M. , Cogdill Alexandria P. , Johnson Daniel H. , Johnson Sarah B. , Wani Khalida M. , Ledesma Debora A. , Hudgens Courtney W. , Wang Jingjing , Khan Md Abdul Wadud , Joon Aron Y. , Peng Weiyi , Li Haiyan S. , Arora Reetakshi , Tang Ximing , Raso Maria Gabriela , Zhang Xuegong , Foo Wai Chin , Tetzlaff Michael T. , Diehl Gretchen E. , Clise-Dwyer Karen , Whitley Elizabeth M. , Gubin Matthew M. , Allison James P. , Hwu Patrick , Ajami Nadim J. , Diab Adi , Wargo Jennifer A. , Watowich Stephanie S. 
Published: June 2022

Abstract
Immunotherapies such as anti-CTLA-4 immune checkpoint blockade (ICB) have revolutionized cancer treatment, yet quality of life and continuation of therapy can be constrained by off-target tissue damage or immune-related adverse events (irAEs). At present, there is limited understanding of irAE mechanisms, hampering development of approaches to mitigate their damage. We addressed this problem by generating animal models of intestinal irAE. Our results show that disruption of homeostatic immunity by genetic predisposition to intestinal inflammation or acute gastrointestinal infection sensitizes mice to anti-CTLA-4-mediated intestinal toxicity. Inflammation-prone mice treated with anti-CTLA-4 showed neutrophil accumulation, systemic interleukin-6 (IL-6) release, and dysbiosis. Significantly, IL-6 blockade combined with antibiotic treatment improved anti-CTLA-4 therapeutic efficacy and reduced intestinal irAEs. Immune signatures were validated in biopsies from patients who developed colitis during ICB, supporting the utility of our models. This study provides new pre-clinical models, mechanistic insight into irAEs, and potential approaches to enhance ICB efficacy while mitigating irAEs.
Citation Format: Yifan Zhou, Yusra B. Medik, Bhakti Patel, Daniel B. Zamler, Sijie Chen, Thomas Chapman, Sarah Schneider, Rachel L. Babcock, Taylor T. Chrisikos, Laura M. Kahn, Allison M. Dyevoich, Elizabeth M. Park, Alexandria P. Cogdill, Daniel H. Johnson, Sarah B. Johnson, Khalida M. Wani, Debora A. Ledesma, Courtney W. Hudgens, Jingjing Wang, Md Abdul Wadud Khan, Aron Y. Joon, Weiyi Peng, Haiyan S. Li, Reetakshi Arora, Ximing Tang, Maria Gabriela Raso, Xuegong Zhang, Wai Chin Foo, Michael T. Tetzlaff, Gretchen E. Diehl, Karen Clise-Dwyer, Elizabeth M. Whitley, Matthew M. Gubin, James P. Allison, Patrick Hwu, Nadim J. Ajami, Adi Diab, Jennifer A. Wargo, Stephanie S. Watowich. Intestinal toxicity to CTLA-4 blockade driven by IL-6 and myeloid infiltration [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 5545.
Abstract 5558: Discovery of a novel Claudin 6 X 4-1BB bispecific antibody with potent anti-tumor activity through conditional 4-1BB activation
Authors: Li Jian , Jiang Wenqing , Liu Yan , Wang Zhengyi , Chen Xi , Guo Taylor B. 
Published: June 2022

Abstract
Background Claudin 6 (CLDN6) is a tight junction transmembrane protein normally only expressed during embryonic development, but is aberrantly expressed in a variety of tumors, including ovarian cancer, testicular cancer, hepatocellular and lung adenocarcinoma. Here, we generated a CLDN6 X 4-1BB bispecific antibody (BsAb) which could conditionally activate T cells through 4-1BB stimulation upon CLDN6 engagement, positioning it as a potential novel immunotherapy for ovarian cancer and other CLDN6 positive tumors.
Methods CLDN6 X 4-1BB BsAb was evaluated for its antigen binding through cell-based binding assay. In vitro function of the antibody was confirmed in a 4-1BB signaling reporter assay and primary human PBMC assay. In vivo efficacy of the antibody was further demonstrated in 4-1BB humanized syngeneic mouse model. Ex vivo analysis of tumor infiltrating and peripheral immune cells was conducted by FACS. Safety parameters such as liver enzymes and pathology upon antibody administration were also assessed.
Results CLDN6 X 4-1BB BsAb showed strong binding to several ovarian cancer cell lines with different levels of CLDN6 expression. Functional evaluation of CLDN6X4-1BB BsAb indicated that the activation of 4-1BB signaling was dependent on CLDN6 expression on tumor cells and the activity was stronger than reference 4-1BB monoclonal antibody urelumab. In a humanized 4-1BB mouse model, CLDN6X4-1BB BsAb showed tumor growth inhibition superior to the combination of anti-CLDN6 and anti-4-1BB monospecific antibodies, and the treatment effect was associated with an increase in tumor infiltrating CD45 and CD8 cells as well as CD8/Treg ratio. From the safety perspective, there were no significant changes in liver enzymes or liver histopathology following repeated BsAb administration, suggesting little risks for liver toxicity commonly induced by other 4-1BB agonist antibodies.
Conclusions We have successfully generated a novel CLDN6-targeted 4-1BB bispecific antibody which could induce potent 4-1BB stimulation and anti-tumor activity in a CLDN6-dependent manner while minimizing the risk of liver toxicity. Taken together, these data support further development of CLDN6 X 4-1BB bispecific antibody towards IND and clinical trial in 2022.
Citation Format: Jian Li, Wenqing Jiang, Yan Liu, Zhengyi Wang, Xi Chen, Taylor B. Guo. Discovery of a novel Claudin 6 X 4-1BB bispecific antibody with potent anti-tumor activity through conditional 4-1BB activation [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 5558.
Abstract 5562: Development of a TERT-specific peptide/adjuvant vaccine in C57BL/6 mice
Authors: Marshall Jason D. , Song Yurong , Zarkesh Hamid , Matthews Rebecca L. , Sanders Chelsea , Difilippantonio Simone , Pinto Ligia A. , Sei Shizuko , Shoemaker Robert H. 
Published: June 2022

Abstract
Telomerase plays a vital role in cell senescence and cellular replication and has been described as a leading regulator in several human cancers, including prostate, thyroid, breast, colon, and bladder cancer. Telomerase is responsible for elongating telomere length and prolonging cellular lifespan as well as acting as a transcriptional modulator in cancer signaling pathways. Because of its enhanced expression in primary tumor cells as well as incipient tumor-initiating stem cells and with limited distribution in normal somatic cells, the catalytic component of telomerase, TERT (telomerase reverse transcriptase), is regarded as a high-impact target for immunotherapeutic agents and vaccines. In order to derive a mouse TERT (mTERT)-specific vaccine which could be useful in a preventive approach, we implemented an epitope-mapping stratagem by which pools of 30-mer peptides overlapping by 5 spanning the entire mTERT sequence were used to immunize C57BL/6 mice. Several immunogenic peptides were identified by matrixed peptide pool IFN-ɣ ELISPOT screening in a 2-part process that first identified positive pools, then identified individual peptides. 15-mer and 31-mer versions of the top 7 immunogenic mTERT peptides were synthesized and used as a peptide pool combined separately with several adjuvants to optimize immunogenicity. Results suggested a peptide sequence-specific preference for TLR3-mediated Hiltonol versus TLR9-mediated CpG-based adjuvants. In addition, the majority of T cell responses specific to the TERT peptides was identified through flow cytometry as belonging to the CD4 compartment, although one class I-restricted epitope was also identified. Multifunctional CD4+ T cells expressing IFN-ɣ, TNF-α, IL-2, and CD107a were identified specific to several mTERT peptides. In vivo cytotoxic effects exerted on TERT peptide pool-loaded target cells were also uncovered that were specific to a CpG-adjuvanted version of the vaccine. Finally, multiple versions of the mTERT peptide/adjuvant vaccine with highest immunogenicity scores are being tested in a syngeneic graft mouse model using subcutaneous implantation of lung cancer-derived SPON10 cells expressing mTERT. If proven efficacious, these results will support the feasibility of a TERT peptide/adjuvant approach for prophylactically engendering broad antitumor immunity to TERT-expressing cancers. Funded by NCI Contract No. HHSN261200800001E
Citation Format: Jason D. Marshall, Yurong Song, Hamid Zarkesh, Rebecca L. Matthews, Chelsea Sanders, Simone Difilippantonio, Ligia A. Pinto, Shizuko Sei, Robert H. Shoemaker. Development of a TERT-specific peptide/adjuvant vaccine in C57BL/6 mice [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 5562.
Abstract 5580: Incorporation of pro-memory transcription factors in fourth generation CARs enhances CAR T cell immunotherapy against solid tumors in an immunocompetent murine model
Authors: Reed Steven J. , Tower Samantha J. , Toumi Ryma , Kalia Vandana , Sarkar Surojit 
Published: June 2022

Abstract
A major obstacle in current T cell-based immunotherapy against solid tumors is the widely observed T cell exhaustion and loss of functionality within the tumor microenvironment (TME). We, and others, have demonstrated that chronic antigenic signaling is the predominant factor that drives TCR tumor-reactive, and CAR T cell exhaustion in the TME. To combat this exhaustion, we have engineered CD19-targeted third generation CAR constructs to express pro-memory transcription factors associated with longevity, polyfunctionality and/or enhanced responsiveness to immune checkpoint blockade in cancer immunotherapy. Using an immunocompetent murine model of syngeneic solid tumors expressing truncated human-CD19 (hCD19t), we demonstrate that ectopic expression of pro-memory transcription factors in the 4th generation transcription factor-CARs (TF-CARs) augments CAR T cell therapeutic efficacy against solid tumors. Amongst CAR T cells recovered from established solid tumors, the 4th generation TF-CAR T cells retained a memory-precursor effector (MPEC) T cell like phenotype, while the 3rd generation CAR T cells largely displayed a terminally exhausted phenotype (TEx). Importantly, the inclusion of select pro-memory transcription factors did not compromise CAR T cell proliferation or expression of the effector cytokines IFN-γ and TNFα following restimulation. In addition to superior control of primary tumors, the TF-CAR T cells instilled greater long-term protection from tumor relapse in mice, which cleared primary tumors (6/7) compared to 3rd generation CAR T cells (3/7). Collectively, these data present incorporation of pro-memory transcription factors as an attractive engineering strategy to intrinsically combat CAR T cell exhaustion in the TME and promote long-term CAR T cell memory and protection from tumor relapse.
Citation Format: Steven J. Reed, Samantha J. Tower, Ryma Toumi, Vandana Kalia, Surojit Sarkar. Incorporation of pro-memory transcription factors in fourth generation CARs enhances CAR T cell immunotherapy against solid tumors in an immunocompetent murine model [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 5580.
Abstract 5585: Inhibition of CSF1R enhances the antitumor efficacy of DC derived exosomes by modulating immunosuppressive tumor microenvironment
Authors: Barnwal Anjali , Bhattacharyya Jayanta , Ateeq Bushra 
Published: June 2022

Abstract
Dendritic cell (DC) derived exosomes (Dex) provide many advantages over DC vaccines such as cost effectiveness, stability, sensitivity to the systemic microenvironment. Though, Dex showed better therapeutic outcome in murine models, however, desired outcome was not achieved in clinical trials as it failed to induce robust immunity to modulate the immunosuppressive tumor microenvironment (TME). Colony stimulating factor-1 (CSF-1) binds to its receptor (CSF-1R) and recruits tumor associated macrophages (TAMs) and myeloid derived suppressor cells (MDSCs) in the TME which eventually creates the tumor immunosuppressive. Hence, in this study we used PLX-3397, a small molecule inhibitor of CSF-1R to enhance the antitumor efficacy of Dex. In a syngenic B16-F10murine melanoma model, we found that the combination treatment delayed the tumor growth and improved the survival compare to the mono therapy. In TME, the combination treatment significantly depleted the TAMs and MDSCs and increased the infiltration of lymphocytes (TILs). Additionally, Th1 population were found significantly higher in tumor as well as in spleen with mice received both Dex and PLX3397. In conclusion, PLX-3397 enhanced the in vivo antitumor efficacy of Dex by modulating the immunosuppressive microenvironment in tumor.
Citation Format: Anjali Barnwal, Jayanta Bhattacharyya, Bushra Ateeq. Inhibition of CSF1R enhances the antitumor efficacy of DC derived exosomes by modulating immunosuppressive tumor microenvironment [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 5585.
Abstract 5589: BYON4228 is a pan-allelic SIRPα antibody that potentiates killing of antibody-opsonized tumor cells and lacks binding to T cells
Authors: van Helden Mary , Zwarthoff Seline , Olsman Hugo , Paradé Marc , Mattaar Ellen , de Laat Karin , Lodewijks Imke , Boersema Paul , Driessen-Engels Lilian , Sanderink Jorien , Kappers Wendy , van den Dobbelsteen Diels , Ubink Ruud , Arends Roel , Rouwendal Gerard , Verheijden Gijs , van der Lee Miranda , Dokter Wim , Van den Berg Timo 
Published: June 2022

Abstract
Preclinical data have established CD47-SIRPα interactions as a myeloid immune checkpoint in cancer, which is corroborated by preliminary evidence from the first clinical studies with CD47 blockers. However, the ubiquitously expressed CD47 mediates functional interactions with other ligands as well, and therefore targeting of the primarily myeloid cell-restricted inhibitory immunoreceptor SIRPα may represent a better strategy. Here, we present preclinical results on a novel clinical candidate, BYON4228. BYON4228 is an antibody directed against SIRPα and recognizes both of the common allelic variants of human SIRPα which maximizes its potential clinical application in the broad human population. Notably, in contrast to several other anti-SIRPα antibodies in development, BYON4228 does not recognize the closely related T cell-expressed SIRPγ that has been reported to mediate interactions with CD47 as well, which are known to be instrumental in T cell extravasation and activation. BYON4228 binds to the N-terminal part of SIRPα and its epitope overlaps with the CD47-binding site. BYON4228 therefore prevents binding of CD47 to SIRPα and thus blocks inhibitory signaling through the CD47-SIRPα axis. Functional studies show that BYON4228 potentiates both macrophage- and neutrophil-mediated elimination of hematologic and solid cancer cells in vitro in the presence of several different tumor targeting antibodies like trastuzumab, rituximab, daratumumab and cetuximab, illustrating the broad potential clinical benefit and application of BYON4228. Single intravenous infusion of up to 100 mg/kg BYON4228 to male and female cynomolgus monkeys was well tolerated and did not elicit any adverse effects. Collectively, this defines BYON4228 as a pan-allelic anti-SIRPα antibody without T cell SIRPγ recognition that promotes the destruction of antibody-opsonized cancer cells. Clinical studies are planned to start in 2022.
Citation Format: Mary van Helden, Seline Zwarthoff, Hugo Olsman, Marc Paradé, Ellen Mattaar, Karin de Laat, Imke Lodewijks, Paul Boersema, Lilian Driessen-Engels, Jorien Sanderink, Wendy Kappers, Diels van den Dobbelsteen, Ruud Ubink, Roel Arends, Gerard Rouwendal, Gijs Verheijden, Miranda van der Lee, Wim Dokter, Timo Van den Berg. BYON4228 is a pan-allelic SIRPα antibody that potentiates killing of antibody-opsonized tumor cells and lacks binding to T cells [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 5589.
Abstract 5605: BH3120: A novel bispecific antibody targeting 4-1BB and PD-L1 with well balanced efficacy and safety profiles
Authors: Xu Jiangcheng , Liu Yang , Wang Jing , Fan Fei , Gu Haitao , Zhang Lanxin , Wang Jun , Song Ding , Guo Ailong , Zhang Hongjuan , Su Kaixuan , Su Jiaojiao , Li Lijuan , Cai Jingmei , Zhang Aihong , Liu Jiawang , Lee Kyoungwoo 
Published: June 2022

Abstract
4-1BB (CD137, TNFSF9) is a promising co-stimulatory signaling mediator of T cells and NK cells, and agonistic monoclonal antibodies targeting 4-1BB are under clinical investigations aiming to observe sufficient and prolonged anti-tumor efficacy. However, these trials have resulted in limited efficacy or safety, and different bispecific approaches are being explored to improve the profiles. BH3120, a bivalent bispecific antibody generated by Pentambody(TM) platform targeting 4-1BB and PD-L1 simultaneously, demonstrates strong and prolonged antitumor efficacy as monotherapy in in vivo studies, and favorable safety profiles up to 200mg/kg/dose in non-human primates. Moreover, combination of BH3120 with an immune checkpoint inhibitor shows synergistically enhanced anti-tumor efficacy. Supported by these results, IND enabling studies of BH3120 are on-going and clinical evaluations are planned from later in 2022.
Citation Format: Jiangcheng Xu, Yang Liu, Jing Wang, Fei Fan, Haitao Gu, Lanxin Zhang, Jun Wang, Ding Song, Ailong Guo, Hongjuan Zhang, Kaixuan Su, Jiaojiao Su, Lijuan Li, Jingmei Cai, Aihong Zhang, Jiawang Liu, Kyoungwoo Lee. BH3120: A novel bispecific antibody targeting 4-1BB and PD-L1 with well balanced efficacy and safety profiles [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 5605.