bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2189: Generating Merkel cell polyomavirus-specific T cells from healthy donors for adoptive immunotherapy
Authors: Davies Sarah , Barrett John , Muranski Pawel J. , Brownell Isaac 
Published: September 2020

Abstract
Merkel Cell Carcinoma (MCC) is an aggressive neuroendocrine skin cancer that is highly immunogenic. Approximately 80% of MCC tumors are virus positive (VP-MCC) and express Merkel cell polyomavirus (MCPyV) T antigens that drive oncogenesis. As VP-MCC have a low mutation burden with few predicted neoantigens, viral oncogenes are thought to be primary targets for anti-cancer immunity. Immune checkpoint inhibitors improve MCC survival, yet not all patients have durable responses. VP-MCC patients who fail checkpoint inhibition or who have immune dysfunction may benefit from adoptive cellular therapy using virus-specific T cells from HLA-matched donors. As the risk of graft versus host disease is low with virus-specific T cells, this approach is being investigated for other viral diseases. We set out to generate MCPyV-specific T cells from healthy donors for potential adoptive immunotherapy. Naïve and memory T cells from donors were magnetically isolated prior to stimulation with autologous monocyte-derived dendritic cells pulsed with 15-mer overlapping peptide libraries of MCPyV T antigens. T cells were serially re-stimulated with peptide-pulsed irradiated, autologous PHA-blasts up to five times. Cultures were maintained in either standard growth cytokines (IL-2, IL-7, and IL-15) or a pro-inflammatory cytokine cocktail. T cell phenotype and reactivity were evaluated by flow cytometry. We found that standard cytokine conditions were unable to promote growth of MCPyV-specific mature T cells. Altering growth conditions to include a cocktail of pro-inflammatory cytokines promoted expansion of polyfunctional Th1 CD4+ T cells specific for MCPyV T antigen peptides. These cells produced TNFα and upregulated the activation markers CD154 and CD137 upon cognate antigen exposure. Cells were generated without bias for particular HLAs. These results suggest that peptide-based expansions may be a suitable platform to generate allogeneic adoptive T cell immunotherapies for patients with VP-MCC.
Citation Format: Sarah Davies, John Barrett, Pawel J. Muranski, Isaac Brownell. Generating Merkel cell polyomavirus-specific T cells from healthy donors for adoptive immunotherapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2189.
Abstract 2219: OnxoVEXmGM-CSF promotes systemic response to PD-L1 /PD-1 blockade in multiple mouse syngeneic tumor models
Authors: Cooke Keegan , Estrada Juan , Mitchell Petia , Zhan Jinghiu , Beltran Pedro J. , Qing Jing , Canon Jude 
Published: September 2020

Abstract
Inhibition of the immune-checkpoint axis that involves PD-L1/PD-1 has improved responses and outcomes for certain cancer patients, but there remains unmet need as only a fraction of patients respond to these therapies. Talimogene laherparepvec (T-VEC) is an FDA-approved, first-in-class oncolytic immunotherapy based on a modified herpes simplex virus type 1 (HSV-1) designed to selectively replicate in tumors and produce granulocyte-macrophage stimulating factor (GM-CSF) to enhance a tumor-antigen specific adaptive immune response. Intratumoral treatment with T-VEC has been shown to promote an inflammatory tumor microenvironment both preclinically and clinically. Combining T-VEC with immune checkpoint inhibitors is of high interest to potentially broaden and deepen the clinical responses in checkpoint-resistant tumors. In the current study, we evaluated the efficacy of OncoVEXmGM-CSF (an HSV modified like T-VEC, except that it produces murine GM-CSF) in combination with anti-PD-1/PD-L1 treatment in multiple syngeneic mouse tumor models. Bilateral tumor models were used, where only one tumor was treated with OncoVEXmGM-CSF (representing the local oncolytic effect), allowing the evaluation of systemic abscopal effect in the uninjected contralateral tumors. OncoVEXmGM-CSF in combination with anti-PD-L1/PD-1 enhanced tumor growth inhibition in both treated and contralateral tumors in the A20 and MC38 syngeneic models and overcame anti-PD-L1 resistance in the CT26 model. The combination treatment also led to a significant increase in median overall survival compared to either agent as a monotherapy. In addition, tumor antigen epitopes were identified by combining exome sequencing and MHC/HLA-binding prediction algorithms. Antigen-specific T cell response was measured in an IFN-γ ELISPOT assay using splenocytes from treated mice. OncoVEXmGM-CSF induced and /or enhanced systemic T cell responses directed against both tumor neoantigens and tumor-associated antigens. Together, these data reveal that OncoVEXmGM-CSF treatment can cause direct tumor lysis along with the potentiation of an adaptive, systemic T cell-mediated anti-tumor immune response that can be enhanced by the addition of PD-L1/PD-1. Our study provides a strong rationale for the ongoing clinical evaluation of the combination of T-VEC and PD1-/PD-L1-targeted therapy in cancer patients.
Citation Format: Keegan Cooke, Juan Estrada, Petia Mitchell, Jinghiu Zhan, Pedro J. Beltran, Jing Qing, Jude Canon. OnxoVEXmGM-CSF promotes systemic response to PD-L1 /PD-1 blockade in multiple mouse syngeneic tumor models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2219.
Abstract 2230: MG1131, a novel TIGIT-targeting monoclonal antibody, enhances anti-tumor immune responses by modulating NK and T cell activity
Authors: Lee Jeewon , Kim Munkyung , Nam Hye-mi , Sheen Joong Hyuk , Song Eun Jung , Yum Hye In , Lim So Jung , Park Hye-Young 
Published: September 2020

Abstract
As the recent rise of immune checkpoint inhibitors has resulted in durable clinical outcomes in cancer patients, the need for a newer and more widely effective target for immunotherapy has been vigorously sought in the field; T cell immunoreceptor with Ig and ITIM domain (TIGIT) is an immune checkpoint molecule expressed on CD8+ T cells, CD4+ T cells, NK cells, and regulatory T cells (Treg). TIGIT induces exhaustion of effector T cells (Teff) and NK cells in the tumor microenvironment via engagement with its ligand PVR (CD155) which is dominantly expressed on malignant tumor cells. After initial screening processes from a synthetic library, MG1131 clone was chosen based on the strongest binding affinity to human TIGIT and the superior PVR-blocking activity. MG1131 was cross-reactive with the cynomolgus monkey TIGIT, but not with the mouse TIGIT. Our in vitro efficacy data demonstrated that MG1131 activated NF-κB signaling in T cells, and enhanced NK-mediated tumor killing activities in a PVR-dependent manner. In vitro Treg suppression assays showed that MG1131 inhibited immunosuppressive functionality of Treg, leading to restoration of proliferation and IFN-γ secretion capacities of Teff even in the presence of Treg. In addition, expression levels of TIGIT on CD8+ T cells from PBMCs of cancer patient samples were higher compared with other immune inhibitory molecules such as PD-1, Tim-3, CTLA-4, or LAG-3, and the blockade of TIGIT by MG1131 resulted in increased IFN-γ secretion. Thus, our data indicate that MG1131 is a promising candidate for cancer immunotherapy by modulating NK and T cell functions.
Citation Format: Jeewon Lee, Munkyung Kim, Hye-mi Nam, Joong Hyuk Sheen, Eun Jung Song, Hye In Yum, So Jung Lim, Hye-Young Park. MG1131, a novel TIGIT-targeting monoclonal antibody, enhances anti-tumor immune responses by modulating NK and T cell activity [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2230.
Abstract 2234: Development of caninized monoclonal antibodies against PD1
Authors: Kocikowski Mikolaj , Dziubek Katarzyna , Vojtesek Borek , Argyle David , Hupp Ted , Parys Maciej 
Published: September 2020

Abstract
Immune blockade of inhibitory immune checkpoint (IC) mediated by Programmed cell death protein 1 (PD1) significantly increases survival of patients with advanced melanoma and other cancers. Dogs constitute a unique model for studying cancer types relevant to humans. Canine malignancies occur spontaneously and share many pathogenic pathways as well as therapy responses with their human counterparts. Dogs have a fully functional immune system, share the owners' lifestyle, environmental exposures, and their genome is more similar to the human one than the murine one is. Canine cancer research may be a superior alternative to mouse studies in the context of immunotherapy development. Unfortunately, IC-blocking antibodies are not available for companion animals. Monoclonal antibody against canine ICs has been previously developed by our group using mouse hybridoma technology. While functional, it couldn't be used clinically due to immunogenicity. To create a viable therapeutic, the antibody sequence was caninized. The murine constant regions of heavy and light chains were substituted with corresponding canine sequences. Following that, the variable regions' structural frameworks were replaced with canine sequences generated based on a canine library of antibody sequences.Additionally, we developed an antibody against the PDL1 protein using a previously established canine antibody phage library. The PD1 and PDL1 antibodies are being characterized by ELISA and cell-based blocking assays, T-cell activation assays and growth assessment of the impact on spheroid growth in patient-derived cultures.The characterized antibodies will widen the availability of canine IC blockers and pave the path for further research in comparative oncology.
Citation Format: Mikolaj Kocikowski, Katarzyna Dziubek, Borek Vojtesek, David Argyle, Ted Hupp, Maciej Parys. Development of caninized monoclonal antibodies against PD1 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2234.
Abstract 2251: Analysis of cancer survival using peripheral blood immunological parameters
Authors: Williams R. Michael , Zuniga Joaquin , Granados Julio , Feris Edmond Tato , Yunis Edmond J. 
Published: September 2020

Abstract
The purpose of this study is to use Immunological Evaluation of Peripheral Blood NK cell number to predict survival in the War of the Immune System against cancer. Comparison of the two survival curves starts with the null hypothesis: there is no difference between the top 50% NK vs bottom 50% NK survival curves. P value is derived from Test Statistic found using log rank test. Breast cancer patients and colon cancer patients were evaluated. Both showed statistically significant differences in survival based on NK Cell number. Eight breast cancer patients had local radiation which showed in every one that the peripheral blood NK cell number decreased during radiation and returned to baseline values after radiation ended. In colon cancer patients the level of quantitative IgM and IgA defined a difference in overall survival. This was not the case for breast cancer patients. Survival was evaluated over a 9+ year period in a single California practice.
Citation Format: R. Michael Williams, Joaquin Zuniga, Julio Granados, Edmond Tato Feris, Edmond J. Yunis. Analysis of cancer survival using peripheral blood immunological parameters [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2251.
Abstract 226: Pathways of nucleotide synthesis in NSCLC
Authors: Fan Teresa W-M , Sun Qiushi , Higashi Richard M. , Lane Andrew N. 
Published: September 2020

Abstract
Tracer-based mapping of metabolic networks is a powerful approach for revealing metabolic reprogramming in human cancer. Nucleotide synthesis and turnover is critical for cell proliferation and is tightly regulated [1,2]. We have developed NMR and tandem MS methods for determining the active pathways of the synthesis of free nucleotides and nucleotide sugars including UDP-Glucose and UDPGlcNAc using multiplexed stable isotope resolved metabolomics (mSIRM)[3] in a variety of models including freshly resected lung tumor tissue, mouse PDX and organoids. Using multiple isotopic labels (13C, 2H and 15N) we determined the relative contributions to purine and pyrimidine nucleotide synthesis of both exogenous glucose, glutamine, serine and glycine and metabolically-derived intracellular precursors. We have used these approaches to compare the relative importance of different metabolic pathways in NSCLC under various conditions to assess the role of the tumor microenvironment, and how these pathways are impacted by arsenite and selenite. Our findings indicate that the substrates for de novo nucleotide synthesis may differ profoundly between cancer cell lines and fresh human lung cancer tissues; for purines, the latter preferred glucose to exogenous serine or glycine but not the former. Pyrimidine nucleotides also utilize glucose for ribose synthesis via the pentose phosphate pathway, but both glucose and glutamine for the pyrimidine rings depending on the conditions and cell type. This distinction in substrate utilization in nucleotide synthesis in human cancer tissues should be considered when targeting one-carbon metabolism for cancer therapy.
Acknowledgements: This work was supported in part by grants: 1R01ES022191-01 (to TWMF and RMH), 1P01CA163223-01A1 (to ANL and TWMF), and 1U24DK097215-01A1 (to RMH, TWMF, and ANL).
References
1. Lane, A.N. & Fan,T. W-M. (2015) Regulation of nucleic acid metabolism in mammalian cells. Nucl.Acids Res. 43, 2466-85
2. Fan, T. W-M. et al. (2019) De novo synthesis of serine and glycine fuels purine nucleotide biosynthesis in human lung cancer tissues. J. Biol. Chem. 294, 13464-13477
3. Yang, Y., Fan, W. W-M., Lane, A.N. & Higashi, R.M. (2017) Chloroformate Derivatization for Tracing the Fate of Amino Acids in Cells by Multiple Stable Isotope Resolved Metabolomics (mSIRM). Anal. Chim. Acta 976, 63-73
Citation Format: Teresa W-M Fan, Qiushi Sun, Richard M. Higashi, Andrew N. Lane. Pathways of nucleotide synthesis in NSCLC [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 226.
Abstract 2283: A novel GUCY2C - CD3 bispecific engages T cells to induce cytotoxicity in gastrointestinal tumors
Authors: Mathur Divya , Root Adam , Bugaj-Gaweda Bozena , Tan Xingzhi , Fang Wei , Bisulco Stephanie , Golas Jonathan , Fernandez Diane , Kearney Jessica , Upeslacis Eric , Yao Johnny , Rosfjord Edward , Stevens Chad , Kobylarz Keith , King Lindsay , Narula Jatin , Kelleher Kerry , Schaer David , Kamperschroer Cris , Buetow Bernard , Rohde Cynthia , Moreau Allison , Wong Gilbert , Sapra Puja 
Published: September 2020

Abstract
Gastrointestinal malignancies, including colorectal cancer (CRC) remain an area of high unmet need. Here we demonstrate tumor selective and potent in vitro and in vivo efficacy with PF-07062119, a novel T cell engaging CD3 bispecific against tumors expressing the Guanylyl Cyclase C (GUCY2C) receptor, a target expressed in more than 90% of CRC, and in other gastrointestinal cancers. Additionally, to address immune evasion mechanisms, combinations of the GUCY2C-CD3 bispecific are explored with immune checkpoint blockade therapy, as well as with chemotherapeutic and anti-angiogenic agents that could enhance immune infiltration into tumors. Our preclinical in vivo data demonstrate that GUCY2C-positive tumors can be targeted with an anti-GUCY2C/anti-CD3ϵ bispecific, with selective drug biodistribution to tumors. PF-07062119 showed potent T cell mediated anti-tumor activity in several human xenograft models of CRC, using adoptive transfer of human T cells, including those with KRAS and BRAF mutations, as well as in models with syngeneic tumors in immunocompetent human CD3 transgenic mice. PF-07062119 activity was further enhanced when combined with anti PD-1/PD-L1 treatment or in combination with chemotherapy or anti-angiogenic therapy. A combination of immunohistochemistry, flow cytometry and CyTOF analyses was used to demonstrate the mechanism of action of PF-07062119 in single agent and combination studies in vivo. Toxicity and pharmacokinetic studies were done in cynomolgus macaques and indicated a monitorable and manageable toxicity profile. These data highlight the potential for PF-07062119 to demonstrate efficacy and improve patient outcomes in CRC and other gastrointestinal malignancies. A clinical Phase I study has been initiated in patients with CRC, gastric and esophageal adenocarcinomas (NCT04171141).
Citation Format: Divya Mathur, Adam Root, Bozena Bugaj-Gaweda, Xingzhi Tan, Wei Fang, Stephanie Bisulco, Jonathan Golas, Diane Fernandez, Jessica Kearney, Eric Upeslacis, Johnny Yao, Edward Rosfjord, Chad Stevens, Keith Kobylarz, Lindsay King, Jatin Narula, Kerry Kelleher, David Schaer, Cris Kamperschroer, Bernard Buetow, Cynthia Rohde, Allison Moreau, Gilbert Wong, Puja Sapra. A novel GUCY2C - CD3 bispecific engages T cells to induce cytotoxicity in gastrointestinal tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2283.
Abstract 2300: Deleterious germline mutations in the BRCA1 gene are associated with increased risk for cancers of the female reproductive system other than breast and ovarian as well as other cancers
Authors: Middlebrooks Candace , Pantin Kenzhane , Stacey Mark , Snyder Carrie , Casey Murray J. , Shaw Trudy , Bailey-Wilson Joan E. , Lynch Henry T. 
Published: September 2020

Abstract
Introduction: Mutations within the BRCA1 gene have been linked to up to an 80% lifetime risk of breast cancer as well as increased risk for ovarian, pancreatic and melanoma cancers. In this study we examined families with known germline mutations in BRCA1 after long-term follow-up to determine whether carriers experience higher rates of other cancers that have not yet been associated with germline mutations in the BRCA1 gene.
Methods: We studied 127 Hereditary Breast and Ovarian Cancer (HBOC) syndrome families (N = 23,078 individuals who have been followed at Creighton University) in which a causal mutation in the BRCA1 gene was identified. We performed survival analysis and a mixed effects cox regression with age at follow-up or cancer event as our time variable and presence or absence of BRCA1-related or other cancers (separate analyses) as our indicator variable.
Results: The survival curves showed a significant age effect with carriers having a younger age at cancer onset for BRCA1-related (as expected) as well as other cancers than that of non-carriers. The cox regression models were also highly significant (P = 1.77E-37 and P = 1.04E-07 for the BRCA1-related and other cancers, respectively). Of the cancers with enough samples to do stratified analyses, uterine, skin, lymphoma and colon cancers occurred at higher rates and at earlier ages in mutation carriers.
Conclusions: These analyses support the hypothesis that the BRCA1 mutations carriers of HBOC syndrome have increased risk for early onset of several additional cancer types, especially cancers that arise in estrogen-influenced tissues.
Citation Format: Candace Middlebrooks, Kenzhane Pantin, Mark Stacey, Carrie Snyder, Murray J. Casey, Trudy Shaw, Joan E. Bailey-Wilson, Henry T. Lynch. Deleterious germline mutations in the BRCA1 gene are associated with increased risk for cancers of the female reproductive system other than breast and ovarian as well as other cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2300.
Abstract 2301: Indications for systematic prostate biopsy in men with negative multi-parametric magnetic resonance imaging
Authors: Molokwu Chidi N. , Gkikas Christos , Bardgett Harry , Lee Nicola , Ali Faisal , Chahal Rohit , Singh Rajindra 
Published: September 2020

Abstract
Introduction: Multiparametric Magnetic Resonance Imaging (mpMRI) is a valuable tool in the prostate cancer diagnostic pathway, and MRI-influenced biopsy has been shown to be superior to systematic biopsy alone for detecting clinically significant prostate cancer (csPCa), defined as the presence of any Gleason ≥ 4. Negative predictive value of mpMRI for csPCa varies widely in published reports, with a median of approximately 88%. Counselling patients with negative mpMRI (PIRADS score &lt;3)to decide whether or not to proceed with systematic biopsy or PSA monitoring could be challenging. Several studies have shown that a PSA density (PSAD) ≥ 0.15 is an indication for systematic biopsy. We analysed the clinical, radiological and pathological features of patients with negative mpMRI but csPca on systematic biopsy to identify other criteria that may inform the need for systematic biopsy when mpMRI is negative.
Methods: For 18 months between Nov 2017 and May 2019, all men on our prostate diagnostic pathway with negative mpMRI were offered systematic biopsy. The criteria for pre-biopsy mpMRI was any man suitable for radical surgery or radiotherapy, plus one or more of PSA ≥ 3, palpable lesion on digital rectal examination, or family history of PCa in a first degree relative (father or brother). mpMRI was performed with a 1.5-Tesla magnet and included T2, DWI and DCE sequences. Systematic biopsy was TRUS-guided, with 8-16 biopsy cores.
Results: Of 589 mpMRI scans in 573 men, 216 (37%) had negative mpMRI. Of these, 141 (65%) proceeded with systematic biopsy. Among the men that had biopsy, Gleason 3+3 was detected in 12 men (9%) and Gleason ≥ 4 in six (4%). Important pre-biopsy features in men with Gleason ≥ 4 were PSAD ≥ 0.15 (n=3), artefact on MRI from hip joint prosthesis (n=1), and family history (n=2). There were no unusual histological variants seen on the positive biopsy cores.
Conclusion: Most men with negative mpMRI can avoid prostate biopsy and be managed with PSA monitoring. Based on our experience, we recommend systematic biopsy in men with negative mpMRI who have PSAD ≥ 1.5, family history or any imaging artifact that may alter image interpretation.
Citation Format: Chidi N. Molokwu, Christos Gkikas, Harry Bardgett, Nicola Lee, Faisal Ali, Rohit Chahal, Rajindra Singh. Indications for systematic prostate biopsy in men with negative multi-parametric magnetic resonance imaging [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2301.