bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract CT529: A Phase 1b Study of CG0070 combined with nivolumab in cisplatin ineligible patients with muscle invasive bladder cancer
Authors: Li Roger , Sexton Wade , Spiess Phillipe , Gilbert Scott , Pow-Sang Julio , Zhang Jingsong , Borjas Gustavo , Grandi Paola , Burke James , Jain Rohit , Conejo-Garcia Jose 
Published: June 2022

Abstract
Background: Up to 50% of patients with muscle invasive bladder cancer (MIBC) are unable to receive neoadjuvant chemotherapy, creating an unmet clinical need for alternative systemic treatment. Results from recent neoadjuvant immune checkpoint blockade (ICB) studies signal pCR rates between 31-42%. However, there was a clear dichotomy in response between patients with high vs. low pre-treatment lymphocytic infiltration. In tumors exhibiting immune excluded or immune desert phenotypes, therapeutic strategies to attract CD8+ T cells infiltration prior to ICB may be beneficial. CG0070 is an oncolytic adenovirus designed to preferentially replicate through a transcriptionally regulated promoter that is up-regulated in RB-pathway-defective cells (&gt;70% of MIBC). In addition, CG0070 expresses GM-CSF to attract antigen presenting cells to the tumor microenvironment. We hypothesize that combination therapy using intravesical CG0070 and systemic Nivolumab is 1) safe and 2) can enhance local and systemic treatment response in the neoadjuvant setting against MIBC.
Methods: This is a phase Ib trial evaluating 2 doses of nivolumab (4 weeks apart) with 6 weekly intravesical CG0070 followed by cystectomy. Dose-limiting toxicities (DLTs) will be assessed in 6 DLT-evaluable patients in a safety lead-in phase. The combination would be declared tolerable if the incidence of DLTs is &lt;33%, and the study expanded to 30 patients. Key eligibility: cT2-T4aN0-1M0 stage, no autoimmume disease within 2 years, and no concurrent invasive upper tract carcinoma or other active cancer. The primary objective is to evaluate the safety of combination therapy according to CTCAE v5.0. The secondary objective is to assess the changes in the lymphocytic infiltration following combination therapy and to assess the antitumor efficacy of combination therapy. Exploratory endpoints include assessing the predictive value of E2F expression, tumor mutational burden, immune infiltration, and various peripheral blood for treatment response. Study Progress: Study is actively accruing. Clinical trial information: NCT04610671. An update on the study will be provided at the time of presentation.
Citation Format: Roger Li, Wade Sexton, Phillipe Spiess, Scott Gilbert, Julio Pow-Sang, Jingsong Zhang, Gustavo Borjas, Paola Grandi, James Burke, Rohit Jain, Jose Conejo-Garcia. A Phase 1b Study of CG0070 combined with nivolumab in cisplatin ineligible patients with muscle invasive bladder 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 CT529.
Abstract LB002: Development of fully human anti-CD19 &CD22 bispecific tandem CAR-T for the treatment of resistant or relapsed B cell malignancies
Authors: Nguyen Jenna , Zhang Gening , Zhang Keming , Jiang Ning , Feng Ryan , Wong Jeffrey , Luu Annie , Chen Yan , Zhao Kehao 
Published: June 2022

Abstract
Background: CD19 CAR-T has revolutionized the cancer immunotherapy for B cell malignancies. However, 40-50% patients have relapsed post current CD19 monospecific CAR-T treatment within 24 months. It has been shown that the resistance mechanism relates to either lack of persistency of the CAR-T in patients or due to CD19 target escape during treatment. CD19 and CD22 are co-expressed on B cells during B cell maturation and on most B cell malignancies. We have developed a fully human anti-CD19 and CD22 bispecific tandem CAR, aiming to overcome CD19 target escape mechanism and be more persistent with improved production process.
Methods: Utilizing mRNADis࣪ mRNA display and live cell selections, we have discovered a set of human anti-CD19 and anti-CD22 scFvs with a broad affinity range and broad epitope coverage. We have generated EPC-001, an optimal CD19/CD22 bispecific tandem CAR-T candidate, by precise engineering of multiple pairs of CD19/CD22 tandem scFvs with monospecific and bispecific target binding properties, linker length and scFv orientation.
Results: EPC-001 demonstrated both mono-specific and bivalent CD19 and CD22 target cell engagement, which led to CAR-T cell mediated cytotoxic cancer cell killing, cytokine release and CAR-T proliferation. EPC-001 showed improved Tscm and Tcm early phenotype and demonstrated potent anti-tumor activity in Raji-luciferase disseminated animal model, as well as persistent CAR-T activity when mice re-challenged with additional tumor cells. Furthermore, we have developed CD19 and CD22 knockout Raji animal models and demonstrated the in vivo mechanism of EPC-001 in overcoming CD19 or CD22 target escape resistance mechanism.
Conclusion: EPC-001 is a promising candidate that potentially prevents target escape by bivalent targeting of CD19 and CD22 simultaneously and overcome target escape with mono-specific engagement and CAR activation. EPC-001 has been advanced into clinic for proof of concept in investigator-initiated trial to treat CD19 CAR-T resistant/relapsed patients.
Citation Format: Jenna Nguyen, Gening Zhang, Keming Zhang, Ning Jiang, Ryan Feng, Jeffrey Wong, Annie Luu, Yan Chen, Kehao Zhao. Development of fully human anti-CD19 &CD22 bispecific tandem CAR-T for the treatment of resistant or relapsed B cell malignancies [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 LB002.
Abstract LB006: In vivo programming of myeloid cells by mRNA mediated delivery of novel Fc alpha fusion receptor activates anti-tumor immunity
Authors: Zhao Hongyun , Shcherbakova Inna , Prod’homme Thomas , McCreedy Bruce , Wang Yuxiao , Getts Daniel 
Published: June 2022

Abstract
Immunotherapy has revolutionized cancer treatment. However, for the majority of patients with advanced solid tumors, sustained clinical benefit has yet to be achieved. Myeloid cells such as monocytes and macrophages readily accumulate in tumors, in some cases contributing up to 75% of the tumor mass. Reprogramming circulating and tumor associated myeloid cells to activate their ability to elicit anti-tumor adaptive immunity by phagocytosis, cytokine secretion and antigen presentation is an attractive approach to harness and orchestrate systemic anti-tumor immunity. It remains challenging to specifically target and activate myeloid cells in vivo. To overcome this hurdle, we have developed a novel in vivo myeloid cell engineering platform: Fc-alpha Receptor Fusion Constructs. Unlike other chimeric antigen receptors (CARs) the construct was engineered by fusing a tumor recognition scFv with the alpha chain of human Fc receptors. The stable expression and function of these receptors requires endogenously expressed Fc receptor gamma chain, a protein with limited expression to immune cells, mostly myeloid cells. Here, we present that intravenous infusion of lipid-nanoparticle (LNP) encapsulating the Fc-alpha Receptor Fusion Construct mRNA results in the uptake and expression of the construct by myeloid cells. In immunodeficient xenograft models of hepatocellular carcinoma and triple negative breast cancer, delivery of LNP mRNA encoding for GPC3 or TROP2 targeted Fc-alpha Receptor Fusion Constructs resulted in tumor killing, confirming the ability of this approach to program myeloid cells. Furthermore, in the B16 syngeneic melanoma model, treatment with the melanoma antigen GP75 targeted Fc-alpha Receptor Fusion Constructs was also associated with the initiation of broad systemic immune responses, characterized by tumoral accumulation of activated CD8+ T cells, reduced tumor associated Tregs and activation of antigen presenting cells in spleen. Together these studies highlight the potential of Fc-alpha Receptor Fusion Construct delivered directly in vivo to program myeloid cells to recognize and kill cancer.
Citation Format: Hongyun Zhao, Inna Shcherbakova, Thomas Prod’homme, Bruce McCreedy, Yuxiao Wang, Daniel Getts. In vivo programming of myeloid cells by mRNA mediated delivery of novel Fc alpha fusion receptor activates anti-tumor immunity [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 LB006.
Abstract LB008: Characterization of immune correlates of clinical activity for Nous-209, an off-the-shelf immunotherapy, with pembrolizumab for treatment of tumors characterized by microsatellite instability (MSI)
Authors: D'Alise Anna Morena , Leoni Guido , Langone Francesca , Micarelli Elisa , Cotugno Gabriella , Overman Michael James , Fakih Marwan , Le Dung , Faivre Théa , Scarselli Elisa 
Published: June 2022

Abstract
Tumors with microsatellite instability (MSI) are caused by a deficiency in DNA mismatch repair (dMMR) system that leads to the accumulation of mutations within microsatellite regions. These types of mutations can determine a shift of the translational reading frame, generating Frame Shifted Peptides (FSPs). FSPs are tumor-specific neoantigens. Nous-209 is an off-the-shelf vaccine encoding 209 FSPs shared across dMMR/MSI tumors (Leoni et al., Cancer Res, 2020). The combination of the Nous-209 genetic polyvalent cancer vaccine and pembrolizumab has been demonstrated to be safe, highly immunogenic, with promising early signs of clinical efficacy in 12 patients with 7 durable confirmed PRs, 2 durable SDs and 3 PDs observed (Overman et al., SITC Nov 13, 2021 Poster number: 410). Here, we explore immune correlates potentially associated with the clinical outcome with the aim to address the Nous-209 contribution to the activity of pembrolizumab in this patient population. Several immunological analyses were performed on biological samples collected before and after treatment with Nous-209. Analyses were performed on paired blood and tumor biopsy samples. In periphery, vaccine immunogenicity was demonstrated by ex-vivo interferon-gamma ELISpot assay in 67% of subjects in dose level 1 (n=3), and 100% (n=7) of patients in dose level 2 with a mean of ≈1,500 IFN-γ SFCs/million PBMCs at the peak of the immune response. In 3 patients with partial response whose pre/post tumor biopsies were available, the intratumoral TCR repertoire was expanded and diversified post treatment with Nous-209. Moreover, in one out of these three patients it was possible to track vaccine-induced neoantigen specific TCR in the tumor biopsy post Nous-209 treatment. Overall, these results indicate that neoantigen specific CD8+ T cells, induced by Nous-209, expand and diversify upon treatment, and successfully traffic to and infiltrate the tumor microenvironment to exert anti-tumor activity.
Citation Format: Anna Morena D'Alise, Guido Leoni, Francesca Langone, Elisa Micarelli, Gabriella Cotugno, Michael James Overman, Marwan Fakih, Dung Le, Théa Faivre, Elisa Scarselli. Characterization of immune correlates of clinical activity for Nous-209, an off-the-shelf immunotherapy, with pembrolizumab for treatment of tumors characterized by microsatellite instability (MSI) [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 LB008.
Abstract LB022: A hybrid epithelial to mesenchymal transition in ex-vivo cutaneous squamous cell carcinoma tissues
Authors: Pulford Christopher S. , Uppalapati Chandana K. , Montgomery McKale R. , Hull Elizabeth E. , Leyva Kathryn J. 
Published: June 2022

Abstract
While most cases of cutaneous squamous cell carcinoma (cSCC) are benign, invasive cSCC is associated with higher mortality and is often more difficult to treat. As such, understanding the factors that influence the progression of cSCC are important. Aggressive cancers metastasize through a series of evolutionary changes, collectively called the epithelial-to-mesenchymal transition (EMT). During EMT, epithelial cells transition to a highly mobile mesenchymal cell type with metastatic capacities. While changes in expression of TGF-β, vimentin, and E-cadherin are hallmarks, EMT is not an “all or none” process. Using patient-derived cSCC and adjacent normal tissues (ANT), we observed a significant increase in mRNA expression of TGF-β (p&lt;0.05), TGF-βR2 (p&lt;0.001), and E-cadherin (p&lt;0.005) in cSCC tissues by qPCR. Immunoblots performed on homogenized tissues yielded significant and parallel increases in protein expression of TGF-β (p&lt;0.05) and E-cadherin (p&lt;0.05). We also observed increased expression of the EMT-associated transcription factors Zeb1 and Snai1 in cSCC tissue sections using immunohistochemistry. Interestingly, we observed a significant increase in expression of vimentin (p&lt;0.01) by immunoblot and differential expression of four oncogenic and EMT-associated miRNAs; miR-31 expression was significantly higher in cSCC tissues (p&lt;0.001), while we observed a significant decrease in expression of miR-34a (p&lt;0.05), miR-200b, and miR-200c in cSCC tissues. Examination of ANT and cSCC tissue sections using immunofluorescence and immunohistochemistry showed differential, and reverse, expression of E-cadherin and vimentin among cells within an individual tumor. Collectively, our data support a hypothesis that cSCC tumors are undergoing a hybrid EMT program, where there is variation in expression of EMT markers by cells within a tumor mass that may be facilitating invasion. This hybrid EMT program may be promoting both survival and invasiveness of the tumors. A better understanding of this hybrid EMT process may influence therapeutic strategies in more invasive disease.
Citation Format: Christopher S. Pulford, Chandana K. Uppalapati, McKale R. Montgomery, Elizabeth E. Hull, Kathryn J. Leyva. A hybrid epithelial to mesenchymal transition in ex-vivo cutaneous squamous cell carcinoma tissues [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 LB022.
Abstract LB029: Comprehensive structure-function evaluation of the SHOC2 holophosphatase reveals disease mechanisms and therapeutic opportunities
Authors: Kwon Jason , Hajian Behnoush , Bian Yuemin , Amor Alvaro , Fuller James , Fraley Cara , Baker Laura , So Jonathan , Mayhew David , Sykes Abbey , Persky Nicole , Yang Xiaoping , Root David , Perry Charles , Lemke Christopher , Hahn William , Aguirre Andrew 
Published: June 2022

Abstract
Receptor tyrosine kinase (RTK)-RAS signaling through the downstream mitogen activated protein kinase (MAPK) cascade regulate cell proliferation and survival. The SHOC2 holophosphatase functions as a key regulator of RTK-RAS signaling by removing an inhibitory phosphorylation on RAF family proteins to potentiate MAPK signaling. SHOC2 forms a ternary complex with MRAS and PP1C, and human germline gain-of-function mutations of this complex result in congenital RASopathy syndromes. However, the structure and the assembly of this complex are poorly understood. Here, we use cryogenic electron microscopy (cryo-EM) to resolve the structure of the SHOC2-PP1C-MRAS holophosphatase to 2.9Å resolution. Furthermore, we define the biophysical principles of SHOC2 holoenzyme interactions, elucidate the assembly order of the complex, and systematically interrogate the functional consequences of nearly all possible missense variants of SHOC2 through deep mutational scanning. We demonstrate that SHOC2 binds PP1C and MRAS through a concave surface created by the leucine-rich repeat region and further engages PP1C through the N-terminal disordered region containing a degenerate RVxF motif. Initial complex formation is mediated by SHOC2-PP1C interactions and is stabilized by binding of GTP-loaded MRAS. These observations define how clinical mutants in Noonan-like syndrome and cancer stabilize interactions of complex members to enhance holophosphatase activity. Together, this integrative structure-function model comprehensively defines key binding interactions within the SHOC2 holophosphatase, informing therapeutic development.
Citation Format: Jason Kwon, Behnoush Hajian, Yuemin Bian, Alvaro Amor, James Fuller, Cara Fraley, Laura Baker, Jonathan So, David Mayhew, Abbey Sykes, Nicole Persky, Xiaoping Yang, David Root, Charles Perry, Christopher Lemke, William Hahn, Andrew Aguirre. Comprehensive structure-function evaluation of the SHOC2 holophosphatase reveals disease mechanisms and therapeutic opportunities [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 LB029.
Abstract LB034: Evaluation of a novel single-cell RNA sequencing methodology for use in clinical trial settings
Authors: Corney David , Han Yang , Qiu Yu , Fan Yongjun , Stephens Michael , O'Hara Andrea , Turner Laure , Mozdzierz Christopher , Latif Haythem , Zhou Ginger 
Published: June 2022

Abstract
Bulk RNA sequencing (RNA-seq) is regularly employed for transcriptional profiling but provides only a snapshot of the average population. Particularly when studying disease, understanding differences in diverse cells is essential thus single-cell resolution is a necessity due to significant cellular heterogeneity. High-throughput droplet- and microfluidic-based approaches for performing single-cell RNA-seq (scRNA-seq) are invaluable techniques for uncovering changes in cells such as differential gene expression and epigenetic states in cancer research. A challenge for scRNA-seq, however, is sample preparation as typically tissues must be processed immediately after collection. We and others have reported alternative approaches to stabilize samples prior to analysis such as cryopreservation of cells and tissues and methanol-based fixation of cells. However, the inclusion of these approaches is still limited in many settings due to the challenging logistics involved in sample collection. To further broaden the ability of researchers to deploy scRNA-seq, we report our experiences from testing a pre-commercial workflow developed by 10x Genomics to resolve these sample management limitations. The use of paraformaldehyde (PFA) to fix samples at the collection site allows samples to be transported to remote laboratories for downstream processing without sacrificing integrity or data quality. This advance has enabled new possibilities for sample accessibility, throughput, and batched analysis in basic and translational research settings. Furthermore, this approach also allows for analysis of transcriptome-wide gene expression at high sensitivity with simultaneous cellular readouts. Here we report a case study comparing the PFA method to standard approaches, and highlight advantages and potential applications previously not possible with reported sample preparation strategies.
Citation Format: David Corney, Yang Han, Yu Qiu, Yongjun Fan, Michael Stephens, Andrea O'Hara, Laure Turner, Christopher Mozdzierz, Haythem Latif, Ginger Zhou. Evaluation of a novel single-cell RNA sequencing methodology for use in clinical trial settings [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 LB034.
Abstract LB041: Differential response to progranulin in proliferative and metastatic SW13 cell subtypes
Authors: Okonya Chika , Montgomery McKale R. , Pascual Agnes S. , Uppalapati Chandana , Leyva Kathryn J. , Hull Elizabeth E. 
Published: June 2022

Abstract
The SW13 human adrenocortical carcinoma line exists in proliferative SW13- and metastatic SW13+ subtypes which interconvert by epigenetic mechanisms in an epithelial to mesenchymal transition (EMT) process. This work investigates the contribution of progranulin to the maintenance of and conversion between the SW13 subtypes. A prognostic biomarker in cancer, progranulin is a pleotropic signaling molecule composed of 7 highly conserved granulin repeats. Each granulin unit has independent and sometimes opposing activity in the regulation of diverse cellular activities including proliferation, chemoresistance, lysosomal function, migration, wound healing, and inflammation. Thus, the ultimate biological activity of progranulin is context-dependent as it relies on the expression of diverse intracellular and extracellular proteases. Treatment with exogenous progranulin increases growth of SW13- cells but not SW13+ cells, a finding which suggests differential processing. As the metastatic SW13+ subtype produces more progranulin than the SW13- subtype, these data are consistent with an inability of SW13+ to process endogenous progranulin to the mitogenic granulin unit(s). Immunoblotting with antibodies specific for granulin repeats indicates that progranulin is processed differently in each subtype. In this work, we focused on lysosomes as a potential site for differential processing of progranulin for several reasons. First, lysosomes play a role in EMT. Second, lysosomal proteases have been shown to process progranulin and progranulin itself plays a role in lysosome maturation. Finally, preliminary data suggest that there are differences in lysosomal function and pH between the two subtypes. Ongoing experiments address the benefits of lysosomal acidification and the role that differential processing of progranulin may play on the maintenance and interconversion of the SW13 subtypes.
Citation Format: Chika Okonya, McKale R. Montgomery, Agnes S. Pascual, Chandana Uppalapati, Kathryn J. Leyva, Elizabeth E. Hull. Differential response to progranulin in proliferative and metastatic SW13 cell subtypes [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 LB041.