bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1632: Antibody mediated crosslinking of CD38 triggers costimulatory signaling and promotes T cell effector function
Authors: Hwang Mun Kyung , Wang Anlai , Song Zhili , Dai Shujia , Zhang Bailin , Theilhaber Joachim , Pao Lily , Wiederschain Dmitri , Zhu Chen 
Published: July 2021

Abstract
CD38 is a multi-functional ecto-enzyme that regulates NAD+ metabolism. Monoclonal antibodies against CD38, including daratumumab and isatuximab have been successfully developed to treat patients with multiple myeloma, a cancer known to express high levels of CD38. However, CD38 is also expressed by normal immune cells, including B, NK, myeloid and T cell subsets. Using monoclonal antibodies against CD38, we show that CD38 crosslinking can augment T cell antigen receptor signaling, leading to enhanced T cell proliferation and cytokine production. Gene profiling analysis supports the contention that anti-CD38 ligation promotes T cell activation. Studies of CD38 mutants demonstrate that the co-stimulatory effect of anti-CD38 is independent of the ecto-enzymatic activity of CD38. Further analysis of activated CD4 T cells by mass spectrometry shows that CD38 is in close proximity with multiple adhesion and co-stimulatory molecules, including LFA-1, ICOS and OX40. These data support a role for CD38 as a co-stimulatory molecule in T cells, independent of its enzymatic activity.
Citation Format: Mun Kyung Hwang, Anlai Wang, Zhili Song, Shujia Dai, Bailin Zhang, Joachim Theilhaber, Lily Pao, Dmitri Wiederschain, Chen Zhu. Antibody mediated crosslinking of CD38 triggers costimulatory signaling and promotes T cell effector function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1632.
Abstract 1673: Uveal melanoma study patients with low CD163:CD3 ratio in tumor biopsy and low serum IL-6 showed enhanced tumor shrinkage (TS) and overall survival (OS) on tebentafusp
Authors: Hassel Jessica C. , Benlahrech Adel , Stanhope Sarah , Naidoo Revashnee , Leach Emma , Collins Laura , Abdullah Shaad , Ranade Koustubh , Sacco Joseph 
Published: July 2021

Abstract
Background: Tebentafusp, an investigational TCR–anti-CD3 bispecific fusion protein (ImmTAC) that targets gp100 and activates T cells, has shown monotherapy activity in metastatic melanoma [1-3]. In a phase I/II trial enrolling metastatic uveal melanoma patients we explored biomarkers of clinical outcomes.
Methods: The effect of CD163+ macrophages on ImmTAC-mediated T cell proliferation and melanoma cell killing was assessed in vitro. Advanced uveal melanoma HLA-A*02:01+ patients (N = 127) were treated with weekly 68mcg tebentafusp after intra-patient dose escalation (NCT02570308). Serum samples (up to N=123) were profiled for 11 cytokines and chemokines. Digital image analysis of IHC enumerated immune cells per mm2 in tumor biopsies (up to N=112). Median cutoff was used for biomarker correlations with outcomes.
Results: In vitro, increasing numbers of CD163+ macrophages resulted in greater inhibition of ImmTAC-mediated T cell proliferation and killing of MEL624 melanoma cells. The numbers of tumor infiltrating T cells (CD3, CD4, CD8) and CD163+ macrophages at baseline were not associated with TS. However, below median CD163:CD3 ratio was associated with greater TS (odds ratio OR=2.9, p=0.014) and OS (hazard ratio HR=0.4, p=0.001), attributable to CD163:CD8 (OR=3.6, p=0.004) but not CD163:CD4 (OR=1.9, p=0.2). Low serum IL-6 levels at baseline trended with TS (OR=2.1, p=0.09) and OS (HR=0.3, p&lt;0.001). Subset with below median CD163:CD3 in tumor biopsies and serum IL-6 had the best outcomes (Table).
Conclusions: Uveal melanoma patients with low levels of pre-treatment CD163:CD3 in tumor biopsy and serum IL-6 may derive the most benefit from tebentafusp. This hypothesis will be tested in samples from a randomized trial of tebentafusp (NCT03070392). [1] NCT01211262; ASCO 2019 [2] Clinical Cancer Research; 2020[3] #195; ESMO IO; 2020
Subset% with tumor shrinkageMean change in tumor SLD ± S.E.1-year OS %All biomarker evaluable43 (N=95)5.4 ± 3 (N=95)58 (N=105)Low IL-6/Low CD163:CD370 (N=27)-9.4 ± 6.1 (N=27)93 (N=30)Low IL-6/High CD163:CD330 (N=20)10.2 ± 5.0 (N=20)64 (N=22)High IL-6/Low CD163:CD340 (N=20)14.2 ± 7.7 (N=20)41 (N=22)High IL-6/High CD163:CD329 (N=28)9.9 ± 4.0 (N=28)32 (N=31)
Citation Format: Jessica C. Hassel, Adel Benlahrech, Sarah Stanhope, Revashnee Naidoo, Emma Leach, Laura Collins, Shaad Abdullah, Koustubh Ranade, Joseph Sacco. Uveal melanoma study patients with low CD163:CD3 ratio in tumor biopsy and low serum IL-6 showed enhanced tumor shrinkage (TS) and overall survival (OS) on tebentafusp [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1673.
Abstract 1695: Activation of B cells by CD73 blocking antibodies
Authors: Hair James , Garcon Fabien , Hsueh Michelle , Dallaway Laura , Bibikova Elena , Torchia Maria Letizia Giardino , Moody Gordon , Schuller Alwin , Dovedi Simon J. , Cooper Zachary A. , Sachsenmeier Kris , Kumar Rakesh , Eyles Jim , Wilkinson Robert W. 
Published: July 2021

Abstract
The catabolism of ATP into immunosuppressive adenosine contributes to the dysfunction of tumor infiltrating leukocytes (TIL). CD73 is an ectonucleotidase which catabolizes conversion of AMP to adenosine and is expressed on a range of immune cells including B cells. Oleclumab (MEDI9447) is a monoclonal antibody specific for human CD73 and is currently in clinical development for the treatment of cancer. B cells constitute a significant proportion of human TIL; however, their importance to Immuno-Oncology (IO) treatments remains unclear. Recent publications demonstrate that B cells sustain inflammation and predict response to immune checkpoint blockade in human melanoma, their presence within the tumor microenvironment is correlated with improved prognosis in several human tumor types, and CD73 expression has been shown to vary on different human B cell subtypes. Further investigations into the role of CD73 in control of human B cell function are therefore warranted. We show that blockade of CD73 by oleclumab and other monoclonal antibodies on peripheral blood B cells from healthy human donors upregulates expression of CD69, CD83 and CD86, and induces secretion of IL-6, MIP-1α and MIP-1β. Activation is mediated by antibodies that block and internalize CD73 and is reduced by pharmacological inhibition of BTK, thus highlighting involvement of the canonical B-cell receptor signaling pathway. Furthermore, our analyses highlight a differential effect of CD73 blockade on individual B-cell populations, with the most robust increases in activation marker expression being observed on naïve subsets that retain expression of IgD. Our research has identified that oleclumab activates human peripheral blood B cells. Given the renewed interest in B-cell biology in IO, this is an area we believe warrants further clinical investigation.
Citation Format: James Hair, Fabien Garcon, Michelle Hsueh, Laura Dallaway, Elena Bibikova, Maria Letizia Giardino Torchia, Gordon Moody, Alwin Schuller, Simon J. Dovedi, Zachary A. Cooper, Kris Sachsenmeier, Rakesh Kumar, Jim Eyles, Robert W. Wilkinson. Activation of B cells by CD73 blocking antibodies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1695.
Abstract 1751: Decoding the immune system response to leptomeningeal metastasis
Authors: Remsik Jan , Tong Xinran , Sener Ugur , Li Min Jun , Wilcox Jessica , Isakov Danielle , Derderian Camille , Chabot Kiana , Schietinger Andrea , Boire Adrienne 
Published: July 2021

Abstract
For decades, the central nervous system was considered to be an immune privileged organ with limited access to systemic immunity. However, the leptomeninges, the cerebrospinal fluid (CSF)-filled anatomical structure that protects the brain and spinal cord, represent a relatively immune-rich environment. Despite the presence of immune cells, complications in the CSF, such as infectious meningitis and a neurological development of cancer known as leptomeningeal metastasis, are difficult to treat and are frequently fatal. We show that immune cells entering the CSF are held in an ‘idle' state that limits their cytotoxic arsenal and antigen presentation machinery. To understand this underappreciated neuroanatomic niche, we used unique mouse models and rare patient samples to characterize its cellular composition and critical signaling events in health and disease at a single-cell resolution. Revealing the mediators of CSF immune response will allow us to re-evaluate current therapeutic protocols and employ rational combinations with immunotherapies, therefore turning the patient's own immune system into an active weapon against pathogens and cancer.
Citation Format: Jan Remsik, Xinran Tong, Ugur Sener, Min Jun Li, Jessica Wilcox, Danielle Isakov, Camille Derderian, Kiana Chabot, Andrea Schietinger, Adrienne Boire. Decoding the immune system response to leptomeningeal metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1751.
Abstract 1775: Metformin-mediated natural killer cell cytotoxicity in head and neck squamous cell carcinoma
Authors: Crist McKenzie , Lehn Maria , Wise-Draper Trisha 
Published: July 2021

Abstract
Head and Neck Squamous Cell Carcinoma (HNSCC) is the 6th most common cancer worldwide. Even with intensive treatment, up to 50% of patients will relapse. Checkpoint inhibitors, including antibodies targeting programmed death 1 (PD-1), have dramatically improved survival outcomes but only elicit a response in 20% of patients. PD-1 is expressed on both T-cells and Natural Killer (NK) cells, and depletion of NK cells has been linked to poor prognosis in several solid tumors. NK cells are essential to the innate immune response, do not require MHC-1 expression for recognition, and can stimulate an anti-cancer response through release of cytotoxic granules and direct killing of cancer cells. Upregulation of several interleukins including IL-6, which induces the JAK/STAT3 pathway and subsequently inhibits cancer cell apoptosis, is correlated with a poor prognosis in HNSCC patients. Importantly, inhibition of phosphorylated STAT3 (pSTAT3) increases NK-specific cancer cytotoxicity, NK cell cytokine release, and anti-tumor cell chemokines. Therefore, we hypothesize that impaired NK cell cytotoxicity results in a poor response to immunotherapy. We have shown that a common anti-diabetes drug with anti-cancer properties, metformin, downregulates NK pSTAT3 with subsequent increase in cytotoxicity of peripheral NK cells in HNSCC patients. Metformin also decreases pSTAT3 pathway related cytokine release from HNSCC cell lines. However, it remains unclear whether metformin-mediated enhanced NK cytotoxicity was through a direct effect on NK cells or indirect through inhibition of pSTAT3 in tumor cells and subsequent decrease in inhibitory cytokine release. In addition, inhibiting pSTAT3 could lead to further activation of innate immunity through activation of NK cell cytotoxicity complementing current PD-1 inhibitor therapy and improved treatment response. Here we report the contribution of metformin-mediated direct and indirect effects on NK cell cytotoxic functions and the combined effect of metformin and pembrolizumab using patient samples from a clinical trial and ex vivo models. Understanding metformin-mediated regulation of pSTAT3 and downstream pathways will provide necessary insight to potentially overcome resistance to PD-1 inhibitors and identifying novel treatment combinations for this disease.
Citation Format: McKenzie Crist, Maria Lehn, Trisha Wise-Draper. Metformin-mediated natural killer cell cytotoxicity in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1775.
Abstract 1917: Immunomodulatory effects of a novel, enhanced potency gibbon ape leukaemia virus (GALV) fusogenic membrane glycoprotein-expressing herpes simplex virus platform with increased efficacy combined with anti PD-1 therapy
Authors: Roulstone Victoria , Kyula Joan , Thomas Suzanne , Kuncheria Linta , Bommareddy Praveen K. , Smith Henry , Whittock Harriet , Coffin Robert S. , Harrington Kevin 
Published: July 2021

Abstract
Oncolytic viral immunotherapies are attractive because they are self-amplifying, can kill tumors through multiple, immunologically visible mechanisms and have the ability to promote anti-tumor immune responses. RP1 is a novel, enhanced potency oncolytic HSV that has been genetically engineered to express human GM-CSF and the gibbon ape leukemia virus fusogenic membrane glycoprotein with the R sequence deleted (GALV-GP R-), providing constitutive fusion activity. GALV-GP R- binds pit-1 receptors on human and rat, but not mouse, cells to mediate cell-cell fusion. RP1 potently kills human tumor-derived cells, including a panel of melanoma and head and neck cell lines, as demonstrated here. In vivo, using a human melanoma model in nude mice, higher titres (2-3 log) of virus were retrieved from tumors treated with the virus expressing GALV-GP R- (i.e. RP1) versus an equivalent non-GALV-GP R- expressing virus. No virus was retrieved from uninjected tumors. In addition to enhanced direct effects on injected tumors, contralateral uninjected tumors were significantly smaller in groups treated with RP1 versus the GALV-GP R- non-expressing virus despite restriction of virus replication to the injected tumor. This effect was seen in nude mice, i.e. without an adaptive immune system, suggesting contribution of innate (e.g. NK cell-mediated) immunity to the contralateral effects observed. In the immunocompetent mouse 4434 melanoma model, RP1 also reduced tumor burden in both injected and uninjected tumors, again with absolute restriction of virus replication to injected tumors. Animals treated with RP1 had splenomegaly and a population of tumor-infiltrating PD-L1+ cells within injected tumors at one week post-treatment, albeit without a contribution of fusion mediated by GALV-GP R- in this model. FACS-based analysis identified these PD-L1+ cells as predominantly CD45+/CD11b(med/low)/LY6G+ neutrophils. Co-treatment with RP1 and an anti-mouse PD-1 antibody increased anti-tumor effects and the levels of CD3+ cells in uninjected tumors. Data from detailed RNAseq transcriptional analyses from injected and uninjected tumors will also be presented.
Citation Format: Victoria Roulstone, Joan Kyula, Suzanne Thomas, Linta Kuncheria, Praveen K. Bommareddy, Henry Smith, Harriet Whittock, Robert S. Coffin, Kevin Harrington. Immunomodulatory effects of a novel, enhanced potency gibbon ape leukaemia virus (GALV) fusogenic membrane glycoprotein-expressing herpes simplex virus platform with increased efficacy combined with anti PD-1 therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1917.
Abstract 1985: Activation of EGFR/IGF1R - beta catenin - CD44 pathway in periampullary cancer
Authors: Maji Suvendu , Bankura Biswabandhu , Panda Chinmay Kumar , Alam Neyaz 
Published: July 2021

Abstract
Background: Periampullary cancer (PC) is a global medical burden, although infrequent but less than 5% of patients experience an overall survival of five years or more. The study aims to analyze the importance of Epidermal Growth Factor Receptor (EGFR)/Insulin-Like Growth Factor 1 Receptor (IGF1R) - Beta-catenin (β-catenin)- CD44 pathway in the development of periampullary cancer of Indian patients. Materials and Methods: Expression profile of EGFR, IGF1R, β-catenin, and CD44 was verified by immunohistochemical analysis in primary tumor samples (N=14) and respective adjacent normal tissues. Results: In periampullary carcinoma patients, a high level of EGFR expression was seen in 64% of the samples along with co-expression of IGF1-R in 77.8% samples. Furthermore, the high expression of EGFR and IGF1R significantly correlated with the increased expression of β-catenin along with CD44 expression of the tumors. Conclusion: The EGFR/IGF1R - β-catenin- CD44 pathway seems to be important in the development of PC with clinical importance.
Key-words: Periampullary cancer; EGFR; IGF1R; β-catenin; CD44
Key Messages: Interplay of EGFR, IGF1R, β-Catenin and CD44 expressions is important phenomena in the development of PC.
Citation Format: Suvendu Maji, Biswabandhu Bankura, Chinmay Kumar Panda, Neyaz Alam. Activation of EGFR/IGF1R - beta catenin - CD44 pathway in periampullary cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1985.
Abstract 2006: The contributions of iron regulatory proteins 1 and 2 to ferroptosis activation and ferroptotic cell death
Authors: Hermann Evan , Oliveira Thais , Montgomery McKale 
Published: July 2021

Abstract
The essentiality of iron for cell growth and proliferation, coupled with its capacity to promote damaging free radical production, has made it a desirable target for cancer treatment and prevention. One such approach may be through the activation of ferroptosis, a form of iron-mediated programmed cell death. However, we must first understand how cancer cells manipulate the homeostatic regulators of iron metabolism to promote malignancy before we can fully harness iron's therapeutic potential. The iron regulatory proteins 1 and 2 (IRP1 and IRP2) are the master regulators of intracellular iron homeostasis because they coordinate the expression of proteins involved in iron storage, uptake, and utilization. Yet, the roles and regulation of IRPs during cellular ferroptosis remain unknown. The primary objective of this work was to examine the reciprocal relationship between ferroptosis activation and IRP mRNA binding activity. Utilizing tetracycline-inducible plasmids, we found that overexpression of IRP1 or IRP2 significantly increases sensitivity to ferroptotic cell death in HEK293T cells. Intriguingly however, ferroptosis induction by erastin treatment differentially influences IRP1 and IRP2 mRNA binding activity in a cell-type dependent manner, with those cell types expressing higher levels IRP2 exhibiting increased sensitivity to ferroptosis activation. Yet, IRP2 knockout cells are still subject to ferroptotic cell death, as are cells that lack IRP1 expression. Collectively, our findings suggest that while increased expression of IRP1 and IRP2 can promote ferroptotic cell death, expression of IRP1 or IRP2 is sufficient to convey sensitivity to ferroptosis activation. To identify mechanism driving increased IRP mRNA binding activity during cellular ferroptosis, we are currently assessing both iron-dependent and -independent regulators of IRP1 and IRP2 function and stability. As iron is an essential, yet potentially toxic nutrient, such findings will be important because they are expected to provide novel insights for exploiting the toxic nature of iron without compromising the essential homeostatic control mechanisms.
Citation Format: Evan Hermann, Thais Oliveira, McKale Montgomery. The contributions of iron regulatory proteins 1 and 2 to ferroptosis activation and ferroptotic cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2006.
Abstract 2179: Identification of ROS1 alterations in ctDNA from colorectal cancer patients in China
Authors: Wang Mojin , Zhu Lili , Huang Depei , Shen Xudong , Zhang Hushan , She Xueke 
Published: July 2021

Abstract
Background: ROS proto-oncogene 1 (ROS1) is an oncogenic driver involved in various cancer types for which has FDA approved therapies. ROS1 has shown to undergo genetic rearrangements in a variety of human cancers including glioblastoma, non-small cell lung cancer (NSCLC), ovarian cancer, gastric adenocarcinoma and colorectal cancer. The rearrangements create fusion proteins in which the kinase domain of ROS1 becomes constitutively active and drives cellular proliferation. Although previous data have reported ROS1 fusions occur in 0.2% to 2.4% of colorectal cancers, the frequency and type of ROS1 alterations in Chinese CRC patients have not been fully reported.
Methods: This study queried data from 1,083 colorectal cancer samples which underwent a targeted next-generation sequencing assay performed by 3DMed Clinical Laboratory Inc., a College of American Pathologists (CAP) certified and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory of 3D Medicines Inc. between January, 2017 and June, 2020 in China, to identify the incidence of ROS1 alterations detected in ctDNA in colorectal cancer patients. The detected genetic alteration types included single-nucleotide variants (SNVs), copy number variations (CNVs) and gene rearrangements/fusions.
Results: ROS1 alterations were found in 114 patients among the 1,083 (10.5%) CRC patients' cohort, including 72 males and 42 females, median age was 58 years old. The ROS1 alterations included 110 (96.5%) SNVs, 3 (2.6%) CNVs and 1 (0.9%) GOPC-ROS1 fusion. Among the 110 single nucleotide variants, we identified 91 (82.7%) of ROS1 SNVs were nonsynonymous mutations. The top 5 co-occurring mutations in samples with ROS1 alterations were TP53 (71, 62.2%), CYP2C19 (48, 42.1%), APC (48, 42.1%), KRAS (46, 40.3%) and DPYD (42, 36.8%).
Conclusion: Our study indicated that ctDNA can be used as a nonvasive methodology to detect cancer-specific genetic aberrations in plasma for CRC. ROS1 alterations occurred modestly in Chinese colorectal cancer patients. Co-occurring mutations may provide different biological subsets of patients with ROS1-mutant colorectal cancer to reveal patient outcomes and response to therapy. Further investigation could be focused on the effect of ROS1 nonsynonymous mutations on the ROS1 proteins in vitro to identify whether these are more actionable than currently recognized.
Citation Format: Mojin Wang, Lili Zhu, Depei Huang, Xudong Shen, Hushan Zhang, Xueke She. Identification of ROS1 alterations in ctDNA from colorectal cancer patients in China [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2179.