bluuebunny/crossref_metadata_2025_split huggingface dataset:
A cell-based platform to potentiate oncolytic virus: Potential approach for cancer therapies.
Authors: Nguyen Duong , Gomez Alberto , Alamillo Ashley , Neuharth Forrest , Minev Ivelina , Herrmann Thomas , Haertl Barbara , Schneider Laura Edith , Minev Boris , Draganov Dobrin , Santidrian Antonio F. 
Published: February 2020

21 Background: Oncolytic virotherapy has been pursued by multiple companies and institutions with few candidates reaching the clinic and demonstrating limited efficacy. The therapeutic potential of oncolytic viruses can be severely restricted by innate and adaptive immune barriers. To overcome this obstacle, we load and protect tumor selective CAL1 oncolytic vaccinia virus into adipose-derived stem cells (AD-MSC) to generate a new therapeutic agent called SNV1(SuperNova1). Methods: SNV1s were generated by incubating AD-MSC with CAL1 virus. SNV1 was analyzed for its ability to kill cancer cell lines and protect virus in the presence of active neutralizing antibodies and complement. In animals, SNV1 was intratumorally injected in various xenograft and syngeneic models. Viral biodistribution was also evaluated by PCR. Immune infiltration were analyzed using flow cytometry. Results: Compared to the naked virus, SNV1 showed improved protection against the humoral barriers and efficient eradication of various human cancer cell lines in vitro. Intratumoral SNV1 treatment showed statistically significant and potentiated tumor growth inhibition compared to control or CAL1 naked virus treatment in all tested models (prostate, breast, melanoma, colon, and prostate cancers). Importantly, local administration of SNV1 induced systemic therapeutic effects. Five days after SNV1 administration, tumor infiltrating lymphocytes (TILs) from both treated and untreated tumors showed increased CD4 and CD8 T-cell populations. As well as decreased frequency of Tregs, and improved effector to Treg ratios, which was associated with inhibition of tumor growth at the treated tumor site and also at distant untreated sites. Ongoing and persistent virus infection could be detected in the treated tumor as late as 15 days after administration. Conclusions: This study demonstrates the ability of our cell-based platform to protect and potentiate oncolytic vaccinia virus by circumventing the innate and adaptive immune barriers, resulting in enhanced oncolytic virotherapy. These findings provide fundamental rationale for the development of cell-based platforms to maximize the therapeutic potential of various oncolytic viruses.
AVM0703 as a novel stand alone or combination therapy for lymphoma.
Authors: Taylor Margaret , Rylatt Colleen , Lee-Diaz Stephanie , Ashok Arya , Jarzyna Peter , Parthasarathy Vaishnavi , Poulin Kendra , Zahid Yumna , Deisher Theresa 
Published: February 2020

42 Background: Chemotherapy remains a vital part of cancer treatment. There is an urgent need to reduce the toxicities associated with chemotherapy-based treatments especially in the pediatric and young adult population where the risk for chemo-induced secondary cancers is high. AVM0703 is a new treatment option that can be used as a stand-alone or in combination with chemo for relapsed/refractory lymphoma patients. AVM0703 is effective at lymphoablating while sparing red blood cells, platelets, and hematopoietic stem cells. AVM0703 is a novel patent-pending formulation of a repurposed drug without the toxic excipients unlike existing formulations. AVM0703 has anti-tumor activity in an immunocompetent mouse model of B-cell lymphoma (A20) as both a stand-alone treatment and in combinations with current therapeutics. Methods: Wild-type BALB/c mice were implanted with A20 tumor cells suspended in a 50% Matrigel mixture and implanted subcutaneously. Palpable tumors were visible within seven days. Mice were dosed with either high-dose AVM0703 alone, or in combination with intraperitoneal cyclophosphamide and fludarabine. Mice were then monitored for tumor growth and changes in body weight. Results: Mice dosed repeatedly with AVM0703 survived 20 days longer than mice dosed with placebo and displayed no significant toxicity or body weight loss. In a separate study, mice treated with 2 doses of Cy/Flu had a loss of tumors similar to 1 dose of AVM0703 + 1 dose of Cy/Flu. Additionally, when compared to standard treatments like CHOP, in the same A20 lymphoma model, the AVM0703 + Cy/Flu combination had better tumor efficacy than 2 cycles of CHOP. Unlike 2XCHOP treatment, which induced greater than 30% body weight loss and death of 18% of the mice due to drug toxicity, the AVM0703 + Cy/flu combination had no observed toxicity or body weight loss. Conclusions: AVM0703 can reduce the number of chemotherapy cycles without affecting efficacy and decrease the toxicities associated with chemo and will help to provide a better quality of life for patients.
Correlation between immune-related adverse events and outcomes in nivolumab/ipilimumab combination therapy for metastatic melanoma.
Authors: Rauwerdink Daan , Frederick Dennie T. , Sharova Tatyana , Boland Genevieve Marie 
Published: February 2020

58 Background: Systemic immune checkpoint blockade therapy anti-PD1 nivolumab combined with anti-CTLA-4 ipilimumab is an effective therapy for metastatic melanoma. The treatment, however, has a high frequency of immune related adverse events. Interestingly, immune-related adverse events in anti-PD1 and anti-CTLA4 monotherapy have been associated with an improved overall survival in melanoma. Whether immune-related events correlate with enhanced outcomes in ipilimumab/nivolumab combination therapy is unknown. Methods: Clinical data from patients diagnosed with untreated cutaneous stage IV melanoma receiving ipilimumab/nivolumab combination therapy between 2015-2018 at the Massachusetts General Hospital (MGH) and have been analyzed retrospectively. Tumor response was measured using RECIST criteria. Primary endpoints were frequencies and characteristics of immune-related adverse events, overall survival, and response to therapy. Results: A total of 57 patients received ipilimumab/nivolumab combination therapy. During a mean follow-up period of 26 months, 28 (49%) patients completed the therapy. Immune-related adverse events were observed in 45 (79%) patients, with rash (28%), colitis (23), hepatitis (21%) and fever (21%) being the most frequent. Overall survival was 29 months in patients with immune-adverse related events and 14 months in the group without any adverse events (p-value < 0.01). The onset of hypophysitis correlated with tumor response (p = 0.02) and hepatitis showed a trend in a correlation to response of therapy (p = 0.06). Conclusions: Our study demonstrates the association between improved overall survival and the onset of immune-related adverse events in ipilimumab/nivolumab combination therapy. A trend correlated with improved outcomes and onset of immune-related adverse events was seen in hepatitis and was significantly associated with hypophysitis, however these results must be interpretated carefully as larger studies must confirm our findings. Despite small study size, we are the first to describe an association between immune-related adverse events in ipilimumab/nivolumab combination therapy.
Inflammation and cell proliferation signatures: Implications for response to immune checkpoint inhibition therapies.
Authors: Glenn Sean , Pabla Sarabjot , Kato Shumei , Van Roey Erik , Conroy Jeffrey M. , Wang Yirong , Nesline Mary , Burgher Blake , Giamo Vincent , Andreas Jonathan , Lenzo Felicia L. , Kurzrock Razelle , Morrison Carl 
Published: February 2020

67 Background: Progress in unraveling the complex tumor immune microenvironment (TIME) has aided our understanding of the host immune response to ICI therapies. To gain further insight, we associate a 160-gene tumor inflammation signature (TIS) with cell proliferation status and response to ICI. Methods: 242 FFPE tumor samples from lung, RCC and melanoma were evaluated by RNA-seq to measure expression levels of 394 immune related genes. TIS (weak, moderate, strong) and cell proliferation status (poor, moderate, high) were determined by algorithmic analysis of selected gene pathways. All cases were evaluated for association with ORR to ICIs using RECIST criterion. Furthermore, 13 pre-post ICI treated biopsy pairs were studied to understand the dynamics of these signatures following treatment. Results: In both weakly and moderately inflamed tumors, ORR was highest in moderately proliferative tumors 32.6% (15/46) and 37.8% (14/37), respectively (Table). Surprisingly, in strongly inflamed tumors, both highly and moderately proliferative tumors had a high response rate of 55% (11/20) and 43.2% (16/37), whereas poorly proliferative tumors have a significantly lower response rate of 12.5% (3/24; p= 0.03). 6 of 13 pre-post ICI treated cases demonstrated increased inflammation post treatment, with 83% (5/6) demonstrating concurrent decrease in cell proliferation. Conclusions: Together, TIS and cell proliferation predict response to ICI in NSCLC, RCC and melanoma. The data suggests that in strongly inflamed and highly proliferative tumors, the cell proliferation signal could be attributed to antigen stimulated T-cell proliferation, whereas in other categories of inflammation, moderately proliferative tumors contain signal from both immune cells and tumor cells. Further studies are required to determine the relationship between these signatures in hot and cold tumors. [Table: see text]
Using bioinformatic tools to examine similarities between human PDL-1 protein and common tobacco (Nicotiana tabacum).
Authors: Dib Elie G. , Hill Nicholas , Wollard Jessica , Yoo Ji Woon , Dib Joe E. , Ganguly Anutosh , Cho Clifford 
Published: February 2020

70 Background: Human CD274 receptor, known as programmed cell death 1 ligand 1 (RefSeq NP_054862.1), is an inhibitory ligand for Programmed cell death protein 1 (PD1). We aimed in this bioinformatic experiment to identify a homologous PDL-1 protein in plants. Methods: We chose to use tBLASTn because it compares a protein query sequence against a nucleotide sequence database dynamically translated in all six reading frames (both strands). We chose the EST database and restricted our search to plants (Viridiplantae). Results: Using the FASTA sequence of PDL-1 protein, the tBLASTn of the CD274 protein produced a single hit to Nicotiana tabacum (Common tobacco) cDNA, accession number FG181602.1 with E value of 2e-13 and score of 75.9. We translated the FASTA FG181602.1 through ExPASy and after inspecting the results of the 6 open reading frames (ORFs) in comparison with the matching homologous plant protein obtained through tBLASTn above, we found this “novel” protein which we named "PDL1LI". It has the following amino acid sequence: MHAVRRHRGEMHKVALLHNSFLIISILGSYADDFRVMVPTRRLTAARGHSVVLGCEFSPHFGPNPDLSSLVLTWQRQEDSRVVHSFYYERDQLAKQSSAYRNRTALFVTELSKGNASVRIENVGVTDAGRYLCTVSTNQGTNKAELQLDYGAFYTEPRLTINVNSSDVLLQYETEGFPAPVVIWKGEDGENLTDRMKTSVQSNEEMGLYYIKSSYTAPNTPLSLTFTLENHLLHQYLQRPVSYTGGQNSCFYQFIAPVVVS Gor4 shows that our novel PDL1LI protein is 181 amino acids long with 36% alpha helix, 18% extended strand and 46% random coil sequence. According to BLASTp, this protein contains an immunoglobulin domain found in the Ig superfamily in the first half of the protein, and specific domain hits to the Ig_HHLA2, V-set, and IGv domains, with e-values of 1.37e-28, 2.23e-08, and 1.73e-06. Conclusions: Of all the plants, we found a single homology for our original protein PDL1 only in Nicotiana tabacum. We named this novel protein PDL1LI. Tobacco has been implicated in the etiology of several cancers including lung cancer, bladder cancer, head and neck cancers, etc. A wet lab experiment is underway to isolate our novel protein PDL1LI and to study its properties including any possible inhibitory actions on T cells. If confirmed, then we would have elucidated a new carcinogenic mechanism of tobacco.
Glycoprotein D, a checkpoint inhibitor of early T-cell activation, to improve immunogenicity and efficacy of an HPV-16 vaccine in preclinical studies.
Authors: Ertl Hildegund , Xiang Zhiquan , Li Yan , Luber Andrew , Magowan Colin , Zhou Xiang 
Published: February 2020

71 Background: CD8+ T cells can inhibit tumor progression, but their induction is hampered by the low immunogenicity of most tumor antigens. HSV-1 glycoprotein D (gD), when genetically expressed as a fusion protein with tumor antigens, serves as a checkpoint inhibitor of the B and T cell attenuator (BTLA)-herpes virus entry mediator (HVEM) pathway, which acts early during T cell activation. HSV-1 gD thereby augments antigen-driven CD8+ T cell responses. We describe the immunogenicity and efficacy of a chimpanzee adenoviral vector (AdC) vaccine containing a detoxified E7/E6/E5(AdC-gDE765dt) sequence of HPV-16 fused into gD. Methods: The frequency of HPV-16 E7-specific CD8+ T-cells was assessed by tetramer staining in C57/Bl6 mice 14 days after a single IM vaccination with AdC vectors encoding wild-type or mutant HPV-16 oncoproteins expressed within gD, a non-HVEM-binding form of gD or without gD. Efficacy was tested in a TC-1 tumor cell challenge model with mice receiving no treatment or a single IM vaccine injection 3 days after tumor cell transplantation. Mice were followed for 80 days. Results: The addition of gD increases HPV-16 E7-specific CD8+ T-cell frequencies approximately 10-fold. T cell responses are similar to AdC vaccines expressing wild-type or mutant oncoproteins within gD. All AdC-gDE765dt treated mice show delayed tumor progression after a single vaccination with 50% of animals remaining tumor-free at study completion. Conclusions: These results show that the addition of gD, an early checkpoint inhibitor, which acts locally at the site of T cell stimulation, to an HPV-16 vaccine markedly improves the vaccine’s immunogenicity and efficacy. AdC-gDE765dt is currently in GMP manufacture for Phase 1 investigation in HPV-16 infected patients.
First-in-human study of the cancer peptide vaccine, TAS0313, in patients with advanced solid tumors: Phase I dose-finding part results.
Authors: Yamamoto Noboru , Sato Jun , Kondo Shunsuke , Koyama Takafumi , Yonemori Kan , Iwasa Satoru , Shimizu Toshio 
Published: February 2020

73 Background: TAS0313 is a cancer vaccine cocktail containing three long peptides, with a total of 12 cytotoxic T lymphocyte (CTL) epitope peptides. These peptides were derived from eight cancer-associated antigens that are highly expressed in various cancers. We report the results of a phase I part examining the tolerability, safety, potential efficacy, and immunological responses of 9 and 27 mg TAS0313 in patients (pts) with advanced solid tumors. Methods: The enrolled pts had at least one of the following HLA types: HLA-A*02:01, -A*02:06, -A*02:07, -A*11:01, -A*24:02, -A*31:01, or -A*33:03. TAS0313 was subcutaneously administered on Days 1, 8, and 15 of Cycles 1 and 2 and on Day 1 of Cycle 3 or later in 21-day cycles until disease progression, or unacceptable toxicity. Tolerability was assessed in at least six pts during the first cycle. Tumor response was evaluated using RECIST v1.1. The antigen specific CTL and IgG were analyzed post treatment by blood samples. Optional serial tumor biopsies were performed for tumor infiltrating leukocyte (TIL) analysis. CTL, IgG, and TIL were measured by ELISPOT assay, Luminex assay, and IHC (CD8 positive), respectively. Results: Seventeen pts were enrolled in 9mg (n = 10) and 27mg (n = 7) groups. There was no serious adverse drug reaction (ADR) in any patient. All ADRs were of grade 1 or 2, with the most frequent being dermatological injection site reaction, in 7/10 (70%) and 6/7 (86%) pts and pyrexia, in 1/10 (10%) and 2/7 (29%) for the 9 and 27mg groups, respectively. The best overall response was stable disease, in 2/10 (20%) and 2/7 (28%) pts. One patient with cancer of unknown origin received prolonged administration (over 10 months) of the 9mg dose. Increment of CTL and IgG by treatment were detected in 9 and 27mg groups. TIL counts were increased in 2/3(67%) and 3/4(75%) in 9 and 27mg groups compared with pre-treatment samples, respectively. Conclusions: TAS0313 demonstrated safety, tolerability, and immunological responses in pts with advanced solid tumors in the 9 and 27mg groups. A phase II part, evaluating the efficacy of combination therapy with pembrolizumab in pts with urothelial carcinoma and monotherapy in glioblastoma pts, is currently underway. Clinical trial information: JapicCTI-183824.
The effect of lysosomal-associated membrane protein-1-targeting of Epstein–Barr virus nuclear antigen 1 (EBNA1) on immune response and tumor growth in preclinical studies.
Authors: Sinha Pratima , Rosean Claire Buchta , Heiland Teri 
Published: February 2020

74 Background: Epstein-Barr virus (EBV) is an oncogenic γ-herpes virus that infects > 90% of the global population. EBV is the primary cause of infectious mononucleosis and is associated with several epithelial and lymphoid malignancies, including nasopharyngeal carcinoma, gastric carcinoma, non-Hodgkin’s and Hodgkin’s lymphoma. Of these, nasopharyngeal carcinoma is particularly prevalent in East and Southeast Asia and is highly metastatic. Current treatment strategies for nasopharyngeal carcinoma are limited to radiation and chemotherapy, demonstrating a need for new, targeted therapies. Most nasopharyngeal carcinomas express EBNA1, a DNA-binding protein involved in maintenance of the episomal virus genome that is required for EBV latency and associated transformation. Targeting EBNA1 allows for an immunotherapeutic approach, by exploiting the potential of the immune system to recognize tumor cells through their expression of this viral antigen. Methods: We designed a DNA vaccine encoding EBNA1 using the UNITE (UNiversal Intracellular Targeted Expression) platform. The UNITE platform is based in part on lysosomal targeting technology which results in enhanced antigen presentation and a balanced T cell response. Results: We report that the EBNA1-UNITE vaccine induced IFNγ-producing effector memory (EM) CD4+ T and CD8+ T cells with complete rejection of EBNA1-expressing tumors observed in 50% of mice. Mice rejecting tumors were protected from rechallenge with CT26-EBNA1, demonstrating that antigen-specific memory was induced in these animals. Tumor microenvironment (TME) analysis showed vaccine-induced mobilization of effector cells, including tumor infiltration of IL-12-producing type 1 dendritic cells, iNOS-producing M1 macrophages, activated EM CD4+T, and CD8+TNFα+T cells. Furthermore, increased PD-1+CD8+T cells in the TME suggests that a combination strategy with PD-1/PD-L1 blockade may be beneficial in a therapeutic setting. Conclusions: This pre-clinical data suggests that the EBNA1-UNITE vaccine has the potential to be used as an immunotherapeutic agent against EBV-associated cancers.
Association of vitamin D intake with decreased risk of immune checkpoint inhibitor-induced colitis.
Authors: Tyan Kevin , Grover Shilpa , Dougan Michael , Sullivan Ryan J. , Giobbie-Hurder Anita , Blum Steven , Ishizuka Jeffrey Joseph , Qazi Taha , Elias Rawad , Vora Kruti , Ruan Alex , Martin-Doyle William , Eastman Lauren , Davis Meredith , Gargano Maria , Haq Rizwan , Buchbinder Elizabeth Iannotti , Ott Patrick Alexander , Hodi F. Stephen , Rahma Osama E. 
Published: February 2020

89 Background: There is a lack of predictive markers informing on the risk of colitis in patients treated with immune checkpoint inhibitors (ICIs). The aim of this study was to identify potential factors associated with development of ICI colitis. Methods: We performed a retrospective analysis of melanoma patients at Dana-Farber Cancer Institute who received PD-1, CTLA-4, or combination blockade between May 2011 to October 2017. Clinical and laboratory characteristics associated with pathologically confirmed ICI colitis were evaluated using multivariate logistic regression analyses. External validation was performed on an independent cohort from Massachusetts General Hospital. Results: The discovery cohort included 213 patients of whom 37 developed ICI colitis (17%). The odds of colitis were higher in patients treated with ipilimumab either as monotherapy or in combination with nivolumab compared to those treated with pembrolizumab. Vitamin D use was recorded in 66/213 patients (31%) before starting ICIs. In multivariable regression analysis, vitamin D use conferred significantly reduced odds of developing ICI colitis (OR 0.35, 95% CI 0.1–0.9). These results were confirmed in the validation cohort of 169 patients of whom 49 developed ICI colitis (29%). Pretreatment neutrophil/lymphocyte ratio (NLR) ≥5 predicted reduced odds of colitis (OR 0.34, 95% CI 0.1–0.9) only in the discovery cohort. Conclusions: This is the first study to report that among patients treated with ICIs, vitamin D intake is associated with reduced risk for ICI colitis. This finding is consistent with prior reports of prophylactic use of vitamin D in ulcerative colitis and GVHD. This observation should be validated prospectively in future studies. [Table: see text]
SALVO: Single-arm phase II study of ipilimumab and nivolumab as adjuvant therapy for resected mucosal melanoma.
Authors: McWilliams Robert R. , Holtan Shernan , Pond Gregory Russell , Zakharia Yousef , Curti Brendan D. , Domingo Musibay Evidio , Olszanski Anthony J. , Kottschade Lisa A. , Hauke Ralph J. 
Published: February 2020

TPS65 Background: Mucosal melanoma is a rare and, therefore, poorly studied malignancy. Patients with resected primary tumors have a median time to recurrence of 5.5 months. While no one adjuvant therapy is of proven benefit for patients, immunotherapy has shown activity in metastatic mucosal melanoma. Methods: We are performing a single arm, phase II clinical trial through the Midwest Melanoma Partnership/Hoosier Cancer Research Network (6 sites) for resected mucosal melanoma. The primary endpoint is recurrence free survival (RFS), and it will include 36 subjects. Patients must have had an R0 or R1 resection of a mucosal melanoma (sinonasal, anorectal, vulvar, or other), and register within 90 days of surgery. Adjuvant radiation is allowed prior to registration but not required. Therapy consists of ipilimumab (1 mg/kg) and nivolumab (3 mg/kg) IV q3w x 4, then 480 mg nivolumab x 1 year. Statistical power is calculated to be 85% to detect a change in RFS from 5.5 months to 9.5 months, with a one sided alpha of 0.05. Enrollment began Sept 2017, with current participation from 6 large volume centers in the United States, with 17 patients enrolled as of Sept 2019. Full accrual is anticipated to complete by year end 2020. Patients will be followed for RFS and OS. Translational studies will include mutational burden, c-kit, BRAF, NRAS status, and serum markers of immunity -- including soluble PD-L1 and Bim. Clinical trial information: NCT03241186.
Measurement of the differential cross sections of natLi(d,d0) for EBS purposes
Authors: Ntemou E. , Preketes-Sigalas K. , Aslanoglou X. , Foteinou V. , Kokkoris M. , Lagoyannis A. , Misaelides P. , Patronis N. , Provatas G. , Vlastou R. 
Published: February 2020

In the present work, the 6,7Li(d,d0)6,7Li elastic scattering differential cross sections were measured in the energy range Elab = 900 – 2000 keV for EBS purposes, using thin lithium targets, made by evaporating natLiF and isotopically enriched 6LiF powder on self-supporting carbon stripping foils, with an ultra-thin Au layer on top for charge normalization purposes. The experiment was carried out in deuteron beam energy steps of 5 to 30 keV, depending on the fine structure of each studied cross section, and for the laboratory scattering angles of 125˚, 140˚, 150˚, 160˚, and 170˚.