bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-184: The immunotherapeutic role of indoleamine 2,3-dioxygenase (IDO) in head and neck squamous cell carcinoma: a systematic review
Authors: Lin Daniel J. , Ng James C. , Huang Lei , Robinson Max , O'Hara James , Wilson Janet A. , Mellor Andrew L. 
Published: August 2019

Abstract
Background: Novel cancer immunotherapy includes application of immune checkpoint inhibitors to the treatment of solid tumors. The body’s own immune system is thereby harnessed to tip the balance in favor of antitumor activity. The intracellular enzyme indoleamine 2,3-dioxygenase (IDO) is a critical regulator of the tumor microenvironment (TME) via tryptophan metabolism. Programmed death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) are immune checkpoints involved in T-cell inhibition and immunosuppression. Another immune checkpoint, IDO1, breaks down tryptophan into its metabolites which results in immunosuppression in the TME.
Aim: To assess the evidence on IDO in head and neck squamous cell carcinoma (HNSCC).
Methods: Medline, EMBASE using Ovid, Scopus, Web of Science, Cochrane Library databases, and ClinicalTrials.gov were searched from inception until present day.
Results: We included 32 studies. Of those, 5 involved cell lines, 7 assessed tumor immunohistochemistry, 6 measured IDO gene transcription, and 14 reported on clinical trials. The human cell lines studied commonly were SCC4, SCC15, and SCC25 in which IDO expression and activation by the Stimulator of Interferon Genes (STING) pathway played a central role. Retrospective immunohistochemistry studies of lower lip, oral cavity, tongue, tonsil, and larynx found that relatively high IDO expression correlated with worse survival. Gene transcription studies showed increased IDO in tumors that expressed PD-L1 and harbored human papillomavirus (HPV). Phase I/II clinical trials showed 1) objective responses (34%) and disease control rates (62%) for IDO1 inhibitor in combination with a PD-1 inhibitor, 2) consistent safety profile in combination versus monotherapy, and 3) IDO gene expression as a predictive biomarker for response to PD-L1 therapy.
Conclusions: IDO is integral to TME immunity in HNSCC particularly in HPV positive tumors, modulating existing therapies and application in combinatorial immunotherapy. Retrospective studies have shown the presence of IDO in the TME and suggest a link to prognosis and prediction of HNSCC treatment outcome. However, the exact mechanism of IDO-driven immune modulation in the HNSCC TME remains unclear. We now require prospective longitudinal studies to track IDO activity and expression throughout HNSCC treatment, thence optimise IDO-based immunotherapy.
Citation Format: Daniel J. Lin, James C. Ng, Lei Huang, Max Robinson, James O'Hara, Janet A. Wilson, Andrew L. Mellor. The immunotherapeutic role of indoleamine 2,3-dioxygenase (IDO) in head and neck squamous cell carcinoma: a systematic review [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-184.
Abstract LB-188: Breast cancer immunotherapy using magnetized HSV1716
Authors: AL-Janabi Haider , Conner Joe , Howard Faith , Hunt Stuart , Taher Zainab , Staniland Sarah , Muthana Munitta 
Published: August 2019

Abstract
Background: Oncolytic viruses (OV) are encouraging new immunotherapies for cancer. OVs, replicate in cancer cells inducing immunogenic cell death (ICD) and activating antitumor immunity. To date, clinical use has focused on intratumoral delivery due to concerns over inadequate tumor targeting following systemic administration. We hypothesize that magnetizing OVs and magnetic guidance strategies will improve systemic delivery by protecting the viruses from inactivating immune mechanisms and non-specific adsorption.
Methods: To investigate this, we synthesized and characterized complexes of magnetized oncolytic herpes simplex virus (HSV1716) co-assembled with biocompatible magnetic nanoparticles (MAG) derived from magnetotactic bacteria (AMB-1) to give MAG-HSV1716 complexes. Characterization of the physical, chemical and oncolytic potential of our MAG-HSV1716 was performed. The safety and efficacy of our nanomedicine in combination with magnetic guidance strategies were also assessed in vivo.
Results: Stable MAG-HSV1716 complexes of ~160nm diameter successfully infected human and murine breast cancer cells in a dose-dependent manner, and induced tumor oncolysis. Following MAG-HSV1716 infection a significant increase in viral replication (ICP0, gB, ICP8), ICD (HMGB1, CALR, ATP) and apoptotic (CASP 3, CASP8, FASL) signals were detected. Intravenous delivery of MAG-HSV1716 resulted in reduced tumour burden in the presence of magnetic guidance (MAG-HSV1716 448.3mm³ vs. HSV1716 670.6mm³; p ≤ 0.05, n=6-9 mice/group) and an increase in tumor-infiltrating T-cells, NK cells and neutrophils. Furthermore, MAG-HSV1716 were protective in the presence of neutralizing Abs both in vitro and in vivo.
Conclusion: This study indicates that magnetizing HSV1716 results in viral protection from neutralizing antibodies and in combination with magnetic guidance reduces tumor burden and induces anti-tumor immunity.
Citation Format: Haider AL-Janabi, Joe Conner, Faith Howard, Stuart Hunt, Zainab Taher, Sarah Staniland, Munitta Muthana. Breast cancer immunotherapy using magnetized HSV1716 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-188.
Abstract LB-201: BIL06v immunizations generate antibodies specific for non-functional P2X7 (nfP2X7) that target solid tumors in vivo
Authors: Oliphant Chris J. , Freeman Elle , Gilbert Simon , Lara Romain , Huang Edwin , Barden Julian , McNulty Shaun 
Published: August 2019

Abstract
P2X7 is an ATP-gated purinergic receptor characterized by a biphasic response. Short term exposure to high ATP concentrations triggers opening of a cation channel, whilst prolonged exposure triggers opening of a non-selective pore that disrupts intracellular homeostasis, leading to cell death. Increasing numbers of studies have described a role for P2X7 in malignant tumors, including breast, prostate, colorectal and lung, and P2X7 has been shown to play critical roles in mediating various cancer cellular responses, such as cell proliferation, migration, invasion, and survival. We have described a form of P2X7 that is highly expressed on several cancers, which we term non-functional P2X7 (nfP2X7) that is unable to open a non-selective pore. Non-functional-P2X7 can form when P2X7-expressing cells undergo prolonged exposure to high ATP concentrations found in the local tumor microenvironment. This conformational change results in the exposure of a unique epitope composed of amino acids 200-216, known as the E200 peptide epitope. The E200 peptide epitope has been shown to be a safe and selective target for antibodies against solid tumors. Using the E200 peptide epitope we have prepared a peptide vaccine adjuvanted by Alhydrogel 2%, which we have termed BIL06v, for the therapeutic treatment of solid tumors. A similar vaccination approach was used to generate antibodies for a topical therapeutic that was shown to be safe with indications of efficacy in a Phase 1 clinical trial to treat basal cell carcinoma. Using preclinical in vivo models, we have investigated the tractability of BIL06v as a therapeutic against tumors. In mice and human, BIL06v can break immune tolerance and drive the production of antibodies specific for nfP2X7. A formal toxicology study has demonstrated both immunogenicity and safety in rats following repeated treatment with BIL06v. Furthermore, BIL06v treatment has been shown to improve host outcomes in syngeneic mouse models of disease. Therefore, targeting nfP2X7 with a peptide conjugate vaccine, such as BIL06v, presents a novel and safe therapeutic approach for the treatment of multiple malignancies.
Citation Format: Chris J. Oliphant, Elle Freeman, Simon Gilbert, Romain Lara, Edwin Huang, Julian Barden, Shaun McNulty. BIL06v immunizations generate antibodies specific for non-functional P2X7 (nfP2X7) that target solid tumors in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-201.
Abstract LB-203: Metformin enhances the efficacy of tumor membrane vesicle (TMV)-based vaccine immunotherapy in a murine model of breast
Authors: Munoz Luis E. , Bommireddy Ramireddy , Huang Haley , Kim Janet , Selvaraj Periasamy 
Published: August 2019

Abstract
Breast cancer remains the most commonly diagnosed cancers among women, with over 250,000 new cases per year in the United States. Immunotherapy has emerged as a promising treatment of breast cancer, however response rates to therapy remain far from ideal. In this study, we investigated the combinatorial effect of tumor membrane vesicle (TMV)-based vaccine immunotherapy, to induce an anti-tumor immune response, with the type 2 diabetes drug metformin, which has been reported to exert anti-tumor effects by maintaining CD8 T cell activity in the tumor microenvironment. Our results show that TMV vaccination inhibits primary tumor growth in preclinical tumor models, while combination with metformin resulted in greater inhibition of primary growth. Importantly, TMV vaccination reduced the metastatic burden in the lungs while combination with metformin further abrogated metastatic spread. Interestingly, TMV vaccination alone induced a significant increase in T cell infiltration to the tumor, while combination with metformin caused a decrease in the accumulation of T cells, despite having better outcomes. Further, we show that metformin is capable of reducing PD-L1 expression within the tumor microenvironment in both tumor cells as well as myeloid-derived suppressor cells, providing insight for the improvement of TMV-based immunotherapy.
Citation Format: Luis E. Munoz, Ramireddy Bommireddy, Haley Huang, Janet Kim, Periasamy Selvaraj. Metformin enhances the efficacy of tumor membrane vesicle (TMV)-based vaccine immunotherapy in a murine model of breast [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-203.
Abstract LB-206: The synergistic antitumor effect of the combination of three transgenes delivered by the oncolytic vaccinia virus, KLS-3020
Authors: Shin Jaeil , Hong Soon-Oh , Kim Minjung , Choi Heonsik , Kim Sujeong 
Published: August 2019

Abstract
Oncolytic viruses that selectively kill cancer cells are a promising platform for fighting cancer. Vaccinia virus is a good candidate for the oncolytic virus because it has several advantages such as a proven safety profile, broad host tropism, and larger capacity to harbor multiple transgenes.
We removed three viral genes (C11R, K3L, and J2R) from wild-type vaccinia virus to obtain a backbone virus, which is selectively replicating in cancer cells. Then, we inserted three transgenes (PH20, sPD1-Fc, and IL-12) into the backbone virus to boost up the antitumor efficacy, which is the final construct named KLS-3020.
We investigated the biological activity of transgenes with the intratumorally injected backbone viruses containing each single transgene in syngeneic mouse tumor models. At first, the backbone virus expressing PH20, an enzyme which can degrade the tumor extracellular matrix, showed enhanced virus spread compared to the empty backbone virus in melanoma or colon cancer. Likewise, locally expressed sPD1-Fc, which is a fusion protein of the extracellular domain of PD-1 and Fc region of an immunoglobulin, resulted in the increase of INF-γ+CD8+ and INF-γ+CD4+ T cells in melanoma, indicating T cell re-activation in the tumor site. Lastly, delivered IL-12 in lung cancer mouse model resulted in a significant increase of T-bet+CD4+ T cell populations, indicating the oriented differentiation of helper T cell into T helper 1 (Th1) cells.
We compared the efficacy of oncolytic vaccinia virus containing a combination of three transgenes (KLS-3020) with ones expressing each single gene in syngeneic mouse tumor models and observed that KLS-3020 could control tumor growth more effectively than every backbone virus having a single gene. Finally, we evaluated the anti-tumor efficacy of KLS-3020 in various types of mouse tumor models. Intratumorally injected KLS-3020 could suppress the growth of various tumors without significant body weight loss. Our results suggest that enhanced virus spread combined with the immune-stimulatory activity of KLS-3020 synergistically increase antitumor efficacy in a broad range of tumor types.
Citation Format: Jaeil Shin, Soon-Oh Hong, Minjung Kim, Heonsik Choi, Sujeong Kim. The synergistic antitumor effect of the combination of three transgenes delivered by the oncolytic vaccinia virus, KLS-3020 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-206.
Abstract LB-214: Imputation of single cell cancer genotypes
Authors: Zelikovsky Alex , Mandric Igor , Skums Pavel , Mandoiu Ion , Pasaniuc Bogdan , Srivastava Pramod 
Published: August 2019

Abstract
Recent advances in sequencing technologies and emerging single cell sequencing promise to profoundly impact cancer studies. One of the most important problems is reconstruction of history of cancer mutations. Existing methods model cells DNA as haplotypes and reconstruct perfect (or almost perfect) phylogeny of mutations from single cell DNA sequencing data. In this paper we propose to reconstruct genotypes (rather than haplotypes) which in absence of repeated and omitted mutations is equivalent to reconstruction of the mutation phylogeny. Single cell genotype reconstruction is proposed to perform in two steps - first the sequencing data are used for imputation of cell genotypes treated as individual human genomes and then the resulted genomes are fitted to perfect phylogeny by eliminating 4-gamete rule violations using integer linear programs. Our simulation results show advantage of single cell genotype imputation over existing methods.
Note: This abstract was not presented at the meeting.
Citation Format: Alex Zelikovsky, Igor Mandric, Pavel Skums, Ion Mandoiu, Bogdan Pasaniuc, Pramod Srivastava. Imputation of single cell cancer genotypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-214.
Abstract LB-219: Derivation of mathematical modeling for the diffusion and penetration of monoclonal antibody delivery into tumor
Authors: Kim Hyeongi , Kim Yangjin , Lee Yong-Jin , Kim Jin-su 
Published: August 2019

Abstract
Background: Commonly malignant solid tumor have an abundant tumor-associated cellular matrix (ECM). Although radioimmunothrepy (RIT) have proven to be effective and precise treatment in cancer, yet RIT has a limited performance in solid tumor, due to highly distributed ECM inside solid tumor tissue. Previously, we designed the combination RIT to enhance the penetration of monoclonal antibody (mAb), where we investigated that, using Relaxin which contain oncolytic adenovirus (OA) as combination therapy decreases tumor associated ECM. In this study, we developed mathematical modeling to explain and describe the diffusion and penetration of mAb inside the tumor with ECM. To obtain the model parameters in our developed mathematical model, we performed related experiments such as immunofluorescence and qRT-PCR.
Methods: We developed the reaction-diffusion partial differential equations (PDE) for describing the dependency of cancer cell, ECM density, diffusion and penetration of mAb and ECM modulated therapy that include our experimental data, also to overcome the classical limitation of PDE method. Model included the rapid decrease of ECM by OA, and density dependent diffusion coefficient. Initial condition for solving the PDE was derived using our experimental result. Diffusion coefficient for mAb and OA was modelled for simulating actual behavior of mAb and OA. Various condition of ECM density, and structure were modelled that derives the actual result of distribution of collagen. To confirm the mathematical prediction, we designed in vitro experiment with same condition as used as “in model”.
Results: Using our developed model, we successfully described relationship between ECM and mAb transport by OA, and investigated the change of ECM. Diffusion and penetration of mAb and OA were well described from tumor vessel and tumor surface. Regardless of ECM structure, all ECM structure were degraded after spreading of OA. In addition, our model simulation results predicted that mAb uptake dramatically increased in combination approach and was more than mAb alone treatment. Our developed mathematical model predicted the optimal schedule of OA pretreatment and it shows great results more than mAb pretreatment. Pretreatment results with OA shows a great anti-tumor effect more than mAb pretreatment in experimental data. Our model could well predicted and matched the experimental results. Collectively, in our study, we suggested new theoretical mathematical model framework to explain various ECM condition with drug transport
Citation Format: Hyeongi Kim, Yangjin Kim, Yong-Jin Lee, Jin-su Kim. Derivation of mathematical modeling for the diffusion and penetration of monoclonal antibody delivery into tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-219.
Abstract LB-258: EGFR and c-MET cooperate to enhance PARP inhibitor resistance in hepatocellular carcinoma
Authors: Dong Qiongzhu , Du Yi , Zhao Xixi , Li Hui , Liu Chunxiao , Wei Yongkun , Hung Mien-chie 
Published: August 2019

Abstract
Poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors are currently used in the clinic for the treatment of ovarian and breast cancers. However, the therapeutic efficacy of PARP inhibitor (PARPi) in the clinical trial for hepatocellular carcinoma (HCC) has been disappointing. To ensure therapeutic efficacy of PARPi against HCC, a disease often diagnosed at intermediate to advanced stages with no effective treatment options, it is critical to identify not only biomarkers to predict PARPi resistance but also rational combination treatments to overcome this. Here, we demonstrate that EGFR forms a heterodimer with c-MET, and the complex interacts with and phosphorylates Y907 PARP1 in the nucleus contributing to PARPi resistance. Inhibition of both EGFR and c-MET sensitizes HCC cells to PARPi. Combination of EGFRi, METi and PARPi significantly inhibited tumor growth in HCC animal model. Both EGFR and c-MET are known to be overexpressed in HCC. The current report provides a rationale to explain why PARPi does not work in clinical trials for HCC and also suggests an effective combination treatment consisting of EGFR, c-Met, and PARP inhibitors for HCC.
Note: This abstract was not presented at the meeting.
Citation Format: Qiongzhu Dong, Yi Du, Xixi Zhao, Hui Li, Chunxiao Liu, Yongkun Wei, Mien-chie Hung. EGFR and c-MET cooperate to enhance PARP inhibitor resistance in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-258.
Abstract LB-266: A novel computational combination-therapy prediction algorithm (secDrug) identifies the Nampt inhibitor FK866 reverses PI-resistant multiple myeloma
Authors: Kumar Harish , Mukherjee Ujjal Kumar , Chakravarti Sayak , Chen Li , ness Brian Van , Mitra Amit Kumar 
Published: August 2019

Abstract
Drug resistance is a major cause of concern in cancer chemotherapy that not only reduces efficacy but also causes toxicity through overdosing. For example, Ixazomib, an oral proteasome inhibitor, has proven to remarkably improve myeloma patient outcomes but is associated with dose limiting toxicities and drug resistance. Therefore, new combination treatment regimens are urgently needed for the treatment of cancers, including multiple myeloma, which can lower the required dose of standard-of-care drug without compromising on treatment efficacy. We will present an optimization-regularization based computational prediction method called secDrug that uses large-scale pharmacogenomics databases to identify novel secondary drug combinations to reverse drug resistance. In this study, we applied secDrug to Ixazomib-resistant cell lines (&gt;100) in the Genomics of Drug Sensitivity in Cancer (GDSC) database and predicted that the following FDA-approved drug classes can be best combined with Ixazomib to overcome resistance in MM: nicotinamide phospho ribosyl transferase or Nampt inhibitor (FK866), HDAC inhibitors (Panobinostat, SAHA), neddylation inhibitor (MLN4924), Raf inhibitor (PLX-4720) and HSP90 inhibitor (17-AAG). Our results corroborate with earlier studies that have indicated these drugs could potentially be used in MM, alone or in combination. To validate our prediction results, we treated our panel of &gt;50 human multiple myeloma cell lines (Ix-sensitive and Ix-resistant HMCLs) with the top predicted drug combination - FK866 + Ixazomib. The results, based on combination index theorem, show that this combination works highly synergistically where the IC50 of ixazomib in MM cells was significantly reduced in presence of FK866. Similar results were obtained for the other top predicted combination regimens. Our findings provide a strong case for using secDrug for predicting secondary drugs in cancers resistant to the standard-of-care therapy. Furthermore, this provides additional evidence in support of combining FK866 with ixazomib to enhance sensitivity or overcome resistance to ixazomib and thereby improve patient outcome. Our future aim is to investigate the mechanism behind the synergism between proteasome inhibitors and the top drugs identified by our algorithm as candidates for secondary combination therapies using next-gen transcriptomics and single-cell approaches.
Citation Format: Harish Kumar, Ujjal Kumar Mukherjee, Sayak Chakravarti, Li Chen, Brian Van ness, Amit Kumar Mitra. A novel computational combination-therapy prediction algorithm (secDrug) identifies the Nampt inhibitor FK866 reverses PI-resistant multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-266.