bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3568: Phosphatidylserine targeting antibody enhances antitumor activity of CAR T cells in mouse melanoma
Authors: Schad Sara , Hirschhorn-Cymerman Daniel , Budhu Sadna , Zhong Hong , Yang Xia , Shan Joseph , King Steven , Merghoub Taha , Wolchok Jedd 
Published: August 2018

Abstract
A viable strategy to treat advanced cancers includes transferring of tumor-specific T cells. T cells that recognize tumor antigens can be expanded and reinvigorated ex-vivo. Furthermore, autologous T cells can be genetically modified to express antitumor T cell receptors or chimeric antigen receptors (CARs). Although the potency and specificity of tumor-specific T cells can be manipulated ex vivo, once reinfused into patients, the T cells are subjected to immunosuppressive mechanisms established by the tumor. An important immune checkpoint regulator within tumors is phosphatidylserine (PS), a phospholipid that is exposed on apoptotic cells, tumor cells and tumor endothelium. Innate immune cells exposed to PS secrete suppressive cytokines and chemokines that can significantly impair the function and activation of antitumor T cells. Antibodies that target PS have been shown to reactivate antitumor immunity by polarizing tumor-associated macrophages into a proinflammatory M1 phenotype, reducing the number of MDSCs in tumors and promoting the maturation of dendritic cells into functional APCs. Our lab has previously shown that a PS targeting monoclonal antibody (mch1N11), in combination with transgenic CD4+ T cells that recognize the melanoma antigen Trp1, can regress very advanced melanomas in all treated mice. Here, we further those studies with data showing that a 2nd-generation CAR T cell that binds Trp1 on the surface of B16 melanoma, in combination with mch1N11 can improve antitumor activity and overall survival in B16 tumor-bearing mice. Additionally, in vitro killing assays with antigen-specific T cells sorted from the tumor reveal that mch1N11 enhances the cytolytic function of these T cells against B16 melanoma. Flow cytometry analysis of local immune responses in the tumors of animals treated with tumor-specific T cells and mch1N11 showed a decrease in anti-inflammatory (M2) macrophages and FoxP3+ regulatory T cells. These findings highlight that diminishing suppressive mechanisms locally with mch1N11 can enhance the efficacy of transgenic TCR and CAR T cells to improve the outcome in patients with advanced-stage melanoma. Our studies may inform the design of clinical trials combining PS targeting antibodies with CAR T cell therapy in solid tumors.
Citation Format: Sara Schad, Daniel Hirschhorn-Cymerman, Sadna Budhu, Hong Zhong, Xia Yang, Joseph Shan, Steven King, Taha Merghoub, Jedd Wolchok. Phosphatidylserine targeting antibody enhances antitumor activity of CAR T cells in mouse melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3568.
Abstract 3570: Adoptive transfer of tumor antigen-specific CTLs requires anti-CTLA-4 and anti-PD-1 to drive tumor eradication
Authors: Shi Lewis Zhichang , Gao Jianjun , Vence Luis , Brando Jorge , Allison James , Sharma Padmanee 
Published: August 2018

Abstract
Adoptive transfer of tumor-reactive T cells (ACT) has led to significant clinical responses in hematologic malignancies. However, its efficacy in solid tumors has been dismal, likely due to the immunosuppression imposed by the tumor microenvironment (TME) of solid tumors. A proven effective strategy to revert the immunosuppressive TME is immune checkpoint blockades (ICBs), including anti-CTLA-4 and anti-PD-1/PD-L1, which have been recently approved by FDA for cancer therapy. Here, using the orthotopic B16-F10 melanoma model, we combine ACT of PMEL-1 Tg+ CTLs that recognize the endogenous melanoma antigen gp100 with dual blockade of CTLA-4 and PD-1, the highly pursued effective combinatorial ICB, to treat established tumors. Although ACT alone transiently suppresses tumor growth, complete tumor regression requires additional dual anti-CTLA-4 and anti-PD-1 blockade. Mechanistically, we demonstrate that the ICOS-Eomes-IFN-γαμμα axis, but not the ICOS-T-bet-IFN-γαμμα axis, in CTLs mediates the therapeutic effects of ACT and ICBs. Our data provide direct evidence that combining ACT of CTLs with ICBs confers long-term protection to tumor challenges, which largely depends on CTL-intrinsic expression of ICOS.
Citation Format: Lewis Zhichang Shi, Jianjun Gao, Luis Vence, Jorge Brando, James Allison, Padmanee Sharma. Adoptive transfer of tumor antigen-specific CTLs requires anti-CTLA-4 and anti-PD-1 to drive tumor eradication [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3570.
Abstract 3684: HDAC inhibitors restore BRAF inhibitor sensitivity by altering PI3K and survival signaling in melanoma
Authors: Hersey Peter , Gallagher Stuart J. 
Published: August 2018

Abstract
Mutations in BRAF activate oncogenic MAPK signaling in almost half of cutaneous melanomas. Inhibitors of BRAF (BRAFi) and its target MEK are widely used to treat melanoma patients with BRAF mutations but unfortunately acquired resistance occurs in the majority of patients. Resistance results from mutations or non-genomic changes that either reactivate MAPK signalling or activate other pathways that provide alternate survival and growth signaling.Here we show the histone deacetylase inhibitor (HDACi) panobinostat overcomes BRAFi resistance in melanoma, but this is dependent on the resistant cells showing a partial response to BRAFi treatment. Using patient- and in vivo- derived melanoma cell lines with acquired BRAFi resistance, we show that combined treatment with the BRAFi encorafenib and HDACi panobinostat synergistically induced caspase-dependent apoptotic cell death. HDAC inhibition decreased PI3K pathway activity associated with a reduction in the protein level of a number of receptor tyrosine kinases including AXL, YAP, ERBB2 and ERBB3 but not EGFR or ERBB4. Both NOXA and BIM proteins were implicated as causing cell death, but in a cell line specific manner. Independent of these changes, panobinostat reduced c-Myc and pre-treatment of cells with siRNA against c-Myc reduced BRAFi/HDACi drug-induced cell death. These results suggest that a combination of HDAC and MAPK inhibitors may play a role in treatment of melanoma where the resistance is due to activation of MAPK-independent pathways. This work identifies patients that may respond well to this drug combination and demonstrates the necessity of disrupting multiple cell survival pathways in melanoma.
Citation Format: Peter Hersey, Stuart J. Gallagher. HDAC inhibitors restore BRAF inhibitor sensitivity by altering PI3K and survival signaling in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3684.
Abstract 3707: PD-L1 antibody drug conjugate for cancer immune-chemo combination therapy
Authors: Sau Samaresh , Petrovici Alex , Alsaab Hashem , Iyer Arun K. 
Published: August 2018

Abstract
Antibody drug conjugates (ADCs) are a new form of targeted therapy to cancer, consisting of an antibody, a conditionally stable linker, and a cytotoxic drug. Immune checkpoint molecule, such as programmed death ligand-1 (PD-L1) overexpressed in various solid tumors including triple negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC) and it has a crucial role in tumor immune evasion. Blocking the interaction between PD-L1 and PD-1 (programmed death-1 receptor) resurrects tumor immune surveillance, resulting CD8+ cytotoxic T cells activation to attack the tumor cells. This is an emerging anticancer mechanism and more than four antibody inhibitors have been recently FDA approved against PD-1 or PD-L1 biomarker. Targeting PD-L1 in TNBC and NSCLC is an excellent approach for tumor immunotherapy. However, the major challenges of anti-PD-L1 therapy (Atezolizumab) are (i) the transient expression of PD-L1 in tumor microenvironment, (ii) development of anti-PD-L1 resistance, (iii) difficulty of tumor stroma penetration that retard its clinical outcome. To overcome these challenges, we chemically conjugated Atezolizumab (ATZ) with potent chemotherapeutic payload, such as Doxorubicin (Dox) through polyethylene glycol (PEG) linkers. The role of Dox is to break the tumor stroma so that PD-L1 antibody can penetrate to the core of the tumor. Introduction of PEG-linker with high molecular weight ATZ (155 kD) has drastically improved the solubility of ADC and successful chemical conjugation of between ATZ and PEG-Dox was evaluated by MALDI-TOF analysis. Our data has revealed significantly tumor cell killing effect and induction of apoptosis in PD-L1-Dox treated MDA-MB-231 cells. The near infrared imaging of PD-L1 dye conjugate in TNBC and NSCLC patient derived xenograft (PDx) supports the selective tumor targetability. Based on the synergistic anticancer effect and selective tumor targetability demonstrated in this study build a strong rational of using PD-L1 ADC approach for cancer immune-chemo therapy and diagnosis.
Citation Format: Samaresh Sau, Alex Petrovici, Hashem Alsaab, Arun K. Iyer. PD-L1 antibody drug conjugate for cancer immune-chemo combination therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3707.
Abstract 3730: Structure determination, mode of action and safe delivery of an improved K6L9-type peptide
Authors: Shrestha Tej B. , Yu Jing , Bossmann Stefan , Troyer Deryl 
Published: August 2018

Abstract
There is a significantly increased interest in using antimicrobial peptides for anticancer therapy. D-K6L9, LKLLKKLLKKLLKLL is an antimicrobial peptide that has been explored. It kills cancer cells by depolarizing their cell membranes, thus inducing apoptosis. Further modification of the peptide for increased toxicity and safe packaging into a delivery vehicle for targeted delivery is highly desired for the in vivo applications. Here, the peptide was modified with two extra amino acids (serine and alanine) at both C and N terminals, resulting in SA-LKLLKKLLKKLLKLL-AS. The sequence and structure of the modified peptide were determined by means of 2D 1H-1H -COSY, NOESY, and TOCSY-NMR spectroscopy. The 3D structure of the peptide in the solution phase was generated by CNS software using a distance constraint generated by NOE spectroscopy. The 3-D structure of SA-D-K6L9-AS is maintained, as well as the amphiphilicity required for insertion into cell membranes. This peptide was tested on the following mouse cancer cell lines: GL 26 (glioma), B16-F10 (melanoma lung metastases) and 4T1 (metastasizing breast cancer). The LC50 values of the modified peptide were found to be 0.707 µM for B16-F10, 6.237 µM for 4T1 and 1.707 µM for GL 26, which is 5- 10 fold more active than the original D-K6L9. To explore the findings using the modified peptide, SA-D-K6L9-AS tagged with a rhodamine dye was incubated with GL 26 cancer cells. Sequential confocal imaging (every 30 seconds) revealed that the peptide gets internalized into the cytoplasm in less than 5 min and then localizes in the mitochondria. This peptide is found to be toxic to neuronal stem cells and monocytes as well. To avoid the non-specific toxicity of the peptide for in vivo applications, highly mesoporous silica nanoparticles (MSN) were synthesized. The peptide was loaded into the MSN. MSN were further coated with a polysilazane as a “gift wrap” after loading the peptide. This gift wrap can hold the contents inside the MSN, showing no toxicity at 24 hours and subsequent slow release of the peptide payload into the cytoplasm within 72 hours. This gift wrapping of the highly toxic peptide into the MSN could be very useful for in vivo cancer therapy by means of targeted delivery to the cancer site with appropriate surface modification of MSN.
Citation Format: Tej B. Shrestha, Jing Yu, Stefan Bossmann, Deryl Troyer. Structure determination, mode of action and safe delivery of an improved K6L9-type peptide [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3730.
Abstract 3757: Targeting the IDO/TDO pathway through degradation of the immunosuppressive metabolite kynurenine
Authors: Coma Silvia , Cavanaugh Jill , Nolan James , Tchaicha Jeremy , McGovern Karen , Stone Everett , Lamb Candice , Karamitros Christos , Blazek John , Garrison Kendra , Georgiou George , Manfredi Mark , Zhang Xiaoyan Michelle 
Published: August 2018

Abstract
The tryptophan/kynurenine pathway has been clinically validated in several tumor types with small-molecule IDO1 inhibitors in combination with checkpoint inhibition. Indoleamine-pyrrole 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2) are upregulated in a number of tumor types, metabolizing tryptophan to form immunosuppressive kynurenine. We are developing Kynureninase (Kynase), a kynurenine depleting enzyme, to treat IDO1 and TDO2 positive tumors. The human Kynase has been successfully engineered to vastly increase catalytic activity and stability toward kynurenine over the wild type enzyme. In mice, Kynase achieved prolonged Kynurenine degradation (≥5 days) in plasma and tumor draining lymph node (TDLN), leading to anti-tumor activity as a single agent and in combination with check point inhibitors in mouse syngeneic tumor models. Kynase demonstrated superior tumor growth inhibition and survival benefit relative to a leading IDO1 inhibitor epacadostat in these models. The effects of Kynase on a number of immune cell types, both in vitro and in vivo, are being investigated. Human Kynase has also shown a favorable PK profile and kynurenine degradation in non-human primates, and Kynase variants are now moving toward development candidate selection for treatment of cancers where both IDO/TDO pathways play a significant immunosuppressive role.
Citation Format: Silvia Coma, Jill Cavanaugh, James Nolan, Jeremy Tchaicha, Karen McGovern, Everett Stone, Candice Lamb, Christos Karamitros, John Blazek, Kendra Garrison, George Georgiou, Mark Manfredi, Xiaoyan Michelle Zhang. Targeting the IDO/TDO pathway through degradation of the immunosuppressive metabolite kynurenine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3757.
Abstract 3825: INCAGN02390, a novel antagonist antibody that targets the co-inhibitory receptor TIM-3
Authors: Waight Jeremy , Iyer Priyadarshini , Breous-Nystrom Ekaterina , Riordan Christina , Findeis Mark , Underwood Dennis , Connolly Joseph , Sanicola-Nadel Michele , Nastri Horacio , Scherle Peggy , Hollis Gregory , Huber Reid , Stein Robert , Dijk Mark van , Wilson Nicholas S. 
Published: August 2018

Abstract
Unprecedented rates of durable clinical responses have been observed for antibody-based therapeutics targeting immune checkpoint proteins such as cytotoxic T lymphocyte antigen-4 (CTLA-4) or programmed death receptor-1 (PD-1). Nonetheless, a significant number of patients experience de novo resistance or relapse due to adaptive resistance mechanisms. T-cell immunoglobulin and mucin domain containing-3 (TIM-3) is an inhibitory receptor involved in immune tolerance often co-opted by tumors to prevent successful antitumor responses. Accordingly, TIM-3 is frequently expressed on myeloid and so-called exhausted T and NK cells within the tumor microenvironment. Targeting the TIM-3 pathway in preclinical models has provided additional rationale for pharmacologic modulation of this axis in cancer patients. INCAGN02390 is a novel and fully human Fc-engineered IgG1κ antibody developed to antagonize the TIM-3 pathway for the treatment of human malignancies. INCAGN02390 forms a high-affinity interaction with TIM-3, occluding access to the CC'-FG binding cleft and blocking phosphatidylserine binding. In addition, INCAGN02390 elicits rapid receptor internalization, potentially obviating interactions with other described or undescribed ligands. INCAGN02390 also enhances IFN-γ production from T cells undergoing tonic TCR stimulation when combined with PD-1 blockade. Finally, to demonstrate combinatorial potential, we show potent antitumor activity of an anti-mouse TIM-3 antibody in concert with other checkpoint antibodies in vivo. In summary, these data support assessment of INCAGN02390 in patients with advanced or metastatic solid tumors.
Citation Format: Jeremy Waight, Priyadarshini Iyer, Ekaterina Breous-Nystrom, Christina Riordan, Mark Findeis, Dennis Underwood, Joseph Connolly, Michele Sanicola-Nadel, Horacio Nastri, Peggy Scherle, Gregory Hollis, Reid Huber, Robert Stein, Mark van Dijk, Nicholas S. Wilson. INCAGN02390, a novel antagonist antibody that targets the co-inhibitory receptor TIM-3 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3825.
Abstract 3834: Antibodies targeting Resokine, a soluble immune modulator, inhibit tumor growth in syngeneic mouse models
Authors: Ogilvie Kathy , Ng Cherie , Nangle Leslie , Ampudia Jeanette , Chang Joon , Cubitt Andrea , King David J. , Mendlein John 
Published: August 2018

Abstract
A number of non-canonical functions have been established for proteins generated from the tRNA synthetase gene family. One of these, termed Resokine, is derived from histidyl tRNA synthetase and plays an important role in controlling immune cell activation. Circulating levels are sufficient to down-regulate the extent of T cell activation that can be achieved in vitro. A panel of specific monoclonal antibodies have been generated and tested for their anti-tumor activity in mouse syngeneic tumor models. Antibodies to Resokine demonstrated anti-tumor activity across three different tumor models. Treatment of subcutaneous CT26 tumors resulted in improved efficacy compared to treatment with antibodies that block the PD-1/PD-L1 interaction. Significant efficacy was also observed in the difficult to treat subcutaneous B16F10 melanoma and 4T1 breast tumor models. In addition anti-Resokine demonstrated significant activity in a tumor seeding model using B16F10 melanoma which resulted in inhibition of tumor nodules in the lung, and was more efficacious than a combination of antibodies to PD-L1 and CTLA-4. Combinations of anti-Resokine antibody with either anti-PD-1 or anti-PD-L1 demonstrated at least additive, and potentially synergistic activity in these models. Animals with long-term tumor regressions were re-implanted with viable tumor cells, and demonstrated long-term immune memory with rejection of the newly implanted tumors. To understand the mechanism of anti-Resokine antibody therapy, cell depletion studies were carried out in the B16F10 tumor model. In these experiments activity of anti-Resokine antibodies was demonstrated to be dependent upon the presence of CD8 T cells and also NK cells, but independent of CD4 T cells. The immune based mechanism of antibodies to Resokine was further demonstrated by re-challenge of mice that had regressed tumors upon treatment. Tumor re-growth was not observed even in the absence of further treatment whereas control mice grew tumors at the normal rate, suggesting that immune memory had been induced. Antibodies to Resokine offer an exciting new potential option for immunotherapy of cancer, which has significant activity as monotherapy and is compatible with more established modalities. Anti-Resokine antibodies are currently being developed to initiate clinical evaluation.
Citation Format: Kathy Ogilvie, Cherie Ng, Leslie Nangle, Jeanette Ampudia, Joon Chang, Andrea Cubitt, David J. King, John Mendlein. Antibodies targeting Resokine, a soluble immune modulator, inhibit tumor growth in syngeneic mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3834.
Abstract 3938: The alkylphosphocholine erufosine induces ER and mitochondrial stress in OSCC cells
Authors: Ansari Shariq S. , Sharma Ashwini , Ali Doaa M. , Köng Rainer , Berger Martin R. 
Published: August 2018

Abstract
Endoplasmic reticulum (ER) plays an essential role in cell function and survival. Accumulation of unfolded or misfolded proteins in the lumen of the ER activates the unfolded protein response (UPR), resulting in ER-stress and subsequent apoptosis. The alkylphosphocholine erufosine is a known Akt-mTOR inhibitor in oral squamous cell carcinoma (OSCC). In the present study we decipher a new facet of erufosine's mechanism of action and evaluate its role to induce ER and mitochondrial stress leading to autophagy, apoptosis and ROS induction. The cellular toxicity of erufosine was determined by MTT assay after 24h, 48h and 72h exposure in two OSCC cell lines, HN-5 and SCC-61. Based on these results, HN-5 cells were exposed to erufosine at concentrations corresponding to IC25, IC50 and IC75 concentrations, and then their mRNA was isolated and analyzed by Illumina Chip array. Gene expression and gene set enrichment analyses were performed to identify core KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways and GO (Gene Ontology) terms. A positive enrichment of ER stress upon erufosine exposure was observed, which was verified at protein level for the ER stress sensors and their downstream mediators. Upon erufosine exposure, calcium influx into the cytoplasm of the two OSCC cell lines was also observed. A differential regulation of genes and positive enrichment of processes pertaining to autophagy and apoptosis was also observed upon erufosine exposure. Autophagy was confirmed by increased acidic vacuoles and LC3-B levels. Apoptosis was confirmed by nuclear staining, annexin-V and immuno-blotting of caspases. The induction of mitochondrial stress upon erufosine exposure was predicted by gene enrichment analysis and shown by erufosine's effect on mitochondrial membrane potential, ATP and ROS production in OSCC cells. These data show that ER and mitochondrial targeting by erufosine represents a new facet of its mechanism of action as well as a promising new framework in the treatment of head and neck cancers. They furthermore support the future evaluation of erufosine as a therapeutic approach in cancer treatment alone, or in combination.
Citation Format: Shariq S. Ansari, Ashwini Sharma, Doaa M. Ali, Rainer Köng, Martin R. Berger. The alkylphosphocholine erufosine induces ER and mitochondrial stress in OSCC cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3938.