bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3585: T cell receptor-stabilized regenerated CD8ab cytotoxic T lymphocytes for cancer immunotherapy
Authors: Minagawa Atsutaka , Hotta Akitsu , Kawai Yohei , Yasui Yutaka , Uemura Yasushi , Yasukawa Masaki , Nakatsura Tetsuya , Kaneko Shin 
Published: August 2018

Abstract
The use of antigen-specific T cell derived induced iPSCs as a cell source for regeneration of cytotoxic T lymphocytes (CTLs) have advantages in rejuvenation profile, and reproducible number of CTLs. However for the safe and efficient regenerated T cell immunotherapy, strict antigen specificity is essential. Here we report CD8αβ T cells differentiated from T cell-derived iPSCs underwent additional rearrangement of the T cell receptor (TCR) α-chain gene at the CD4/CD8 double positive stage during in vitro differentiation and lost antigen specificity. CRISPR knockout of a recombinase gene in the T-iPSCs successfully prevented this additional TCR rearrangement. Moreover, when CD8αβ T cells were differentiated from non-T cell-derived but antigen-specific TCR-transduced iPSCs, they showed monoclonal expression of the transduced TCR. TCR stabilized regenerated CD8αβ T cells effectively inhibit tumor growth in xenograft cancer models. These approaches could contribute to safe and effective regenerative T cell immunotherapies.
Citation Format: Atsutaka Minagawa, Akitsu Hotta, Yohei Kawai, Yutaka Yasui, Yasushi Uemura, Masaki Yasukawa, Tetsuya Nakatsura, Shin Kaneko. T cell receptor-stabilized regenerated CD8ab cytotoxic T lymphocytes for cancer immunotherapy [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 3585.
Abstract 3586: A universal killer T-cell for adoptive cell therapy of cancer
Authors: Dillard Pierre , Mensali Nadia , Myklebust June Helen , Hebeisen Mickael , Skorstad Gjertrud , Myrhe Marit Renee , Fåne Anne , Gaudernack Gustav , Kvalheim Gunnar , Inderberg Else Marit , Wälchli Sebastien 
Published: August 2018

Abstract
T cell-mediated immunotherapy of cancer has achieved remarkable results in hard-to-beat cancers. The main challenge of adoptive T-cell transfer (ACT) is its labor intensive and costly production and logistics as well as its dependency on the quality of the patient's T cells. To overcome these hurdles we have designed a universal cell line for TCR expression by modifying the FDA-approved NK cell line, NK-92. Advantages of using this cell line is that it is easy to expand and can readily be genetically engineered. However, tumor cell recognition and killing by NK-92 is not antigen specific. This can be controlled by introducing an antigen receptor, such as a chimeric antigen receptor (CAR) or, as in the current work, a TCR. We herein present evidence that NK-92 can be modified to become a T cell-like lymphocyte which we named UK-92 cell (Universal Killer). UK-92 expressing a therapeutic TCR showed conserved binding capacity to the cognate pMHC. Phosphoflow cytometry results indicated that the introduced TCR was able to mediate intracellular signaling upon either crosslinking or cognate pMHC binding. Our data showed that both early and late TCR signalling players were activated in a TCR-specific manner (anti-CD3/anti-CD28 stimulation) and further in a pMHC specific manner. In vitro functional assays using TCRs isolated from both CD8 and CD4 T cells demonstrated that UK-92-TCR could be stimulated in a pMHC-specific manner and, importantly, could kill tumor cells specifically even in a tumor-like microenvironment such as spheroids. We have now shown in vitro that UK-92 cells are as specific and potent as redirected T cells to kill target cells. Finally, encouraging in vivo data showed that mice receiving UK92 cells expressing a therapeutic TCR experienced reduction in tumor load and enhanced survival compared with control mice. If confirmed, the use of UK92 as a universal cell line might pave the way to truly off-the-shelf therapeutic effector cells for cancer immunotherapy and leading to drastic reduction of cell production time, logistic and cost.
Citation Format: Pierre Dillard, Nadia Mensali, June Helen Myklebust, Mickael Hebeisen, Gjertrud Skorstad, Marit Renee Myrhe, Anne Fåne, Gustav Gaudernack, Gunnar Kvalheim, Else Marit Inderberg, Sebastien Wälchli. A universal killer T-cell for adoptive cell therapy of cancer [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 3586.
Abstract 3588: ACTallo: A novel approach using gamma-delta T cells to allogeneic cellular therapy to treat cancer
Authors: Dao Mo , Mata Melinda , Alten Leonie , Nowicka Aleksandra , Kuttruff Sabrina , Missel Sarah , Mohamed Ali , Weinschenk Toni , Bulliard Yannick , Walter Steffen 
Published: August 2018

Abstract
Adoptive cellular therapy (ACT) has dramatically changed the landscape of cancer immunotherapy; however, the complex manufacture of individualized products from late-stage, heavily pre-treated cancer patients, together with high cost-of-goods, encourages the development of simpler ‘off-the-shelf' alternatives. The unique properties of γδ (gamma-delta) T cells make them a seductive candidate for effective allogeneic ACT. In contrast to αβ T cells, γδ T cells are endowed with intrinsic antitumor activity while unable to induce graft-versus-host disease. γδ T cells have a high proliferative potential before exhibiting exhaustion. Moreover, in the context of αβ TCR-engineered ACT, γδ T cells pose a lesser risk of off-target toxicity, due to the absence of expression of endogenous αβ TCR and hence, risk of mispairing with the engineered αβ TCR.
Here, we will present the ACTallo® platform, which combines the unique properties of γδ T cells with Immatics' XPRESIDENT® target/TCR discovery platform. The ACTallo® process selectively expands Vγ9Vδ2 T cells that are retrovirally-transduced to co-express CD8 together with a tumor-specific αβ TCR. Over a period of 45 days or less, ACTallo® γδ T cells can expand &gt;30,000 fold. γδ T cells obtained this way recognize tumor cells, express cytokines, degranulate and kill tumor cells specifically. In addition, ACTallo® γδ T cells show no signs of exhaustion after expansion, as evidenced by the lack of expression of PD1, TIM3 or LAG3. ACTallo® is intended to overcome the limitation of autologous cellular therapies towards off-the-shelf approach, by combining the large-scale expansion potential of allogeneic γδ T cells with novel TCRs against XPRESIDENT® mass-spectrometry guided tumor-specific targets.
Citation Format: Mo Dao, Melinda Mata, Leonie Alten, Aleksandra Nowicka, Sabrina Kuttruff, Sarah Missel, Ali Mohamed, Toni Weinschenk, Yannick Bulliard, Steffen Walter. ACTallo: A novel approach using gamma-delta T cells to allogeneic cellular therapy to treat cancer [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 3588.
Abstract 3593: Noncoding RNAs in early detection of radiation-induced late pulmonary effects
Authors: Yadav Marshleen , Song Feifei , Qamri Zahida , Chakravarti Arnab , Jacob Naduparambil K. 
Published: August 2018

Abstract
Normal tissue toxicity is an undesired outcome in patients receiving radiation therapy, manifested as acute radiation syndromes (ARS) and as late effects in survivors. The purpose of the study is to develop biomarkers for assessing the extent of lung inflammation and early detection of delayed and late radiation toxicities such as pneumonitis and pulmonary fibrosis. Circulating miRNAs offer great promise as diagnostic predictive biomarkers due to their high abundance, high stability and sensitivity. A longitudinal analysis of evolutionarily conserved noncoding RNAs was done using NanoString platform in serum samples from leukemia patients and pneumonitis-prone BALB/c mice exposed to clinically relevant doses of whole-body, organ-targeted/protected irradiation to compare the treatment-induced alterations. The associated immune response was evaluated by cytokine multiplexing and gene expression analysis and imaging with micro-CT. Bleomycin and targeted miRNA knockout mice models were used to evaluate functional significance of the identified biomarkers. Quantification of time-dependent alterations in serum and plasma miRNAs from rodents samples collected after thoracic, gut versus whole-body exposure have identified a panel of five miRNAs that are capable of providing an early readout of delayed lung toxicities. The specificity of the candidate miRNAs as potential early indicators of lung injury was confirmed in a bleomycin model of acute lung injury where an overlapping miRNA signature was observed in serum. Among these conserved miRNAs, serum miR-21 and miR-29a were found significantly elevated in two weeks in lung irradiated animals with concomitant increase in proinflammatory cytokines. The significance of the markers was further validated in serum miRNA profile of leukemia patients who exhibited pneumonitis symptoms post radiation therapy. The functional role of miR-21 in promoting radiation-induced inflammation was evident from compromised response of genes associated with inflammation in irradiated miR-21-/- mice. Our study has identified a panel of evolutionarily and functionally conserved sensitive miRNA biomarkers that facilitate rapid and early detection of late pulmonary toxicities in leukemia and lung cancer patients who receive therapeutic radiation. Analysis of circulating biomarkers will potentially assist in making therapeutic and follow-up decision based on individual's own physiologic response and developing strategies for timely mitigation and treatment.
Citation Format: Marshleen Yadav, Feifei Song, Zahida Qamri, Arnab Chakravarti, Naduparambil K. Jacob. Noncoding RNAs in early detection of radiation-induced late pulmonary effects [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 3593.
Abstract 36: Novel age-related tumor promoting and inhibiting genes in breast cancer
Authors: Wang Bingzhi , Gu Xiang , Zhu Haiyan , Sun Luzhe 
Published: August 2018

Abstract
During aging, besides genetic alterations, genes with altered expression may promote breast cancer development. Using linear regression modeling, we identified 148 up-regulated and 189 down-regulated genes during aging, by analyzing the whole transcriptome profiling data of matched normal tissues from 82 female patients with age and menopausal status available from The Cancer Genome Atlas data. We also compared matched tumor and normal samples, 3356 up-regulated and 3124 down-regulated genes were identified to be affected by tumorigenesis. Overlapping of tumorigenesis-associated genes with age-dependent genes resulted in 14 up-regulated and 24 down-regulated genes with both age and tumorigenesis. These genes were significantly predictive in relapse free survival, indicative of their potential tumor promoting or suppressive functions respectively. To test this hypothesis, we selected two up-regulated genes-DYNLT3 and P4HA3, and two down-regulated genes-ALX4 and WDR86 to investigate their function in controlling breast cancer malignancy because they are novel genes to breast cancer. We found that knockdown of DYNLT3 or P4HA3, and overexpression of ALX4, significantly reduced breast cancer cell proliferation, migration and colony forming capacity in soft agar, while overexpression of WDR86 did not show any inhibitory activity in breast cancer cells. Consistent with the in vitro data, knockdown of DYNLT3, P4HA3 and overexpression of ALX4 inhibited tumor growth and lung metastasis when breast cancer cells were orthotopically implanted in mice, whereas such inhibition was not observed in mice when WDR86-overexpressing breast cancer cells were implanted. Taken together, our results support that some age-related genes harbor tumor promoting or inhibiting functions. Thus, proper modulation of their expression has potential to prevent or slow down the progression of breast cancer.
Citation Format: Bingzhi Wang, Xiang Gu, Haiyan Zhu, Luzhe Sun. Novel age-related tumor promoting and inhibiting genes in breast cancer [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 36.
Abstract 360: The role of polybromo1 in stress response
Authors: Porter Elizabeth G. , Dykhuizen Emily C. 
Published: August 2018

Abstract
Polybromo1 (PBRM1) is mutated in 3.5% of human cancers with the highest incident in renal clear cell carcinoma (40%). PBRM1 is a member of the PBRM1-Brg-Associating Factors (PBAF) chromatin remodeling complex and is characterized by six tandem bromodomains. PBRM1 acts as a tumor suppressor and when deleted along with VHL, the most frequently mutated gene in RCCC, tumors develop in mice. We have previously shown that PBRM1 regulates the expression of genes involved in cell adhesion, apoptosis, and negative cell proliferation in a RCCC cell line. Additionally, we have demonstrated that four of the six bromodomains work together to regulate binding of the complex to chromatin, gene expression, and tumor suppression in RCCC, which correlates with pattern of PBRM1 missense mutations found in RCCC patient tumors. Through this work we identified histone 3 lysine 14 acetylation (H3K14Ac) as the chromatin mark essential for PBRM1 binding. While H3K14Ac is generally found at active promoters, it is also induced at the promoters of stress genes when cells experience stressors such as metabolic stress, osmotic stress, ER stress, or reactive oxygen species (ROS) stress. Knockdown of PBRM1 in normal epithelial cells leads to an increase in proliferation and a partial epithelial to mesenchymal transition (EMT), consistent with low grade ROS. RNA-seq analysis further confirmed a role for PBRM1 in regulating stress response genes. Although loss of PBRM1 increases proliferation in epithelial cells, it also increases cell vulnerability to high levels of ROS. Together this suggests that PBRM1 can be growth promoting or growth inhibiting to cells depending on the cells environment and stress response needs.
Citation Format: Elizabeth G. Porter, Emily C. Dykhuizen. The role of polybromo1 in stress response [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 360.
Abstract 3600: Early detection of esophageal adenocarcinoma using near-infrared lectin-based imaging
Authors: Neves Andre A. , Pietro Massimiliano Di , O'Donovan Maria , Waterhouse Dale J. , Bohndiek Sarah E. , Brindle Kevin M. , Fitzgerald Rebecca C. 
Published: August 2018

Abstract
Background: Long procedure times and sampling error frequently limit the efficacy of endoscopic surveillance for Barrett's esophagus (BE). Near-infrared (NIR) fluorescence imaging minimizes optical scattering and tissue autofluorescence. We assessed, in an ex vivo setting, the feasibility of using a topically applied NIR dye-labeled lectin for the detection of early neoplasia in BE.
Methods: We recruited consecutive patients undergoing endoscopic mucosal resection (EMR) for BE-related early neoplasia. EMR specimens were freshly collected and sprayed at the bedside with a fluorescent lectin and then imaged ex vivo. A maximum of two punch biopsies were collected from each EMR under NIR light guidance. Fluorescence intensity from dysplastic and nondysplastic areas within EMRs were compared and from punch biopsies with different histological grades.
Results: We analyzed 29 EMR specimens from 17 patients. Dysplastic regions showed significantly lower fluorescence across whole EMR specimens (P &lt; 0.001). A 41% reduction in fluorescence was found for dysplastic compared to nondysplastic punch biopsies (P &lt; 0.001), with a sensitivity and specificity for dysplasia detection of 80% and 82.9%, respectively.
Conclusion: NIR imaging using fluorescently-labeled lectins can distinguish dysplastic from nondysplastic Barrett's mucosa ex vivo. We are currently planning a first-in-human study to validate this imaging platform.
Citation Format: Andre A. Neves, Massimiliano Di Pietro, Maria O'Donovan, Dale J. Waterhouse, Sarah E. Bohndiek, Kevin M. Brindle, Rebecca C. Fitzgerald. Early detection of esophageal adenocarcinoma using near-infrared lectin-based imaging [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 3600.
Abstract 3601: Targeting USP7/PTEN axis regulates the metastatic competency of bone marrow-resident melanoma cells
Authors: Vishnoi Monika , Boral Debasish , Liu Haowen N. , Sprouse Marc L. , Yin Wei , Davies Michael A. , Oliva Isabella C. Glitza , Marchetti Dario 
Published: August 2018

Abstract
Recurrence is the major cause of melanoma death due to cell dissemination from primary/metastatic tumor (CTCs). During asymptomatic periods, these cells reside in bone marrow (bone-marrow resident tumor [BMRT cells]) and remain quiescent. We hypothesized that disseminated tumor cells survive in bone marrow (BM) during these periods and evolve to metastatic potency during disease progression. First, we isolated CTC-enriched, Lin-neg population from clinically advanced melanoma patients and performed biomarker expression and mutational profiling to confirm presence of putative CTCs. Lin-neg CTC population contained unique transcriptomics signature with elevated melanoma markers expression (BAGE, MAGEA1, B4GALNT1, S100A3). Further, downstream IPA analysis demonstrated that an upregulation of transcripts for genes involved in cell survival and pro-development functions with concomitant decrease in cell proliferative and inflammation properties. Second, we implanted Lin-neg population in murine xenograft models and isolated HLA+/ Melan-A+ cells population from blood and BM at endpoint. Expression of human (HLA-ABC) and melanoma markers (Melan-A, S100, NG2, CD146) on BMRTCs and CTCs was confirmed by employing: (a) immunofluorescence staining, (b) single-cell DEPArrayTM and CellSearchTM capture, (c) genomic profiling, and (d) organ-site colonization of CTCs with concomitant to BMRTCs in BM. Third, we discovered distinct transcriptomic signature of BMRTCs vs CTCs by differential gene expression profiling. Subsequent pathway analysis showed top five altered canonical pathways in BMRTCs: protein ubiquitination pathway, EIF2, actin cytoskeleton, systemic lupus erythematosus and hypoxia signaling. Of note, a strikingly elevated expression of PTEN in BMRTCs was detected. Fourth, because PTEN binds to USP7, a key component of protein ubiquitination pathway, we evaluated USP7/PTEN axis in CTC-driven BMRTCs modulated metastatic competency. The use of two clinically approved USP7 inhibitors to study their effects on the proliferative capacity of BMRTCs led to a significant reduction of CTCs at metastatic sites. This study provides critical insights to identify biomarkers of melanoma recurrence during the asymptomatic periods of the disease, fostering application of USP7 inhibitors for innovative melanoma therapies for patients with metastasis undetectable disease and/or yet to develop metastasis.
Citation Format: Monika Vishnoi, Debasish Boral, Haowen N. Liu, Marc L. Sprouse, Wei Yin, Michael A. Davies, Isabella C. Glitza Oliva, Dario Marchetti. Targeting USP7/PTEN axis regulates the metastatic competency of bone marrow-resident melanoma 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 3601.
Abstract 3604: Centrosome amplification in epcam-captured circulating tumor cells from metastatic cancer patients
Authors: Singh Ashok , Denu Ryan A. , Sperger Jamie M. , Weaver Beth A. , Burkard Mark E. , Lang Joshua M. 
Published: August 2018

Abstract
Background: Genomic instability and evolution of cancers is linked to chemotherapy sensitivity and resistance in patients with metastatic cancer. Taxane-based chemotherapies operate by promoting chromosomal instability (CIN) by increasing multipolar mitoses. Breast tumors with CIN are more sensitive to paclitaxel compared to tumors without CIN. There is a critical need for new biomarkers based on biological evaluation of mechanisms of response and resistance in metastatic cancer. Although CIN is difficult to detect directly, centrosome amplification (CA) is a common mechanism of CIN. In this study, we develop an assay to detect CA in circulating tumor cells (CTCs) as a minimally invasive assay to evaluate sensitivity to taxane-based chemotherapies.
Methods: Blood samples from patients with metastatic breast and prostate cancer were collected and processed for nucleated cells using a Ficoll gradient and magnetic depletion of CD45-positive cells. EpCAM-positive CTCs were captured using an exclusion-based sample preparation technology known as the VERSA (Versatile Exclusion-based Rare Sample Analysis) platform. CTCs were defined as cells positive for Hoechst, cytokeratin and negative for multiple immune and endothelial cell markers (CD45/CD11b/CD14 and CD34). EpCAM-captured CTCs were also stained with pericentrin and centrin to identify CA and evaluated for pericentrin (whole centrosome marker) and centrin (centriole marker) protein-staining intensity, number and size.
Results: CA was detected in a subset of CTCs from patients with metastatic breast and prostate cancer patients. As a control, centrosomes were also analyzed in matched peripheral blood mononuclear cells from the same patients. CA was heterogeneous with 100% of patients demonstrating some degree of CA (&gt;4 centrioles), ranging from 15-48% of CTCs.
Conclusion: In conclusion, we report the presence of CA in EpCAM-captured CTCs from metastatic cancer patients. Evaluation of CA in CTCs using pericentrin and centrin staining may serve as a predictive biomarker of taxane based chemotherapy response and resistance. We are recruiting taxane-naïve metastatic cancer patients to test the hypothesis that CA and/or CIN predict taxane sensitivity.
Citation Format: Ashok Singh, Ryan A. Denu, Jamie M. Sperger, Beth A. Weaver, Mark E. Burkard, Joshua M. Lang. Centrosome amplification in epcam-captured circulating tumor cells from metastatic cancer patients [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 3604.