tbuckley/cabot-search huggingface dataset:
Abstract LB-139: The effects and mechanisms of TNF-α/TNFR2 in regulatory T cells on microenvironment and progression in gastric cancer
Authors: Yang Qu, Gang Zhao, Hui Li
Journal: Cancer Research (2019)

Abstract Background: Regulatory T cells (Tregs) are potent immunosuppressive cells of the immune system. They facilitate the survival and progression of tumor through their ability to suppress the antitumor immunity. The expression of tumor necrosis factor receptor type II (TNFR2) on Tregs is reported to identify the maximally suppressive Treg population in both mice and human. According to our previous research, expression of TNFR2 appeared to correlate better than CD25+ and CD127− with FoxP3 expression. Aim: The effects and mechanisms of TNF-α/TNFR2 in regulatory T cells on microenvironment and progression in gastric cancer are needed to be studied. Methods: The expression and phenotype of TNFR2 + Tregs in peripheral blood and tumor tissues of 33 cases of gastric cancer patients and in peripheral blood of 15 normal controls were detected by flow cytometry. The ratio of Foxp3+Tregs and TNFR2+Tregs of 145 cases of gastric cancer patients was analyzed by multicolor immunofluorescence assay. We analyzed their relationship with gastric cancer stage, metastasis and other clinical indicators by clinical and pathological data. Results: Flow cytometry showed that the expression of TNFR2 in human peripheral blood Tregs was significantly higher than that in conventional T cells (Tconvs) in peripheral blood CD4 + T cell subsets of gastric cancer patients and healthy individuals (P&amp;lt;0.05). The proportion of TNFR2 + cells in peripheral blood Tregs cells was significantly higher in patients with gastric cancer than in normal subjects (P &amp;lt;0.05). Tregs and Tconvs cells expressed very low level of CTLA-4 and TIM-3 in both normal controls and gastric cancer patients. Multicolour immunofluorescence showed that the ratio of Foxp3 + Tregs and TNFR2 + Tregs was increased in the tumor tissue, and TNFR2 + Tregs cells showed a tendency to increase with tumor progression and lymphatic metastasis. Higher levels of infiltration of TNFR2+ Tregs cells are significantly associated with patients’ OS (P&amp;lt;0.05) and DFS (P&amp;lt;0.05). Conclusion: Our findings revealed that TNFR2 could be a promising molecular marker associated with poor prognosis. The mechanism by which TNFR2+Tregs promote tumor survival and progression in gastric cancer is still needed further research. Citation Format: Yang Qu, Gang Zhao, Hui Li. The effects and mechanisms of TNF-α/TNFR2 in regulatory T cells on microenvironment and progression in gastric cancer [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-139.
More Transplanted Kidneys
Authors: C M MACLEOD, C A HALL, L A FROHMAN
Journal: BMJ (1964)

More Transplanted KidneysWhen chronic renal failure ceases to respond to conventional therapy the clinician is faced with two alternatives.The one is to treat the patient symptomatically in order to minimize physical and mental distress during the terminal illness.The other is to consider one of the newer but unestablished forms of treatment-namely, renal transplantation or use of the artificial kidney.The public is becoming increasingly aware of these, and relatives of uraemic patients are seeking advice on them from their doctors.Indefinite intermittent dialysis with an artificial kidney, as pioneered by B. H. Scribner and his colleagues,' can be remarkably successful in maintaining the life of a patient who has no renal function.Their first patient is alive and reasonably well four years after starting treatment.However, this requires admission to hospital once or twice weekly and is exceedingly expensive to administer, as S. Shaldon and his colleagues pointed out in our pages last year.2It is there- fore not, surprising that some workers are turning to renal transplantation as a possible supplement to this treatment.Renal transplantation, which has been considered in these columns several times recently,35 has had some spectacular clinical successes, but they are a minority against which must be offset the pain, discomfort, and bitter disappointment of many failures.At a recent international meeting in Washington sponsored by the United States Academy of Sciences' the results of most groups active in this field were pooled.As might have been expected from animal experi- ments the results with transplants between close relatives were considerably better than those from unrelated donors.But transplants from unrelated live donors were no better than the results with transplants from unrelated dead donors.However, the follow-up periods were not very long from which to judge results.R. Shackman, W. J. Dempster, and 0. M. Wrong' have recently reported on their experience with renal transplantation using live donors at the Hammer- smith Hospital.Of seven transplants performed, one is functioning fairly well more than two and a half years after operation; the patient is at work and free from symptoms.In this case the donor was a brother who shared with the recipient all the erythrocyte groups that were tested.The recipient was treated with total-body irradiation and post- operative local irradiation to the kidney.He also received hydrocortisone and prednisone.The relative values of these different agents is difficult to assess, and it would seem likely 1
The impact of newly approved drugs on clinical and operational strategies for multiple myeloma clinical trials.
Authors: Bhavani Krishnan, Bernadette Collins, Michael Jeffrey Cho, Tanya Partridge, Durga Vighnay, Marie Given, Sari Heitner Enschede, Katarzyna Bochenska, Jeff Paul Hodge
Journal: Journal of Clinical Oncology (2019)

e19511 Background: The global burden of multiple myeloma (MM) has increased steadily in last 3 decades. The IARC reports there were ~160,000 new cases worldwide in 2018. There has been an increase in the development and approval of more effective targeted therapy options (new immunomodulatory agents, proteasome inhibitors, and monoclonal antibodies); this, coupled with high adoption of these therapies presents a major challenge in enrollment of current ongoing clinical trials. We assessed the impact of near-term regulatory approvals on clinical trial enrollment. Methods: Public domain clinical trial enrollment data from MM studies (Phase I, I/II, II) closed/completed between 2011-2018 were used to determine enrollment trends pre and post 2014. We leveraged real-world medical claims data to project/model adoption of recently approved drugs in the U.S.; additionally, drug sales volume data was used to evaluate ex-US national adoption trends. The utilization rates of 5 recently approved drugs by regimen and line of treatment was determined. Results: In the U.S., there is a 13% increase in median enrollment duration with a corresponding 25% decrease in median p/s/m enrollment in MM studies, irrespective of phase, where enrollment was completed between 2015 -2018 compared to 2011-2014. We hypothesize that one of the factors for this increase in enrollment timeline is the approval and adoption of newly approved therapies post 2014. Two of the five recently approved drugs show a steady increase in the number of patients treated over 2016, 2017 and 2018, while one of the drugs plateaus over the same period. Outside of the U.S., our analysis confirms the existence of gaps in time to approval /adoption of recently approved drugs; for example, we observe a two-year delay in approval/adoption for one of the drugs in France compared to the other countries in Western Europe. Conclusions: There are over 10 investigational MM drugs currently in development which are anticipated to be granted approval between 2019-2021. Factoring the real-world adoption of near-term drug approval into global clinical and operational strategies offers insights into mitigating potential future enrollment challenges.
Abstract 3004: Anticancer effects and associated molecular changes of <i>Carica papaya</i> against prostate cancer
Authors: Surya Pratap Singh, Sivapar V. Mathan, Arpit Dheeraj, Dhanir Tailor, Rana P. Singh, Arbind Acharya
Journal: Cancer Research (2019)

Abstract Carica papaya (papaya), from the family of Caricaceae, is a perennial plant originating from the Southern part of Mexico. Carica papaya leaf extract (CPE) has been traditionally used to treat various diseases, including infectious diseases and cancer. However, the anticancer effects and molecular mechanism of CPE are elusive. The aim of our study is to examine the anticancer effects of aqueous leaf extract of Carica papaya against prostate cancer (PCa). We investigated the effect of CPE on LNCaP, DU145 and PC-3 PCa cells. CPE treatment (5, 10, 25µl/ml) significantly reduced the cell proliferation and induced cell death in PCa cells. Furthermore, we found that CPE induced G1, S and G1 as well as G2/M phase cell cycle arrest in LNCaP, DU145, and PC-3 cells, respectively. At molecular level, the cell cycle arrest was associated with decreased expression of CDK 4, cyclin D1, cyclin B1, and PCNA. CPE induced cell death was associatedwith depolarization of mitochondrial membrane potential, increase in ratio of Bax/Bcl2, cleavage of caspase-3 and cleaved -Poly(ADP-ribose) polymerase (PARP). CPE treatment also reduced mitochondrial fission and induced mitochondrial fusion by reducing the level of Drp1 protein. Further, we observed that CPE increased the expression of E-cadherin and decreased the expression of N-cadherin and vimentin. We checked the CPE toxicity in C57BL/6 male mice. We found that oral administration of CPE(0.25%, 0.5% and 1% v/v) in drinking water did not show any significant changes in body weight, water consumption and food intake as compared to control group. Collectively, CPE inhibited cell proliferation, induced cell death via apoptosis, mitochondrial fusion, epithelial marker and reduced mesenchymal markers.In vivo toxicity study with CPE treatment via drinking water was found to be non-toxic. These findings suggest that CPE has potential as anticancer therapeutic option for prevention and treatment of prostate cancer. Citation Format: Surya Pratap Singh, Sivapar V. Mathan, Arpit Dheeraj, Dhanir Tailor, Rana P. Singh, Arbind Acharya. Anticancer effects and associated molecular changes of Carica papaya against prostate cancer [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 3004.
Abstract LB-036: Tetraspanin 5 expressing macrophages promote mammary tumor growth
Authors: Mohammed Ridha Moamin, Peter Monk, Angela Cox, Penelope Ottewell, Julien Saint-Pol, Eric Rubinstein, Munitta Muthana
Journal: Cancer Research (2019)

Abstract Rationale: Tetraspanins (TSPANs) have emerged as key players in regulating tumor cell migration, invasion, and metastasis. Whilst we know TSPANs are expressed by macrophages very little is known regarding their role in Tumor Associated Macrophages (TAMs). We have shown that all 33 TSPAN members are differentially expressed by macrophages; however, following exposure to tumor-derived factors we see a significant increase in TSPAN5. We hypothesize that TSPAN5 plays a role in supporting the pro-tumor activities of TAMs and targeting tetraspanins in cancer may be a novel therapeutic approach. Objectives: To determine TSPAN5 expression by macrophages in vitro and in situ in human breast cancer tissue and investigate the role of TSPAN5 in regulating the pro-tumor phenotype of TAMs. Methodology: Expression of TSPAN5 was confirmed at the gene and protein level by qPCR, flow cytometry, western blotting, immunocytochemistry and by immunohistochemistry in formalin fixed breast cancer tissue. Accell siRNA knockdown was performed to determine the role of TSPAN5 in macrophage phenotype and function. NextSeq500 was performed to identify how TSPAN5 influences gene expression in BMDMs prepared from C57Bl/6 wild-type (WT) and TSPAN5 knockout (KO) mice. The role of TSPAN5 in a mammary carcinoma model in C57BL/6 WT and TSPAN5KO mice was also determined. Findings: TSPAN5 was up-regulated by tumor-conditioned macrophages both in vitro and in vivo. This expression was also evident in TAMs located in patient derived breast cancer tissue (n=30). Interestingly, 64% of TAMs expressed TSPAN5 and these cells were the main source of TSPAN5 in human breast tumors (77%). Knockdown of TSPAN5 promoted a pro-inflammatory macrophage phenotype and NextSeq500 (n=3) revealed significant changes in genes involved in cell adhesion (Fn1, Cdh11, Lamb1, Cyr61, Postn and Wisp2) and immune regulation (PTGS2, GPX8 and Crip2) in BMDMs from TSPAN5KO mice compared to WT mice. Genetic and antibody ablation of TSPAN5 in C57BL/6 significantly reduced primary EO771 tumors and enhanced the survival of tumor bearing mice. Interestingly, clodronate depletion of macrophages in TSPAN5KO mice promoted mammary tumor growth. Conclusion: Our study demonstrates for the first-time expression of TSPAN5 by TAMs in breast cancers and the pro-tumor properties of TSPAN5 in primary and metastatic mammary tumor growth. Citation Format: Mohammed Ridha Moamin, Peter Monk, Angela Cox, Penelope Ottewell, Julien Saint-Pol, Eric Rubinstein, Munitta Muthana. Tetraspanin 5 expressing macrophages promote mammary tumor growth [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-036.
High-dimensional cytometric analysis of colorectal cancer reveals novel mediators of antitumour immunity
Authors: Natasja L de Vries, Vincent van Unen, Marieke E Ijsselsteijn, Tamim Abdelaal, Ruud van der Breggen, Arantza Farina Sarasqueta, Ahmed Mahfouz, Koen C M J Peeters, Thomas Höllt, Boudewijn P F Lelieveldt, Frits Koning, Noel F C C de Miranda
Journal: Gut (2019)

Objective A comprehensive understanding of anticancer immune responses is paramount for the optimal application and development of cancer immunotherapies. We unravelled local and systemic immune profiles in patients with colorectal cancer (CRC) by high-dimensional analysis to provide an unbiased characterisation of the immune contexture of CRC. Design Thirty-six immune cell markers were simultaneously assessed at the single-cell level by mass cytometry in 35 CRC tissues, 26 tumour-associated lymph nodes, 17 colorectal healthy mucosa and 19 peripheral blood samples from 31 patients with CRC. Additionally, functional, transcriptional and spatial analyses of tumour-infiltrating lymphocytes were performed by flow cytometry, single-cell RNA-sequencing and multispectral immunofluorescence. Results We discovered that a previously unappreciated innate lymphocyte population (Lin – CD7 + CD127 – CD56 + CD45RO + ) was enriched in CRC tissues and displayed cytotoxic activity. This subset demonstrated a tissue-resident (CD103 + CD69 + ) phenotype and was most abundant in immunogenic mismatch repair (MMR)-deficient CRCs. Their presence in tumours was correlated with the infiltration of tumour-resident cytotoxic, helper and γδ T cells with highly similar activated (HLA-DR + CD38 + PD-1 + ) phenotypes. Remarkably, activated γδ T cells were almost exclusively found in MMR-deficient cancers. Non-activated counterparts of tumour-resident cytotoxic and γδ T cells were present in CRC and healthy mucosa tissues, but not in lymph nodes, with the exception of tumour-positive lymph nodes. Conclusion This work provides a blueprint for the understanding of the heterogeneous and intricate immune landscape of CRC, including the identification of previously unappreciated immune cell subsets. The concomitant presence of tumour-resident innate and adaptive immune cell populations suggests a multitargeted exploitation of their antitumour properties in a therapeutic setting.
Abstract 1470: Development &amp; characterization of a new oncolytic immunotherapy platform based on herpes simplex virus type 1
Authors: Suzanne Thomas, Linta Juncheria, Victoria Roulstone, Joan N. Kyula, Howard L. Kaufman, Kevin J. Harrington, Robert S. Coffin
Journal: Cancer Research (2019)

Abstract A number of oncolytic viruses have shown single agent clinical activity and evidence of clinical synergy with immune checkpoint blockade. However, not all patients respond, and as yet most of the promising clinical data have been generated in patients with melanoma. With the objective of maximally activating a patient's immune system against their own cancer which will then provide enhanced synergy with anti-PD1/L1 blockade, we developed a new oncolytic immunotherapy platform based on herpes simplex virus (HSV). This has the dual objectives of killing tumor to provide abundant release of tumor antigens, and potently activating immune responses against these antigens once released. To augment the natural ability of the virus to kill tumors and activate the immune system, these viruses are each armed with multiple therapeutic genes. Initially, we screened 29 new clinical strains of HSV isolated from volunteers who suffer from cold sores across a panel of human tumor cell lines to select a candidate for further development. This strain was then engineered to provide tumor selective replication (deletion of the genes encoding ICP34.5 and ICP47) and to express a potent fusogenic glycoprotein (GALV-GP R-). These modifications greatly enhance both local and systemic antitumor effects, increase immunogenic cell death, potently activate anti-tumor immunity, and are synergistic with PD-1 blockade in pre-clinical models. A virus expressing both GALV-GP R- and human GM-CSF is currently in a Phase 1/2 clinical trial in approximately 150 patients as a single-agent and combined with PD1 blockade in four solid tumor types. Further viruses express additional immune-activating proteins expected to act at the site of immune response initiation in tumors and draining lymph nodes, in particular an anti-CTLA-4 antibody-like molecule and immune co-stimulatory pathway-activating ligands. Each of these demonstrated increased activity in pre-clinical models, particularly an enhanced anenestic effect. The anti-CTLA-4 expressing virus (RP2) is targeted to enter clinical trials in the first half of 2019. Thus, a modular approach to oncolytic immunotherapy development can rapidly generate multiple clinical candidates with multiple mechanisms of action intended to act synergistically with other approaches to cancer therapy. The latest pre-clinical data utilizing this platform will be presented. Citation Format: Suzanne Thomas, Linta Juncheria, Victoria Roulstone, Joan N. Kyula, Howard L. Kaufman, Kevin J. Harrington, Robert S. Coffin. Development &amp; characterization of a new oncolytic immunotherapy platform based on herpes simplex virus type 1 [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 1470.
Abstract 1055: Evaluation of immune checkpoint inhibitor efficacy in EGFR mutant tumors
Authors: Xuzhen Tang, Li Yang, Hui Qi, Xianzhi Zhai, Fuyang Wang, Xiangnan Qiang, Jie Xu, Xiaoran Qin, Qingyang Gu, Shaoyu Yan, Qunsheng Ji
Journal: Cancer Research (2019)

Abstract Tyrosine Kinase Inhibitor (TKI) of Epidermal Growth Factor Receptor (EGFR) is a first-line therapy for non-small cell carcinoma lung cancer patients with EGFR mutations, but patients often develop resistance to such a target therapy. Recently several PD-1 and PD-L1 inhibitors were approved for treating NSCLC, however, it remains unclear whether EGFR mutant NSCLC would benefit from PD-1/PD-L1 treatment. PD-1 response in cancer patients is closely associated with oncogenic mutation status, tumor microenvironment, PD-L1 expression and tumor mutation burden (TMB); however, the lack of pre-clinical models limited the investigation of the checkpoint inhibitors in EGFR mutant tumors. Here we use human PBMC reconstitution system for immune-humanization, and established a series of IO-Xenograft models (IO-CDX and IO-PDX) with cancer cell lines (IO-CDX) or patient-derived tissues (IO-PDX) that contain various EGFR mutations, including EGFR 19 del, L858R, T790M, and EGFR over-expression, amplification and fusion. We treated these models with either EGFR TKI (erlotinib, afatinib or osimertinib) or nivolumab, a PD-1 inhibitor. The predictive biomarkers including PD-L1 expression and TMB were analyzed by whole exom sequencing (WES) and FACS for tumor infiltrating lymphocytes (TILs), respectively. We found that 3 TKI-resistant PDX models bearing EGFR T790M mutation exhibited lower TILs than those bearing EGFR wild type or exon 19del mutation. Of the 8 IO-CDX or IO-PDX humanized models we have examined, those exhibiting higher TILs achieved better responses to nivolumab treatment. The 3 most sensitive models are EGFR amplification (wt), EGFR over-expression (wt) and EGFR exon 19del. In contrast, the EGFR T790M model from H1975 cell line was observed with hyper-progressive disease after nivolumab treatment. We will also discuss the contribution of PD-L1 expression and TMB to nivolumab in other models. In summary, these well-established IO-CDX and IO-PDX models can provide a human-resembling immune system for of immune therapeutics and combination with targeted therapies, and help to facilitate the understanding of relationship among tumor microenvironment, driver oncogenic mutations and drug response. Citation Format: Xuzhen Tang, Li Yang, Hui Qi, Xianzhi Zhai, Fuyang Wang, Xiangnan Qiang, Jie Xu, Xiaoran Qin, Qingyang Gu, Shaoyu Yan, Qunsheng Ji. Evaluation of immune checkpoint inhibitor efficacy in EGFR mutant tumors [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 1055.
Abstract 2719: Metabolic product of inositol-trisphosphate 3-kinase B confers chemotherapy resistance by managing redox homeostasis
Authors: Chaoyun Pan, Jaemoo Chun, Austin Boese, Jihoon Kang, Jie Li, Lingtao Jin, Sumin Kang
Journal: Cancer Research (2019)

Abstract How altered metabolism contributes to chemotherapy resistance in cancer cells remains unclear. Through a metabolism-related kinome RNAi screen, we identified inositol-trisphosphate 3-kinase B (ITPKB) as a critical enzyme that contributes to cisplatin-resistant tumor growth. We demonstrate that inositol (1,3,4,5) tetrakisphosphate (IP4), the product of ITPKB, plays a critical role in redox homeostasis upon cisplatin exposure by reducing cisplatin-induced ROS through inhibition of a ROS-generating enzyme NADPH oxidase 4 (NOX4), which promotes cisplatin- resistant tumor growth. Mechanistically, IP4 competes with the NOX4 cofactor NADPH for binding and consequently inhibits NOX4. Targeting ITPKB with shRNA or its small molecule inhibitor resulted in attenuation of NOX4 activity, imbalanced redox status, and sensitized cancer cells to cisplatin treatment in patient-derived xenografts. Our findings provide insight into the crosstalk between kinase-mediated metabolic regulation and platinum-based chemotherapy resistance in human cancers. Our study also suggests a distinctive signaling function of IP4 that regulates NOX4. Furthermore, pharmaceutical inhibition of ITPKB displayed synergistic attenuation of tumor growth with cisplatin suggesting ITPKB as a promising synthetic lethal target for cancer therapeutic intervention to overcome cisplatin resistance. Citation Format: Chaoyun Pan, Jaemoo Chun, Austin Boese, Jihoon Kang, Jie Li, Lingtao Jin, Sumin Kang. Metabolic product of inositol-trisphosphate 3-kinase B confers chemotherapy resistance by managing redox homeostasis [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 2719.