bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4923: Analysis of companion diagnostic potentials for multifaceted PD-L1 assays
Authors: Caldara Jeni , Krueger Joseph S. , Ergon Elliott , Kearney Staci , Vennapusa Bharathi 
Published: August 2019

Abstract
In vitro diagnostic (IVD) approvals of qualitative immunohistochemical (IHC) assays offer unique patient selection strategies by equipping pathologists with new tools to assess tumor status including tumor immune landscape. PD-L1/PD-1 checkpoint therapies require accurate diagnostic tools for optimal patient selections, however the interpretation of these tests may be very complicated upon manual assessment. As assessment criteria have increased in complexity, an accurate quantitative approach is needed to objectively and consistently interpret challenging paradigms. Recent IVD tests have multifaceted paradigms which assess both tumor and immune positivity. Although the Ventana PD-L1 SP263 and the Dako PD-L1 22C3 qualitative diagnostics are guiding immunotherapy decisions, interpretation of the results may be subjective and challenging in many cases. This creates a further level of complexity as tumor cell positivity, and immune cell presence and positivity must be assessed in combination.
In this study, we have used Flagship Biosciences’ image analysis platform (cTA®) to explore the use of artificial intelligence (AI) and machine learning in the context of complex PD-L1 assays to provide accurate and precise quantification that allows for objective interpretation of the IVD. Non-small cell lung cancer (NSCLC) and urothelial carcinoma (UC) samples were stained with the SP263 and 22C3 PD-L1 assays and image analysis was used to provide an interpretation status based upon the IVD scoring paradigms. A comparison of the cTA results across both tests and tissue indications was also performed to explore how we may further support cross-platform PD-L1 solutions that provide adaptable and objective quantification.
The use of Flagship’s cTA platform to identify per-cell biofeatures, using machine learning, may successfully quantify PD-L1 staining in various cell populations. The ability to independently assess these populations allows for a consistent and unbiased method for the assessment tumor status for PD-L1 immunotherapy treatment decisions.
Citation Format: Jeni Caldara, Joseph S. Krueger, Elliott Ergon, Staci Kearney, Bharathi Vennapusa. Analysis of companion diagnostic potentials for multifaceted PD-L1 assays [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 4923.
Abstract 494: Immune cell screen of tumor micro environment of PD-L1 in positive/negative bladder cancer, melanoma, and lung cancer
Authors: Gonzalez Rachel , Fu Wei , Logis Evelin , Chen Casey , Cone Tiffany , Merritt Sonia , Wang Yiran , Wang Guanli , Ma Donghui 
Published: August 2019

Abstract
PD-L1/PD1 immune therapy has been very successful for some patients. Treatment is usually based on PD-L1 tumor expression levels in tumors; however some patients with positive tumors have shown no response to therapy. Recent, clinical trials have shown that treating patients with more than one immune therapy target results in better outcome suggesting the importance of understanding PD-L1 tumor micro environment. In this study, we look at a number of immune cell markers with PD-L1 expression to see if patterns of the immune cells infiltrating the tumor micro environment vary. PD-L1 expression in the tumors was assessed by multiple PD-L1 antibodies since no single PD-L1 antibody has been FDA approved for all tumor types. Immuno-histo chemistry (IHC) screen used 2 recombinant rabbit monoclonal antibodies (clone OR-5E3 and OR-5H8), one mouse anti PD-L1 clone UMAB229, and the FDA approved antibodies clones (SP142 and 28-8). Immune cell markers used in the IHC screen were CD3, CD8A, CD20, CD68, FOXP3, LAG3 and TIM3. The screen was done on sequential sections of bladder, melanoma, and lung tumors. Variation existed between five PD-L1 antibodies in their sensitivity and specificity to detect PD-L1 in the different tumor types; however, the differences were usually associated with the ability to detect low expressing tumors. Immune cell markers CD3, CD8A, CD20, CD68, FOXP3, LAG3, and TIM3 cell markers all produced strong staining if positive cells were present; however, they vary in number and distribution pattern throughout the three types of tumor. For example, when lung or bladder tumors presented strong PD-L1 staining at the edge of the tumor they often had a number of CD3E or CD8A immune positive cells present, this was not the case for CD20 which were foci clusters or scatter through the tumors. FOXP3 and CD68 staining were scarce event in all three tumor types. Although this study was limited to small sample size 10 tumors each it did show differences in the amount and distribution of immune cells in the 3 different types of tumor positive for PD-L1 expression.
Citation Format: Rachel Gonzalez, Wei Fu, Evelin Logis, Casey Chen, Tiffany Cone, Sonia Merritt, Yiran Wang, Guanli Wang, Donghui Ma. Immune cell screen of tumor micro environment of PD-L1 in positive/negative bladder cancer, melanoma, and lung 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 494.
Abstract 496: Block age effect on automated quantitative T cell count using multiplex immunfluorescence
Authors: Vidal Igor D. , Hicks Jessica , Davis Christine , Heaphy Christopher , Marzo Angelo Michael De 
Published: August 2019

Abstract
Introduction: Formalin fixation and paraffin embedding is the universal mechanism of tissue preservation. While the data showing detrimental effect on slide storage at room temperature1,2, the evidence supports that paraffin blocks archived at room temperature for as little as two years or as long as 25 years exhibited stable staining for the most of antigens evaluated. 3
Description of experimental procedures: In order to evaluate the effect of block age in inflammatory markers with immunofluorescence, two sets of antibodies were assembled and distributed in two distinct panels of five colors each, using the opal technology based on thyramide signal amplification. The first panel comprised foxp3, p63, CD3, CD4, CK8 and the second, p63, CD3, CD8 and CK8. Both panels were applied to a TMA with samples between sixteen to eighteen years old and compared to one with samples with less than one year old, fixed in FFPE. For each TMA construction, carcinoma prostatic tissue and matched normal prostate not inflamed tissue from forty patients were punched multiple times (between four to six) within regions of interest of each case. The slides were scanned and the image analysis performed. Statistic evaluation was performed using STATA13. The immunofluorescent count was validated using chromogenic CD3 stain controls using separate test TMAs.
Unpublished data: The analysis showed an increased number in CD3 positive T-cells in tumor areas, when compared to normal ones. For block age, there was no significant difference between old and new blocks.
Conclusion: The number of positive T cells for CD3 comparing new and old blocks of FFPE tissue shows no significant difference.
Citation Format: Igor D. Vidal, Jessica Hicks, Christine Davis, Christopher Heaphy, Angelo Michael De Marzo. Block age effect on automated quantitative T cell count using multiplex immunfluorescence [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 496.
Abstract 4960: Studying the impact of gut microbiome to hepatocellular cancer in an orthotopic murine model
Authors: Qi Xiaoqiang , Yang Ming , Stenberg Joseph , Li Guangfu , Staveley-O’Carroll Kevin 
Published: August 2019

Abstract
Background and Objective: As one of the most important components of human body, gut microbiota play a vital role in human health by participating in metabolomics and maintaining immunological homeostasis. Microbiota dysbiosis is significantly associated with initiation and progression of different diseases. Due to close anatomical and functional connection between gut and liver (gut-liver axis), gut microbiota are found to impact the development of liver diseases including hepatocellular cancer (HCC) without fully understanding mechanisms. The overall objective of present study is to investigate how microbiota modulate HCC growth by regulating intrahepatic immune response.
Methods: Administration of carbon tetrachloride in combination with transplant of oncogenic hepatocytes by intrasplenic injection was used to make an orthotopic mouse model of HCC. A specific antibiotics cocktail (ABX) was selected to inhibit some kinds of gut microbiota. 16s rRNA sequencing was used to characterize gut microbiota profile in mice with the different treatments. Magnetic resonance imaging (MRI) was used to monitor tumor growth. Adoptive transfer of tumor antigen-specific CD8+ T cells following the treatment was used to investigate how ABX administration impacted intrahepatic immune response. Flow cytometry and multiplex cytokine assay were used to detect the alteration of effector CD8+ T cell in phenotype, proliferation, and function. Immunohistochemistry (IHC) was used to investigate immune cell tumor-infiltration.
Results: The established murine model reflects the typical features of human HCC. ABX oral administration significantly changed gut microbiota composition, particularly in abundance of P. aeruginosa and Muribaculaceae. ABX-mediated alteration of gut microbiota significantly retarded HCC progression. Interestingly, ABX treatment was found to prevent adoptively transferred tumor antigen-specific CD8+ T cell from tumor-induced immune tolerance, as higher frequency of effector CD8+ T cell was detected in ABX-treated tumor-bearing mice compared to that in control tumor-bearing mice. Correspondingly, ABX treatment resulted in the increase in expression of CD69 and enhanced production of IFN-γ in tumor antigen-specific CD8+ T cells relevant to that in control mice.
Conclusion: Modulating microbiota with antibiotics is able to shape intrahepatic immune responses and therapeutically suppress tumor growth, providing a new option in HCC control.
Citation Format: Xiaoqiang Qi, Ming Yang, Joseph Stenberg, Guangfu Li, Kevin Staveley-O’Carroll. Studying the impact of gut microbiome to hepatocellular cancer in an orthotopic murine model [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 4960.
Abstract 4993: The Kynurenine Pathway as a possible resistance mechanism to immunotherapy in sarcomas
Authors: Nafia Imane , Savina Ariel , Bessede Alban , ITALIANO Antoine 
Published: August 2019

Abstract
Background: Sarcomas are heterogenous malignant mesenchymal neoplasms known to be particularly resistant to immunotherapy, which thus calls the interest of the elucidation of related resistance mechanisms. We recently demonstrated an increase in Kynurenine Pathway (KP) activity in the plasma of patients undergoing Pembrolizumab and metronomic cyclophosphamide. The KP has already been described to favor tolerance and immune escape through the degradation of L-Tryptophan and production of a series of metabolites including L-Kynurenine. While Indoleamine 2,3 dioxygenase (IDO1), a first rate-limiting enzyme of the KP still represents an attractive therapeutic target, the exact functional role of the KP upon immunotherapy has not yet been clearly elucidated.
Methods: Using a preclinical syngeneic mouse model of sarcoma based on the inoculation of murine sarcoma MCA205 cell line, we investigated the modulation of the KP upon PDL1 blockade. Besides the evaluation of tumor growth and survival, intratumoral biopsy was performed and used for further gene expression analysis by RT-qPCR. More precisely, KP enzymes- and key cytokines-encoding genes were assessed. Using the same experimental setting on satellite mice, intratumoral microdialysis was performed on day 13 post-tumor inoculation and kynurenine contents were quantified within the tumoral microenvironment.
Results: PDL1 blockade, using a specific anti-PDL1 antibody (provided by Genentech), exhibited a clear anti-tumoral effect associated with an intratumoral inflammatory cytokines signature driven by Ifng, Tnfa and Il2. Interestingly, Ifng level was significantly and positively associated with response to anti-PDL1. As regards to KP enzymes, a slight upregulation of the tryptophan-degrading enzymes Ido1 and Ido2 was detected while no changes were observed for Tdo2. An increase of kynurenine-degrading enzymes, including Kmo (encoding for Kynurenine monoamine oxygenase) and Kynu (encoding for kynureninase), was also detected thereby suggesting that PDL1 blockade favors Kynurenine degradation as a possible compensatory mechanism. These results were confirmed by intratumoral microdialysis in the satellite study. Indeed, anti-PDL1 was able to decrease the Kynurenine to Tryptophan ratio(Kyn / Trp) while increasing intratumoral production of kynurenines catabolites.
In conclusion, this new set of data on a preclinical sarcoma model highlights for the first time that PDL1 blockade deeply modulates the Kynurenine Pathway with an effect not exclusively associated to the upper part of the pathway and thus warrants further investigation.
Citation Format: Imane Nafia, Ariel Savina, Alban Bessede, Antoine ITALIANO. The Kynurenine Pathway as a possible resistance mechanism to immunotherapy in sarcomas [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 4993.
Abstract 4997: Responsiveness to immune checkpoint inhibitors in RET dependent cancers
Authors: Hegde Aparna , Huang Le , Liu Shuang , Hess Kenneth , Cabanillas Maria , Hu Mimi , Busaidy Naifa , Sherman Steven , Simon George , Blumenschein George , Papadimitrakopoulou Vassiliki A. , Hong David S. , Meric-Bernstam Funda , Heymach John , Subbiah Vivek 
Published: August 2019

Abstract
Background: The RET receptor tyrosine kinase can be oncogenically activated by gene fusions or point mutations. Multikinase inhibitors such as cabozantinib, lenvatinib, and vandetanib have demonstrated activity in RET dependent (RET+) malignancies. Recent development of selective RET inhibitors is poised to alter their treatment paradigm. However, the responsiveness of RET+ malignancies to immune checkpoint inhibition (ICI) is unknown. We compared the time to progression (TTP) on ICI with non-ICI therapy in patients with malignancies harboring activating RET mutations/fusions.
Methods: A retrospective chart review of all RET+ patients who were referred to the phase 1 clinical trials program at MD Anderson Cancer Center between September 2014 and October 2018 was conducted. Patients who had not discontinued treatment or had discontinued treatment for reasons besides disease progression were censored. Time to progression was estimated using Kaplan-Meier analysis.
Results: Out of 72 patients who had received systemic therapy for RET+ malignancies, 39 (54.2%) harbored RET mutations (RETm) and 33 (45.8%) harbored RET fusions (RETf). Nineteen patients (26.4%) received ICI and 53 (73.6%) received non-ICI therapy. Thirty four patients (47.2%) had medullary thyroid cancer, 29 (40.3%) had NSCLC and 9 (12.5%) had other types of cancer. PD-L1 expression was only available for 7 patients of which 5 (71.4%) were positive (≥ 1%). Patients had received a median of 1 (1-7) prior lines of therapy. Overall median TTP (mTTP) was 10.5 months (95% CI 6.7-30.1). Hazard ratio for ICI vs. non-ICI therapy was 1.73 (0.70, 4.26) p=0.25 in patients with RETf and 8.0 (2.27, 28.2) p=0.0025 in patients with RETm.
Conclusions: In patients with RET+ malignancies, mTTP was shorter with ICI compared to non-ICI therapy. The effect of type of therapy was dependent on the type of RET pathway aberration, with a statistically significant higher risk of progression in RETm malignancies treated with ICI compared to non-ICI therapy.
Time to ProgressionRETTherapyNmTTP (months)Freedom from Progression at 6 months (%)Freedom from Progression at 12 months (%)FusionNon-ICI218.36335FusionICI123.03624MutationNon-ICI3231.98273MutationICI75.6430
Citation Format: Aparna Hegde, Le Huang, Shuang Liu, Kenneth Hess, Maria Cabanillas, Mimi Hu, Naifa Busaidy, Steven Sherman, George Simon, George Blumenschein, Vassiliki A. Papadimitrakopoulou, David S. Hong, Funda Meric-Bernstam, John Heymach, Vivek Subbiah. Responsiveness to immune checkpoint inhibitors in RET dependent cancers [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 4997.
Abstract 5012: Targeting CD39 with a first-in-class inhibitory antibody prevents ATP processing and increases T-cell activation
Authors: Lerner Alana G. , Kovalenko Maria , Welch Megan , Cruz Tracy dela , Jones Jeff , Wong Clifford , Spatola Bradley , Eberhardt Meghan , Wong Andrew , Fung Wanchi , Lagpacan Leanna , Losenkova Karolina , Yegutkin Gennady , Soros Vanessa , Corbin John , Beers Courtney , Moesta Achim K. 
Published: August 2019

Abstract
The ATP/Adenosine pathway in the tumor microenvironment (TME) has emerged as an important immune-regulatory pathway. The ATPase CD39 is highly expressed in the TME, both on infiltrating immune cells and tumor cells across a broad set of cancer indications. CD39 processes pro-inflammatory extracellular ATP to ADP and AMP, which is then processed by CD73, to immunosuppressive adenosine. Inhibiting the enzymatic function of CD39 has the potential to shift the immunosuppressive milieu of the TME in a 2-pronged fashion: 1) Enhancement of immunostimulatory extracellular ATP released by damaged and/or dying tumor cells and 2) Inhibition of the generation and accumulation of suppressive adenosine within the TME, thereby unleashing an immune-mediated anti-tumor response.
Tizona has generated a novel first-in-class fully human anti-CD39 antibody, TTX-030, that inhibits CD39 ATPase enzymatic function with sub-nanomolar affinity and potency. TTX-030 is specific for CD39 and binds to CD39+ cancer cell lines and primary human leukocytes with high affinity. TTX-030 is capable of inhibiting CD39 at elevated ATP concentrations reported in the TME. Enzymatic inhibition by TTX-030 has demonstrated: preservation of pro-inflammatory extracellular ATP, reduction of adenosine accumulation, and inhibition of phosphate release by a variety of CD39-expressing cells, including tumor cells and immune cells. In vitro functional assays using stimulated PBMCs exposed to exogenous ATP demonstrated increased proliferation of both CD4+ and CD8+ T cells in the presence of TTX-030 and increased secretion of the pro-inflammatory cytokines IFN-γ, TNF-α, and IL-2. Treatment of mice with a mouse-specific CD39 inhibitory antibody in a syngeneic tumor model significantly decreased tumor growth.
In summary, TTX-030 is a selective and potent CD39 enzymatic inhibitor, capable of preventing adenosine-mediated immune suppression and increasing T-cell activation. Inhibition of CD39 with TTX-030 represents a unique therapeutic target aimed at modulating the immunosuppressive TME in cancer.
Citation Format: Alana G. Lerner, Maria Kovalenko, Megan Welch, Tracy dela Cruz, Jeff Jones, Clifford Wong, Bradley Spatola, Meghan Eberhardt, Andrew Wong, Wanchi Fung, Leanna Lagpacan, Karolina Losenkova, Gennady Yegutkin, Vanessa Soros, John Corbin, Courtney Beers, Achim K. Moesta. Targeting CD39 with a first-in-class inhibitory antibody prevents ATP processing and increases T-cell activation [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 5012.
Abstract 5029: OT-101/Chemotherapy- A novel mechanism of action (MOA) in glioblastoma immunization therapy
Authors: Hwang Larn , Nam David , Uckun Fatih , Trieu Vuong 
Published: August 2019

Abstract
Background: Escalating Intratumoral heterogeneity (IH) resulting in xenogenization which is countered by overexpression of TGF-β2. OT-101 is a TGF-β2-specific Phosphorothioate Antisense. Here we report the results of a randomized Phase 2b clinical trial (NCT00431561) comparing the safety and efficacy of OT-101 versus temozolomide (TMZ) in adult patients with WHO grade III/IV high-grade glioma. We took advantage of the known xenogenization activity of alkylating agent such TMZ to explore the impact of xenogenization on survival on treatment with OT-101.
Methods: This is a phase 2b, multi-national, multi-center, open-label, active-controlled, randomized parallel group dose-finding study to evaluate the efficacy and safety of OT-101 in adult patients with recurrent high-grade glioma, administered intratumorally as continuous high-flow microperfusion over a 7-day period every other week.
Results: A total of 134 patients, 89 patients in the OT-101 test group and 45 patients in the temozolomide (TMZ) group. OT-101 was superior to TMZ in doubling the number of pts in the good survival group, 64 of 97 pts (66%); whereas, only 14 of 45 pts (31%) treated with TMZ did (p=0.0001).
mOSOT-101TMZSubseq. TMZSubseq. TMZ (or other alkylating agent)Prev. TMZNoYesNoYesNo4.2mos (N=14)26.2mos (N=30)5.6mos (N=8)13.2mos (N=9)Yes4.8mos (N=19)29.5mos (N=34)6.6mos (N=14)36.6 mos (N=14)
There were two cases of neutropenia in the 90 pts treated with OT-101 versus 8, 10, and 8 pts with leukopenia, neutropenia, and thrombocytopenia, respectively, among 45 pts treated with TMZ (2% vs. 56%, p&lt;0.0001).
Conclusions: Improved survival was achieved by repeated exposure to TMZ/alkylating agent. This was further enhanced by OT-101 and consistent with the proposed MOA of OT-101/Chemo as reactivation of immunity during TGF-β suppression and subsequent xenogenization by TMZ.
Citation Format: Larn Hwang, David Nam, Fatih Uckun, Vuong Trieu. OT-101/Chemotherapy- A novel mechanism of action (MOA) in glioblastoma immunization therapy [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 5029.