bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tumor-infiltrating lymphocytes to predict survival to anthracycline/taxane-based neoadjuvant chemotherapy in breast cancer.
Authors: Ou Qiyun , Yu Yunfang , Xiao Xiaoyun , Luo Baoming 
Published: February 2018

2 Background: Current guidelines have limited information regarding tumour-infiltrating lymphocytes (TILs) were predictive in breast cancer survival treated with neoadjuvant chemotherapy, although some studies suggest a benefit. We quantify the prognostic value of this biomarker for neoadjuvant chemotherapy in patients with breast cancer. Methods: PubMed and EMBASE were searched until March 2017 for studies that investigated the association of TILs with survival for anthracycline/taxane-based neoadjuvant chemotherapy in breast cancer. Overall survival (OS) and disease-free survival (DFS) were combined using random-effects meta-analysis calculated as combined hazard ratio (HR) with 95% credible intervals (CIs). The interaction test was adopted in order to determine the differential effect according to the histology subtypes and TILs subsets. The PROSPERO registry number is CRD42017072133. Results: We identified 16 studies comprising 2,523 patients were entitled. According to histology subtypes analysis indicated that TILs were not prognostic markers for DFS and OS in overall population, but high TILs were related to improved DFS (HR = 0.73, 95% CI, 0.63 – 0.86) and OS (HR = 0.65, 95% CI, 0.51 – 0.83) in triple negative breast cancer (TNBC) patients, and high TILs were also related to better DFS (HR = 0.62, 95% CI, 0.40 – 0.96) in HER2–positive patients. For TILs subsets, our results indicated that high TILs were prognostic markers for DFS (HR = 0.94, 95% CI, 0.89 – 0.98) and OS (HR = 0.74, 95% CI, 0.58 – 0.94). In an ad-hoc analysis, increasing CD8+ lymphocytes were associated with improved DFS (HR = 0.46, 95% CI, 0.33 – 0.65) and OS (HR = 0.41, 95% CI, 0.24 – 0.71), high CD8/FOXP3 ratio was correlated with prolonged DFS (HR = 0.43, 95% CI, 0.29 – 0.63) and OS (HR = 0.45, 95% CI, 0.26 – 0.76), while rich FOXP3+ lymphocytes were associated with reduced DFS (HR = 1.47, 95% CI, 1.01 – 2.15) in overall population. Conclusions: The present results reveal TILs as a predictor of survival to anthracycline/taxane-based neoadjuvant chemotherapy in breast cancer patients. Furthermore, predictive benefit appears to be influenced by breast cancer subtypes and TILs subsets as well.
Microarray to reveal LncRNA profile and the role of lncCUEDC1 in BCSCs.
Authors: Zhang Fengchun , Xu Ying chun , Yan Ning 
Published: February 2018

3 Background: Recently, a growing amount of reports have shown that long non-coding RNAs (lncRNAs) are involved in breast cancer development, progression and metastasis. However, the correlation between lncRNAs and breast cancer stem cells (BCSCs) has been poorly explored. Methods: We initially isolated BCSCs from mammosphere-cultured cells; then, microarray analyses were carried out to detect the lncRNA signature in BCSCs. In addition, bioinformatics analyses, including Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG), were consulted to explore the functional roles of lncRNAs on BCSCs. Results: A total of 142 aberrantly expressed lncRNAs in BCSCs were identified, and of those lncRNAs, 25 were downregulated and 117 were upregulated compared to non-BCSCs. In addition, some of these lncRNAs were randomly selected and verified by RT-PCR and sanger sequencing. Notably, bioinformatics data showed that the lncRNAs that were detected were largely associated with stemness-related signalling pathways. Additionally, an interacting network between lncRNAs and its mRNAs was constructed to further depict the lncRNA functional activities. Furthermore, we found that lncCUEDC1 negatively regulated phenotype and biological functions of BCSCs in vitro. Conclusions: Our work establishes the lncRNAs signature in BCSCs for the first time. These findings provide us with evidence to explore the functionalities of lncRNAs in BCSCs and indicate that lncCUED1 is a prospective target for BCSCs.
Therapeutic effects of 2B8T2M, a novel fusion of ALT-803, an IL-15 superagonist, with 4 single-chains of anti-CD20 antibody in combination with expanded natural killer cells against rituximab sensitive and resistant Burkitt lymphoma (BL).
Authors: Chu Yaya , Kham Su Nang , Alter Sarah , Jeng Emily , Rhode Peter R. , Barth Matthew John , Lee Dean Anthony , Wong Hing C. , Cairo Mitchell S. 
Published: February 2018

32 Background: Patients retreated with rituximab often relapse which limit patient treatment options (Goldman/Cairo, Leukemia, 2013). Our group has successfully expanded functional and active peripheral blood NK cells (exPBNK) to target BL (Chu/Cairo, et al, Can Imm Res, 2015). 2B8T2M was generated by fusing ALT-803, an IL-15 superagonist, to four single-chains of rituximab (Liu/Wong, et al, JBC, 2016). 2B8T2M displayed tri-specific CD20 binding activity, activated NK cells to enhance antibody-dependent cellular cytotoxicity, and induced apoptosis of B-lymphoma cells (Liu/Wong, et al, JBC, 2016). Methods: ALT-803 and 2B8T2M were generously provided by Altor BioScience Corporation. NK expansion, NK receptors expression and cytotoxicity were examined as we previous described (Chu/Cairo, et al, Can Imm Res 2015). IFNg and granzyme B levels were examined by ELISA assays. Equal doses of IgG, Rituximab, ALT-803, Rituximab+ALT-803, obinutuzumab (obinu, generously provided by Christian Klein, PhD from Roche) were used for comparison. Results: 2B8T2M significantly enhanced exPBNK cytotoxicity against rituximab-sensitive Raji cells compared to the controls IgG, Rituximab, ALT-803, Rituximab+ALT-803, obinu (p < 0.001, E:T = 1:1). 2B8T2M also significantly enhanced exPBNK cytotoxicity against rituximab-resistant Raji-2R cells (p < 0.001, E:T = 1:1) and resistant Raji-4RH cells (p < 0.001, E:T = 1:1). Furthermore, 2B8T2M significantly enhanced IFN-g and granzyme B production from exPBNK against Raji, Raji-2R and Raji-4RH compared to IgG (p < 0.001), rituximab (p < 0.001), ALT-803 (p < 0.001), Rituximab+ALT-803 (p < 0.001), and obinutuzumab (p < 0.001). Conclusions: 2B8T2M compared to rituximab, ALT-803 or obinutuzumab significantly enhanced exPBNK in vitro cytotoxicity against rituximab-sensitive and –resistant BL cells. The in vivo functions of 2B8T2M with exPBNK using humanized NSG models are under investigation.
Development of a quantitative PD-L1 assay using laser capture microdissection (LCM)-based reverse phase protein microarray (RPPA) workflow: Implications for precision medicine.
Authors: Pierobon Mariaelena , Baldelli Elisa , Hodge K. Alex , Sereni Maria Isabella , Ludovini Vienna , Bellezza Guido , Crino Lucio , Liotta Lance A. , Petricoin Emanuel 
Published: February 2018

35 Background: FDA approved IHC-based companion/complementary assays are routinely used to measure PD-L1 for treatment selection. However, IHC cut-point values vary across platforms and are based on subjective analysis that requires antigen retrieval methods. Even in highly selected populations of PD-L1 “positive” patients, clinical benefits are seen only in subgroups of patients. We tested the feasibility of utilizing LCM and RPPA as a new methodology for quantitative, operator independent measurements of PD-L1 on tumor cells. Methods: PD-L1 quantification by RPPA was compared to IHC on 23 lung cancers (LC). Tumor cells were isolated from the surrounding microenvironment using LCM. The E1L3N clone from Cell Signaling was used to quantify PD-L1 expression by RPPA and IHC. Reproducibility across antibody clones was then assessed on LCM procured tumor epithelia from 10 FFPE LC and 71 snap-frozen ovarian cancers (OC). PD-L1 measurements were compared between the Cell Signaling E1L3N and the Ventana SP-142 clone. A quantitative PD-L1 calibrated assay was developed and assessed with the pilot population data. Results: Of the 23 LC, 5 were PD-L1 positive by IHC. The 5 IHC-positive patients had the greatest level of PD-L1 expression by RPPA indicating that the RPPA platform correlates with IHC. However, RPPA quantification showed a dynamic range ~ 4-fold across IHC negative samples. Correlation between PD-L1 detection with the E1L3N and the SP-142 clone in the OC was significant (R2 = 0.85), indicating great concordance across clones. Results were confirmed in the 10 LC samples (R2 = 0.87). Conclusions: The LCM-RPPA workflow captures PD-L1 expression on a continuous quantitative scale. This quantitative output correlated with IHC although it captures a much broader dynamic range in both IHC negative and positive populations. PD-L1 quantification by LCM-RPPA may be less dependent upon the clone used for the detection than IHC. Because the detection is unconstrained by antigen retrieval issues as well as subjectivity of IHC interpretation, this approach may generate a more accurate cut-point of therapeutic response prediction.
A phase 1b study of the anti-PD-1 monoclonal antibody BGB-A317 (A317) in combination with the PARP inhibitor BGB-290 (290) in advanced solid tumors.
Authors: Friedlander Michael , Meniawy Tarek , Markman Ben , Mileshkin Linda R. , Harnett Paul , Millward Michael , Lundy Joanne , Freimund Alison E. , Norris Christie , Wu John , Paton Virginia , Wang Lai , Gao Bo 
Published: February 2018

48 Background: The release of tumor-associated antigens may enhance the response to immunotherapy. BGB-A317, a humanized IgG4 variant monoclonal antibody engineered to have no Fc gamma receptor binding, targets the programmed cell death-1 (PD-1) receptor. It is being developed in solid and hematologic malignancies at a dose of 200 mg IV Q3W. BGB-290, a potent inhibitor of PARP 1/2, is hypothesized to promote neoantigen release that may potentially increase the efficacy of BGB-A317. A phase 1 study identified 60 mg BID as the recommended Phase 2 dose (RP2D) for BGB-290. This study consists of initial dose escalation to determine the maximum-tolerated dose (MTD), safety, pharmacokinetic (PK) profile, and preliminary antitumor activity of the combination, followed by expansion into ovarian, breast, prostate, gastric, bladder, pancreatic and small cell lung cancers. Methods: Cohorts of 6–12 patients with advanced solid tumors were treated in each of 5 planned dose levels (DLs). In DLs 1–3, BGB-290 doses ranged between 20–60 mg PO BID with BGB-A317 2 mg/kg IV Q3W. In DLs 4–5, BGB-290 doses were 40 or 60 mg BID; A317 was given at 200 mg IV Q3W based on PK data from a single agent Phase 1 study. Results: As of 31 March 2017, 43 patients [median age 63 years (34–75)] were treated in DLs 1–5. Three patients experienced four dose-limiting toxicities: grade 2 nausea (DL4), grade 2 nausea and grade 2 vomiting (DL5), and grade 4 autoimmune hepatitis (DL5). MTD was identified as BGB-A317 200 mg IV Q3W + BGB-290 40 mg PO BID. The most common adverse event (AE) considered related to both study drugs was fatigue. Immune-related AEs of Grade ≥3 were elevated alanine aminotransferase/aspartate aminotransferase (n = 3), autoimmune hepatitis (n = 3), and hepatitis (n = 1). Complete or partial response was observed in 11 patients, 4 of whom had confirmed PR or CR. Plasma/serum exposure of BGB-290 and BGB-A317 were consistent with those in single-agent trials. Conclusions: The combination of BGB-A317 and BGB-290 was generally well tolerated in patients with advanced solid tumors. These results support the continuation of this trial with enrollment into the disease-specific cohorts. Clinical trial information: NCT02660034.
IFNγ mRNA signature (IFNγ sig), circulating tumor DNA (ctDNA), and survival in NSCLC or urothelial cancer (UC) treated with durvalumab (D).
Authors: Higgs Brandon W. , Morehouse Chris , Kuziora Michael , Brohawn Philip Z. , Sridhar Sriram , Raja Rajiv , Angra Natasha , Abdullah Shaad Essa , Ranade Koustubh 
Published: February 2018

51 Background: Associations between early reduction in plasma ctDNA, pretreatment tumoral IFNγ sig, liver metastases and outcomes, and between tumor mutational burden (TMB) and CD274 (PD-L1) mRNA or IFNγ sig in TCGA were evaluated in NSCLC and UC pts treated with D. Methods: Pts received 10 mg/kg Q2W of D in a Phase 1/2 study in advanced solid tumors. RNAseq measured a 4-gene IFNγ sig; top tertile was IFNγ sig+. Pts with PD-L1 expression (Ventana SP263) ≥ 25% tumor cells in NSCLC or ≥ 25% tumor or immune cells in UC were PD-L1+. 70 genes were assayed for DNA variants (Guardant360) in plasma ctDNA pre/posttreatment. TCGA was used to calculate TMB; ≥ median TMB was high. Results: IFNγ sig+ NSCLC or UC pts had higher response and longer median PFS and OS compared with PD-L1+, PD-L1- and IFNγ sig- pts (Table). Responders showed significant decreases in ctDNA mean variant allele frequency (VAF) posttreatment with D; pts with progressive disease showed increased VAF. Pts with decreased VAF at week 6 had longer median PFS and OS compared with those with VAF increases. VAF changes were not associated with IFNγ sig. NSCLC without liver metastases had higher IFNγ sig (P < 0.001) than pts with liver metastases. In TCGA NSCLC and UC, IFNγ sig+ correlated with high TMB; CD274 mRNA did not. Conclusions: IFNγ sig correlated with outcomes and with TMB in NSCLC and UC. CtDNA VAFs were reduced in NSCLC or UC responders after treatment and correlated with longer survival, suggesting utility as an early indicator of clinical benefit. Clinical trial information: NCT01693562. [Table: see text]
Observational analysis of IDO-1 expression in MEL samples assessed using an RNAscope assay.
Authors: Newton Robert Charles 
Published: February 2018

53 Background: IDO-1 catalyzes the degradation of trp to kyn and can promote tumor escape from host immunosurveillance. IDO-1 expression evaluation has potential importance in identification of a population with worse prognosis and is important in the clinical evaluation of IDO-1 inhibitors. We have developed an optimized assay for IDO-1 specific message detection using RNAscope technology (RST) and applied it to an analysis of human melanoma (MEL) samples. Methods: 25 MEL samples were evaluated for IDO-1 by IHC and the samples used to optimize the RST assay. IDO-1 expression could be demonstrated in tumor cells (TC) as well as in immune cells (IC) infiltrating the tumor and in IC in the peritumoral area. A scoring method was developed to classify IDO-1 expression in all three populations. An H-score of 5 or greater was used as an arbitrary cutoff for IDO-1 positivity. An additional 27 MEL samples, collected as part of the ECHO202/KN037 study of epacadostat in combination with pembrolizumab, were evaluated. Results: IHC for IDO-1 showed 24% positive samples for tumor expression. As expected based on enhanced sensitivity, RST identified 56% as positive – 83% of the samples were positive by both assays. With IHC, 60% were positive for intratumoral IC expression of IDO-1 while RST identified 68% as positive for IC expression – 93% of the samples were positive by both methods. Analysis of the samples from the ECHO 202 study showed that 85% were positive for TC IDO-1 expression, while 59% were positive for IC IDO-1 expression with 52% positive for both. Of 22 PD-L1+ samples, 20 were positive for IDO-1 in either TC or IC. Of PD-L1- samples, 4 were positive for IDO-1 in either TC or IC. There was a trend toward higher IDO-1 expression in PD-L1+ tumors. In this data set there was no association of IDO-1 expression with BRAF mutation status, elevated LDH or prior exposure to immune therapies. Conclusions: RST detection has the potential to provide a robust and quantitative assay to evaluate IDO1 expression in TC and IC. Further refinement of this assay and determination of its utility in assessing predictors of patient response in MEL patients undergoing combination therapy with epacadostat and pembrolizumab will take place in ECHO-301/KN252 (NCT02752074).
Reversing immune checkpoint inhibitor resistance with adenoviral IL-24 and p53 tumor suppressor immune gene therapy.
Authors: Chada Sunil , Wiederhold Dora B , Menander Kerstin , Ahn Hyomin , Oh Eonju , Yun Chae-Ok , Sobol Robert E. 
Published: February 2018

64 Background: Immune checkpoint inhibitors represent an important advance in cancer therapeutics. However, most cancer patients either do not respond or become resistant to this therapy. Methods: We evaluated the ability of tumor suppressors p53 and IL-24, delivered via adenoviral vectors, to reverse immune checkpoint inhibitor resistance and induce abscopal therapeutic effects in the highly immune therapy resistant murine B16F10 melanoma tumor model. To mimic clinical conditions of immune checkpoint inhibitor resistance, animals with established tumors were treated with anti-PD-1 before intra-tumoral delivery of adenoviral vectors encoding tumor suppressors p53 (Ad-p53) or IL-24 (Ad-IL24). Results: Anti-PD-1 had minimal or no therapeutic efficacy when compared to PBS controls. However, there was a reversal of anti-PD-1 resistance in animals treated with Ad-p53, or Ad-IL24, in combination with anti-PD-1. Evaluation of primary tumor growth using ANOVA confirmed synergistic effects of the combination treatments over either agent used as monotherapy (p = 0.0001 for p53, p = 0.002 for IL-24). We also observed statistically significant decreases in contralateral abscopal tumor growth in animals whose primary tumors were treated with either Ad- p53 or Ad-IL24 (p = 0.046, and p = 0.0021, respectively) or in combination with anti-PD-1 (p = 0.02 p53, and p < 0.0001 for IL-24) as compared to animals treated with anti-PD-1 alone. With respect to survival, combined tumor suppressor + anti-PD-1 therapy resulted in a statistically significant increase in survival compared to: a) tumor suppressor therapy alone (p = 0.01 for either Ad-p53 and or IL-24) and b) anti-PD-1 therapy alone (p < 0.001 for p53, and p = x for IL-24). Conclusions: Overall, these results indicate that IL-24 and p53 tumor suppressor immune gene therapy can reverse immune checkpoint inhibitor resistance in primary tumors, and induce abscopal effects inferring the activation of systemic anti-tumor immune responses that reverse resistance to immune checkpoint inhibitor therapy.
Intratumoral administration of the alpha-Gal glycolipid AGI-134 to induce tumor regression in a mouse model of melanoma.
Authors: Shaw Stephen M. , Wigglesworth Kim , Middleton Jenny , Vainstein Haras Abi , Sorani Ella , Tabakman Rinat , Carmi Levy Irit , Kristian Sascha A. 
Published: February 2018

68 Background: AGI-134 is a fully synthetic alpha-Gal glycolipid for intratumoral (i.t.) treatment of solid tumors to induce a patient-specific anti-tumor immune response. AGI-134 recruits pre-existing anti-Gal antibodies to the injected lesion, leading to complement activation and enhanced tumor antigen processing. Using the B16.F10 murine melanoma model, we have previously demonstrated that AGI-134 evokes a robust abscopal anti-tumor effect, with treatment of a primary lesion protecting mice from the growth of distant lesions. In the current study, we investigated the response of injected tumors to AGI-134 administration. Methods: Tumors were induced by s.c. injection of B16.F10 or ovalbumin expressing B16 (B16.OVA) cells into the flank of α1,3galactosyltransferase knock out mice. After reaching a treatable size, the tumors were injected twice, 24 hrs apart, with PBS or 1-1.25 mg AGI-134, and tumor growth monitored for up to 32 days. In addition, to measure the activation of complement after treatment with AGI-134, tumors were processed 2 hours after treatment and the i.t. concentration of complement fragment C5a determined by ELISA. Results: Almost 50% of AGI-134-treated B16.F10 tumors fully regressed vs. 24% in the PBS controls. Moreover, AGI-134 treatment had a significant survival benefit, with 23% of AGI-134-treated mice dying or requiring euthanisia due to tumor mass by Day 27 post treatment vs. 43% in the PBS groups (p < 0.05, Mantel-Cox test). In the B16.OVA model, 67% of the AGI-134 treated tumors fully regressed vs. 0% in PBS-treated mice in two independent assays. Comparison of C5a levels in B16.F10 tumors 2 hrs after AGI-134 or PBS treatment demonstrated that AGI-134 induced significant complement activation within injected tumors. Conclusions: Having previously shown that AGI-134 induces an abscopal effect that protects mice from the development of secondary tumors, we now show that AGI-134 also induces regression of injected tumors: AGI-134-treatment induces the activation of complement within the tumor and leads to complete regression of the tumor in significantly more AGI-134-treated mice than PBS-treated. Clinical trials with AGI-134 are planned for 2018.
Tumor infiltrating lymphocyte recruitment in patients with early stage breast cancer after intramammary IRX-2 cytokine immunotherapy.
Authors: Page David B. , Pucilowska Joanna , Berinstein Neil Lorne , Egan James E. 
Published: February 2018

7 Background: The IRX-2 biologic is an injectable immunotherapy containing cytokines derived from stimulated lymphocytes. In preclinical models, IRX-2 activates T-cells, natural killer (NK) cells, macrophages, and dendritic cells, and facilitates maturation of antigen-presenting cells. Stromal tumor-infiltrating lymphocytes (sTILs) are associated with improved outcomes in early stage breast cancer (ESBC), and neoadjuvant IRX-2 increased TILs in a head/neck squamous cell carcinoma trial. We conducted a phase Ib trial to evaluate the feasibility/activity of IRX-2 in ESBC. Methods: Beginning 21 days prior to surgical resection, enrolled operable patients with stage I-III ESBC received the pre-operative IRX-2 regimen consisting of a single low dose of cyclophosphamide (300 mg/m2 to facilitate T-regulatory cell depletion), followed by 10 days of subcutaneous peri-areolar injections of IRX-2 into the affected breast (1 mL × 2 at tumor axis and at 90°). Endpoints were feasibility (primary), sTIL count (secondary), and immune monitoring by flow cytometry and immune transcriptome analysis (Nanostring PanCancer Immune Panel). Results: As of October 2017, 12 patients are enrolled and evaluable. All patients received all planned injections with no treatment-related surgical delays, complications, or grade III/IV toxicities. Treatment was associated with a mean 52% relative increase in sTILs (range –25% to +166%, p = 0.02). RNA expression profiling revealed the greatest increases in Th1 cell signature (mean +28.5%, range -5.3% to +283%), but also increases in CD8+, NK, and DC signatures. PDL1 RNA expression increased in 10/12 patients (mean +131.5%, range –83% to +1112%). In blood, increases in T-cell activation markers (ICOS, HLADR, and CD38) and T-reg depletion were observed at 1-month follow-up. Conclusions: Peri-lymphatic IRX-2 was well tolerated with preliminary evidence of sTIL recruitment, PDL1 upregulation, and peripheral lymphocyte activation. Study enrollment is ongoing, including patients for a pre-neoadjuvant-chemotherapy triple-negative ESBC cohort. Clinical trial information: NCT02950259.