bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I study with pegylated human IL-10 (AM0010) alone or in combination with anti-PD-1 or FOLFOX-immune biomarker update.
Authors: Naing Aung , Infante Jeffrey R. , Hecht J. Randolph , Papadopoulos Kyriakos P. , Wong Deborah Jean Lee , Autio Karen A. , Falchook Gerald Steven , Patel Manish R. , Ott Patrick Alexander , Patnaik Amita , Bendell Johanna C. , Van Vlasselaer Peter , Hong David S. , Tannir Nizar M. , Oft Martin 
Published: November 2019

157 Background: Persistence of activated CD8 T cells is essential for the durability of tumor immune responses. IL-10 is an anti-inflammatory cytokine, PEGylated IL-10 (AM0010) enhances tumor specific CD8 T cell expansion and cytotoxicity. We evaluated tolerability and efficacy of AM0010 alone, with chemotherapy or anti-PD-1 in a phase 1 study. AM0010 alone induces objective anti-tumor responses without auto-immune toxicities. AM0010 with anti-PD-1 was evaluated in RCC (n=8) or NSCLC (n=5) and showed improved response rates (ORR 50 and 40% respectively) compared to published ORR with anti-PD-1 monotherapy. AM0010 and FOLFOX for 2nd LOT pancreatic cancer increased the ORR compared to FOLFOX. Expansion cohorts for AM0010 and FOLFOX in pancreatic cancer (n=20) or with anti-PD-1 in RCC (n=30) or NSCLC (n=30) were evaluated. Methods: Observed tumor responses were monitored using irRC criteria. Immune responses were analysed for 96 serum cytokines. Activation of PBMC derived CD4 and CD8 T cells were analyzed by FACS. The expansion of the T cell repertoire was measured by deep sequencing of the TCR. Results: AM0010 induced systemic, sustained elevation of Th1 and Th2 type cytokines and cytotoxic products of CD8+ T cells. Th17 related cytokines were reduced. In-vitro, AM0010 inhibits activation induced cell death. Phosphorylated STAT3 (p-STAT3) was induced in activated CD8+ T cells in vitro and in tumors. In addition, PD1+ Lag-3+ KI-67+ CD8+ T cells expanded in the blood, remained Tim-3- CTLA-4-. Expansion of PD-1+ Lag-3+ CD8+ T cells correlate with objective tumor response. AM0010 treatment also resulted in the progressive systemic expansion of novel T cell clones, which were not detectable in the patient prior to treatment. This de-novo expansion coincided with tumor responses in several patients. The magnitude of this expansion correlated with the magnitude of objective tumor responses. The immune activation was similar in monotherapy and in the combination arms, suggesting a AM0010 specific and non-redundant mechanism of action. Conclusions: AM0010 has predominantly immune stimulatory activity in cancer patients, alone and in combination with other immune oncology therapies. Clinical trial information: NCT02009449.
Use of CMV gB/pp65 eVLPs to harness the immunogenicity of foreign viral antigens to target solid tumors.
Authors: Anderson David E , Ahmed Tanvir , Soare Catalina , Fluckiger Anne-Catherine , Ontsouka Barthelemy , Diress Abebaw , Bozic Jasminka , Yorke Matthew , Waziri Allen , Kirchmeier Marc , Diaz-Mitoma Francisco 
Published: November 2019

165 Background: Human cytomegalovirus (CMV) is a ubiquitous, generally asymptomatic virus that is present in over 90% of GBM and breast cancer tumors which have comparatively low mutational burdens and predicted neoantigens relative to melanoma or lung cancer. Memory CD4+ and CD8+T cells are most frequently directed against the gB and pp65 antigens, respectively. Thus, CMV gB and pp65 represent highly immunogenic “foreign” antigen components of a vaccine against GBM and breast cancer. Methods: Enveloped virus-like particles (eVLPs) are produced after transfection of HEK 293 cells with a plasmid encoding murine leukemia virus Gag plasmid fused in-frame with CMV pp65 antigen, which gives rise to particles. Co-transfected CMV gB plasmid enables particles budding from the cell surface to incorporate the gB protein into the lipid bilayer. Surface expression of gB and internal expression of pp65 have been confirmed by CryoEM and immunogold labelling. Production and purification of multiple batches at a GMP-compliant manufacturer has demonstrated consistent purity and yields that meet regulatory requirements. Results: eVLPs restimulate IFN-g secreting CD4+ and CD8+ T cells in ex vivo PBMCs from healthy subjects (n=8) at mean frequencies of 0.27% and 1.28%, respectively. eVLP formulation with GM-CSF augments IFN-g and CCL3 secretion in stimulated PBMCs from healthy subjects (n=5), GBM patients (n=5), and breast cancer (n=1) patients to comparable levels. This vaccine candidate also induces de novo CD4+ and CD8+responses in mice. The vaccine induces high titer antibody responses against CMV gB, and the potential for ADCC activity against gB-expressing GBM tumor cells is currently being investigated. Conclusions: CMV gB/pp65 eVLPs address several shortcomings of past theraeputic vaccines, including: 1) the poor immunogenicity of "self" tumor-associated antigens, 2) failure to induce robust CD4+ responses that support CD8+ tumor-specific responses, 3) inclusion of only one or a few epitopes that rapidly encourage tumor cell immunoselection of variants that no longer express the target(s). An IND submission to FDA for a phase I/IIa trial in GBM patients is planned for H1 2017.
Trials in progress: A phase II study of in situ therapeutic vaccination against refractory solid cancers with intratumoral poly-ICLC.
Authors: Kyi Chrisann , Sabado Rachel Lubong , Saenger Yvonne M. , Loging William , Donovan Michael J. , Lehrer Deborah , Mandeli John P , Salazar Andres M. , Friedlander Philip Adam , Bhardwaj Nina 
Published: November 2019

166 Background: Poly-ICLC, a RNA complex, can activate dendritic cells and trigger NK cells to kill tumor cells. It can be given intramuscularly (IM) to induce systemic inflammation and intratumorally (IT) to induce immune infiltration of tumors. Methods: In this phase II study, eligible subjects are head and neck, and skin cancer patients with refractory or metastatic disease. In each treatment cycle, one accessible tumor site was targeted for IT injection of 1 mg of Poly-ICLC 3 times a week for 2 weeks followed by IM boosters biweekly for 6 weeks and then a 2 week rest period. Tumor biopsies were performed at baseline, week 3, and week 26. Pre- and post-vaccination tumors were evaluated by quantitative immunohistochemistry (IHC) and RNA sequencing. Blood samples were collected at baseline and prior to each cycle for immune response evaluations. Results: A phase I pilot portion of this study showed 1 patient who achieved clinical benefit with stable disease (progression-free survival of 6 months). Poly-ICLC was well tolerated with principal side effects of fatigue and inflammation at injection site (< grade 2). One case of grade 3 tumor necrosis was observed. In the patient with clinical benefit, IHC analysis of tumor showed increased CD4(60x), CD8(10x), PD-1(20x), and PD-L1(3x) compared to patients with progressive disease whose tumor biopsies showed unchanged/decreased CD4, CD8, PD-1, and PD-L1 levels over treatment period. Furthermore, RNASeq analysis of the same patient’s tumor and peripheral blood mononuclear cells (PBMC) showed dramatic changes such as upregulation of interferon-stimulated genes, chemokines, and genes associated with T cell activation and antigen presentation indicative of local and systemic immune activation in response to Poly-ICLC treatment. Conclusions: Preliminary findings show that Poly-ICLC is well tolerated in advanced solid cancer patients, and generates local immune response in tumor microenvironment and systemic immune response as evident in the patient achieving clinical benefit. These results warrant further investigation, and are currently being explored in this ongoing larger multicenter adaptive phase II clinical trial. Clinical trial information: NCT01984892.
IgG response against prostate-related antigen as potential biomarker for personalized peptide vaccination in metastatic recurrent breast cancer.
Authors: Saku Shuko , Toh Uhi , Okabe Mina , Iwakuma Nobutaka , Shichijo Shigeki , Yamada Akira , Itoh Kyogo , Akagi Yoshito 
Published: November 2019

167 Background: The aim of this study is to identify the prognostic role of serum value of IgG antibody against prostate related-antigen (PRA), including prostate-specific antigen (PSA), prostate specific membrane antigen (PSMA), and prostate acid phosphatase (PAP) in mrBC patients. Methods: Peripheral blood samples of 77 patients with mrBC were analyzed for serum anti-PRA IgG levels before and after 6th and 12th PPV therapy prospectively. Most of the peptides used for PPV are derived from cancer associated antigens expressing in various types of advanced cancers, but the peptides derived from PRAs were not used in this study. Results: After PPV therapy, total serum levels of anti-PRA IgG were significantly increased in 31 mrBC patients (Group 1) compared with remaining 46 rmBC patients (Group 2). Either serum anti-PSA, anti-PAP, and/or anti-PMSA IgGs showed a significant increase in patients of Group 1 after 6th (p=0.045) and 12th PPV treatment (p < 0.001), irrespective of their intrinsic subtypes. The median PFS and median OS of Group 1 patients were 8.1 and 14.3 months, while those of Group 2 patients were 5.1 and 10.8 months, respectively. Anti-PRA IgG levels were significantly associated with PFS (p=0.0073; HR: 0.37) and OS (p=0.025; HR: 0.43) between these two groups, whereas no significant relation was found with age, clinical response rate, and recurrent metastatic status. Conclusions: The Group 1 patients with elevated anti-PRA IgG may have better prognosis compared to Group 2 patients who showed no IgG elevation after PPV treatment for rmBC. These results indicated a clinical significance between pre-and post- treatment measurement of serum anti-PRA IgGs in mrBC patients receiving PPV therapy, and may be a useful prognostic marker for monitoring the outcome to PPV treatment of breast cancer.
Immune profiling of circulating T cells and TILs following neoadjuvant ipilimumab and chemotherapy in non-small cell lung cancer (NSCLC).
Authors: Yi John , Clarke Jeffrey Melson , Healy Patrick , Wang Xiaofei F. , Shoemaker Debra , Onaitis Mark W. , Dumbauld Chelsae , Osborne Robyn , Crawford Jeffrey , Harpole David , D'Amico Thomas A. , Dunphy Frank , Christensen Jared , Ready Neal , Weinhold Kent 
Published: November 2019

26 Background: Ipilimumab (Ipi) is a humanized CTLA-4 antibody that blocks binding of CTLA-4 to B7, permitting T cell activation through CD28. Phased in Ipi added to chemotherapy (C) may enhance efficacy in NSCLC. Methods: Patients with stage 2 or 3A NSCLC received neoadjuvant carboplatin AUC6 plus paclitaxel 200 mg/m2 every 21 days for 3 cycles and Ipi (10 mg/kg) was given on day 1 for cycles 2 and 3. Blood for immune profiling of circulating T cells was collected at baseline, after chemotherapy alone, and after chemotherapy plus Ipi. Tumor infiltrating lymphocytes (TIL) were derived from 7 available tumors. Polychromatic flow cytometry (PFC) analyses were performed on peripheral blood mononuclear cells (PBMC) and TIL. Objective response rates were assessed according to RECIST 1.1 criteria. Results: Of the 24 patients enrolled on this study, objective responses after 3 cycles of neoadjuvant C plus ipi included 2 PD, 8 SD, and 14 PR. Phenotypic analyses revealed that PBMC from all 24 patients were highly activated following two cycles of Ipi (cycle 3) as evidenced by significantly increased frequencies of CD28, ICOS, HLA-DR, PD-1, and CTLA-4 expressing CD4+ cells; and ICOS, HLA-DR, and CTLA-4 expressing CD8+ cells. The frequencies of Tregs were highly variable among the 24 participants. Two of the 24 participants had levels of MDSC cells above 15%. TIL contained far greater frequencies of activated CD4+ and CD8+ cells than found in the PBMC at cycle 3. Tumor associated antigen (TAA)-specific CD4+ or CD8+ cells were detected at baseline in 4 patients (24%), but their relative frequencies remained unaltered by Ipi therapy. No patients developed detectable de novo TAA reactivities while on Ipi therapy. Conclusions: Combined neoadjuvant Ipi plus chemotherapy produced significantly increased frequencies of highly activated CD4+ and CD8+ populations in the peripheral blood and the tumor microenvironment. TAA-specific CD4+ or CD8+ cells were detected in PBMC at baseline in a subset of patients. No TAA-reactive T cells were detected among the 7 TIL samples analyzed. Analysis for predictive or pharmacodynamic biomarkers is ongoing. Clinical trial information: NCT01820754.
Clinical and immunologic variables associated with outcomes following combination ipilimumab and nivolumab immunotherapy in melanoma.
Authors: Rosner Samuel , Kwong Erica , Panageas Katherine , Postow Michael Andrew 
Published: November 2019

55 Background: Prior studies have shown routine laboratory parameters such as lymphocytes (lymphs) and eosinophils (eos) are associated with outcome in patients (pts) treated with ipilimumab (ipi) or programmed death-1 (PD-1) agents as single drugs. Less is known about these parameters as potential biomarkers for pts treated with ipi + nivolumab (nivo) in combination. Methods: After IRB approval, a single institution, retrospective review was performed of pts with melanoma who received ipi + nivo on phase I-III clinical trials (n=122) as well as via commercial use (n=87). Prior to treatment initiation, routine laboratory parameters were investigated and correlated with overall survival (OS) and disease response by RECIST 1.1 (partial or complete response vs. stable/progressive disease). Absolute as well as relative frequencies of cell counts were examined. Kaplan-Meier estimators and Cox regression were performed. Results: 209 pts, 85 (41%) women and 124 (59%) men, with a median age of 60.5 years were analyzed. Median OS was 44.4 months, 95% CI (32.9, not reached). 23 pts had a complete response (CR) and 87 pts had a partial response (PR), while 39 pts had stable disease (SD) and 49 pts had progressive disease (PD). By univariate analysis, significant favorable factors for OS included: low absolute monocytes, low absolute/relative neutrophils, high relative eos, and high relative lymphs. Low LDH and the neutrophil to lymph ratio were also associated with better OS. None of these factors were significantly associated with response by RECIST 1.1. Conclusions: Routinely assessed laboratory parameters were associated with OS but not disease response among pts receiving ipi + nivo. Some of these factors were similar to those which previously correlated with OS after ipi or nivo as single-agents, suggesting they may be prognostic. Given the ongoing randomized phase III study of ipi + nivo and nivo vs. ipi, there is an opportunity to examine whether these factors are relevant in refining which pts obtain the greatest benefit from ipi + nivo vs. single agent therapy.
Prognostic value of PD-L1+CD4+ T cells in non-small cell lung cancer (NSCLC) patients treated with a PD-1 inhibitor.
Authors: Vetsika Kiriaki E. , Aggouraki Despoina , Lyristi Zacharoula , Koinis Filippos , Georgoulias Vassilis , Kotsakis Athanasios 
Published: November 2019

58 Background: One of the tumour escape mechanisms is the expression of programmed cell death-1 (PD-1) receptor on immune cells. Clinical trials have demonstrated that antibodies against PD-L1 or PD-1 molecules induce objective clinical responses in pre-treated patients with NSCLC. In this study, we evaluated the levels of PD-1+ and PD-L1+expressing- immune cells and their association with the clinical outcome in NSCLC patients. Methods: Peripheral blood was collected from 32 advanced/metastatic pre-treated NSCLC patients before anti-PD-1 therapy (Nivolumab). Flow cytometry was performed to identify and quantify PD-1 and PD-L1 expression on circulating immune cells with anti-tumor function (CD4+ and CD8+ T cells, B cells, Dendritic cells) , as well as on immunosuppressivecells [(CD4+ and CD8+ Treg cells, Bregs, Myeloid-derived Suppressor cells (MDSC)]. Correlation between the levels of PD-1+ and PD-L1+-expressing immune cells, as well as their association with overall (OS) and progression-free survival (PFS) was evaluated; high expression of immune cells was defined as the percentage of the cells above the mean value. Results: PD-1 and PD-L1 expression was detected on all tested immune cells with anti-tumor activity. PD-1 expression was found on all immunosuppressive cells, whereas only CD4+ and CD8+ Treg cells and Granulocytic -MDSCs expressed PD-L1. No PD-L1 expression was observed on Bregs and monocytic-MDSCs. There was no correlation of PD-1 or PD-L1-expressing cells with response to anti-PD1 treatment. A significantly decreased PFS was observed in the low CD4+ PD-L1+ T cells group compared with the high CD4+ PD-L1+ group (3.4 months vs. 5.2 months, p=0.03). Univariate analysis for PFS revealed that the low percentages of CD4+ PDL-1+ T cells were prognostic for shorter PFS (HR= 3.1, p=0.04). On the multivariate analysis, low PD-L1+ CD4+T cells were independently associated with decreased PFS (HR: 3.3, p=0.03). Conclusions: These data provide evidence that PD-L1+ expression on peripheral CD4+ T cells was a significant predictor of better PFS in NSCLC patients. Therefore, PD-L1 expression could be used for the selection of patients who might benefit from PD-1/PD-L1 inhibitors.
Correlation of consistent blood-based gene expression with change in CTLA4 in two large independent clinical studies of patients with advanced melanoma treated with tremelimumab.
Authors: Friedlander Philip Adam , Wassman Karl , Kyi Chrisann , Oh William K. , Bhardwaj Nina 
Published: November 2019

6 Background: We previously reported 16-gene pre- and 8-gene post-treatment response predictive gene signatures in whole blood that were trained in one cohort (N=210) of advanced melanoma patients treated with tremelimumab and validated in an independent test dataset (N=150) for both response and survival.(SITC 2016 Annual Meeting Poster Submission ID: 214348.) Methods: A correlation matrix was calculated for the change between pre- and post-treatment gene expression for all 169 genes in two independent clinical trials. The genes were ranked by their relationship with CTLA4. Comparison was made between the training and test datasets. Reliable biological signals exceeded technical variance of +/- 0.5 fold change. Results: Correlation of the change in gene expression relative to CTLA4 between the 169 genes in two independent datasets was consistent as to fold change and ranking. The literature describes the genes in the Table as playing a role in anti-CTLA4 and PD-1 immunotherapy. We found only ICOS to be predictive of gene response in our 16-gene pre- and 8-gene post-treatment algorithms. Conclusions: Several genes, such as CTLA4, CD28, CXCR3, IL32, FOXP3, CD25, CCR5, and IFNG, are consistently upregulated one to three fold from anti-CTLA4 immunotherapy but are not predictive of response. ClinicalTrials.gov NCT00257205. [Table: see text]
Effect of paclitaxel and carboplatin on tumor-reactive T cells and the efficacy of PD-1 blockade.
Authors: Yan Yiyi , Dronca Roxana Stefania , Liu Xin , Markovic Svetomir , Dong Haidong 
Published: November 2019

65 Background: The addition of chemotherapy to immune checkpoint inhibitors has been explored clinically in solid tumors in order to overcome one of the challenges of immunotherapy: clinical outcomes are variable, with only a subset of patients achieving durable responses. Further understanding of the immunoregulatory mechanisms of chemotherapy in the setting of immunotherapy is crucial for the development of optimal combinatorial chemo-immunotherapeutic strategies to improve clinical outcomes in patients with advanced cancer. Methods: Metastatic melanoma (MM) patients who failed anti-PD-1 single therapy were subsequently treated with paclitaxel and carboplatin in addition to PD-1 blockade. Using peripheral blood (PB) from MM patients and healthy donor, the phenotypic and functional changes in T cells induced by chemotherapy, in the setting of PD-1 blockade, were examined. Results: Paclitaxel and carboplatin, in combination with PD-1 blockade, were able to induce significant clinical responses in a subset of MM patients who were resistant to anti-PD-1 therapy alone. In patients who responded to this combination, a subset of tumor-reactive effector T cells (CD8+CD11a+PD1+GranzymeB+) survived the treatment, with increased frequency after the addition of chemotherapy. This T cell population preserved its effector phenotype, although ongoing PD-1 blockade was needed to improve its anti-tumor activity. In vitro experiments, using CD8+CD11a+PD1+GranzymeB+isolated from healthy donor PB, also demonstrated its ability to survive chemotherapy treatment. In addition, after cultured with chemotherapy, this T cell subset demonstrated higher cytotoxic T cell functions as well as increased chemotherapy efflux. Conclusions: Chemotherapy regulates a subset of tumor-reactive effector T cells (CD8+CD11a+PD1+GranzymeB+) and increases clinical efficacy of PD-1 blockade. This novel effector T cell population underlies the key cellular and molecular immunoregulatory mechanisms of chemotherapy. It serves as a meaningful marker to measure these collaborative effects and to develop the optimal chemo-immunotherapy strategy to improve clinical responses to current immune checkpoint blocking agents.
Analytical validation of an immune response assay for classifying solid tumors.
Authors: Conroy Jeff , Glenn Sean , Burgher Blake , Papanicolau-Sengos Antonios , Andreas Jonathan , Giamo Vincent , Odunsi Kunle , Ernstoff Marc S. , Eng Kevin H. , He Ji , Gardner Mark , Morrison Carl 
Published: November 2019

68 Background: An advanced diagnostic laboratory test (Immune Advance) was developed that analyzes multiple DNA and RNA biomarkers to predict the likelihood of response to checkpoint inhibitors in patients with solid tumors. Using RNA-seq and DNA-seq, the NGS test measures gene expression of immune response genes and overall mutational burden. The studies described here were designed to validate the analytical performance of the test on the Ion Torrent System in our CLIA lab. Methods: Studies were designed to characterize the analytical performance of an immune response NGS assay using total nucleic acids from >100 FFPE tissues representing NSCLC, melanoma, renal cell carcinoma, and bladder cancer. Performance variables with respect to gene-specific amplicon specificity, linearity, and limits of detection were estimated with various sample dilutions and input nucleic acids. The effects of the tumor micro-environment (adjacent benign tissue, necrosis) was evaluated by including these potential interferents in the assay. Analytical precision including intra-assay, inter-assay, and inter-operator reproducibility was measured by testing replicate FFPE tissue sections. Accuracy was determined by comparing select transcript and DNA level variants with those from established IHC, RT-PCR, and NGS assays. Transcript stability in FFPE specimens was evaluated in serial sections from blocks with routine storage and compared to originating matched fresh frozen specimens. Results: RNA stability was demonstrated by high degree of correlation between matched frozen and FFPE samples. Analytic precision was demonstrated by high correlation between RNA-Seq and TaqMan results for genes evaluated. As compared to IHC the results for RNA-Seq were continuous rather than bimodal and allowed for a much more detailed analysis of the immune response. Immune signatures were maintained with variable RNA/DNA input amounts, altered tumor micro-environments, and potential interferents demonstrating tolerance to typical sample types tested. Reproducibility results show little variation between runs and operators. Conclusions: The analytical performance of the Immune Advance assay has been validated for clinical use using FFPE tumor specimens.