bluuebunny/crossref_metadata_2025_split huggingface dataset:
The safety and tolerability of PD-1/PDL-1 inhibitors in hematologic malignancies: A meta-analysis.
Authors: Myint Phyo Thazin , Ali Faisal , Alrifai Taha , Gong Zimu , Nandar Phoo Pwint , Kozma Kelley Elizabeth 
Published: May 2019

e14131 Background: The safety of programmed death receptor and ligand-1 (PD-1/PDL-1) inhibitors in hematologic cancers is not well-defined. We conducted a meta-analysis to investigate their safety. Methods: Pubmed & Cochrane databases were searched from 1968-2018. Full-text articles of clinical trials reporting treatment-related adverse events (AE) of PD-1/PDL-1 inhibitors in hematologic cancers were included. Incidences of all-grade and high-grade (≥grade 3) AEs were pooled and generated with a 95% confidence interval (CI) using a random effect model on STATA. Results: Eight studies (5 nivolumab & 3 pembrolizumab) were identified, with 703 patients and the median age of 34. Six studies were done in patients with relapsed/refractory (R/R) classical Hodgkin Lymphoma, one in R/R diffuse large B-cell lymphoma and one in combined hematologic cancers. There were 1092 total AEs, with a pooled high grade AEs rate of 13% (95% CI 9-17%). High-grade AEs (HAE) are summarized in the Table. Lipase elevation was the most common HAE for nivolumab (pooled incidence of 13%; 95% CI 6-23%), whereas leukopenia was the most common HAE reported with pembrolizumab use (pooled incidence of 36%; 95% CI 10-65%) There were 47 treatment discontinuation due to treatment-related AE. For Nivolumab, there was one treatment-related death (of a heavily pretreated patient) due to fatal pneumonitis. Conclusions: PD-1/PDL-1 inhibitors are well-tolerated in hematologic malignancies with a favorable risk of adverse events and very low treatment-related mortality. The HAE profile of Nivolumab differs from Pembrolizumab, and future studies should assess this heterogeneity further. [Table: see text]
Blocking LILRB and KIR receptors by B57 open conformers induces potent antitumor activity and acts synergistically with checkpoint blockade inhibition.
Authors: Renner Christoph , Curran Michael A. , Kolibaba Julia , Liu Yang , Petrausch Ulf , Zippelius Alfred , Stenner Frank , Rafiei Anahita , Marroquin Belaunzaran Osiris 
Published: May 2019

e14137 Background: HLA open conformers (OC) are defined as HLA class I molecules lacking beta-2-microglobulin (β2m) and peptide. OC can be derived from different HLA I molecules such as HLA-B27, -B57, and –Cw08. OC have a different three dimensional structure when compared to their respective HLA/β2m/peptide counterpart and induce distinct immunological processes by binding to LILRB and KIR molecules, both key receptors of the innate immune system. B57 OC expression is associated with enhanced immunity against viruses and can cause autoimmunity. Its potential anti-tumor activity has not been exploited so far. Methods: B57 OC and control molecules were expressed as IgG4 fusion proteins in CHO cells. The affinity for protein-ligand interaction was measured by surface plasmon resonance (SPR). Human macrophages M1/M2, phagocytosis and NK cytotoxicity were assessed by flow cytometry and cellular assays. Syngeneic pancreatic cancer (Pan02) or colon cancer (MC38) mouse models were used. Mice with tumors of 80mm3were treated twice weekly at 5 mg/kg. Tumor and blood samples were analysed. FDA cancer panels were assessed by IHC for LILRB1-5 expression. Results: B57 OC displays distinct protein-ligand interactions with high affinity binding to LILRB2 & 4, KIR2L1-3, and KIR3DL1. Therapeutic efficacy in pancreatic and colon cancer models was observed with monotherapy (p < 0.01), and combo therapy using PD1 and/or 41BB antibodies (p < 0.0001). Ex vivotumor sample analysis revealed a significant reduction of MDSC & Tregs, and an increase of M1 type macrophages. In addition, loss of MDSC functionality and enhanced CD8+ T cell expansion was noticed. IHC of human tissue demonstrated enhanced LILRB2 expression, notably in colon and lung cancer. Conclusions: B57 OC has a unique binding profile to LILRB and KIR receptors. B57 OC induces anti-tumor activity in diverse syngeneic mouse models and acts synergistically with PD1 or 41BB antibodies. Pre-clinical and human in vitroexperiments demonstrate that B57 OC mode of action is established with inhibition of MDSCs, macrophage polarization to M1 phenotype, activation of NK cells and LILRB blockade on tumor cells, which in turn support the adaptive immune system by increasing CD8+ effector T cells and reducing Treg numbers. B57 OC is a first-in-class therapeutic with robust anti-tumor activity.
Toxicity of PD-1/CTLA-4 inhibitor immunotherapy among elderly patients.
Authors: Kapoor Vidit , Rixe Olivier 
Published: May 2019

e14139 Background: The use of Immune check point inhibitors in advanced metastatic melanoma is becoming increasingly common especially in the elderly population. With metastatic melanoma being mostly a disease of the elderly, the safety and toxicity profile of immune check point inhibitors in this population group continues to remain controversial. Prior studies have hypothesized that due to reduced immune responses in the elderly, toxicity to immune check point inhibitors is expected to be low. In this study we aim to analyze the association of check point inhibitor induced immuno-toxicity with age. Methods: We analyzed 108 patients with stage 4 metastatic melanoma who were treated with anti-PD1 and/or anti-CTLA-4 immunotherapy. Out of these patients, 58 (53.7%) were 65 or more years old and 50 (46.3%) were < 65 years old. Overall, 64 (59.3%) patients had autoimmune side effects; 35 (60.3%) were 65 years or older and 29 (48%) were < 65 years old. The most common side effects were dermatitis (n = 22, 20.4%) and colitis (n = 21, 19.4%). Incidences of various autoimmune side effects were calculated in both groups (65 years or older and < 65 years old). Fisher exact test was used to calculate p values Results: There was a significant difference between the incidence of dermatitis between the two groups. (51.4% in 65 years or older and 24.1% in < 65 years old group, p = 0.04). The incidence of colitis was more in the 65 years or older group (37.1%) as compared to < 65 years group (31.1%) however results were not statistically significant (p = 0.79). Similarly, there was no significant difference in other autoimmune side effects including hepatitis, arthritis, pneumonitis, thyroiditis, hypophysitis, adrenalitis, anemia and thrombocytopenia between the two groups. Also, there was no significant difference in the incidence of different grades of side effects (1 to 4) between the two groups. Conclusions: Patients who are 65 years or older can safely tolerate immunotherapy as compared to patients < 65 years old but with an increased risk of dermatitis. These data should be validated by a larger study population.
Experience with CXCL12 inhibitor NOX-A12 plus pembrolizumab in patients with microsatellite-stable, metastatic colorectal or pancreatic cancer.
Authors: Halama Niels , Pruefer Ulrike , Frömming Anna , Beyer Diana , Eulberg Dirk , Jungnelius Jarl Ulf B. , Mangasarian Aram 
Published: May 2019

e14143 Background: NOX-A12 is an inhibitor of the chemokine CXCL12 which prevents receptor engagement and blocks the formation of chemotactic CXCL12 concentration gradients. The OPERA study (NCT03168139) is a Phase 1/2 study to evaluate pharmacodynamic effects and safety of monotherapy with NOX-A12 as well as safety and efficacy of a combination with pembrolizumab in metastatic microsatellite-stable (MSS) colorectal (CRC) and pancreatic (PaC) cancer where PD-1 inhibition alone has not shown clinical benefit. Methods: Patients received 300 mg NOX-A12 twice weekly during a 2-week monotherapy phase. Biopsies were taken from liver metastases before and after NOX-A12 monotherapy for analysis of immune cell infiltration and cytokine signature. In a combination phase, patients received repeated 21-day cycles of 300 mg NOX-A12 and 200 mg pembrolizumab until progression or intolerable toxicity. Results: 11 of the patients had CRC and 9 PaC. All patients were heavily pretreated with 5 (CRC) and 3 median lines (PaC) of prior treatment. Best responses to last prior treatment was progressive disease for 95% of patients. The AE profile was comparable with the pembrolizumab profile or typical for the underlying diseases. At baseline, mean T cell density at the invasive margin was 327 cells/mm², clearly below the 600 cells/mm² that are predictive for a good prognosis. 2 weeks of NOX-A12 monotherapy induced Th1 cytokines (IFNγ, IL-2, IL-16) in approx. half of the patients. Although there were no objective responses, 25% of patients achieved stable disease; 7 patients showed prolonged time on treatment vs. the prior line of therapy. Updated figures for progression-free survival and overall survival for the whole patient cohort will be presented. Conclusions: In patients with MSS metastatic PaC and CRC cancer with impaired immune systems and a high tumor load that have failed multiple prior lines of therapy, NOX-A12 plus pembrolizumab shows induction of immune response, stable disease in 25% of patients, and prolonged time on treatment vs. prior therapy for 35% of patients. The safety profile of the combination therapy was consistent with that of pembrolizumab in advanced cancer patients. Clinical trial information: NCT03168139.
A phase II, open label, randomized, noncomparative study of eFT508 (tomivosertib) alone or in combination with avelumab in subjects with relapsed/refractory microsatellite stable colorectal cancer (MSS CRC).
Authors: Hubbard Joleen Marie , Patel Manish R. , Bekaii-Saab Tanios S. , Falchook Gerald Steven , Freilich Bradley L. , Dasari Arvind , Knisely Benjamin T , Anderson Marlisa , Chiang Gary Gene , Webster Kevin R , Sperry Sam , Barton Jeremy , Bendell Johanna C. 
Published: May 2019

e14145 Background: Dysregulated translation of messenger RNA (mRNA) plays a role in the pathogenesis of solid tumors. Tomivosertib (T), a potent and highly selective small molecule inhibitor of MNK-1 and 2 blocks activation of eIF4E, a key regulator of mRNA translation, selectively regulating translation of a set of mRNAs. Preclinically, T triggers an anti-tumor immune response and enhances responses to checkpoint inhibitors. Avelumab is a fully human checkpoint inhibitor antibody directed against PD-L1. Methods: Part 1: In a 3+3 dose escalation patients (pts) with MSS CRC failing ≥2 prior therapies for metastatic disease received escalating doses of T, administered orally bid, with a fixed dose of 10 mg/kg avelumab q2w. Part 2: Pts were randomized (2:1) to combination therapy at the recommended phase 2 dose (RP2D) from part 1 or T alone. Primary endpoint is objective response rate. All pts have a pretreatment and on treatment biopsy to evaluate target engagement, tumor infiltrating lymphocytes and biomarkers of immune activation. Results: The RP2D for the combination was 200 mg bid T (single agent RP2D) with 10mg/kg avelumab q2w. At this dose level, 1 of 7 pts experienced a dose limiting toxicity being unable to complete the first 28 day cycle due to low grade (1/2) toxicities (nausea, fatigue, myalgia). In part 2, 30 pts were randomized to combination and 15 to monotherapy (25 male, 20 female: mean age 53.9 years, range 32-80 years). The most common adverse events, irrespective of causality were grade 1/2 gastrointestinal (including nausea, vomiting, abdominal pain, constipation and diarrhea) occurring in 77% (n = 23) of the combination and 67% (n = 10) of the monotherapy arm. Toxicities occurring more frequently in the combination arm included diarrhea, constipation, fatigue, myalgia/arthralgia, hypercalcemia and skin rash. Efficacy evaluation is pending from part 2. One pt with confirmed MSS status in part 1 treated at the RP2D achieved a confirmed Partial Response of greater than 8 months. Conclusions: Preliminary data suggest that the combination of T and avelumab has an acceptable safety profile with robust target engagement and demonstrated initial signs of activity. Updated efficacy and biological biopsy data will be presented at the conference. Clinical trial information: NCT03258398.
Combined treatment of patients with bone metastases from various cancers with nivolumab plus denosumab: A retrospective study.
Authors: Ozaki Yukinori , Miura Yuji , Yamanaka Taro , Takemura Kohji , Kizawa Rika , Takahashi Momoko , Masuda Jun , Kondoh Chihiro , Tanabe Yuko , Takano Toshimi 
Published: May 2019

e14153 Background: Monoclonal antibodies against the programmed cell death protein-1 (PD-1), e.g., nivolumab, have been shown to exhibit antitumor immunity and improve survival in patients with various cancers. Recently, it was reported that bone metastases are unlikely to respond to immunotherapy, while other reports have suggested that synergistic antitumor effect can be obtained by administration of denosumab in combination with PD-1 blockade using nivolumab. However, there are still very limited data on the efficacy and effects on the prognosis of nivolumab administered in combination with denosumab in patients with bone metastases. Methods: We reviewed the medical records and pharmacy database of patients who had received nivolumab plus denosumab treatment from April 2011 to March 2018 at our institution, in order to analyze the prognosis of patients with bone metastases from various cancers. The primary objective was to compare the progression-free survival between patients with and without bone metastases. The impact of combined nivolumab plus denosumab therapy was evaluated as an exploratory endpoint. Results: We extracted 201 patients who had received denosumab for bone metastasis and 45 patents who had received immune checkpoint inhibitor. We analyzed the data of 39 patients who had received nivolumab treatment; of these 39 patients, 10 had additionally also received denosumab for the treatment of bone metastases. The median age of the patients was 65 years (range 41-87); the primary disease was renal cell carcinoma in 17 patients, gastric cancer in 9 patients, melanoma in 6 patients, non-small cell lung cancer in 4 patients, and head and neck cancer in 3 patients. The median progression-free survival following treatment with nivolumab was 2.1 months in the group with bone metastases and 3.5 months in the group without bone metastases (log-rank test; p = 0.0779); the 6-month progression-free survival rate was 26.7% (95% CI: 21.6-69.2) in the patients with bone metastases and 39.3% (95% CI: 10.4-53.3) in those without bone metastases. Concurrent administration of denosumab, age, and the primary disease had no influence on the progression-free survival rate. Conclusions: This retrospective analysis revealed a trend towards lower immune responses in patients with bone metastases, even when nivolumab is administered in combination with denosumab. Immunotherapy for bone metastasis needs to be further explored.
Preclinical characterization and efficacy of 4R9, a novel immune checkpoint blockade targeting CEACAM1 for cancer therapy.
Authors: Lee Jae-Chul , Hur Minkyu , Park Hye-Young , Lee EunHee , Yum Hye In , Nam Hye-mi , Oh Mi-Young , Choi HyungSuk , Kim Jae-Hwan , Cho Byoung Chul , Lim Yang-Mi , Won Jonghwa 
Published: May 2019

e14155 Background: CEACAM1 is one of the several immune checkpoint receptors expressed on T cells that mediate suppression of inflammatory T cell response. It is known that CEACAM1-CEACAM1 homophilic interaction induces downregulation of ZAP70 phosphorylation in response to T cell receptor (TCR) stimulation. Also, CEACAM1 is highly expressed on non-small cell lung cancer (NSCLC) and its expression correlated with cancer progression and poor prognosis. We developed a fully human monoclonal antibody 4R9, human CEACAM1-targeting antibody. Methods: T cell activation of 4R9 was determined by NFAT-luciferase reporter assay with CEACAM1 overexpressing Jurkat stable cells. In vitro efficacy of 4R9 was examined using NK-mediated tumor cell killing assay. The anti-tumor efficacy of 4R9 alone or in combination was studied in vivo in a humanized mouse model engrafted with NSCLC patient-derived tumor xenografts. Results: Anti-CEACAM1 antibody 4R9 binds to CEACAM1 overexpressed in HEK293 or Jurkat cells but not to other CEA family members. 4R9 blocks CEACAM1-CEACAM1 homophilic interaction by binding to N domain of CEACAM1. CEACAM1-CEACAM1 homophilic interaction induced downregulation of ZAP70 phosphorylation in response to TCR stimulation in CEACAM1 overexpressing Jurkat stable cell line, which was rescued by 4R9 resulting in augmentation of NFAT activity and IL-2 expression. NK cell-mediated tumor lysis was increased by 4R9 in a CEACAM1 expression-dependent manner. Out of 49 NSCLC tumor tissues, 20 cases exhibited dominant expression of CEACAM1 over PD-L1 with 6 cases showing > 50% of CEACAM1 positivity. In a single mouse trial using NSCLC PDX-huNSG mouse model, 4R9 (20 mpk, 2qW) suppressed tumor progression more than 30% as monotherapy (10/19) as well as in combination (16/22) with pembrolizumab (5 mpk, 2qW). Moreover, PDX of adenocarcinoma origin with more than 50% of CEACAM1 expression were more efficiently prohibited for progression with 4R9, suggesting potential therapeutic use of 4R9 in patients with NSCLC. Conclusions: Anti-CEACAM1 antibody blocked CEACAM1-mediated negative regulation and restored T/NK cell activities. Different expression patterns of CEACAM1 compared with PD-L1 and efficacies in a single mouse trial support the rationale for developing anti-CEAEAM1 antibody as cancer therapeutics.
Electron microscopic characteristic of local immune processes during regression of developed experimental tumors under the influence of magnetite nanoparticles.
Authors: Zhukova Galina V. , Kit Oleg I. , Bragina Marina I. , Gudtskova Tatiana N. , Shikhlyarova Alla I. , Shirnina Elena A. , Zhadobina Anastasia I. , Zernov Vladimir Alekseevich , Rudenko Mikhail Yu. 
Published: May 2019

e14179 Background: Previously, regression of the developed transplanted tumors under the influence of magnetite nanoparticles (NPs) as monofactor was shown. The purpose of the study was to reveal signs of intercellular interactions in the zone of tumors regressed under the influence of magnetite NPs. Methods: Experiments were carried out on 14 white outbred male rats (180-200 g) with transplanted sarcoma 45 of an initial volume of 0.7-1.3 cm3. After 6 peritumoral injections of magnetite NPs (10 ± 2 nm) in the form of magnetic fluid AM-01 ("AM-Kub", Ekaterinburg) twice a week in a single dose of 17.7 mg/kg, 5 out of 7 rats of the main group demonstrated a regression of the tumor from 1.5-3 cm3 to 0.7 ± 0.2 cm3 (in the control group – 9.7 ± 1.9 cm3, p < 0.01). Ultrathin sections of the tumor tissue of 12 animals (including 7 rats of the main group) were examined in electron microscope JEOL JEM-1011 (Japan). Results: Under effective action of magnetite NPs in tumor tissue, in addition to necrosis, apoptosis and autophagy were marked. In the case of apoptosis, chromatin condensation in compact masses and separation of apoptotic bodies were observed. Significantly more common autophagic cell death was identified by violation of the integrity of the cell membrane and the presence of autophagosomes. Numerous signs of activation of cell-cell interactions with participation of immune cells were observed. Diverse groups of 2-4 contacting cells included macrophages, lymphocytes, plasmocytes, degranulated mast cells, neutrophils in various combinations with distinct signs of the metabolic activity. Invagination of macrophages cytoplasm into the cytoplasm of tumor cells, close adjacency of the cytoplasmic membranes of neutrophils and lymphocytes at considerable length, tight intertwining of mast cell cytoplasmic processes and engulfing of the mast cell granules by macrophages were noted. Conclusions: The results supplement the characteristics of immune processes during the self-dependent antitumor action of magnetite NPs.
Characterizing the gut microbiome of patients with triple-negative breast cancer.
Authors: Swoboda April T. , Sharma Anukriti , Olopade Olufunmilayo I. , Nanda Rita , Gilbert Jack 
Published: May 2019

e14186 Background: The human microbiome has been postulated to play a role in carcinogenesis, and there is evidence that commensal intestinal bacteria are capable of promoting tumor immunosurveillance and controlling the immune system’s response to therapy by modulating the tumor microenvironment. Methods: We characterized the stool microbiome of 30 patients (pts) with triple-negative breast cancer (TNBC) using 16S rRNA gene sequencing. Analysis of composition of microbiomes (ANCOM) was used to identify differential abundant exact-sequence-variants (ESVs) with p-values adjusted using Benjamini-Hochberg False Discovery Rate (pFDR) correction. We correlated the stool microbiome with clinicopathologic features and response to treatment. Results: The cohort included 7 pts with metastatic breast cancer and 23 pts with early-stage disease. 19 pts were treated with neoadjuvant chemotherapy (NACT). Bacteroides ovatus ESV was enriched (pFDR < 0.05) in black pts (n = 14), whereas ESV from Prevotella copri was abundant (pFDR < 0.05) in white pts (n = 13). ESVs from Clostridium and family Ruminococcaceae were enriched (pFDR < 0.05) in pts with distant metastatic recurrence (n = 6) compared to pts without metastatic disease. Notably, we identified specific taxa that differentiated between pts with a pathological complete response to NACT (pCR, n = 6) and those with residual disease (n = 13). ESVs from Bacteroides and Ruminococcaceae were relatively more abundant in pts with a pCR (pFDR < 0.05). Furthermore, among pts with residual disease after NACT, Bacteroides caccae was significantly enriched in pts with a partial response (n = 4) compared to pts with no response (n = 9). Conclusions: To our knowledge, this is the first time that 16S rRNA amplicon sequencing has been used to identify microbial signatures correlating with clinical phenotypes and response to treatment in pts with TNBC. This small study provides insight into the potential role of microbes in novel therapeutic interventions to correct dysbiosis and shift towards a gut microbial ecosystem that enhances the body’s immune response to TNBC.