bluuebunny/crossref_metadata_2025_split huggingface dataset:
Initial results of a phase III investigation of safety/efficacy of nivolumab and ABI-009 (nab-sirolimus) in advanced undifferentiated pleomorphic sarcoma (UPS), liposarcoma (LPS), chondrosarcoma (CS), osteosarcoma (OS), and Ewing sarcoma.
Authors: Chua-Alcala Victoria S. , Kim Katherine , Assudani Nupur , Al-Shihabi Ahmad , Quon Doris , Wong Steven , Chawla Sant P. , Gordon Erlinda Maria 
Published: July 2019

21 Background: Objectives: (1) To investigate the MTD of ABI-009 when given with nivolumab, a PD-1 inhibitor, in previously treated advanced undifferentiated pleomorphic sarcoma, liposarcoma, chondrosarcoma, osteosarcoma and Ewing sarcoma; (2) To investigate the disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) of this combination therapy in the above mentioned patient group, and (3) To correlate PFS with PD-L1 and other biomarker expression in patients’ tumors. Methods: This is an IRB approved protocol with 2 parts. The Phase 1 part is a dose-finding study using the “cohort of three design”, wherein standard doses of nivolumab 240 mg is given iv every 3 weeks (Day 1 of every 21-day Cycle). ABI-009 will be given IV on Days 8 and 15 of each cycle starting on Cycle 2 following the 2nd nivolumab dose. The starting dose of ABI-009 is 56 mg/m2, and sequentially escalating doses are 75, and 100 mg/m2. The Phase 2 part of study will enroll 31 additional patients to further assess efficacy and safety at the MTD. Results: The Phase 1 part of study is closed, after 9 patients were treated successfully at 3 dose levels. No dose-limiting toxicities (DLTs) were observed, the MTD was not reached, and 100 mg/m2 ABI-009 was designated as the recommended phase 2 dose. Safety analysis: At Dose 1 (n=3): Grade 3 treatment-related adverse events (TRAEs) included hyperdyslipidemia (n=1), and hyperglycemia (n=1). At Dose 2 (n=3): Grade 3 TRAEs included increased ALT (n=1). At Dose 3 (n=3): Grade 3 TRAEs included hypophosphatemia (n=1). Seven of 9 patients have discontinued treatment: 5 patients due to PD, 2 with SD opted to stop treatment due to drug-related Grade 2 AEs (pruritus, acneiform rash, and 2 with SD are still on therapy at Dose 3. Conclusions: The primary objective has been met with no DLTs, the MTD was not reached and Dose 3 has been designated as the phase 2 dose of ABI-009 which is on-going. Clinical trial information: NCT03190174.
A phase II single-arm study of CRS-207 with pembrolizumab (pembro) in previously treated malignant pleural mesothelioma (MPM).
Authors: Alley Evan W. , Tanvetyanon Tawee , Jahan Thierry Marie , Gandhi Leena , Peikert Tobias , Stevenson James , Schlienger Katia , Liu Weiqun , Nair Nitya , Honarmand Somayeh , Kindler Hedy L. 
Published: July 2019

29 Background: CRS-207 is a live, attenuated, double-deleted Listeria monocytogenes (LADD) engineered to stimulate immune response to mesothelin. In a phase I trial of 60 MPM patients, 34% of subjects had tumor reduction (range -1 to -47%) following 2 doses of CRS-207 alone. In KEYNOTE-028 pembro showed activity in PDL1+ (≥1% by IHC) MPM, with an objective response rate (ORR) of 20% (5/25) and stable disease in 52% of subjects who had failed or did not receive chemotherapy. Subsequent studies of pembro have shown similar results in MPM. Results from a pre-clinical murine lung tumor model (CT26hMeso) showed anti-PD-1 enhanced LADD-induced tumor response. The study described here evaluated the efficacy of combination therapy of CRS-207/pembro. Methods: Adults with epithelial/biphasic MPM, ≤2 prior lines, progression on pemetrexed and platinum-based therapy, and no prior immunotherapies were enrolled. CRS-207/pembro were administered IV Q3W for 4 cycles, after which pembro continued Q3W and CRS-207 changed to Q6W. Response was assessed Q6W by modified RECIST for MPM (Byrne and Nowak, 2004). The primary endpoint was ORR; secondary endpoints included DOR, disease control rate (DCR), progression-free survival (PFS) and overall survival. Pre- and on-treatment blood and tumor samples were collected. Shedding and blood clearance of CRS-207 were evaluated. Results: 9/10 subjects were evaluable for response. No responses were observed; DCR was 11% (1/9 with SD) and PFS ranged from 3.4 to 8.9 weeks. Most common treatment related adverse events were chills, pyrexia and nausea. 3/10 subjects evaluated were PDL-1 negative by IHC. Of 6 subjects who underwent clearance and shedding evaluation, CRS-207 was detected in blood in 1 at 18-24 hrs after the first CRS-207 dose and cleared by the next evaluation at Day 4; shedding samples (urine, fecal, and saliva) tested negative. Conclusions: The toxicity profile of CRS-207/pembro combination was consistent with the safety profile of each component alone. No evidence of clinical activity was observed. Based on the results and an overall evaluation of the program, the clinical development of CRS-207 was discontinued. (NCT01675765) (NCT02054806). Clinical trial information: NCT03175172.
PTEN/PI3K signaling in cancer and the response to cytokines: From growth factors to immune actors.
Authors: Chandrasekaran Sanjay , Sasaki Maiko , Pollack Brian Paul 
Published: July 2019

35 Background: The PTEN/PIK3 pathway plays an important role in the cellular response to growth factors and aberrant activation of PI3K signaling is a hallmark of many forms of cancer. While the role of PI3K signaling has been well studied in the context of growth factor biology, its role in the cellular response to cytokines such as interferons (IFNs) is less well understood. We examined the impact of PI3K activation on interferon signaling pathways using an in vitro experimental model system. Methods: Cultured human HCT 116 colorectal carcinoma cells and isogenic PTEN (-/-) cells were treated with escalating doses of IFNg, IFNa2b, and IFNl. IFN response was evaluated by measuring MHC Class I and Class II mRNA levels and cell surface expression via RT-PCR and flow cytometry, respectively. Western blots for total AKT, phospho-AKT (pAKT), PTEN, STAT1, and pSTAT1 were performed. Corroborating pharmacologic studies were performed using cultured HPV-negative SqCC/Y1 oSCC cells treated with IFN and the PTEN inhibitor VO-OHpic and AKT activator SC79. Clinical correlates utilizing immunohistochemistry (IHC) on human head and neck cancers were conducted. Results: PTEN (-/-) cells expressed lower basal levels of MHC I and the induction by IFNs were likewise attenuated. Dramatically, PTEN knockout reduced IFN-g- induced surface expression of MHC II by > 50%. Corresponding reductions in MHC I/II mRNA were seen. IHC in patient biopsy samples showed an inverse relationship between phospho-AKT and MHC I expression. We identified a potential explanation of this effect wherein PTEN/PIK3 signaling implicates STAT1, a downstream target of IFN signaling. PTEN inhibition consistently modulated total and phosphorylated levels of STAT1 protein. Conclusions: Much remains unknown about the link between growth factor pathways and the tumor immune response. We demonstrate using an in vitro model that genetic and pharmacologic activation of the PI3K pathway attenuates the immune response to IFNs and represses MHC induction and expression. We present a novel mechanism for explaining this phenomenon linking the PTEN/PIK3 and STAT1 pathways. Further characterization of this interaction in in vitro models is necessary.
A phase I safety study of oncolytic vaccinia virus delivered by adipose stromal vascular fraction cells.
Authors: Minev Boris 
Published: July 2019

39 Background: A major obstacle to the oncolytic virus treatment approach has been the rapid virus elimination by patient’s immune system. We hypothesized that oncolytic viruses would be protected and delivered efficiently to tumor sites by autologous adipose stromal vascular fraction (SVF) cells. Here, we report the results of a study to determine the safety and feasibility of this approach in cancer patients. Methods: In this single-arm, open-label safety study, 24 patients with advanced solid tumors and 2 patients with AML were treated with a single administration of the oncolytic virus ACAM2000 (vaccinia) delivered by SVF cells. Patients received ACAM2000/SVF by intravenous application, or by a combination of intravenous and intratumoral or intra-peritoneal injections. The primary endpoint was safety/tolerability. Secondary endpoints assessed overall survival and induction of immune responses. Blood samples were collected at multiple time points for quantifying vaccinia virus DNA in peripheral blood and to determine the plasma cytokine levels and the effects on several immune cell types. Results: No serious toxicities were reported. Eight subjects reported an AE: self-limiting skin lesions, lasting 7 to 18 days. No infusion-related AEs were reported. No AEs leading to study discontinuation were reported. Viral DNA was detected in all patients immediately following treatment. Interestingly, in 8 patients viral DNA disappeared 1 day and re-appeared 1 week post treatment, suggesting active viral replication, possibly at tumor sites. This viral DNA reappearance correlated with longer survival of these patients. No major increase in cytokine levels was observed in any of the patients. No correlation between cytokine levels and skin lesions was noted. Flow cytometry showed gradual changes suggesting improved immune cell activation status. Tumor size reduction was documented in several patients. Conclusions: Treatment with ACAM2000/SVF in patients with advanced solid tumors and AML is safe and well tolerated, with clear antitumor effects in several patients. These promising initial clinical results merit further investigation of therapeutic utility. Clinical trial information: ISRCTN#10201650.
A phase II trial with the combination of plinabulin (plin) pegfilgrastim (peg): Evaluation of the reversal of peg’s immune-suppressive potential by the addition of plin to peg.
Authors: Blayney Douglas W. , Ogenstad Stephan , Shi Yuankai , Feng Ji Feng , Zhang Qingyuan , Sun Tao , Du Lihua , Huang Lan , Mohanlal Ramon 
Published: July 2019

4 Background: Peg is a long-acting G-CSF used for prevention of Chemotherapy Induced Neutropenia (CIN). Peg stimulates granulopoiesis in bone marrow and causes a temporary overshoot in absolute neutrophil count (ANC). High NLR is a negative prognostic marker in esophageal, renal cancer and melanoma (Zhou, Nature 2016; Ma, Nature 2018). Decreased Lymphocyte-to Monocyte Ratio (LMR) is another negative prognostic marker (Sierzega; Ann Surg Onc 2017). Peg single agent (SA), but not Plin SA, increased NLR, and decreased LMR (Blayney ESMO 2018) after Docetaxel (Doc). We analyzed whether Plin added to Peg would reverse Peg’s immune-suppressive potential by analyzing NLR and LMR with Peg SA and with Plin+Peg. Methods: NLR and LMR were calculated in cycle 1 of Ph2 study BPI-2358-106 with either Peg SA (6 mg; n = 22), Plin SA (20 mg/m2; n = 15) or Peg 6 mg and Plin 20 mg/m2 (Peg+Plin; n = 21). NLR and LMR were calculated after day (D) 8, since Peg increases leukocytes after D8, and were performed through D15. Plin was given D1 of chemotherapy (Doc, Doxorubicin, Cyclophosphamide) in Breast Cancer patients (pts); Peg was given D2. Results: The percentage (%) of pts with grade 4 neutropenia was lowered from 59% with Peg SA to 38% by adding Plin to Peg. The % of pts with an ANC exceeding upper limit of normal (8x10E9/L) was lowered from 50% with Peg SA to 31%, by adding Plin to Peg. The table summarizes the % of patients with NLR ≥ 5 and LMR ≤3.2 over time with Peg SA, Plin SA and Peg+Plin. Peg-induced immune-suppressive NLR and or LMR levels occurred in 50% or more of pts, and in a significantly lower % of pts by adding Plin to Peg (p < 0.0076 for NLR and p < 0.073 for LMR on D13). Conclusions: Peg, but not Plin generates a potentially deleterious NLR and LMR which was significantly reversed by the addition of Plin to Peg. The Peg+Plin combination improves efficacy for CIN and reversed Peg’s potentially immune-suppressive NLR and MLR phenotype. Clinical trial information: NCT03294577. [Table: see text]
Histology could predict a “hot” or a “cold” gastric tumor?
Authors: Zurlo Ina Valeria , Strippoli Antonia , Calegari Maria Alessandra , Martini Maurizio , Cocomazzi Alessandra , Orlandi Armando , Cassano Alessandra , Vita Emanuele , Garufi Giovanna , Di Stefano Brunella , Bagala Cinzia , Bria Emilio , Pozzo Carmelo , Basso Michele 
Published: July 2019

44 Background: The emerging role of immunotherapy (IT) in cancer treatments has increased the research about tumor microenvironment (TME), tumor infiltrating lymphocytes (TILs) function and their TME regulation. Nowadays ongoing trial are showing conflicting preliminary data about the efficacy of IT in advanced gastric cancer (GC). Therefore, we performed this exploratory analysis to evaluate the correlation between histology, TILs density (reported as CD4/CD8 tissue ratio), neutrophil-lymphocytes ratio (NLR) and response outcome in GC patients who underwent cytotoxic neoadjuvant treatment (NAD). Methods: CD4+ and CD8+ expression was assessed by immunohistochemistry (IHC) in pre-NAD biopsies. NLR was calculated on baseline complete blood count. A cut-off value to define low or high NLR has been selected on 3.0, based on literature data. X2 test was used to explore the correlation between histology, CD4/CD8 ratio, NLR and response. Results: We analyzed 10 diffuse and 10 intestinal GC histotypes. In the intestinal-type CD4/CD8 ratio was lower (ratio range 1:15 - 1:20) with a predominant count of CD8+ suggesting a hot and inflamed TME compared to the diffuse cohort (ratio range 1:3 -1:5) where both CD8+ and CD4+ density was lower (p=0.03). Baseline NLR was calculated in 18 out of 20 pts. All intestinal GCs showed a low NLR (<3) while all diffuse GCs displayed a high cutoff (p=0.03). CD4/CD8 ratio resulted associated to histology (p=0.025) and response outcome (p=0.0003). NLR was statistically related to histology (p=0.03) and CD4/CD8 tissue ratio (p=0.03), confirming a different systemic inflammatory status and TME according to histology. Conclusions: Despite the small sample size, our exploratory analysis shows a possible correlation between histology, systemic inflammation and TME behavior (“hot” vs“cold”) described by NLR and TILs concentration (CD4/CD8 ratio) respectively and response to NAD. Intestinal-type seems to be a “hot” tumor whereas diffuse-type appears “cold”. Future clinical trial should analyze the impact of histology and TME features on IT efficacy and the appropriate strategy to convert “cold” tumor increasing TILs density.
Results of a phase II study evaluating trifluridine/tipiracil plus nivolumab in patients with heavily pretreated microsatellite-stable (MSS) metastatic colorectal cancer (mCRC).
Authors: Patel Manish R. , Falchook Gerald Steven , Hamada Kensuke , Makris Lukas , Winkler Robert E. , Gordon Gilad Shalag , Bendell Johanna C. 
Published: July 2019

48 Background: Patients (pts) with colorectal cancer (CRC) with microsatellite instability (MSI) have recently been shown to respond to anti–programmed death (PD)-1 drugs. Preclinical data suggest that trifluridine/tipiracil (FTD/TPI) treatment converts MSS CRC cells to MSI, sensitizing them to the activity of anti–PD-1 drugs. The aim of this phase 2 study was to evaluate this hypothesis. Methods: This was a multicenter, single-arm, safety lead-in, phase 2 study that used Simon’s 2-stage design to evaluate the safety and efficacy of FTD/TPI (35 mg/m2 twice daily on days 1-5 and 8-12 every 28 days) plus nivolumab (3 mg/kg every 2 weeks) in pts with heavily pretreated MSS mCRC. Pts had histologically proven metastatic or locally advanced colorectal adenocarcinoma that was MSS (assessed by a local laboratory based on either previous or fresh biopsy), ≥1 measurable lesion for RECIST and immune-related response criteria (irRC) assessment, and failure of ≥2 previous lines of chemotherapy. Six pts were to be enrolled in the safety lead-in, and in order to proceed to Simon’s stage 2, ≥2 of the first 15 pts had to demonstrate a partial or complete response within 6 months based on irRC assessment. Results: The first 6 dose-limiting toxicity (DLT)-evaluable pts enrolled tolerated dosing with no DLTs. A total of 18 pretreated pts enrolled in the first stage (50% males; median age 56.5 yr), among whom 72% had colon cancer and 100% had MSS disease, 56% with RAS mutations. Pts received a median of 2.5 cycles of study therapy (range 1-8). The most common grade 3/4 adverse events (AEs) were neutropenia (28%); diarrhea (17%); and nausea, abdominal pain, fatigue, and anemia (11% each). No pts discontinued treatment due to AEs. No pts achieved a tumor response (either per RECIST or irRC), and the study did not progress to the second stage. Median (6-month) progression-free survival was 2.8 months (21%) per RECIST and 2.2 months (30%) per irRC. Conclusions: The combination of FTD/TPI and nivolumab was feasible and tolerated at the full dose of both compounds. Adding nivolumab to FTD/TPI did not provide additional clinical benefit in pts with previously treated MSS mCRC. Clinical trial information: NCT02860546.
Production of autologous monocytes stimulated ex vivo with peg-interferon alfa 2b and interferon gamma 1b for intraperitoneal administration in phase I clinical trial.
Authors: Duemler Anna , Green Daniel S , Highfill Steven L. , Stroncek David , Zoon Kathryn , Annunziata Christina M. 
Published: July 2019

5 Background: Monocytes are myeloid cells that reside in the blood and bone marrow and respond to inflammation. At the site of inflammation, monocytes express cytokines and chemokines. Monocytes are cytotoxic to tumor cells in the presence of pro-inflammatory cytokines such as Interferon Alpha and Interferon Gamma. We previously showed that monocytes stimulated with both interferons (IFNs) result in synergistic killing of ovarian cancer cells. We aimed to develop this cell therapy product for clinical application. Methods: Counter flow elutriation was performed on healthy donors. The monocyte-containing, RO-fraction was assessed for total monocyte number, purity, viability, and cytotoxicity with and without cryopreservation. All 5 fractions from the elutriation procedure were also assessed by flow cytometry to measure the percent of immune cell subsets. This procedure is now implemented in a clinical trial where 8 patients completed the apheresis and elutriation process for a total of 13 runs. Results: Iterative monocyte isolation using counter flow elutriation with or without cryopreservation can yield over 2 billion monocytes for each subject with high purity. We show that monocytes are stable, viable, and retain cytotoxic functions when cultured with IFNs. Flow cytometric analysis shows expected heterogeneity in the collected monocytes. In each case, the elutriation run met pre-set release criteria for both total monocyte number and purity requirements for the therapeutic product. Conclusions: We demonstrated that large scale isolation of monocytes can be achieved with elutriation from either healthy donors or patients with advanced, chemotherapy resistant ovarian cancer. Monocytes can be cryopreserved and maintain viability and cytotoxic function in the final cell therapy product prior to infusion. We translated these observations to a currently accruing clinical trial using adoptive cell transfer of autologous monocytes stimulated ex-vivo with IFNs and infused into the peritoneal cavity of patients with advanced, chemotherapy resistant, ovarian cancer. (Protocol NCT00327067). Clinical trial information: NCT02948426.
Low molecular weight heparin (LMWH) enhances immunotherapy (I) activity in pancreatic cancer cells.
Authors: Karamouzis Michalis , Bokas Alexandros , Kyriakopoulou Georgia , Koustas Evangelos , Sarantis Panagiotis , Papakotoulas Pavlos , Schizas Dimitrios , Papalampros Alexandros , Felekouras Evangelos , Liakakos Theodoros , Papavassiliou Athanasios G. 
Published: July 2019

50 Background: The aim is to investigate the effect of LMWH in combination with chemotherapy (C) and I in PC. Methods: BxPC-3, PANC-1, MIA PACA-2 cell lines were exposed in Tinzaparin (T) (0.5, 0.7, 0.9 μΜ) and/or 1 μΜ Nab-Paclitaxel (A) and/or 1 μΜ Gemcitabine (G) and/or 1 μΜ Nivolumab (NI), 1 μΜ, Pembrolizumab (PE) and 1 μΜ ipilimumab (IPI). Protein levels of VEGFR2, p-ERK1/2, p-AKT detected by Western blotting. Cells viability was measured through MTT assay. Results: Increasing protein levels of VEGFR2 was observed in all PC cell lines exposed to a constant dose of T and/or A,G. NI and PE +/- with IPI increased VEGFR2. In NI/PE+IPI+T scheme VEGFR2 levels were decreased (0.1-0.7 folds) in a dose dependent way in mtKRAS cells (PANC1, MIAPACA2). C (G or A) + I decreased VEGFR2 protein levels in mtKRAS cells PANC1 (0.1-0.4 folds), MIAPACA2 (0.1-0.6 folds) in double scheme. T+G/A+NI/PE+IPI scheme increased VEGFR2 in all PC cells. PANC-1 cells were decreased 40% in 0,7T+IPI+(NI or PE) after 48hours. The effect of these schemes on signaling pathways (MEK/EKR, AKT/mTOR) and apoptosis was identified through pERK1/2, pAKT, PARP, cl. caspase-3. Conclusions: These results identify the different effect of I alone or in combination with T and C in PC cells bearing mutant or wild type KRAS. Double or triple combination reduced VEGFR2 protein levels in mtKRAS and not in wtKRAS PC cells. The 0,7T+IPI+(NI or PE) combination decreases cell viability of PC cells through apoptosis. Testing of the combinatorial scheme T+chemo+IPI+(NI or PE) with PANC-1 PC in scid mice is ongoing and will be presented. NC:not changed, -:<20% protein vs control, +:>20% protein vs control, ++:>40% protein vs control. [Table: see text]
Association of intratumoral FoxP3 T-regulatory lymphocytes and perineural invasion in colorectal adenocarcinoma.
Authors: Messersmith Lynn , Williams Grant , Lombardo Jamie , Hickerson Annelies , Campf Jessica , Brady Robert , Collins Ryan , Peoples George Earl , Clifton Guy T. 
Published: July 2019

51 Background: In colorectal cancer, higher densities of lymphocytes in the tumor microenvironment (TME) have been associated with better clinical outcomes. FoxP3+ regulatory T-cells (Tregs) are a subset of lymphocytes that play an immunosuppressive role in the TME. However, the impact of Tregs in the TME in colon cancer prognosis is more controversial. We evaluated the densities of FoxP3+ Tregs at multiple locations in matched endoscopic biopsies and resection specimens from patients with colonic adenocarcinoma to assess concordance of Treg densities between locations, and the association with prognostic factors. Methods: Patients with banked, matched endoscopic biopsies and surgically resected colon adenocarcinoma specimens from a single institution from 2006-2016 were selected for evaluation. Paraffin embedded tissue samples were cut and stained with FoxP3 immunohistochemical stain. The densities of FoxP3 positive cells were counted within a 1 mm2 area at the center of the tumor and at the invasive margin. The densities of FoxP3 positive lymphocytes were compared between the center and invasive margin, and to prognostic factors. Results: 107 matched endoscopic biopsies and surgical resection specimens were evaluated. A moderate-strong correlation was noted in levels of FoxP3+ cells between endoscopic biopsies and resected specimens at the center of the tumor (r= 0.68) and invasive margin (r=0.69). Higher FoxP3 densities were associated with a decreased rate of perineural invasion (P= 0.040). Levels of Tregs in endoscopic biopsies were correlated with the levels in the larger tumor of resected colon adenocarcinoma specimens. There was a weak correlation between increased density of Tregs and lower anatomic stage (R2 = 0.05). Conclusions: Tregs are a potential biomarker that can be evaluated in neoadjuvant immunomodulatory therapies in clinical trials to assess for response. Moreover, Treg levels are associated with perineural invasion, a predictive factor for decreased response to chemotherapy, underscoring the potential for immunomodulatory therapies in colorectal adenocarcinoma.