bluuebunny/crossref_metadata_2025_split huggingface dataset:
A tumor growth rate/overall survival model for atezolizumab as an early predictor of OS in patients with first or second line metastatic urothelial carcinoma.
Authors: Bruno Rene , Claret Laurent , Wu Benjamin , Jin Jin Y , Winter Helen , Cui Na , Derleth Christina Louise , Shen Xiaodong , Girish Sandhya , Rosenberg Jonathan E. , Powles Thomas 
Published: February 2018

62 Background: Standard early endpoints are often poor predictors of overall survival (OS) for immunotherapies. There is a need for new intermediate endpoints to support upcoming combination studies with immune checkpoint inhibitors. We investigated the predictive performance of on-treatment tumor growth rate (TGR) estimates to predict OS in atezolizumab clinical trials in patients (pts) with metastatic urinary carcinoma (mUC). Methods: Atezolizumab showed durable response, prolonged OS and good tolerability supporting its therapeutic use in mUC (Rosenberg, Lancet 2016; Balar, lancet 2017; Powles, EACR-AACR-SIC 2017). A multivariate model linking baseline patient characteristics and TGR (estimated using time profile of sum of longest diameters (SLD) of target lesions, RECIST 1.1) to OS was developed using phase 2 data (IMvigor210) and validated to predict phase 3 trial (IMvigor211). Results: To estimate TGR, patients needed to have at least one post-baseline measurement: n = 365/429 (85%) in IMvigor210 (102 in cohort 1, 1L cisplatin-ineligible and 263 in cohort 2, prior platinum-treated 2L+) and n = 745/902 treated (83%) in IMvigor211 (prior platinum-treated 2/3L). A lognormal model with independent baseline prognostic factors (alkaline phosphatase, ECOG performance status and number of metastatic sites) and estimated TGR was developed. The model predicted OS distributions in the two IMvigor210 cohorts in all comers as well as by PD-L1 expression on tumor-infiltrating immune cells (IC). In IMvigor211, SLD profiles in atezolizumab and chemotherapy arms crossed at about 40 weeks with more initial shrinkage in chemotherapy-treated pts but slower overall TGR in atezolizumab-treated pts. The IMvigor210 OS model predicted OS hazard ratio (HR) in IMvigor211 in all comers with post-baseline tumor scans (model-predicted HR [prediction interval]: 0.80 [0.70-0.92] vs. 0.74 observed) as well as by IC status: 0.66 [0.50-0.87] vs. 0.70 observed in IC23. Conclusions: Model-based TGR is a promising exploratory endpoint and is being investigated to support early decisions in signal-seeking atezolizumab combination trials in mUC.
Preliminary biomarker and pharmacodynamic data from a phase I study of single-agent bispecific antibody T-cell engager GBR 1302 in subjects with HER2-positive cancers.
Authors: Wermke Martin , Alt Juergen , Kauh John S. , Back Jonathan , Salhi Yacine , Reddy Venkateshwar , Bayever Eliel , Ochsenreither Sebastian 
Published: February 2018

69 Background: HER2 is overexpressed in many solid tumors and is a validated therapeutic target. GBR 1302 is a HER2xCD3 bispecific antibody engineered (using Glenmark’s BEAT® platform) to direct T-cells to HER2-expressing tumor cells. GBR1302-101 (NCT02829372) is an ongoing, multicenter, open-label, first-in-human study of GBR 1302 in subjects with HER2-positive cancers to evaluate the safety, tolerability, and preliminary efficacy of GBR 1302, and to elucidate the mechanism(s) by which it redirects T-cells to tumor and enhances cytolytic activity of cytotoxic T-cells. Methods: Adults with progressive HER2-positive solid tumors with no available standard or curative treatment receive intravenous GBR 1302 on Day 1 and Day 15 in 28-day treatment cycles at escalating dose levels, starting at 1 ng/kg. The first 4 cohorts consist of a single subject; subsequent cohorts enroll using a 3+3 design. The primary and secondary efficacy and safety endpoints of this trial will be reported at the end of the study. Preliminary pharmacodynamic (PD) data are reported for cellular biomarkers and cytokines as assessed by FACS and ELISA in peripheral blood. Results: Beginning at 30 ng/kg dosing of GBR 1302 (Cohort 4), numbers of peripheral blood CD3, CD4, and CD8 positive T-cell populations decreased within 6 hours of initiating administration, but recovered to levels at or above baseline by 48 hours. A parallel, transient increase was observed in peripheral blood cytokines (IL-2, IL-6, IL-10, IFN-γ, TNF-α). At doses greater than 30 ng/kg, more pronounced cytokine increases were observed, which normalized at 12 hours. At the highest dose level for which data are available (n = 8 subjects; Cohort 5), changes from baseline in cytokine expression at ~340 hours were greater by ~60-fold for IL-6, ~30-fold for IL-2, ~3-fold for IFN-γ, ~5-fold for TNF-α, and ~18-fold for IL-10. Two subjects treated at 100 ng/kg experienced Grade 1 cytokine release syndrome, evidenced by short-lived fever spikes. Dose escalation is ongoing. Conclusions: Preliminary PD data indicate changes in peripheral T-cell populations and inflammatory cytokines following GBR 1302 treatment. Clinical trial information: NCT02829372.
Live attenuated oral Salmonella platform for effective T- and B-cell targeting of PD-L1.
Authors: Wieckowski Sébastien , Smetak Heiko , Kobl Iris , Podola Lilli , Nugues Anne-Lucie , Slos Philippe , Adda Berkane Amine , Wei Ming , Breiner Klaus M. , Meichle Albrecht , Mansour Marc , Schroff Matthias , Beckhove Philipp , Lubenau Heinz 
Published: February 2018

74 Background: Significant progresses have been recently achieved in cancer vaccines, yet novel immunization solutions to deliver efficiently tumor-associated antigens to professional antigen-presenting cells, and to overcome the peripheral tolerance and the immunosuppressive tumor microenvironment that prevent the eradication of cancer in most of patients, are urgently needed. VAXIMM is developing a unique and versatile oral T-cell vaccination platform based on the FDA-approved live-attenuated Salmonella Typhi strain Ty21a vaccine Vivotif, capable of delivering tumor-associated antigens encoded in DNA expression construct to the gut-associated lymphoid tissue, breaking immune tolerance and inducing effective anti-tumor immunity. Methods: This study summarizes the immunogenicity and antileukemia efficacy of VXM10 vaccines based on the live-attenuated Salmonella Typhimurium strain SL7207, transformed with a eukaryotic expression plasmid encoding different variants of the murine PD-L1 protein. Results: The antileukemia activity of VXM10 was evaluated in the FBL-3 disseminated model of leukemia, in which the tumor cells strongly express PD-L1. Multiple oral administrations of VXM10 vaccines produced a strong anti-tumor effect, with 100% of surviving animals 80 days after challenge with FBL3 leukemia in the highest dose groups. Moreover, 100% of long-term surviving mice resisted re-challenge with FBL-3 cells, demonstrating that vaccination with VXM10 generated a potent memory T cell response against the leukemia. Importantly, full leukemia control was achieved in both prophylactic and therapeutic settings. Upon immunization with VXM10 vaccines, T cell response was raised against PD-L1 epitopes after in vitro restimulation of the splenocytes, and anti-PD-L1 antibodies were detected in the serum. The precise mechanism of action of VXM10 vaccines is currently being investigated. Conclusions: This study provides further evidence that VAXIMM’s oral T-cell vaccination platform can be employed to stimulate anti-tumor immunity against antigens of the immune checkpoint regulatory protein PD-L1. These data paved the way for advancing the development of VXM10 into clinical development.
Improving efficacy of PD-1 blockade in unresponsive lymphoma tumors with in situ vaccination through induction of a highly efficient cross-presenting dendritic cell subset.
Authors: Hammerich Linda , Dhainaut Maxime , Davis Thomas A. , Keler Tibor , Salazar Andres M. , Brown Brian D. , Brody Joshua 
Published: February 2018

76 Background: Low-grade non-Hodgkin’s B-cell lymphomas are generally incurable; preliminary results with anti-PD-1 therapy have yielded low response rates. Tumoral DC infiltration correlates with efficacy of checkpoint blockade and tumor-targeted vaccines represent promising, novel treatment strategies to induce anti-tumor T cells. Methods: A20 lymphoma-bearing mice were treated with a PD-1 blocking antibody with an in situ vaccine (ISV) consisting of intratumoral injections of FMS-like tyrosine kinase-3 ligand (Flt3L), local irradiation (XRT) of the tumor and intratumoral injections of the TLR3 agonist poly-ICLC (pIC). Results: Untreated lymphoma tumors contained very low numbers of DC and treatment with anti-PD1 alone did not induce tumor regression or increase survival. Flt3L treatment resulted in a dramatic increase of IRF8+TLR3+ DC at the tumor site, the draining lymph node and the spleen. XRT of A20 cells induced activation of Flt3L-treated splenic DC in vitro and local XRT of the tumor in vivo induced expression of CD103 on infiltrating TLR3+ DC. Local XRT also enhanced uptake of dying tumor cells by DC. Interestingly, tumor antigens were taken up mainly by CD103+ DC and not CD103- subtypes. CD103+ expression distinguishes a subset of migratory cross-presenting DC. Accordingly, CD103+ DC isolated from the tumor induced proliferation of tumor-specific CD8+ T cells more efficiently than CD103- subsets. The combination of Flt3L with XRT and pIC induced tumor-reactive, IFNg-producing T cells, but delayed tumor growth and improved survival only in 40% of mice. ISV also increased expression of PD-L1 on tumor cells and tumor infiltrating DC. Consistently, combination of ISV with PD-1 blockade led to complete tumor regression and increased long-term survival in the majority of mice. PD-1 blockade also increased the number of tumor-reactive T cells and depletion of CD8+ T cells abrogated the anti-tumor effect. Conclusions: In situ vaccination can improve efficacy of anti-PD-1 in checkpoint-unresponsive lymphoma tumors through induction of a cross-presenting DC subset leading to long-term regression of established lymphoma tumors.
Overall survival in a trial of orally administered CCR2 inhibitor CCX872 in locally advanced/metastatic pancreatic cancer: Correlation with blood monocyte counts.
Authors: Linehan David , Noel Marcus Smith , Hezel Aram F. , Wang-Gillam Andrea , Eskens Ferry , Sleijfer Stefan , Desar Ingrid M.E. , Erdkamp Frans , Wilmink Johanna , Diehl Janet , Potarca Antonia , Zhao Niky , Miao Shichang , Deng Jun , Hillson Jan , Bekker Pirow , Schall Thomas J. , Singh Rajinder 
Published: February 2018

92 Background: The CCL2-CCR2 signaling axis may facilitate migration of myeloid derived suppressor cells to pancreatic cancer resulting in an immune suppressive tumor microenvironment. CCR2 inhibition in patients with non-metastatic pancreatic cancer was previously reported to decrease tumor-infiltrating macrophages/Treg cells and increase effector T cells (Nywening et al, 2016). Here, a CCR2 specific antagonist CCX872 was used in combination with FOLFIRINOX to treat subjects with locally advanced or metastatic, non-resectable pancreatic cancer in a multi-center study. Methods: Fifty subjects (ECOG score ≤ 2) were enrolled, receiving FOLFIRINOX (fluorouracil [5-FU], leucovorin, irinotecan, oxaliplatin) once every two weeks (maximum 12 cycles) plus 150 mg CCX872 QD or BID for 12 weeks. Subjects showing at least stable disease at the end of the 12-week treatment period were eligible to CCX872 treatment until disease progression. In this ongoing study, all subjects are followed for overall survival (OS). Blood samples were taken at baseline and at intervals throughout the active treatment period for hematologic and flow cytometric analysis of circulating immune cell populations. Results: The all-subjects OS at 18 months is 29%. This compares favorably with previously published data: i.e., OS of only 18.6% at 18 months for FOLFIRINOX regimen alone (Conroy et al, 2011). Peripheral blood monocyte counts at baseline inversely correlate with OS (p = 0.0071, Hazard ratio = 1.169) with CCX872 and FOLFIRINOX combination therapy. Overall, circulating monocytes, inflammatory monocytes and monocytic myeloid derived suppressor cells were reduced by treatment. Conclusions: CCX872-B plus FOLFIRINOX resulted in an OS of 29% at 18 months with no safety issues. Better OS was associated with lower peripheral blood monocyte counts at baseline. Clinical trial information: NCT02345408.
The altered expression of Paraoxonase 1 in the gastric carcinoma.
Authors: Kim Sung Soo , Kim Jin Soo 
Published: February 2018

94 Background: High doses inadequate removal of reactive oxygen species result in oxidative stress, which may cause severe metabolic malfunctions and damage to biological molecules including DNA An elevated oxidative status has been found in many types of cancer cells and helicobacter infection. Paraoxonase 1 is one of the endogenous free radical scavenging systems in the human and believed to be involved in the protection against oxidative stress. It has been reported that serum levels of Paraoxonase 1 were lower in patients with pancreatic or gastric cancer than in healthy controls. But there was no study about differential Paraoxonase 1 expression in gastric cancer tissue compared to adjacent non-tumor tissue. In this study, we investigated the changes of Paraoxonase 1 expression in the helicobacter pylori infection and gastric cancer. Methods: 109 gastric cancer tissues and 109 adjacent non-tumor tissues were obtained from 109 patients who received gastrectomy for curative resection. Eighteen H. pylori-positive patients who successfully eradicated were involved. Expression of Paraoxonase 1 and Malondialdehyde was assessed by immunohistochemistry using a tissue microarray method. Results: The intensity of immunohistochemical stain on Malondialdehyde and Paraoxonase 1 was significantly elevated in pre-eradication state compared to post-eradication (1.77 vs 1.05, 1.83 vs 1.11, P< 0.05) of helicobacter infection. The intensity of Malondialdehyde was significantly elevated in gastric carcinoma than adjacent non-tumor area (1.22 vs 0.39, P< 0.05). But intensity of Paraoxonase 1 showed no significant difference in both area (0.55 vs 0.68, P> 0.05). Conclusions: Paraoxonase 1 may be one of antioxidant enzyme in H. pylori induced gastritis. In the gastric carcinoma, it’s role may need further study to conclude.
Immunological changes during intraperitoneal growth of colorectal cancer.
Authors: Heo Seung Chul , Kim Jie-Eun , Shin Rumi 
Published: February 2018

97 Background: Immunoediting other than PD-1 works in colorectal cancer (CRC), except for some MSI high tumors. Study of immune response to cancers in the primary CRC is difficult due to interference by the colonic microorganisms. If a clinical model reflecting tumor progression, free from microbial antigens and characterizing the microenvironment is developed it will help us understand the immunoediting of CRC. We studied immunologic changes, according to the peritoneal tumor progression, in ascites and peritoneal immune cells of CRC patients. These results will provide clues to the immunoediting of CRC and to immunotherapy of peritoneal carcinomatosis. Methods: Ascites and peritoneal cells were collected from CRCs during surgery or malignant ascites drainage. Forty-two immune molecules and ratios of immune cells were assayed. Patients with intestinal perforation or leukocytosis were excluded to remove interference by the foreign antigens. Patients were grouped according to the peritoneal tumor progression (PC stages) as follows; SE-: without peritoneal exposure of cancer cells (T3 or lower T stage, no tumor cells in peritoneal cavity); SE+: with peritoneal exposure without peritoneal seeding (T4, microscopic tumor cells in peritoneal cavity); l-PC: localized peritoneal seeding; g-PC: generalized peritoneal seeding. Molecular and cellular changes were evaluated according to PC stages. Results: Of the 42, five (IL-10, IL-6, VEGF, CCL20 and TGF-b) increased with the PC stage progression, meanwhile IL-18 decreased. CXCL8 was elevated in only g-PC. However, 14 molecules could not be assayed due to lower level than the references and other 3 could be assayed in only some g-PCs. The other 18 were not different among PC stages. Especially, IL-10 is a prognostic factor of peritoneal recurrence in SE+. IL-10 and IL-6 are highly correlated. The ratio of CD56+ cells, but not the others, increased according to PC stages. Conclusions: Intraperitoneal CRC growth accompanied IL-10, IL-6, VEGF, CCL20, TGF-b and NK cell increase, meanwhile IL-18 decrease. IL-10 is a prognostic factor of peritoneal recurrence. Identification of secreting and targeting cells of each molecules as well as immune network will provide the clues to immunoediting of CRC.
Phase I trial of safety of combining BCG with pembrolizumab in patients with high grade superficial bladder cancer unresponsive to previous intravesical therapy.
Authors: Alanee Shaheen Riadh , Robinson Kathy , Sana Sherjeel 
Published: February 2018

TPS111 Background: Bacille Calmette-Guerin (BCG) is the most effective agent in the treatment of high grade superficial bladder cancer (HGSBC); however, not all patients respond to BCG, and recurrent disease is associated with a poor prognosis. The blockade of immune checkpoints of the pathway involving programmed death 1 (PD1) has been shown recently to be effective in cancer therapy. We started the first trial in the United States to combine an anti-PD1 drug (pembrolizumab) with BCG therapy in patients with HGSBC. Methods: The primary objective of the study was to determine the safety of administering a 200 mg fixed dose of pembrolizumab in conjunction with intravesical BCG treatment in HGSBC patients who have failed two courses of induction therapy or one course of BCG induction therapy followed by maintenance therapy. Patients included had to have pathologically documented HGSBC (Ta, T1) at time of restaging, or have pathologically documented high grade CIS of the bladder at time of initial resection for recurrent/persistent bladder cancer. Subjects were treated with six cycles (21 day cycle) of pembrolizumab treatment combined with six consecutive weeks of concurrent BCG installation beginning with cycle 3 of pembrolizumab. The first three subjects were to be treated at a dose of 100 mg pembrolizumab to ensure safety for the combination. If no safety issues were to happen, dosing was to be escalated to 200 mg every three weeks. Our secondary objective was to determine the 19 week and the three, twelve, and twenty-four month post-treatment completion complete response rate. The first patient received cycle 1 of pembrolizumab treatment in July of 2015. As of the date of writing this letter, five patients have completed treatment on this trial. The trial is soon to open a second site at Henry Ford Health System in addition to Southern Illinois University with the goal of full enrollment to be achieved in the next 6 months. Clinical trial information: NCT02324582.
Oral cavity squamous cell carcinoma and Waldeyer ring squamous cell carcinoma PDL-1 expression: A large, retrospective, single institution site series on head and neck squamous cell carcinoma, looking at the relationship with morphology, human papilloma virus and p16.
Authors: Yeoh Chit Cheng , Akaev Iolia , Glaysher Sharon , Chopra Mridula , Krol Anzhela , Rahimi Siavash 
Published: February 2018

TPS119 Background: The most frequent type of epithelial malignancy in oral cavity and Waldeyer's ring (WR) is squamous cell carcinoma (SCC). Patients with Head and Neck SCC (HNSCC) show reduced levels of CD3+, CD4+, and CD8+ T cells compare to healthy controls. SCCs with a higher number of intra-tumoural CD4+ and CD8+ lymphocytes are associated with better prognosis. Programmed death receptor ligand (PD-L1 ) is present on the surface of neoplastic cells in SCC. T cells harbour inhibitory receptors (the so-called immune checkpoints) such as PD-1. Activation of this immune checkpoints results in T cell deactivation. The PD-1/PDL-1 interaction provokes an immunosuppressive effect which allows the tumour to evade immune destruction. However, WR SCCs present some diversities comparing to oral cavity SCC: younger age, frequent neck LN metastasis, often cystic, distinct morphology: often undifferentiated and solid (nonkeratinizing basal cell morphology), better prognosis, often HPV+, often p16+, an increased number of CD56+ cytotoxic NK. Methods: We have a series of 90 cases of epithelial malignancy in oral cavity and Waldeyer's ring (WR)Squamous cell Carcinoma, registered for Ethics IRAS number for Translational study with Immunohistochemistry; Real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR); Fluorescence in Situ Hybridisation (FISH); Next Generation Sequencing; Digital Imaging scanning and visualising microscopy. The Study will show the relationship of PDL-1 expression with morphology, Human Papilloma Virus (HPV) infection and p16 expression, answering if the oral cavity SCC and Waldeyer's Ring SCC express PD-L1 in the same way.
Ten year final results of the TROG 03.04 (RADAR) randomised phase 3 trial evaluating duration of androgen suppression ± zoledronate for locally advanced prostate cancer.
Authors: Joseph David John , Lamb David S , Denham James William , Oldmeadow Christopher , Attia John , Steigler Allison 
Published: February 2018

1 Background: We investigated whether 18 months of androgen suppression (AS) plus radiotherapy (RT) ± 18 months of zoledronate (Z) is more effective than 6 months of neoadjuvant AS plus RT ± Z. Methods: Eligible men with T2a-4, N0, M0 prostatic adenocarcinomas with PSA ≥10 and Gleason score (GS) ≥7 in T2a cases were randomly allocated in a 2x2 factorial trial design to 6 months neo-adjuvant AS using leuprolide (22.5mg i.m. 3 monthly) and radiation (control arm) or followed by treatment factor 1- 12 months AS (22.5mg i.m. 3 monthly), or accompanied by the second treatment factor 2- 18 months Z (4mg i.v. 3 monthly) starting at randomisation, or by both treatment factors. Patients were stratified by centre, baseline PSA, tumour stage, GS, and use of a brachytherapy boost. The primary endpoint was prostate cancer-specific mortality (PCSM). Secondary endpoints included time to PSA, local, distant, bone and soft tissue progressions (PSA, LP, DP, BP and STP) and time to secondary therapeutic intervention and all-cause mortality (STI and ACM). Endpoints were analysed by intention to treat using competing risks methodology. ACM was analysed using Cox regression. Results: Between October 2003 and August 2007 1071 men were randomised with median age 68.7 years. Median follow-up was 10.4 years (IQR 7.9-11.7). No significant interaction was observed between AS and Z. Significant reductions were observed favouring 12 months AS for the primary endpoint: PCSM sHR 0.70 (0.50-0.97), p = 0.035; and for the secondary endpoints: BP sHR 0.61 (0.45-0.83), p = 0.001; DP sHR 0.71 (0.56-0.90), p = 0.004; PSA sHR 0.65 (0.53-0.78), p < 0.001; LP sHR 0.60 (0.39-0.92), p = 0.021; and STI sHR 0.66 (0.53-0.81), p < 0.0001. There were also non-significant reductions favouring 12 months AS in STP (sHR 0.85 [0.62-1.16], p = 0.30) and ACM (HR 0.84 [0.69-1.03], p = 0.10). The addition of 18 months Z did not influence any outcome significantly. Conclusions: 18 months AS+RT is an effective option for locally advanced prostate cancer but the use of 18 months Z is not beneficial. Clinical trial information: NCT00193856.