bluuebunny/crossref_metadata_2025_split huggingface dataset:
Potential therapeutic target for PD1/PDL1 blockade in microsatellite medullary carcinomas based on PDL1 expression by tumor cells and infiltration by numerous PD1+ T lymphocytes.
Authors: Bossard Celine , Ott Eva , Dansette Delphine , Ouary Adrien , Jarry Anne , Bezieau Stephane , Toquet Claire , Mosnier Jean-François 
Published: September 2018

e14599 Background: PD1/PDL1 blockade showed therapeutic efficacy in only microsatellite (MSI) colorectal carcinomas (CRC), however, the profile of PDL1 and PD1 expression in CRC is only partially described. Methods: We thus analyzed on FFPE whole-tissue sections of 80 CRC, the expression profile of PDL1 by tumor and/or immune cells by immunohistochemistry (clone E1L3N) depending on the MSI status and the histological subtype, and correlated to the density of PD1+ and Tbet+ (able to secrete IFNg known to induce PDL1) tumor-infiltrating lymphocytes (TIL). Results: 78% of MSI CRC (32/41) overexpressed PDL1 either by tumor or immune cells versus 46% of MSS CRC (18/39) (p 0.005). This overexpression was heterogeneous within the same tumor in most of cases. Among MSI CRC, PDL1 was preferentially overexpressed in medullary carcinomas (MC, 19/21, 90%) compared with 65% (13/20) in non medullary adenocarcinomas (p 0.06). PDL1 expression by tumor cells was only observed in MSI CRC (19/41, 46% with PDL1 expression in more than 5% of tumor cells – score 1), and preferentially in MC (57% vs 5% in no medullary adenocarcinomas, with PDL1 expression in more than 50% of tumor cells – score 3, p 0.0005). Conversely, PDL1 expression by immune cells was observed in MSI CRC (23/41, 56% with PDL1 expression by more than 5 sheets of 50 positive cells) but also in MSS CRC (18/39, 43%) (p 0.5). The density of PD1+ cells was significantly correlated to the PDL1 expression, as well as the density of Tbet+ TIL. Conclusions: PDL1 expression is 1) heterogeneous in CRC, among CRC but also within the same tumor, 2) preferentially observed in MSI CRC (78%), especially in MC (90%), where PDL1 is expressed by tumor cells, 3) correlated with the density of PD1+ or Tbet+ TIL, and 4) observed in a significant proportion of MSS CRC (46%) by immune cells only. From a clinical point of view, PDL1 expression has to be determined at best in full tissue section and besides its preferential expression in MSI CRC, its significant frequency and expression profil (only by immune cells) in MSS CRC should be taken into account in the future clinical trials testing the efficacy of anti-PD1/PDL1 antibodies.
Analysis of a large patient cohort with nivolumab: Predictive clinical factors for continued benefit after an immune-related adverse event.
Authors: Osman Diaa , Win Khine Zar , Wong Morgan , Phan Alexandria T. 
Published: September 2018

e14600 Background: Nivolumab (NIVO), a PD-1 inhibitor, is used in various advanced malignancies with meaningful and durable outcomes. However, its use can be limited by severe immune-related adverse events (irAEs). We analyzed our large single institution patient cohort who have been treated with NIVO to risk stratify and identify clinical factors associated with continued benefit after irAEs. Methods: 125 patients with advanced malignancies, treated with NIVO during 2011-2016 at the University of New Mexico Comprehensive Cancer Center, were evaluated. Inclusion criteria included a minimum of 1 completed treatment of NIVO (1 or 3mg/kg). Stratifying factors including age, gender, BMI, ethnicity, co-morbidities, pretreatment WBC and albumin, number of treatments received, type of malignancy, number of metastatic sites, overall tumor response rate (ORR), irAEs, and tumor response rates after irAE were identified. Results: Primary sites of cancer for the 125 patients who received NIVO were lung (44, 35%), melanoma (43, 34%), head-neck (8, 6%), renal (14, 11%), Hodgkin’s (16, 13%), 2 patients with more than one malignancy (1 with lung and head-neck, and 1 with lung and melanoma), and other non-approved indications (16, 13%). The overall tumor response rate was 34.4%. Total All CTCAE v4 grades irAEs experienced were 32% (40/125), and 33% (13/40) were severe (grade > 3). Eighteen (18/40, 45%) patients continued to have tumor response after experiencing any grade irAE. The mean age of those experiencing an irAE with subsequent tumor control (CR, PR, or SD) was 72.3 years, mean BMI 28.2 kg/m2, 38.9% were female, 11.1% were non-Caucasian, 61.1% had > 2 co-morbidities, 72.2% with > 2 metastatic sites and the mean albumin was 3.4 g/dl. Conclusions: Patients who had a tumor response after being re-challenged with NIVO, despite experiencing an irAE, were found to be older, had a higher BMI, an increased number of co-morbidities, higher tumor burden, and mean albumin > 3.0g/dl. Risk stratifying these patients prior to starting treatment is possible and can be helpful in anticipating which patients should be re-challenged or will have continued benefit with NIVO after experiencing an irAE.
Immune checkpoint inhibitor treatment of advanced age metastatic melanoma (MM) patients.
Authors: Hegde Upendra P. , Kerr Phil , Masternak Sophie , Brenner Bruce Mark , grant-Kels Jane 
Published: September 2018

e14603 Background: Immune checkpoint inhibitor (ICI) treatment has become effective method of treating mm including in those over 65 years of age. Increasing number of advanced age mm patients (pts.) are eligible for ICI treatment but not much is known about its efficacy and safety in relation to senescent immune system. We are reporting our updated experience of ICI treatment of advanced age mm pts. from a single Institute. Methods: Between 2011 and 2016, 32 eligible pts. diagnosed with mm were treated at the University of Connecticut with ICI including anti CTLA-4 antibody Ipilimumab, anti PD-1 antibody Pembrolizumab or combination of Ipilimumab and Nivolumab at their FDA approved doses on a standard protocol. Pts. were monitored for immune related adverse events (irAE) that were graded and managed with standard immune suppressive regimens Results: 12 out of 32 mm pts. were over 70 years of age (median 82.5 years, range 73-88 years). Nine pts. were treatment naïve, two had previously failed Ipilimumab treatment and one anti-BRAF and anti- MEK targeted therapy. Clinical benefit occurred in 5 out of 12 pts. (Complete response (CR) 3, partial response 1 and stable disease 1). Nine out of 12 pts. developed irAE that included three grade II (fatigue, diarrhea, hypopituitarism each) and 6 grade IV events (skin rash-1, colitis-1, encephalopathy-1, myasthenia gravis-1, and pneumonitis in 2 pts. each respectively). Of note, an 87-year-old male developed polymyalgia rheumatica after second dose of anti PD-1 treatment that responded to steroids, but developed autoimmune diabetes mellitus and pneumonitis following third dose. Two pts. died from irAE that included an 87-year-old woman from treatment refractory myasthenia gravis and 77-year-old male who suffered sudden death during steroid treatment of pneumonitis. Six pts. died of progressive disease including sudden death in a 77-year old woman and a 87-year-old male following five and two anti PD-1 treatments respectively. One pt. died from pulmonary embolism and four pts. are alive, 2 in CR and two with disease. Conclusions: Our experience indicate advanced age mm pts. respond to ICI treatment but have heightened risk of developing serious irAEs.
Effect of adenoviral p53 (Ad-p53) tumor suppressor immune gene therapy on checkpoint inhibitor resistance and abscopal therapeutic efficacy.
Authors: Sobol Robert E. , Chada Sunil , Wiederhold Dora Bocangel , Yun Chae-Ok , Ahn Hyomin , Oh Eonju , Murthy Ravi , Subbiah Vivek , Menander Kerstin B. 
Published: September 2018

e14610 Background: Immune checkpoint inhibitors represent an important advance in cancer therapeutics. However, most cancer patients do not respond or become resistant to this form of immune therapy. Methods: We evaluated the ability of Ad-p53 to reverse immune checkpoint inhibitor resistance and induce abscopal effects in the immune therapy resistant murine B16F10 melanoma tumor model. To mimic clinical conditions of checkpoint inhibitor resistance, animals with established tumors were treated with anti-PD-1 before initiating Ad-p53 intra-tumoral therapy. Results: Anti-PD-1 had minimal therapeutic efficacy compared to control treatment. A statistical analysis of variance (ANOVA) comparison of tumor volumes revealed that the combined effect of Ad-p53 and anti-PD-1 treatment was synergistic and superior to either therapy alone (p = 0.0001). Surprisingly, there was a statistically significant abscopal effect with decreased growth of contralateral tumors not injected with Ad -p53. The Ad- p53 alone (p = 0.046) and Ad- p53 + anti-PD-1 (p = 0.0243) treatment groups both demonstrated a statistically significant decreased abscopal tumor growth compared to treatment with anti-PD-1 alone. Combined Ad- p53 and anti-PD-1 therapy demonstrated a statistically significant increase in survival compared to Ad- p53 therapy alone (p = 0.0167) and anti-PD-1 therapy alone (p < 0.001) by the log rank test. We have initiated a Phase 1 clinical trial of Ad-p53 intra-hepatic arterial therapy in combination with capecitabine for patients with solid tumor liver metastases. In the first cohort of patients at a dose of 2 x 1012viral particles, treatment has been well tolerated with transient fever, chills and rigors. In one patient, decreased SUV uptake on PET scans of distant lymph node metastases suggested possible abscopal effects. Conclusions: These results suggest that Ad-p53 tumor suppressor immune gene therapy may reverse immune checkpoint inhibitor resistance and induce abscopal effects supporting the planned clinical evaluation of combined Ad-p53 and anti-PD-1 therapy in patients resistant to immune checkpoint inhibitor therapy. Clinical trial information: NCT02842125.
A novel phase I/IIa open-label study of IMM-101 in combination with selected standard of care regimens in patients with metastatic cancer or unresectable cancer at study entry.
Authors: Cunningham David , Blay Jean-Yves , Marabelle Aurelien , Stanbury David , Mudan Satvinder , Rosa Brunet Laura 
Published: September 2018

e14627 Background: The MODULATE (IMM-101-011, EUDRACT 2016-001459-28) trial recruits patients with metastatic or unresectable cancer considered for a new line of recognised SOC (1st, 2nd or 3rd line and beyond). IMM-101 is a heat-killed whole cell Mycobacterium obuense (National Collection of Type Cultures [NCTC] 13365) for intradermal injection. Methods: The primary objective of the study is to provide safety data for IMM-101 in combination with several selected SOC regimens. The secondary objectives of the study are to provide safety and tolerability data for extended administration (beyond 28 weeks) of the immunomodulator IMM-101 in combination with a number of selected SOC regimens. A particular focus of the study is to evaluate safety data for the combination of IMM 101 with anti PD1 and with anti-CTLA 4. Pre-clinical data suggests that IMM-101 increases the response to PD1 in a syngeneic in vivo model of EMT6 breast cancer. Furthermore, in a syngeneic B16 melanoma tumour model the combination of IMM-101 with anti-PD1 antibodies increased T effector cells in the tumour and reduced the numbers of T-regulatory cells; significantly shifting the T-cell ratio towards anti-tumour efficacy. Results: The study aims through its translational programme to evaluate the best combination partner for IMM-101 due to the SOCs immunogenic cell death capabilities and supportive immunological activities. MODULATE will monitor selected markers of tumour burden and immunological status in patients taking IMM-101. Conclusions: The MODULATE study will initially recruit patients in the UK and France with US sites added in Q4 2017. Clinical trial information: NCT03009058. [Table: see text]
A clinical trial for the safety and immunogenicity of a DNA-based immunotherapy in men with biochemically (PSA) relapsed prostate cancer.
Authors: Shore Neal D. , Heath Elisabeth I. , Nordquist Luke T. , Cheng Heather H. , Bhatt Kamalnayan , McMullan Trevor , Kraynyak Kimberly , Lee Jessica , Sacchetta Brian , Tagawa Scott T. , Parikh Rahul Atul , Tutrone Ronald F. , Garcia Jorge A. , Whang Young E. , Lin Jianqing , Kelly William Kevin , Csiki Ildiko , Bagarazzi Mark L. ,   PCa-001
Published: September 2018

e14634 Background: Introducing amino acid sequence changes in highly expressed self-antigens for prostate cancer (PCa) patients (pts) might lead to avoidance of immune tolerance. We evaluated a DNA vaccine (INO-5150) including SynCon PSA and PSMA. Administration of INO-5150 to PCa pts along with plasmid encoded adjuvant IL-12 (INO-9012) via electroporation (EP) is postulated to break tolerance, resulting in antigen-specific immune responses which could lead to stabilization of disease progression. Methods: Phase I, open-label, multicenter study of PCa pts post-definitive therapy with a rising PSA ≥ 1.0 ng/ml after surgery, or ≥ 2.0 ng/ml above nadir after RT and PSADT > 3 months, testosterone > 150 ng/dL, no concomitant androgen deprivation therapy and no evidence of metastases within 12 months. We evaluated safety, tolerability and for efficacy signals. INO-5150 low (2 mg, arms A and C) or high (8.5 mg, arms B and D) dose with or without INO-9012 (1 mg) was administered IM followed by EP in total 4 dosing arms on Day 0 and at Wks 3, 12, and 24 in 60 planned pts (15/arm). Pts were followed for 72 Wks. Results: 62 pts, 16 each in arms A and D and 15 in B and C were enrolled. Median age: 69.5 yrs (range 55.4-87.7), Gleason score: 7 (5-10), time from initial diagnosis: 8.2 yrs (0.5-23.8) and ECOG PS: 0 (0-1). As of data cutoff of 23Jan17, 52 pts had EOT visit, 7 withdrawn from treatment and 6 (10%) reported disease progression, 3 biochemical and 3 radiographic. Median serum PSA at enrollment was 4.6 ng/mL (range 1.2, 113.7) and at EOT was 6.5 ng/mL (0.1, 73.6). Median PSADT at enrollment was 8.7 months (3.1, 218.1) and at EOT it was 3.1 months (-23.1, 100.0). Safety: no reports of Grade 4-5 SAEs. 6 Grade 3 SAEs in 5 pts: presyncope, cardiac disorder, fall, neoplasm, ALT and AST elevation. Grade 1-3 AEs reported in 51 (82%) pts: 12 (75%) in Arm A, 13 (87%) B, 13 (87%) C, and 13 (81%) in D. Common AEs were injection site pain (24/39%), swelling (14/23%), erythema (14/23%), all Grade 1-2. Conclusions: INO-5150 (+) and (-) INO-9012 was generally safe and well-tolerated at all 4 dose levels in this patient population. Preliminary data suggest PSA stabilization in some patients. Immune analyses are ongoing. (NCT02514213) Clinical trial information: NCT02514213.
Real world eligibility of treatment-refractory stage IV colorectal cancer patients for palliative intent regorafenib monotherapy.
Authors: Angeles Arkhjamil , Hung Wayne , Cheung Winson Y. 
Published: September 2018

e15007 Background: The CORRECT trial demonstrated overall survival benefits of regorafenib monotherapy in patients with metastatic colorectal cancer (CRC) who were refractory to prior chemotherapy and biological therapy. However, stringent criteria used to determine treatment eligibility in the trial setting may limit its external validity in the real world. We aimed to examine treatment attrition rates and eligibility of regorafenib in routine clinical practice. Methods: All patients diagnosed with metastatic CRC between 2009 and 2014 who received 2 or more lines of systemic therapy at the British Columbia Cancer Agency were identified. During the study timeframe, cetuximab (cmab) and panitumumab (pmab) were only used in the chemo-refractory setting. Data on clinical factors, pathological variables and outcomes were ascertained and analyzed. Eligibility was defined based on criteria outlined in the CORRECT trial. Results: A total of 391 patients were included among whom only 39% were considered eligible for regorafenib. Median age was 61 (range 22-84) years. 247 (63%) were men, 305 (78%) were Caucasian, and 237 (60%) had a colonic primary. The disease burden at diagnosis was high: 267 (81%) had lymph node involvement, and 225 (59%) had distant metastases. In patients previously treated with cmab, main reasons for regorafenib ineligiblity were Eastern Cooperative Oncology Group performance status (ECOG PS) > 1 (26.9%), aspartate aminotransferase (AST) > 2 x upper limit of normal (ULN) (6.5%), and arterio-venous thrombotic or embolic events in the preceding 6 months (6.5%). In the group treated with pmab previously, main reasons for ineligibility were ECOG PS > 1 (46.6%), total bilirubin > 1.5 x ULN (14.1%), and thrombotic or embolic events in the past 6 months (5.7%). Additional analyses showed that regorafenib-eligible patients had increased median overall survival compared to ineligible patients (44.0 vs 37.1 months, P= 0.028). Conclusions: The strict trial eligibility criteria disqualified the majority of real world patients with metastatic CRC for regorfenib. As ineligibility predicts poorer outcomes, trials aimed at serving protocol-ineligible patients are warranted.
Analysis of survival and prognostic factors in metastatic colorectal cancer patients treated with first line bevacizumab.
Authors: Demircan Nazim , Dane Faysal , Ozturk Mehmet Akif , Besiroglu Mehmet , Babacan Nalan , Kaya Serap , Ercelep Ozlem , Simsek Eda Tanrikulu , Halil Suleyman , Koca Sinan , Alan Ozkan , Hasanov Rahib , Yumuk Perran Fulden 
Published: September 2018

e15009 Background: Colorectal cancer is a major cause of mortality worldwide. Survival has been improved by usage of bevacizumab. Our study aimed to analyze survival and prognostic factors in metastatic colorectal cancer patients treated with first-line bevacizumab. Methods: Files of patients were examined retrospectively and 360 patients treated with first-line bevacizumab were included. Data regarding age, gender, family history, location of the primary, histopathology, KRAS status, surgery and chemotherapy were acquired from the files. Overall response rates (ORR) to chemotherapy, progression and exitus dates or dates of last examination were recorded. Median progression-free and overall survival (PFS and OS) were calculated. Survival was analyzed with Kaplan-Meier method. Log-rank test and Cox regression model were used for univariate and multivariate analysis, respectively. Results: 201 (%55,8) of the patients were male and 159 (%44,2) were female. Median age at the time of the diagnosis was 59.5. 260 patients (%72,2) had initially stage IV disease. KRAS was mutant in 125 patients (%34,7). Median PFS was 8.5 months, median OS was 25.3 months and ORR was %51,4. Median PFS was 8.2 and 9.5 months, median OS was 30.4 and 28.1 months, ORR was %62,6 and %58.4 in KRAS wild type and mutant groups, respectively. In patients with left colon cancer median PFS and OS (9.6 and 27.1 months) were superior compared to patients with right colon cancer (7.3 and 19.4 months) (p = 0.005 and 0.016, respectively). Location of the primary, histopathologic grade, primary surgery, metastasectomy and KRAS status affected overall survival significantly (p < 0.05) in univariate analysis. In multivariate analysis, histopathologic grade (p = 0.034) and metastasectomy (p = 0.001) were independent prognostic factors. Conclusions: In our study, response rates and survival of metastatic colorectal cancer patients treated with first-line bevacizumab were similar to previous studies. Left colon cancer patients had superior median PFS and OS compared to right colon cancer patients as shown in recent studies. Histopathologic grade and metastasectomy were independent prognostic factors in correlation with literature.
Treatment patterns of metastatic colorectal cancer (mCRC) in commercially-insured populations in Washington state.
Authors: Snider Jeremy Williams , Fedorenko Catherine R. , Warnick Greg S , Steelquist Jordan , Wang Ed , Anderson Sibyl , Ramsey Scott David , Shankaran Veena 
Published: September 2018

e15011 Background: Few studies have examined patterns of care relating to guideline-recommended therapies for metastatic colorectal cancer (mCRC) in real-world settings. The goal of this study was to investigate treatment patterns for initial and subsequent therapies for mCRC patients in two large commercial plans in Washington State, USA. Methods: We utilized the Hutchinson Institute for Cancer Outcomes Research linkage of Western Washington Cancer Surveillance System (CSS) SEER data with claims from Regence BlueShield and Premera BlueCross (representing 20% of the WA insured population) for patients diagnosed with mCRC between 2012 and 2016. We identified all patients with Stage IV CRC at diagnosis or stage I-III CRC with subsequent claims suggesting metastatic recurrence. We conducted descriptive analysis and multivariate modeling to evaluate the association between age, race, gender, and rurality with receipt of systemic therapy. We examined 1L (first line) regimens received in the first 15 days of treatment, and classified them as adherent or not to NCCN guidelines. In light of recent FDA approval for regorafenib (9/2012) and TAS-102 (9/2015), we examined use of these therapies for refractory mCRC. Results: Among 4,536 CRC cases identified in the database, 426 patients had evidence of metastatic disease and met all inclusion criteria. 87 (20.4%) received no systemic therapy. Of the 339 (79.5%) who received systemic therapy, FOLFOX was the most common 1L regimen (29.5%), followed by FOLFOX+bevacizumab (12.3%). There was evidence of 1L treatment outside of NCCN guidelines – 8.5% of patients received single-agent bevacizumab, and 8.0% received single-agent oxaliplatin. Patients who did not receive systemic therapy were more likely to be older and live in a large metropolitan area. For subsequent therapies, 24 (7.1%) patients received regorafenib, and 5 (1.5%) received TAS-102. Conclusions: In a commercially-insured mCRC cohort, a majority received 1L guideline-based therapy. Many patients did not receive systemic therapy despite current recommendations - further evaluation of factors contributing to these decisions are warranted. Use of regorafenib and TAS-102 was uncommon.