bluuebunny/crossref_metadata_2025_split huggingface dataset:
Feasible and efficient identification of neoantigens for personalized cancer immunotherapy in advanced refractory epithelial cancer patients.
Authors: Chen Fangjun , Zou Zhengyun , Du Juan , Wei Jia , Shao Jie , Su Shu , Ding Naiqing , Wang Qin , Zhou Shujuan , Sun Zhichen , Liu Baorui 
Published: September 2018

3046 Background: Recent genomic and bioinformatic technological advances have made it possible to dissect the immune response to personalized neoantigens encoded by tumor-specific mutations.However, rapid and efficient identification of neoantigens is still fraught with difficulty, and a systematic evaluation of personalized neoantigens based immunotherapy in advanced refractory epithelial tumors is lacking. Methods: Tumor and ctDNA samples from 16 advanced epithelial cancer patients were underwent mutational profiling by cancer-associated genes panel. Neoantigens identification were performed by two strategies: As classic mode, somatic mutations were subjected to in silico analysis to predict potential high-affinity epitopes and mutated peptides were denovo synthesized; Hotspot mutations were matched to our customized driver mutation-derived neoantigens peptide library. Candidate neoepitopes were identified. Approximately 108 neoantigen loaded DC vaccine and 1010 bulk T cells composed of 109 neoantigen reactive CD8+T cells were generated for personlized immunotherapy. Results: Among the sequenced patients, 3 of 4 patients who utilized the classic mode and 6 of 12 patients who performed customized neoantigens library have successfully identified 1~2 neoantigens recognized by autologous T cells, respectively. Subsequently, a total number of 6 patients received immunotherapy targeting personalized neoantigen. To date, one patient with metastatic thymoma is achieving a complete and durable response beyond 9 months. In addition, immune related partial response was observed in another advanced pancreatic cancer patient. The remaining 4 patients achieved prolonged stabilization of disease with median PFS of 8.6 months. Conclusions: Our costomized neoantigens library can provide a novel approach for neoantigens screening in advanced epithelial cancer patients. Besides, targeted sequencing is sufficient for somatic variant and neoantigen identification. The combination of two strategies can accelerate the neoantigen-based translational immunotherapy research into the paradigm of precision medicine.
PD-1 blockade using pembrolizumab in adolescent and young adult patients with advanced bone and soft tissue sarcoma.
Authors: Scheinberg Tahlia , Lomax Anna , Tattersall Martin HN , Thomas David Morgan , McCowage Geoffrey Brian , Sullivan Michael James , Bhadri Vivek 
Published: September 2018

3060 Background: Sarcomas represent 1015% of cancers in adolescent and young adult (AYA) patients, and survival for those with metastatic disease or after relapse is poor. Immunotherapy with checkpoint inhibition has improved outcomes in multiple tumour types, but there are limited data on the efficacy of immunotherapy in advanced sarcomas, particularly within the AYA population. Methods: We retrospectively reviewed AYA patients with advanced bone and soft tissue sarcoma who received self-funded pembrolizumab at Chris OBrien Lifehouse and Childrens Hospital Westmead. Initial response was evaluated after cycle three or four using RECIST v1.1 criteria. Results: Fourteen AYA patients with sarcoma received pembrolizumab 2mg/kg IV every 3 weeks from May 2015 to December 2016. Median age was 24 (14  35), male to female was 7:7, ECOG PS was 0  1 in 6 patients, 2 in 6 patients and 3  4 in 2 patients. Malignancy type included three patients with osteosarcoma (OS), five patients with Ewing sarcoma (ES), two patients with synovial sarcoma (SS), two patients with alveolar soft part sarcoma (ASPS), and one patient with each of embryonal rhabdomyosarcoma (RMS) and clear cell sarcoma (CCS). The median number of pembrolizumab doses was four (range 1  16), with one patient still receiving treatment at the time of last follow up. Treatment was generally very well tolerated with no G3-4 toxicity. One patient with ES had an excellent, sustained response; of the two patients with ASPS one had a radiological partial response with an excellent clinical response and one patient achieved stable disease. Three patients (two ES, one RMS) died of disease prior to first scheduled assessment and thus their response was not evaluable. The remaining 8 patients had progressive disease. Conclusions: Our data suggest further evaluation of the role of pembrolizumab in AYA patients with advanced sarcoma is warranted.
Racial disparities in the use of programmed death-1 checkpoint inhibitors.
Authors: O'Connor Jeremy , Seidl-Rathkopf Kathi , Torres Aracelis Z. , You Paul , Nussbaum Nathan C. , Fessele Kristen L. , Darius Katie , Adelson Kerin B. , Yin Emily , Presley Carolyn Jean , Chiang Anne C. , Ross Joseph S. , Abernethy Amy Pickar , Gross Cary Philip 
Published: September 2018

3068 Background: There are concerns about racial disparities in access to trials of new cancer drugs, including the programmed death 1 checkpoint inhibitors (anti-PD1s). It is unknown whether these disparities extend to anti-PD1 treated patients in real-world practice. Methods: We used retrospective data from Flatiron Health’s electronic health record database, which includes more than 250 cancer clinics and 1.5 million patients with cancer. We identified patients diagnosed after January 1, 2011 who underwent systemic therapy for: advanced non-small cell lung cancer (aNSCLC; n = 13,473), metastatic renal cell carcinoma (mRCC; n = 1,537), and advanced melanoma (n = 1,221). Within each cohort, we identified treatment type (anti-PD1 versus non-anti-PD1). Therapy lines containing study drugs were excluded. We used logistic regressions to model the use of anti-PD1s by race, adjusting for factors such as age, sex, stage at diagnosis and line of therapy. Results: Of 16,231 patients in our sample, 4,643 (28.6%) were treated with anti-PD1s. Racial distributions differed for anti-PD1 treated patients compared to non-anti-PD1 treated patients in the aNSCLC cohort (Table: p < 0.01), but not in the mRCC cohort (p = 0.84) or the advanced melanoma cohort (p = 0.96). In bivariate analyses of patients with aNSCLC, anti-PD1 treatment was associated with other race, male sex, stage II at diagnosis, squamous histology, smoking history and line of therapy (all p < 0.05). Adjusted models showed there were no significant differences in likelihood of receiving anti-PD1s when comparing black and white patients undergoing systemic therapy for aNSCLC (aOR for black vs. white: 0.86, 95% CI 0.72-1.02), mRCC (aOR 0.90, 95% CI 0.53-1.49), or melanoma (aOR 2.02, 95% CI 0.42-14.59). Conclusions: Among patients undergoing systemic therapy in a large national network of cancer clinics, we found no significant racial disparities in the use of anti-PD1s. [Table: see text]
Pembrolizumab therapy for microsatellite instability high (MSI-H) colorectal cancer (CRC) and non-CRC.
Authors: Diaz Luis A. , Marabelle Aurelien , Delord Jean-Pierre , Shapira-Frommer Ronnie , Geva Ravit , Peled Nir , Kim Tae Won , Andre Thierry , Van Cutsem Eric , Guimbaud Rosine , Jaeger Dirk , Elez Elena , Yoshino Takayuki , Joe Andrew K. , Lam Baohoang , Gause Christine K. , Pruitt Scott Knowles , Kang S. Peter , Le Dung T 
Published: September 2018

3071 Background: Mismatch repair deficient cancers harbor high levels of microsatellite instability and somatic mutations. Treatment with anti-PD-1 antibodies has resulted in durable objective responses in MSI-H cancer. As part of the ongoing, global, multicenter phase 2 studies KEYNOTE(KN)164 and KN158, we assessed the efficacy of pembrolizumab in patients (pts) with MSI-H tumors. Methods: Both studies enrolled pts with MSI-H status determined locally by IHC or PCR. KN164 enrolled pts with MSI-H CRC and ≥2 prior therapies, whereas the multicohortKN158 study included pts with MSI-H non-CRC and ≥1 prior therapy. Eligible pts in both studies received pembrolizumab 200 mg Q3W until progression, unacceptable toxicity, or pt/investigator decision. Tumor response was assessed every 9 wk by independent review per RECIST v1.1. Primary endpoint was ORR. Secondary endpoints included DOR, PFS, OS, and safety. Analyses were performed in pts from KN164 and KN158 who had ≥27 wk of follow-up as of Aug 3, 2016 and Oct 19, 2016, respectively. Results: KN164 enrolled 61 pts with MSI-H CRC (90% with ≥2 prior therapies) whereas KN158 included 21 pts with MSI-H non-CRC (42% with ≥2 prior therapies). In KN158 the most common tumor types were endometrial and small intestinal cancer (n = 4 each), cholangiocarcinoma (n = 3), and gastric and pancreatic cancer (n = 2 each). Median follow-up was 7.4 mo for MSI-H CRC and 4.5 mo for MSI-H non-CRC. ORR for MSI-H CRC was 26.2% (95% CI, 15.8%-39.1%), with 15 confirmed responses and 1 unconfirmed response, and ORR for MSI-H non-CRC was 42.9% (21.8%-66.0%), with 8 confirmed responses and 1 unconfirmed response. DCR was 50.8% (n = 31; 37.7%-63.9%) for MSI-H CRC and 66.7% (n = 14; 38.4%-83.7%) for MSI-H non-CRC. Median duration of response was not reached for either MSI-H CRC or non-CRC, and 100% of responses were ongoing. Survival and safety analyses are ongoing. Conclusions: Early results from KN164 and KN158 confirm the robust antitumor activity of pembrolizumab in heavily pretreated pts with MSI-H cancers. Clinical trial information: NCT02628067; NCT02460198.
Mutually exclusive expression of CD73 and PDL1 in tumors from patients (pt) with NSCLC, gastroesophageal (GE) and urothelial bladder carcinoma (UBC).
Authors: Martin Philip , Spitzmueller Andreas , Wu Song , Widmaier Moritz , KORN RENE , Althammer Sonja , Zha Jiping , Higgs Brandon W. , Cooper Zachary , Steele Keith 
Published: September 2018

3079 Background: Tumors use multiple means of immune evasion, notably the programmed death-1 (PD1)/PDL1 pathway. Anti-PD1/PDL1 therapy induces anti-tumor activity and has improved pt outcomes. Activation of the immunosuppressive CD39/CD73/adenosine pathway might play a role in pts who do not benefit from anti-PD1/PDL1 therapies. We evaluated expression of CD73 and PDL1 and explored the association between CD73 and intraepithelial (IE) CD8+ cells (TILs) to begin to understand their potential interplay in cancer. Methods: Immunohistochemistry for PDL1, CD73 and CD8 was conducted on tumors of non-squamous NSCLC (NSq) (n=42), GE (n=50), and UBC (n=50). PDL1 and CD73 were scored by image analysis with Definiens software. IE CD8+ TILs were scored semi-quantitatively by a pathologist (0-2 = low; 3-4 = high). Using the top tertile of PDL1 and CD73 for high expression levels, a Fisher’s meta-analysis was calculated across the three indications. Results: Across all tumors, 25% (35/142) were PDL1 high (+), but CD73 low (-) and another 25% (35/142) were CD73+ but PDL1- (p=0.06, see table). This trend for mutually exclusive high expression of PDL1/CD73 was strongest in GE (p<0.01). In the PDL1+ group 76% (35/46) had high IE CD8+ TILs whereas in the CD73+ group only 35% (16/46) had high TILs (p<0.0001 using a proportions test). In the PDL1+/CD73- pt subset 77% (27/35) were CD8+ high vs only 23% (8/35) in the PDL1-/CD73+ subset. Conclusions: The identification of distinct pt subsets based on high PDL1 and/or CD73 expression suggests that tumors have multiple mechanisms of immune evasion. Increased IE CD8+ TILs were associated with PDL1 expression. The finding that PDL1-/ CD73+ tumors have lower IE CD8+ TILs compared to PDL1+/CD73- tumors suggests a role for CD73 in excluding IE TILs. Larger sample sets are needed to confirm these findings and to further explore any relationship with the tumor microenvironment. Our data suggests potential approaches to identify subsets of pts likely to benefit from immunotherapy targeting PDL1 and CD73. [Table: see text]
A phase I study of novel multi-HLA-binding peptides and a new combination of immune adjuvants against solid tumors.
Authors: Matsui Hiroto , Hazama Shoichi , Tamada Koji , Udaka Keiko , Koki Yasunari , Uematsu Toshinari , Arima Hideki , Furukawa Hiroyuki , Miyakawa Tomoya , Doi Shun , Kitahara Masahiro , Kanekiyo Shinsuke , Tokumitsu Yukio , Tokuhisa Yoshihiro , Sakamoto Kazuhiko , Suzuki Nobuaki , Takeda Shigeru , Yamamoto Shigeru , Yoshino Shigefumi , Nagano Hiroaki 
Published: September 2018

3086 Background: Based on the exploratory analysis of our previous studies of peptide vaccine, we concluded that the combination of adjuvants hLAG-3Ig + Poly-ICLC is essential for controlling negative immune checkpoints and enhancing the induction of CTLs to overcome the traditional peptide studies. Another issue with peptide vaccines is human leukocyte antigen (HLA) restriction. Hence, we developed novel multi-HLA-binding peptides derived from the tumor antigens, HSP70 and GPC3, and confirmed the high expression in many types of cancer. Methods: For the identification of peptides, HSP70- and GPC3-derived peptides that have high binding affinity to each of HLA-A2402, 0201, and 0206 were selected as candidate peptides by a binding prediction system (NEC Corporation). We then identified priority candidate peptides by using a peptide-binding assay. Using peripheral mononuclear blood cells from cancer patients, CD8+ T lymphocytes were stimulated with the candidate peptides, and an enzyme-linked immunospot assay was performed. Finally, we identified HSP70- and GPC3-peptide. In this phase I study of a novel peptide cancer vaccine for metastatic solid cancer, primary objective was to evaluate its safety and toxicity. Secondary objective was to examine the immune and clinical response, and also to determine the recommendable dose. This study used a three-tiered dose-escalation strategy with 3 patients’ cohorts. In addition to the 3 scheduled cases, 3 more cases were added and 6 cases were enrolled at the recommended dose. Results: Twelve HLA-A*24:02-, 02:01-, and 02:06-matched patients (esophagus, 3; colon, 4; liver, 3; pancreas, 1; stomach, 1) were treated in this study. No severe adverse effects related to the treatment were encountered. Peptide-specific CTL induction with HSP70 and GPC3 was observed in 10 and 11 patients, respectively. We observed decreased tumor marker expression in 6 cases, and disease control was observed in f5 patients (4, 3, 8, 2, 2 months, respectively). Conclusions: The combination cancer vaccine therapy using multi-HLA-restricted peptides and hLAG-3Ig + Poly-ICLC was safe and effective for treating solid tumors; it therefore warrants further clinical studies. Clinical trial information: UMIN000020440.
Consensus molecular subgroups (CMS) of colorectal cancer (CRC) and first-line efficacy of FOLFIRI plus cetuximab or bevacizumab in the FIRE3 (AIO KRK-0306) trial.
Authors: Stintzing Sebastian , Wirapati Pratyaksha , Lenz Heinz-Josef , Neureiter Daniel , Fischer von Weikersthal Ludwig , Decker Thomas , Kiani Alexander , Vehling-Kaiser Ursula , Al-Batran Salah-Eddin , Heintges Tobias , Kahl Christoph , Kullmann Frank , Moehler Markus H. , Scheithauer Werner , Held Swantje , Modest Dominik Paul , Jung Andreas , Kirchner Thomas , Tejpar Sabine , Heinemann Volker ,   FIRE-3 Investigators
Published: September 2018

3510 Background: FIRE-3 compared 1st-line therapy with FOLFIRI plus either cetuximab or bevacizumab in 592 KRAS exon 2 wt mCRC patients. CMS is grouping CRCs according to their gene-signature in 4 different types. Relevance of CMS for the treatment of mCRC remains unclear. Methods: Patients were grouped according to tumor CRC-CMSs. Using ALMAC’s Xcel tissue array, gene signatures of FIRE-3 tumor samples were analyzed. Survival was compared using Kaplan-Meier estimation and log-rank tests. Hazard ratios (HR) were estimated according to the Cox proportional hazard method. Results: CMS classification could be determined in 385 specimens available from the ITT population (n = 592). In this KRAS exon 2 wt population (n = 385), frequencies were: CMS1 (10.4%), CMS2 (36.6%), CMS3 (11.7%), CMS4 (29.1%), non-consensus (12.2%). In RAS wt (n = 315), frequencies were: CMS1 (11.1%), CMS2 (38.1%), CMS3 (9.5%), CMS4 (29.5%), non-consensus (11.7%). Independent of the treatment, CMS was a strong prognosticator for ORR (p = 0.023), PFS (p < 0.001) and OS (p < 0.001). For data on CMS and treatment efficacy in the RAS wt population see the following table. Conclusions: CMS classification is prognostic for mCRC. The survival benefit in RAS wt previously observed for FOLFIRI cetuximab vs. FOLFIRI bevacizumab is not significantly different across CMS groups, although there are trends when comparing OS HR between categories with CMS4 showing the best HR. [Table: see text]
Comparison of long-term survival outcomes between laparoscopic and open surgery for mid or low rectal cancer treated with preoperative chemoradiotherapy: 7-year follow-up of COREAN trial.
Authors: Park Ji Won , Jeong Seung-Yong , Kang Sung-Bum , Joo Jungnam , Song Mi Kyung , Lim Seok-Byung , Choi Hyo Seong , Kim Duck-Woo , Chang Hee Jin , Kim Dae Yong , Jung Kyung Hae , Kim Tae-You , Kang Gyeong Hoon , Chie Eui Kyu , Kim Sun Young , Sohn Dae Kyung , Kim Jae-Sung , Lee Hye-Seung , Kim Jee Hyun , Oh Jae Hwan 
Published: September 2018

3518 Background: Laparoscopic surgery for rectal cancer has been used widely. However, recent two randomized trials raised concerns about short-term oncologic safety of laparoscopic surgery for rectal cancer. The aim of this study was to evaluate the long-term oncologic safety of laparoscopic surgery for rectal cancer based on 7-year data from the Comparison of Open versus laparoscopic surgery for mid or low REctal cancer After Neoadjuvant chemoradiotherapy (COREAN) trial. Methods: COREAN trial was a non-inferiority, randomized controlled trial. Between April, 2006, and Aug, 2009, eligible participants with mid or low rectal cancer treated with preoperative chemoradiotherapy were randomly assigned (1:1) to laparoscopic (n = 170) or open surgery (n = 170). Seven-year outcomes included overall and disease-free survival, and local recurrence. Log-rank test and stratified Cox regression analysis were used for survival analysis. Analysis was by intention to treat. Results: The median follow-up times were 84 months (IQR: 61.5-97.0). No differences were found between laparoscopic and open surgery group in terms of overall and disease-free survival, and local recurrence (7-year overall survival: 83.2% [laparoscopic] vs 77.3% [open], p = 0.48; 7-year disease-free survival: 71.6% [laparoscopic] vs 64.3% [open], p = 0.20; 7-year local recurrence: 3.3% [laparoscopic] vs 7.9% [open], p = 0.08). Stratified Cox regression analysis adjusted for ypT, ypN and tumor regression grade showed no significant difference between groups in terms of overall and disease-free survival, and local recurrence. The hazard ratios for overall survival, disease-free survival and local recurrence (open vs laparoscopic surgery) were 0.96 (95% CI = 0.58-1.57), 1.03 (95% CI = 0.70-1.53), and 2.28 (95% CI = 0.82-7.16), respectively. Conclusions: The 7-year analysis confirm the long-term oncological safety of laparoscopic surgery for rectal cancer treated with preoperative chemoradiotherapy. The use of laparoscopic surgery does not compromise the long-term survival outcomes in rectal cancer. Clinical trial information: NCT00470951.
Colorectal cancer (CRC) patients surveyed by 18FDGPET-CT (PET-CT): An open-label multicenter randomized trial (NCT 00624260).
Authors: Sobhani Iradj , Baumgaertner Isabelle , Itti Emmanuel , Luciani Alain , Layese Richard , Natella Pierre Andre , Gornet Jean Marc , Andre Thierry , Goujon Gael , Aparicio Thomas , Taieb Julien , Bachet Jean-Baptiste , Ducreux Michel , Tournigand Christophe , Hemery Francois , Durand-Zaleski Isabelle , Bastuji Garin Sylvie 
Published: September 2018

3520 Background: Curative surgery is the best therapy of CRC and recurrences. We assessed whether adding semi-annual PET-CT to the usual surveillance would be cost-effective in high risk recurrent CRC patients. Methods: CRC patients (stage II tumor perforated, stages III and IV) in remission after curative surgery were randomly assigned (1:1) to trimester usual surveillance (control) or usual surveillance + semi-annual course PET-CT (intervention) for a 3-yr follow up period. Every 3 months, multidisciplinary committee decided about recurrence by yes/no/doubtful. If yes, curative surgery alone (when relevant), or chemotherapy alone (unresecable recurrence) were conducted; additional exams could be performed if doubtful. Primary composite endpoint (failure) comprised unresectable recurrence & death. The economic assessments according to standards (CHEERS) were performed and costs were compared between groups. Statistical tests for calculation of the relative risk (RR) were used and survival was analyzed using Kaplan-Meier method, Log-Rang test and Cox models. Results: Baseline characteristics of 239 patients (120/119) enrolled in 12 centers were balanced. The failure rate was 29.2% (31 unresectable recurrences & 4 deaths) and 23.5% (27 & 1) in Interventional vs Control, respectively with no significant difference (RR = 1.24, 95% CI: 0.81-1.90; P = .32). Similar results were observed in multivariate analysis (Cox models) adjusted for stage and tumor differentiation (HR = 1.33, 95% CI: 0.8-2.19, P = .27). Period until the unresectable recurrence was significantly shorter in Interventional (median = 7; IQR: 3-20 months) than in Control group (14.3; 7.3-27; P= 0.016). This was consistent with lower elevation (median; IQR) of tumour marker in interventional (3.8; 2.8-19) than in control group (10; 5.2-28.6) at the first recurrence time as compared to the baseline (p = 0.007). Overall (mean; SD) cost (euros)/patient was higher in the PET-Scan (9385; 11658) than in the control group (7027; 7656). Conclusions: Although recurrences were detected earlier in PET-CT group, the strategy was less effective, more expensive. This exam should not be advised routinely. Clinical trial information: NCT 00624260.