bluuebunny/crossref_metadata_2025_split huggingface dataset:
Radiomic biomarkers for the prediction of immunotherapy outcome in patients with metastatic non-small cell lung cancer.
Authors: Trebeschi Stefano , Kurilova Ieva , Călin Adriana M. , Lambregts Doenja M. J. , Smit Egbert F. , Aerts Hugo , Beets-Tan Regina GH 
Published: September 2018

e14520 Background: PD-1 checkpoint inhibitors have recently been approved for the treatment of patients with metastatic NSCLC. Predicting to what extent patients will benefit from these treatments is challenging. Research on predictive biomarkers focus on genetic and histological markers from biopsies, necessarily limited to parts of the tumor. Radiomics is a novel approach to quantify characteristics of the tumor on medical imaging, which may have potential value as non-invasive biomarkers. In this study, we explored the value of radiomic data from primary tumors to predict overall survival (OS) in patients with metastatic NSCLC treated with Nivolumab Methods: We retrospectively selected 64 metastatic NSCLC patients treated in 2ndline setting with Nivolumab (240 mg q 2 weeks until progression). Inclusion criteria were: primary tumor in situ with contrast enhanced CT scan (thorax abdomen; slice thickness ≤3mm) within 6 weeks before the start of the treatment. Exclusion criteria were: presence of atelectasis or fusion with other structures and presence of multiple lung lesions at first scan. A certified radiologist delineated the tumors on CT from which we extracted 1696 Radiomic features. Unsupervised feature selection was performed. Multivariate Cox Regression was used to model the OS based on the selected features, as well as, histopathological type (adeno vs squamous), age at the start of the treatment, and extent of metastatic disease ( < 5, 5–10, or > 10 metastasis) Results: The selection resulted in three textural features derived from a Laplacian of Gaussian (LoG): regions dissimilarity (GLRLM_rlnun), entropy (GLSZM_ze), and uniformity. The resulting model was significant (p = 0.005). Both regions dissimilarity (HR = 0.11, 95% CI 0.03–0.46, p = 0.002) and entropy (HR = 0.20, 95% CI 0.06–0.67, p = 0.009) were significant predictors of OS. Subtype and disease extent were close to significance (p = 0.099) Conclusions: Results indicate that more heterogeneous tumors with irregular patterns of intensities showed better OS. The availability of CT scans makes Radiomics a potentially valuable adjunct to other clinical biomarkers. Further validation of our findings in larger cohorts are warranted
Combination of biomarker and clinicopathologic characters to circle out beneficiaries through second-line immunotherapy: A meta analyse.
Authors: Zhang C , Zhong Wenzhao , Dong Zhong yi , Wu Yi-Long 
Published: September 2018

e14535 Background: Programmed cell death ligand 1 (PD-L1) expression had been proposed as predictive biomarker to immune-checkpoint inhibitors. Yet treatment responses are not always consistent with this single agent in the second-line therapy of non-small cell lung cancer (NSCLC). Whether combination of PD-L1 and clinicopathologic characters could circle out optimal beneficiaries are still unknown. Methods: We performed a meta-analysis of randomized control trials that compared immune-checkpoint inhibitors against chemotherapy in second-line therapy. Data including smoking status, EGFR status, KRAS status and histology were extracted as subgroup analyse to estimate the potential predictor of efficacy for anti PD-1/L1. Results: Five clinical trials that compared immune-checkpoint inhibitors against chemotherapy for second-line therapy were included. Both PD-L1 positive (HR = 0.64, 95%CI = 0.56-0.73, P < 0.00001) and PD-L1 negative (HR = 0.88, 95%CI = 0.78-1.00, P = 0.05) favored anti PD-1/L1. Subgroup analyse indicated that adenocarcinoma (ADC) as well as squamous cell carcinoma (SCC) preferred anti PD-1/L1. Never smokers may not benefit from anti PD-1/L1 but current/ever smokers did (HR = 0.70, 95%CI = 0.63-0.79, P < 0.00001). Patients with EGFR mutation could not gain benefit from anti PD-1/L1 while the EGFR wild type could (HR = 0.67, 95%CI = 0.60-0.76, P < 0.00001). Both KRAS mutation (HR = 0.60, 95%CI = 0.39-0.92, P = 0.02) and wild type/unknown (HR = 0.81, 95%CI = 0.67-0.97, P = 0.02) were apt to anti PD-1/L1. Conclusions: Regardless of PD-L1 status, immune-checkpoint inhibitors could achieve better efficacy than chemotherapy in second-line therapy. Current/ever smokers without EGFR mutations may benefit more from anti PD-1/L1. Combination of PD-L1 and strongly relevant clinicopathologic characters should be considered to tailor optimal patients for anti PD-1/L1.
Utilizing IL-7 to generate melanoma antigen T cell receptor-modified cells for adoptive transfer in the absence of activation.
Authors: Wang Siao-Yi , Scurti Gina , Dalheim Annika , Moore Tamson , Nishimura Michael 
Published: September 2018

e14552 Background: Metastatic melanoma remains a fatal disease as many patients fail to respond to novel therapies. Presently, we have an ongoing trial utilizing T cell receptor (TCR)-modified cells reactive to the melanoma antigen, tyrosinase, for treatment of metastatic melanoma (NCT01586403). Current protocols using viral vectors to generate cells for adoptive transfer require activation in the presence of IL-2. While IL-2 stimulates proliferation and production of mature effector cells, it also induces T cell exhaustion. We hypothesize that tyrosinase-reactive TCR-modified cells generated in the absence of activation have an increased potential for expansion, persistence, and anti-melanoma activity. In these studies, we investigate whether IL-7, a homeostatic regulator, facilitates the transfer of a tyrosinase-reactive TCR to lymphocytes without activation. Methods: Gene-modified cells were generated using a lentiviral vector including alpha and beta chains of a TCR reactive to tyrosinase and a truncated CD34 molecule as a transduction marker. Peripheral lymphocytes from normal human donors were transduced with lentivirus following no treatment, treatment with IL-7, or activation in the presence of IL-2. Transduced CD34 positive cells were isolated using magnetic activated cell sorting (MACS) and injected intravenously into NOD scid gamma (NSG) mice. Results: We found that IL-7 treatment improved transduction in non-activated cells and resulted in expression levels of CD34 and TCR variable beta chain 12 (vbeta12) comparable to cells activated in the presence of IL-2. When non-activated tyrosinase-reactive TCR-modified human T cells were adoptively transferred into NOD NSG mice, the cells were detectable in the peripheral blood of mice up to 7 days after transfer. Conclusions: These findings suggest that generating melanoma antigen TCR-modified cells in the absence of activation for adoptive transfer is feasible with IL-7 treatment. Ongoing studies in NSG mice transplanted with melanoma will help determine whether non-activated gene-modified cells will improve the efficacy and longevity of cell therapy for melanoma and other malignancies.
Autophagy (A) inhibition to enhance combined immunotherapy (I) and anti-EGFR treatment (E) in colorectal cancer (CRC).
Authors: Karamouzis Michalis , Koustas Evangelos , Mihailidou Chrysovalantou , Schizas Dimitrios , Papavassiliou Athanasios G. 
Published: September 2018

e14554 Background: Resistance to E impairs survival of metastatic CRC (mCRC) patients. The aim of this study is to assess the preclinical activity of triple inhibition of E, I and A in CRC. Methods: RKO and Colo-205 cell lines were treated with E [cetuximab (C) / panitamumab (P)] and/or I [pembrolizumab (PE) or nivolumab (NI) with/without ipilimumab (IPI)] and/or autophagy inhibitor 3-Methyladenine (3-MA). Phosphorylated EGFR (pEGFR), p62 (SQSTM1), MAP1LC3 (LC3B) and PARP protein levels were detected by Western blotting. Cell viability was determined by MTT Assay. Tumor volumes were determined from 3D cell culture on Corning Matrigel Matrix as well as the apoptotic cell death. Results: E+I combination compared to E alone decreased pEGFR and increased A activation through p62 downregulation and LC3II activation. Similar results were shown for cell viability/apoptosis. Cells were also treated with C or P combined with I plus 3-MA. Triple inhibition suppresses EGFR and blocks A. Compared to E+I, triple inhibition reduced more cell growth/viability. Caspase-3 activity was increased as well as proportion of apoptotic cells (Table). Conclusions: Τhese results indicate that the combinatorial inhibition of A, E and I represents a promising treatment strategy in mCRC that needs further testing. [Table: see text]
In silico analysis of non-synonymous SNPs (nsSNPs) and outcomes in non-small cell lung cancer (NSCLC) patients (pts) treated with immunotherapy (IT).
Authors: Patel Kruti , Stein Matthew K , Morris Lindsay Kaye , Byrd Kenneth P , Weksler Benny , Schwartzberg Lee Steven , Fenton Moon Jung , Vanderwalde Ari M. , Martin Michael Gary 
Published: September 2018

e14563 Background: Role of biomarkers in predicting benefit from IT in NSCLC is still evolving. These drugs are expensive and benefit less than 50% who receive them, despite PD-L1 status. We hypothesized cancers with increased pathogenic mutations would generate a more robust immune response resulting in increased benefit. Methods: We retrospectively identified NSCLC pts who received next-generation sequencing (NGS) from 2013-2015 by Caris. Pts were divided into those who received IT (IT+) during any line of therapy and those who only received conventional chemotherapy (IT-). PDL-1 status was determined by IHC. In silico analysis with PolyPhen-2 (Harvard) was utilized to predict the significance of nsSNPs. The total pathogenic coding changes (SUM) were defined as the sum of the known pathogenic mutations (MUTp) and pathogenic nsSNPs (pnsSNPs). Outcomes were compared for those with a SUM above (SA) and at or below (SB) the median. All p-values were two-sided: survival outcomes were compared by the log-rank test. Results: 149 NSCLC pts were identified, 99 IT- and 50 IT+. Of 99 IT- and 50 IT+, median age was 65 vs 64; 47% vs 40% females; 57% vs 74% white, 39% vs 18% black; 66% vs 60% adenocarcinoma, 21% vs 30% squamous; 13% vs 6% nonsmokers; 15% vs 6% received a TKI. Median nsSNPs for both were 4. In both groups the mutational burden (MB)- MUTp plus nonsynonymous changes without in silico prediction - did not predict survival (p = 0.27 and p = 0.50). 51% and 52% nsSNPs were predicted-damaging in IT+ and IT-. The median SUM in IT+ was 2 (0-7) and IT- was 2 (0-11). SUM did not predict OS in all comers (p = 0.17). SUM did not predict OS in IT- (p = 0.10) nor in IT+ (p = 0.19), though strong trend in opposite directions were seen. In SB pts, IT+ compared with IT- had no impact on OS (p = 0.38). In SA pts, IT+ had superior outcomes compared to IT- (OS 423d v 244, p = 0.01). PDL1 status did not predict OS in pts that received IT. Conclusions: While MB and PDL1 did not predict outcomes with IT, SA predicted improved OS with IT+ over IT- suggesting the combination of pnsSNPs and known pathogenic lesions may predict benefit from IT. These results need to be validated in a prospective trial but may help select pts that should receive IT.
Defining adverse events of anti-programmed-death-1 (Anti-PD1) agents using FDA adverse event reporting system (FAERS).
Authors: Xiao Kun , Lian Zhesi , Collins Robert , Dimou Anastasios , Garrett-Mayer Elizabeth , Drabkin Harry A. 
Published: September 2018

e14568 Background: Anti-PD1 inhibitors are a promising therapeutic option in oncology. They have received FDA-approval in treating metastatic and relapsed non-small cell lung cancer, kidney cancer, head-and-neck cancer, and melanoma. Yet its adverse event profile is still being defined. The FAERS database contains information on adverse events and medication error reports submitted to the FDA and serves to support the post-marketing safety surveillance program for drug and therapeutic biologic products. Methods: We searched the FAERS database from January 1, 2015 to June 30, 2016. Only initial cases reported by an MD or pharmacist for treatment of cancers of the lung, kidney, head and neck, or melanoma were included. Cases with incomplete starting, ending or event dates were excluded. The primary outcome was time from drug initiation to onset of the event. Cox proportional hazard model was used to evaluate the association between time to AE and age, gender, disease, and time of report. Results: A total of 105 adverse events (AEs) were identified. Of those AEs, 68 were related to nivolumab, 35 to pembrolizumab, and 2 to atezolizumab. Fifty-six AEs were seen in lung cancer patients, whereas 46 were in melanoma, 2 in kidney cancer and 1 in a head and neck cancer patient. Thirty-three AEs involved pulmonary complications, 30 gastrointestinal systems, 17 endocrine, and 9 were constitutional in nature. The median onset of AEs from the start of therapy was 31 days (range: 2 - 459 days). Using a Cox regression analysis, pembrolizumab was associated with a longer time to AEs compared to nivolumab (HR 0.48, 95%CI: 0.26 - 0.89). Also age between 60 and 70 was associated with a longer time to the onset of AEs compared to age < 60 (HR 0.61, 95%CI: 0.37-0.99). Conclusions: FAERS is a vigilance system to monitor AEs from anti-PD1 inhibitors. Pembrolizumab and age between 60 and 70 were associated with less AEs. Ongoing data accrual will increase the statistical power and analysis of AEs from anti-PD1 inhibitors in greater detail.
Nonconventional responses and survival benefit of immunotherapy in advanced lung cancer.
Authors: Yogarajah Meera , Kuszyk Brian S , Stroud Chipman Robert Geoffrey , Cherry Cynthia R. , Walker Paul R. 
Published: September 2018

e14572 Background: Objective response rates (ORR) utilizing RECIST or WHO criteria have been traditionally used as clinical endpoints to assess efficacy of cytotoxic chemotherapy. However in the era of immunotherapeutic agents, response rate assessment can be misleading due to nonconventional responses resulting in premature discontinuation of treatment. Wolchok et al proposed immune-related response criteria (irRC) to assess immune responses in melanoma. He also noted that stable disease which is not indicative of antitumor activity could be a potential surrogate marker of better clinical outcome. Brahmer et al reported nonconventional pattern of responses with Nivolumab in lung cancer. Methods: A retrospective chart review was done to assess differences in responses utilizing both RECIST v1.1 and irRC criteria in lung cancer patients treated with Nivolumab. Patients who received minimum of 4 cycles of Nivolumab were included in the study. The CT scans were reviewed by a senior radiologist. We reviewed 64 patients treated with Nivolumab between 4/30/2015 to 6/21/2016 and 30 patients were found eligible. Results: Patient characteristics. Male 53%; median age 61 years; squamous 47%; adeno 40%; small cell 13%; Median cycles of Nivolumab 6. Response rates utilizing both criteria was essentially similar with only 2 patients showing dis-concordant responses (6.6%). We utilized RECIST responses criteria for further analysis. Partial response (PR) 2/30; stable disease (SD) 12/30; progressive disease (PD) 15/30 and not evaluable (NE) 1/30. ORR 6.6%. Kaplan–Meier curve was used to analyze difference in survival between patients with PR+SD and PD. The median survival for PD was 9 months and PR+SD was not reached at median follow up of 1 year. Overall survival at 1 year for PD 33% and PR+SD 60% (p = 0.048). Hazard ratio for PD was 3.060 (p = 0.60). Conclusions: Patients with stable disease had a better survival and should be considered as responders though traditionally not included in the ORR. However irRC did not help in differentiating nonconventional immune responses in lung cancer patients. [Table: see text]
Toxicities associated with checkpoint inhibitor immunotherapy: The Karmanos Cancer Center experience.
Authors: Nagasaka Misako , Alhasan Roba S , Crosby Marcus , Thummala Nithin , Kim Seongho , Abrams Judith , Sukari Ammar 
Published: September 2018

e14575 Background: PD-1 inhibitors work by re-instating the natural anti-cancer immune-mediated cytotoxicity. Although this new class of therapy offers hope for many advanced stage cancer patients (pts), data on pts who are more likely to experience adverse events (AE) are not available. Methods: Data from pts who received at least one dose of PD-1 inhibitors before August 31, 2016, were captured from our institution’s pharmacy database. AE of anemia, neutropenia, thrombocytopenia, acute kidney injury, hypothyroidism, transaminitis, pneumonitis, colitis and fatigue were recorded and graded based on CTCAEv4. Baseline pt characteristics were statistically compared between subjects who received PD-1 inhibitors on a clinical trial vs as part of standard of care (on vs. off-study) by Fisher’s exact test for categorical variables and Kruskal-Wallis test for continuous variables. Univariable and multivariable logistic regression models were fit to assess associations between toxicities (Grade0-1 vs. Grade2+) and predictors (age, agent, primary tumor, and trial status). Results: 231 pts received at least one dose of PD-1 inhibitors prior to data cut-off. Median age was 65 (24-92) off trial (n = 125) and 59. 5 (25-79) on trial (n = 106). There were 117 (51%) non-small cell lung cancer (NSCLC), 41 (18%) renal cell carcinoma (RCC) and 73 (32%) others. 24 (10%) melanoma, 18 (8%) Hodgkin’s lymphoma (HL), 9 (4%) head and neck squamous cell carcinoma (HNSCC), 8 (4%) small cell lung cancer (SCLC) were included in others. 129 (56%) had nivolumab alone, 50 (22%) had pembrolizumab alone and the rest 52 (23%) received combination treatment. Pts participating in a clinical trial had higher odds to experience grade 2 or more pneumonitis than those not on a trial (unadjusted p = 0.038). On trial pts had lower odds to experience grade 2 or more fatigue than those receiving the agent as standard of care (unadjusted p = 0.026) which remained significant after adjusting age, agent (single agent vs combination) and primary tumor (adjusted p = 0.004). Conclusions: In our observation, pneumonitis was seen more on clinical trials whereas fatigue was seen less.
A phase 1 trial of JS001, a monoclonal antibody targeting programmed death-1 (PD-1) in patients with advanced or recurrent malignancies.
Authors: Yang Sheng , Yang Jianliang , Han Ying , Qin Yan , Han Xiaohong , Dong Lihou , Feng Hui , Song Haifeng , Sun Yan , Shi Yuankai 
Published: September 2018

e14581 Background: JS001, a humanized IgG4 anti-PD-1 antibody, showed potent anti-cancer activity in preclinical models. Notably, in vivo study suggests it promotes the proliferation of CD62L-CD45RA- effector memory cell effectively. A phase 1 dose escalation study was conducted to assess its safety, tolerability, pharmacokinetic (PK) profile and preliminary efficacy. Methods: This trial used a 3+3 design across 3 dose levels: 1, 3, 10 mg/kg/dose. At each level, two schedules were assessed: single dose and repeated doses every 2 weeks (up to 6 doses). JS-001 was administered as a 60-minute i.v. infusion. A dose limiting toxicity (DLT) was defined as a Grade≥3 drug-related adverse event (AE) occurring within 28 days of last dosing. Results: At the time of analysis, among 19 patients (pts) enrolled (single dose: 9 pts; multiple doses: 10 pts), no DLT was reported. Most treatment-related AEs were grade 1-2, including fever, diarrhea, rash, influenza-like symptoms, fatigue, mucositis, elevated transaminase and decreased lymphocyte count. One patient experienced grade 3 pneumonia. Although the cause of pneumonia is difficult to determine, and further assessment is ongoing, it resolved after prompt management. No treatment-related death occurred. The preliminary PK profile supports a biweekly schedule, and results in detail are under analyzing. 15 pts with evaluable lesions received response evaluation. Best responses were 1 CR (Hodgkin lymphoma, HL), 5 PR (HL: 3; soft tissue sarcoma, STS: 1; diffuse large B-cell lymphoma: 1) and 5 SD (non-small cell lung cancer: 3; head and neck cancer: 2), yielding a disease control rate of 11/15. Remarkably, a patient with STS achieved dramatic tumor shrinkage after a single injection of JS001. Biomarker analysis is in progress. Conclusions: JS001 is well tolerated and the preliminary efficacy results are promising. Updated data on the expansion cohorts at 3mg/kg and 10mg/kg will be presented. Clinical trial information: NCT02836834. Clinical trial information: NCT02836834.
HDAC and PD-1 inhibition in humanized triple-negative breast cancer xenografts.
Authors: Capasso Anna , Lang Julie , Pitts Todd M. , Francoeur Paul , Davis Sarah Lindsey , Lieu Christopher Hanyoung , Bagby Stacey M , Tentler John J. , Piscopio Anthony d , Diamond Jennifer Robinson , Pelanda Roberta , Eckhardt S. Gail 
Published: September 2018

e14604 Background: There is great interest in investigating immune checkpoint inhibition in combination with novel agents, however, preclinical studies are limited by the lack of immune-competent human cancer cell line xenograft models. We developed a “hematopoietic” humanized mouse model to address this unmet need. HDAC inhibitors (HDACi) induce T-cell chemokine expression and enhance response to PD1 inhibitors in lung cancer models. We evaluated the combination of OKI-179, a novel Class I HDACi and nivolumab in our humanized mouse model. Methods: BRGS newborn pups were transplanted with CD34+ cells purified from umbilical cord blood. At 16 weeks, MDA-MB-231 cells were implanted in the flanks of the mice. When the average tumor size reached ~150-300 mm3, the mice were randomized into vehicle, nivolumab, OKI-179, or the combination treatment according to % chimerism. At the end of the treatment, mice were euthanized and tissues were collected for further analysis. Results: We observed a statistically significant improvement in tumor growth inhibition with the combination of OKI-179 and nivolumab (%TGI = 77%) as compared to single agent nivolumab (45%TGI). Nivolumab treatment led to a significant decrease in PD-1 expression on T cells. We also observed an increased number of TILs (CD8+ T cells) and T cells in the lymph nodes of treated mice suggesting T cell expansion. All mice were highly chimeric and responding tumors exhibited an increase in CD44 high IFN+ T cells. We observed a higher CD8% and a higher effector memory % (HLADR+, CD45RO+) in these mice. Conclusions: We successfully established a humanized TNBC human cancer cell line xenograft model, with tumor engraftment occurred in all humanized mice. Mice treated with nivolumab demonstrating the development of lymph nodes that were populated by activated T cells. The combo resulted in superior tumor growth inhibition. These preliminary results demonstrate that human immunity and PD-1 expressing T cells exist in these models and provide the basis for planned immunotherapy combination studies.