bluuebunny/crossref_metadata_2025 huggingface dataset:
Genomic characterization of brain metastases (BM) in high-grade serous ovarian cancer (HGSOC).
Authors: Duchnowska Renata , Supernat Anna Maria , Pęksa Rafał , Łukasiewicz Marta , Stokowy Tomasz , Umińska Monika , Iżycka-Świeszewska Ewa , Kowalczyk Anna , Och Waldemar , Rucinska Monika , Olszewski Wojciech P , Mandat Tomasz , Jarosz Bozena , Bieńkowski Michał , Biernat Wojciech , Jassem Jacek
Published: May 2019

e13580

Background: BM are a rare occurrence in ovarian cancer (OC) and their molecular characteristics is virtually unknown. DNA damage repair (DDR) deficiency is prevalent in OC, and co-mutated TP53 and any DDR denotes high tumor mutation burden (TMB). We genetically characterized a unique series of high-grade serous ovarian cancer (HGSOC) patients who developed BM to identify alterations of potential clinical relevance. Methods: Whole-exome sequencing (2x150bp, SureSelectXT Library Prep Kit, Illumina’s NovaSeq platform) was performed in matched BM, primary tumors (PT) and normal tissue. DNA was extracted from FFPE samples using QIAamp DNA FFPE Tissue Kit (Qiagen, Germany). All mutations were checked with Catalogue of Somatic Mutations in Cancer (COSMIC) and Integrative Genomics Viewer (IGV). Results: Study group included 10 HGSOC patients (International Federation of Gynecology and Obstetrics classification (FIGO) II-IV, mean age at diagnosis 48 years, range 35-59). Median time from primary HGSOC diagnosis to BM was 38 months (range, 18 to 149). TP53 somatic mutations were found in both primary tumor (PT) and BM in 8 patients. The other 2 cases harbored TP53 mutations not reported in COSMIC catalogue: p.S60L and intronic TP53 mutation preceding p.I322 (IGV). In 9 cases TP53 mutations coexisted with germline or somatic DNA damage repair deficiency. Four cases contained BRCA1 mutations (all germline), and none harbored germline BRCA2 mutation. Other mutated genes included MLH1 (2 somatic, 2 germline), ATR (4 germline, 1 somatic), AMT (1 somatic), RAD50 (1 somatic), ERCC4 (1 somatic), FANCD2 (1 somatic) and RPA1 (1 germline). Three mutation signatures defined in the COSMIC database were indentified in BM: 6, 20 and 30. In 6 cases these mutations were shared in PT, and in another 4 their presence in PT could not be determined due to technical reasons. Median survival from BM was 31 months (range, 5 to 184). Conclusions: Genomic analysis of BM provides an opportunity to identify potentially clinically informative alterations. Mutational profiles in PT are generally reflected in BM. Detected genetic alterations suggest their potential sensitivity to PARP inhibitors and immunotherapy.
Management of brain metastases in tyrosine kinase inhibitor-treated epidermal growth factor receptor-mutant non-small-cell lung cancer from the perspective of long-term radiation brain damage: A multi-institutional retrospective analysis.
Authors: Zhuang Hongqing , Wang Xin , Yuan Zhiyong , Wang Enmin , Wang Junjie
Published: May 2019

e13587

Background: To investigate the relationship between the timing of SRS intervention and the complications of cerebral radiation necrosis(CRN) and its impact on the cognitive function and quality of life(QOL) in patients with brain metastases of lung adenocarcinoma who received TKI treatment. Methods: A total of 361 targets from 257 patients with brain oligo-metastases of lung adenocarcinoma who received Cyberknife treatment between 2010 and 2017 were collected from three Cyberknife centers. The difference in brain necrosis between patients with or without TKI application was statistically counted. Logistic regression analysis was used to analyze the effect of applying TKI on the occurrence of CRN in patients, and the effect of SRS before and after TKI resistance on CRN. The effects of CRN on the cognitive function and quality of life of surviving patients were analyzed. Results: The rate of CRN in the TKI group was significantly higher than that in the non-TKI group. The incidence of brain necrosis in patients undergoing SRS after drug resistance was significantly higher than that in patients undergoing SRS before drug resistance. Regression analysis showed that combination of TKI with SRS, and SRS after TKI resistance were important influencing factors for CRN. The follow-up results of currently surviving patients showed that the occurrence of brain necrosis seriously affected the cognitive function and QOL of patients. Conclusions: Long-term radiation-induced brain damage needs to be seriously monitored in lung adenocarcinoma patients with brain metastasis undergoing combination of radiotherapy and TKI. Clinicians need to pay attention to this problem and make reasonable recommendations for radiotherapy and TKI treatment.
Real-world outcome analysis of EGFR-mutated lung adenocarcinoma with brain metastases.
Authors: Kuan Feng-Che , Yang Wei-Hsun , Lai Hung-Yi , Huang Chun-Chieh , Yang Cheng-Ta , Shi Chung-Sheng
Published: May 2019

e13588

Background: BM represent a common problem in EGFR-mutated lung adenocarcinoma. The updated Lung-molGPA elucidates the survival in patients with non-small-cell lung cancer and BM by incorporating the effect of EGFR gene alterations. However, the nature history and differences of prognostic implication between common and uncommon EGFR mutations remain unsolved. Methods: By retrospective analysis of Chang-Gung Research Database (CGRD), patients with EGFR-mutated lung adenocarcinoma and BM were included into analysis of PFS and OS. EGFR mutations were categorized into exon 19 deletions (Del19), exon 21 Leu858Arg substitution (L858R) and uncommon mutations. Kaplan-Meier method was used to estimate survival, and multivariate Cox proportional hazard models was performed to estimate adjusted hazard ratios (HR) and 95% confidence interval (CI). The p-value was set to be statistically significant at 0.05 or less. Results: From April 1, 2014 to June 30, 2015, 269 out of 818 patients with EGFR-mutated lung adenocarcinoma and BM were included, of which 115 patients with Del19, 131 patients with L858R, and 23 patients with uncommon EGFR mutations. The baseline characteristics were balanced in age, gender, KPS, ECM, number of BM, and timing of BM. In comparison with those with L858R, uncommon mutations is a poor prognostic factor for PFS (HR 2.24, 95% CI: 1.34-3.75, p = 0.002). The median PFS of Del 19, L858R, and uncommon EGFR mutations were 10.4, 10.0, and 3.2 months, respectively (log-rank p = 0.03). Besides, the median OS of Del 19, L858R, and uncommon EGFR mutations were 18.1, 17.4, and 12.5 months, respectively (log-rank p = 0.05). In comparison with those treated with gefitinib, afatinib treatment is a good prognostic factor for PFS and OS (PFS, HR 0.57, 95% CI: 0.35-0.94, p = 0.03; OS, HR 0.48, 95% CI: 0.26-0.91, p = 0.03). The median PFS of those treated with sequential WBRT, concurrent WBRT and TKI alone were 11.0, 8.5, and 10.3, respectively (log-rank p = 0.63). In addition, the median OS of those treated with sequential WBRT, concurrent WBRT and TKI alone were 18.7, 15.2, and 18.2 months, respectively (log-rank p = 0.50). Conclusions: Among patients with EGFR-mutated adenocarcinoma, common and uncommon EGFR mutations have distinct natural history and prognostic implications in patients with BM.
Presenting symptoms and patient prognosticators in neoplastic meningitis: A single institution experience.
Authors: Ghatnekar Shilpa , Hachem Hilal , Patel Rima , Dowd Richard , Godara Amandeep , Chang Hong , Jeyapalan Suriya A.
Published: May 2019

e13593

Background: Neoplastic meningitis (NM) occurs in 5-15% of cancer patients, with less than 15% surviving one year. Untreated, median survival is estimated at 1.5-2 months. The purpose of this study is to identify the presenting symptoms of NM disease and the patient characteristics which are prognostic of overall survival (OS). Methods: We performed a single-institution retrospective analysis of 123 patients diagnosed with NM disease at TMC between January 2006 and January 2016. Patients were identified via cytopathology and radiology. Patient data was obtained from the hospital electronic medical record. Survival analysis was generated using Kaplan-Meier methods and chi square tests for categorical data. Results: Breast cancer was the most common primary malignancy (22%, n = 27), followed by lymphoma (19%, n = 23), and lung cancer (15%, n = 18). The most common presenting symptoms were headache (33%, n = 41), extremity weakness (33%, n = 41), and gait abnormalities (25%, n = 31). Median age and Karnofsky performance status (KPS) at diagnosis were 56 years [18-93] and 58 [10-100], respectively. Median OS was 4.08 months [0-130], with a 23% one-year survival rate. Higher KPS was associated with a significantly improved OS (p < 0.05). Although survival was worse in the age group > 67 yrs compared to < 45 yrs the difference was not significant (p = 0.053, 95% CI (0.994- 2.944)). Conclusions: To our knowledge, this is one of the largest analyses of patient characteristics and outcomes in NM. Results show that KPS, when adjusted for confounders, is an important prognostic biomarker. In contrast to other studies, age was not a significant prognosticator of survival. Headaches combined with extremity weakness were the most common presenting symptoms of NM disease. When present together in the cancer patient, the treating physician should strongly consider further workup for the presence of NM disease.
Computational design of novel tetra-specific antibody (PD-1/CD47/VEGF/TGF-ß) with IgG-like architecture against non-small cell lung cancer (NSCLC).
Authors: Zhao Lei , Zhang Fan , Li Lingling , Chen Shixue , Hu Yi
Published: May 2019

e14002

Background: Although monoclonal antibodies (mAbs) are widely used for the treatment of cancer, the acquired resistance is one of the prime obstacles for cancer treatment. There is an urgent need to development of novel antibodies with potent anti-tumor activities and specificities against cancer. Due to the complexity and heterogeneity of cancer, mAb with a single target could not be significantly improved to combat cancer. Nowadays, bispecific antibodies with the capacity to blockade of multiple targets or binding sites are showing improved therapeutic efficacy against cancer both in clinical trials and preclinical studies, suggesting that multi-specific antibodywith great potential for administration of cancer in near future. Although more than 30 bispecific antibodies with IgG architecture are being explored in clinical trials, tetra-specific antibody with IgG-like architecture against NSCLC has not been reported. Methods: Recently, we have successfully solved the correct assembling of heavy-heavy chain and heavy-light chain of multi-specific antibody through the Lock-and-Key and FabX technologies we have previously described. By using these two technologies, we have designed the tetra-specific antibody with IgG-like architecture against NSCLC. Then, we have performed long-time molecule dynamic simulation (6 µs) to evaluate and improve the structure stability of tetra-specific antibody. Results: With the benefits of tetra-specific antibody and whole IgG architecture, the tetra-specific antibody PD-1/CD47/VEGF/TGF-ßexhibits potent anti-tumor efficacy than the parent antibody Atezolizumab, Hu5F9-G4, Bevacizumab or Fresolimumab and the combination of these parent antibodies. Conclusions: Tetra-specific antibody with IgG-like structure shows the advantages in cancer treatment. Antagonism of PD-1, CD47, VEGF and TGF-ß through multi-specific antibody could be a promising anti-tumor strategy against NSCLC.
AGEN2373 is a conditionally-active agonist antibody targeting the costimulatory receptor CD137 for the treatment of human malignancies.
Authors: Galand Claire , Xiao Yanping , Mundt Cornelia , Morin Benjamin , Chand Dhan , Riordan Christina , Venkatraman Vignesh , Ward Rebecca , Gombos Randi , Lim Min , Costa Matthew , Joyce Cailin , Ignatovich Olga , Findeis Mark , Underwood Dennis , Stein Robert Benjamin , van Dijk Marc , Wilson Nicholas , Savitsky David
Published: May 2019

e14005

Background: Agonist antibodies targeting CD137 are potent inducers of tumor-reactive T cell proliferation, cytokine production, and cytotoxicity, and have been explored clinically for their ability to enhance immune cell-mediated destruction of tumor cells. Despite early signs of clinical activity, the development of first-generation anti-CD137 antibodies has been hampered by on-target dose-limiting hepatotoxicity or poor clinical activity. Subsequent CD137 therapies have therefore sought to localize CD137 agonism to the tumor microenvironment (TME) to potentially improve tolerability in patients. However, these approaches may also limit the potential benefit of CD137 signaling outside the TME that contributes to anti-tumor immunity, such as T cell priming in tumor draining lymph nodes. Here we describe the pharmacologic and non-clinical safety profile of a next-generation anti-CD137 monospecific antibody, AGEN2373. Methods: Flow cytometry and surface plasmon resonance-based binding, superantigen-driven immune cell activation, and luminescent reporter cell line assays were developed to test the ability of AGEN2373 to induce CD137 signaling. A non-clinical, multi-dose safety study was conducted wherein cynomolgus monkeys were injected intravenously with 100 mg/kg doses of AGEN2373. Results: AGEN2373 engages cell-expressed human and cynomolgus monkey CD137, and provides potent CD137 co-stimulation only in the presence of CD137 ligand and/or Fc gamma receptor-expressing antigen presenting cells. No changes in clinical parameters, importantly no sign of liver toxicity, were observed after administration of AGEN2373 in cynomolgus monkeys. Conclusions: AGEN2373, a novel conditionally-active anti-CD137 agonist antibody that is well-tolerated in non-human primates, is expected to have clinical activity in patients with human malignancies by its ability to selectively enhance tumor immunity in the context of immune co-stimulation.
Measuring T-cell avidity and enrichment using acoustic force-based technology.
Authors: Anderson Leif Stefan , Braster Rens , Sitters Gerrit , Candelli Andrea , Schumacher Ton N. , Scheper Wouter
Published: May 2019

e14010

Background: The key driver for effective immune cell therapies is the overall binding strength of the immune cell and the target cell (e.g. tumor cells). The overall strength is known as ‘avidity’, a parameter reflecting interaction efficiency. The key to success for immune cell therapies is generating effective and long-lasting immune responses. The avidity of an immune cell to its target is predicative of its function, but current techniques to measure avidity are low-throughput and ineffective. Herein, we describe the use of acoustic forces to discriminate immune cells based on their avidity to tumor cells. The force required to separate a cell from its target is called the ‘rupture force’, and in this study, we were able to identify the rupture forces of tumor specific and non-specific T cells and enrich these different populations for downstream characterization. Methods: T cells from a healthy donor were transduced with either a non-relevant, or a melanoma recognizing T cell receptor and selected with puromycin resistance. Melanoma cells were seeded in the flow cell and allowed to adhere overnight to form a monolayer. For confocal experiments CFSE and Cell Trace far red stained T cells were mixed in a 1:1 ratio before co-culturing them in the flow cell. An acoustic force ramp was applied within the flow cell and cell detachment was monitored. Results: T cells engineered with a melanoma antigen-recognizing T-cell receptor needed 6 times more force than non-specific T cells to be separated from the melanoma target cells. Furthermore, 1.4 to 3.6-fold enrichment of high-avidity T cells was obtained from a mixed population of specific and non-specific T cells using acoustic forces. Conclusions: These findings indicate that melanoma-specific T cells bind with a higher avidity than non-specific T cells and that they can be separated with this approach. In conclusion, we demonstrate a novel method to measure cell avidity and sort cells by utilizing acoustic forces.
Receptor-triggered lymphocyte apoptosis PC to replace Cy/Flu PC for CART.
Authors: Deisher Theresa , Ashok Arya , Jarzyna Peter , Zahid Yumna , Poulin Kendra , Lee-Diaz Stephanie , Parthasarathy Vaishnavi , Taylor Margaret
Published: May 2019

e14011

Background: Chimeric antigen receptor T-cell (CAR-T) therapy is a relatively novel regimen for the treatment of acute lymphoblastic leukemia that has already shown promising results. Two FDA-approved CAR-T therapies, Kymriah and Yescarta have an 80% success rate in sending patients into remission. However, both of these treatments require preconditioning (PC) with chemotherapy to ensure CarT expansion and engraftment. Chemotherapy severely compromises patient’s immune-system, a further economic burden up to $70K per patient due to hospitalization, and fuels side effects of CAR-T therapy such as cytokine release syndrome (CRS) and neuroedema, driven by the release of IL-6 and GM-CSF respectively. Also, up to one third of cancer patients are too frail to tolerate chemotherapy and do not qualify for potentially life-saving therapies. A single acute dose of AVM0703 induces lymphodepletion equivalent to chemotherapy, and transiently eliminates the sites in the spleen where therapeutic cells accumulate without inducing toxicities associated with chemotherapy. Methods: Mice with subcutaneously implanted melanoma were preconditioned with AVM0703 prior to treatment with a mouse Pmel CAR-T therapy. Tumor growth was tracked and spleens were analyzed after dissection for binding of labeled CAR-T cells. In a separate study, four human patients were dosed with low doses of AVM0703 and the levels of released cytokines in the blood were quantified. Results: The mice demonstrated reduced T-cell sequestration in the spleen as noted by a reduction of fluorescently labeled cells. AVM0703 alone significantly delayed tumor growth, and as PC before Pmel T-cells, dramatically improved CAR-T-driven delay of tumor growth. In humans, a significant increase in beneficial IL-2 and IL-15 was observed, as well as a lack of released IL-6. In addition, existing literature demonstrate that AVM0703 reduces the release of GM-CSF. Conclusions: AVM0703 shows efficacy as preconditioning agent in a mouse solid tumor model of melanoma, reduces the binding of CAR-T cells in the spleen, and stimulates the release of beneficial cytokines. AVM0703 could be a non-toxic, effective preconditioning agent for patients receiving CAR-T therapy.
Safety and efficacy of PD-1 blockade-activated multiple antigen specific cellular therapy alone or in combination with apatinib in patients with advanced solid tumors: A pooled analysis of two prospective trials.
Authors: Liang Lijun , Wen Yixuan , Hui Kaiyuan , Jiang Xiaodong
Published: May 2019

e14014

Background: The cancer-cell-killing property of Multiple Antigen Specific Cellular Therapy (MASCT) may be enhanced by blocking PD-1 in vitro and reversing vascular endothelial growth factor (VEGF)/VEGF receptor 2-mediated immunosuppression with apatinib. We analyzed pooled data from our phase Ⅰ/Ⅱ trials to assess the toxicity and efficacy of PD-1 blockade (SHR-1210)-activated MASCT (aMASCT) alone or in combination with apatinib in patients with advanced solid tumors. Methods: Patients with selected types of advanced solid tumors received aMASCT alone (n = 32) or aMASCT plus apatinib (500 mg q.d., n = 38) after standard treatment. The primary endpoint was the safety profile; antitumor response, progression-free survival (PFS), and overall survival (OS) were the secondary endpoints. Circulating regulatory T cells (Tregs) were quantified before and after aMASCT infusion. Results: Treatment-related adverse events (AEs) occurred in 18/32 (56.3%) and 25/38 (65.8%) patients in the aMASCT and aMASCT plus apatinib groups, respectively; fever and chills were the most frequently observed AEs. No serious AEs were reported, and apatinib did not increase immunotherapy-related toxicity. The objective response rate was improved with aMASCT plus apatinib group compared with aMASCT group (34.2% and 18.8%, respectively); PFS was longer (median, 6.0 and 4.5 months, respectively, P < 0.05), but OS was not improved (median, 10.0 and 8.2 months, respectively, P = 0.098). Multivariate analyses indicated that two or more cycles of aMASCT treatment was an independent favorable prognostic factor of PFS and OS. Circulating Tregs decreased in both groups after one cycle of aMASCT treatment (P < 0.05). Conclusions: Treatment with aMASCT plus apatinib was safe and effective in advanced solid tumors. Apatinib plus aMASCT may be beneficial for patients with advanced solid tumors. Clinical trial information: NCT02844881; NCT02858232.
Phase Ia clinical trial of adoptively transferring peripheral blood-derived cytotoxic T lymphocytes targeting individual neo-antigens to treat patients with advanced solid tumor.
Authors: Li Bo , Zhang Xiaoshi , Liu Geng , Qiu Si , Liang Zhaoduan , Liu Mingming , Gao Yan , Xu Rui-hua
Published: May 2019

e14025

Background: Adoptive transfer of tumor infiltrating lymphocytes (TILs) targeting neo-antigens mediates complete and durable regression of solid tumor. However, the limited availability of fresh tumor samples hinders the application of TILs treatment. Based on neo-antigen specific T cells occurring in the circulation, we carried out a phase Ia clinical trial that adoptive transfer of peripheral blood-derived cytotoxic T lymphocytes (CTLs) targeting individual neo-antigens administrated patients with advanced solid tumor. Methods: This phase Ia clinical trial (NCT02959905) is designed to test the safety and objective response of CTL targeting individual neo-antigens treatment. Patients underwent apheresis on day -25, 0, 25, 50, 85 and 110, then CD8+T cells were isolated from peripheral blood and co-cultured with autologous dendritic cells pulsed with neo-antigens, which generated the infused CTLs targeting neo-antigens. On day 0, 25, 50, 85, 110 and 135, patients received CTLs respectively, which were prepared prior to 25 days. Patients received evaluations on day 55 and 140, and were followed up from day 150 for 32 weeks. The survival of the infused CTLs was analyzed according to the sequence of CDR3 regions of the T-cell receptor. Results: Until October 16th, 2018, a total of 10 patients were enrolled, 9 patients were infused 0.35-4×108 of CTLs for 1-6 times in this trial, in which 8 cases were metastatic melanoma and 1 case was colorectal cancer. Of the 10 participants who were enrolled, 7 participants had been evaluated, in which 1 case was evaluated as partial response (PR), 1 case was evaluated as iPR (evaluated as PR based on iRECIST), 3 cases were evaluated as stable disease (SD), 2 case were evaluated as progression of disease (PD), the objective reaction rate was 28.57%, and the disease control rate was 71.4%. All the subjects had safe tolerance, and the highest grade of adverse events related to adoptive cell transfer was grade 2. Neo-antigen specific CTLs persistently occurred in peripheral blood of 2 participants with PR or iPR for 140 days. Conclusions: Adoptively transferring peripheral blood-derived cytotoxic T lymphocytes targeting individual neo-antigens to treat patients with advanced solid tumor was safe under our current dose and preliminarily efficient. Clinical trial information: NCT02959905.
Influence of agomelatine and trastuzumab on the HER2/neu(+), MT1 (+) and MT2 (+) chemo and immunoresistant breast cancer cells lines from the previously treated patients by targeted therapy with trastuzumab.
Authors: Tavartkiladze Alexandre , Revazishvili Pati , Gvajaia Ani
Published: May 2019

e14056

Background: Agomelatine is a melatonin receptor agonist (MT1 and MT2) and a 5-HT2C receptor antagonist. Melatonin is a lipophilic compound that is capable of binding to cell surface receptors, cytosolic sites (calmodulin), and directly to nuclear DNA binding sites (nuclear receptors RZR/RORα). Its direct antioxidant, antimitotic, antiestrogenic, prodifferentiating and antimetastatic effects have been well characterized. Nitric oxide (NO) is an inorganic free radical gas synthesized from L-arginine by a family of isoenzymes called NO synthases. Two of these are constitutively expressed and a third is inducible by immunological stimules. The NO released by the constitutive enzymes acts as an important signaling molecule in the cardiovascular and nervous systems and NO released by the inducible NO synthase (iNOS) is generated for long periods, by cells of the immune system among others, and has been shown to be cytostatic/cytotoxic for tumor cells and a variety of microorganisms. Methods: We have studied oncostatic/citostatic influence by ATP-TCA method of agomelatine and agomelatine + trastuzumab solution on the cellular cultures Her2/neu (+), MT1 and MT2 receptor (+) mammary ductal adenocarcinoma (17 cases). Data of ATP-TCA test in healthy patients breast’s cellular cultures with only trastuzumab were used as control. In parallel, we have studied expression of enzyme universal nitric oxide synthase (u-NOS) in cellular cultures of mammary ductal adenocarcinoma all three cells lines using Western blot method. The findings were compared to the data of u-NOS expression in healthy patients breast’s breast cellular cultures. Results: The study demonstrated that influence of citostatic effect of only agomelatine by ATP-TCA method are increased by 32.5% and citostatic effect of agomelatine + trastuzumab by ATP-TCA method also are increased by 45% in compared to control. Expression of universal nitric oxide synthase (u-NOS) is increased in case of mammary ductal adenocarcinoma by 14.2% in case only agomelatine and by 26.7% in case agomelatin + trastuzumab compared to control. Conclusions: Results of this research describe the positive role of agonists melatonin receptors (agomelatin) in the treatment previously treated and after progressed breast cancer (while this mechanism in details is unknown for us) and increased expression of NOS indicate the possibly augmentation sensitivity the cells lines for the citostatics medicines.
Expecting the unexpected.
Authors: Nelson Blessie Elizabeth , Murphy Adrian Gerard , Zimmerman Jacquelyn W.
Published: May 2019

e14066

Background: Myasthenia gravis is an autoimmune neuro-muscular disorder traditionally seen in bi-modal distribution in young women or older men. Discovery of immunotherapy has brought hope in survival outcomes for patients with malignant melanoma, lung, renal and head/neck cancers but it also opens Pandora’s box of immune-related toxicities for which early recognition and appropriate clinical management are paramount. Here we describe a case of immunotherapy induced myasthenia gravis de novo. Methods: A 77-year-old man with HPV+ stage IVA squamous cell carcinoma of the tongue presented with sudden onset orthopnea and dyspnea on exertion for the past day. One week ago, he received his second cycle of nivolumab as part of his neoadjuvant therapy. He was seen at an outside hospital and was found to be acute hypercapnic respiratory failure and placed on BiPAP. He was started on antibiotics for community-acquired pneumonia with levofloxacin and doxycycline and transferred to a tertiary care center for further management. On further evaluation, he endorsed diplopia, blurry vision, fluctuating muscle weakness that is worse at the end of the day, change in voice and proximal muscle weakness. His exam was consistent with bilateral ptosis, weak hip flexion and shoulder abduction, positive sniff test and poor vital capacity and negative inspiratory force values suggestive of impending respiratory and diaphragmatic failure secondary to myasthenic crisis. He was admitted to the ICU and placed on BiPAP and frequent NIF and VC monitoring. He was started on pyridostigmine but showed no clinical improvement on day 1 and hence was initiated on plasmapheresis from day 2 for a total of 10 days. Results: Investigations showed positivity of Ach-R modulating and binding and blocking antibodies with negative voltage gated calcium channel antibodies. EMG revealed decrement of the compound muscle action potential in the repetitive stimulation test indicative of myasthenia gravis. He responded well to the above treatment and underwent successful left partial glossectomy and weaned off mechanical ventilation and has been cancer free so far. He is doing well on maintenance prednisone and pyridostigmine. Conclusions: There is a significant 30.4% MG-specific-related mortality due to immunotherapy alone which this case demonstrates the importance of vigilance and early detection for effective treatment and management. It highlights need for the oncological world and our colleagues in various other disciplines of healthcare to identify and mitigate the effects of immunotherapy which has become our hope in beating cancer.
SLAMF8, a novel biomarker for personalized immune checkpoint blockade therapy in gastrointestinal cancer.
Authors: Zhang Qun , Cheng Lei , Hu Jing , Li Li , Yang Mi , Kong Linghui , Yu Lixia , Wei Jia , Liu Baorui , Qian Xiaoping
Published: May 2019

e14078

Background: Immune checkpoint inhibitors have brought great breakthroughs in cancer therapy. Activated immune response is known to be the prerequisite for exerting immunotherapy efficacy. Epstein-Barr virus (EBV) infection is associated with longer survival in gastric cancer (GC) patients due to enhanced anti-tumor immune response, and therefore it was reportedly played an important role in modulating immune checkpoint blockade therapy efficacy. However, molecular dimensions underlying the good response to immune checkpoint inhibitors in presence of EBV infection are still unclear. The aim of this study is to identify a gene signature related to EBV induced anti-tumor immune response, and select a tag gene from this signature to predict which patients are most likely to benefit from immune checkpoint blockade therapy. Methods: Two large transcriptome datasets from Gene Expression Omnibus(GEO) database (GSE51575 and GSE62254) were used to screen gene signature for EBV infected gastric cancer tissues. We further selected genes that showed a trend towards differential co-expression independent of EBV infection status. The tag gene of this differential co-expression signature was finally identified by bioinformatics analysis. To make an external validation, we performed RNA sequencing in 20 colorectal caner (CRC) tissues and 20 GC tissues, respectively. Meanwhile, tissue microarrays of CRC cohort (36 paired tumor and normal tissues) and GC cohort (75 paired tumor and normal tissues) were used to analyze the association of SLAMF8 with CD8 protein expression by immunohistochemistry (IHC). Results: Analysis of GEO datasets indicated 788 genes as feature gene cluster for EBV-positive gastric cancer, from which 290 genes were selected to be characterized by differential co-expression in either EBV-positive or EBV-negative gastric cancers. SLAMF8 was identified as the tag gene for this differential co-expression signature. This signature, tagged by SLAMF8, was successfully validated by our RNA sequencing data in presence of its good performance in dividing CRC and GC patients into two subsets. Moreover, we observed a significant association between SLAMF8 and CD8 expression in our CRC and GC tissue samples, in terms of either mRNA or protein level. Conclusions: SLAMF8, a potential indicator for T cell‐mediated immune response induced by EBV infection, may be served as a biomarker for individualized immune checkpoint blockade therapy in gastrointestinal cancer. Further SLAMF8 guided drug sensitivity tests are warranted to validate our results.
Immunotherapy: Auto-immune toxicity as a predictive factor of response.
Authors: Valery Marine , Vallet Emilie , Lassoued Donia , Maingon Philippe , Tilleul Patrick , Spano Jean-Philippe , Bellanger Agnes , Gobert Aurelien
Published: May 2019

e14086

Background: PD-1 and PD-L1 inhibitors have now demonstrated their efficacy. Finding predictive or pre-emptive response factors is crucial and the role of immune-related adverse events (irAEs) is widely debated. The aim of our study was to evaluate the correlation between the occurrence of irAEs and overall survival, according to the time of onset. Methods: We retrospectively collected efficacy and safety data from patients treated with nivolumab, pembrolizumab and atezolizumab for metastatic cancer between July 2015 and January 2019 at the Pitié-Salpêtrière Hospital. Progression-free survival (PFS) and overall survival (OS) were analyzed for the global population, for patients who had an irAES, according to the time of onset (before or after 12 weeks). Results: 158 patients were treated with anti-PD1/PD-L1: 125 patients for NSCLC, 12 for melanoma, 11 for clear cell renal cancer, 5 for bladder cancer, 3 for digestive adenocarcinoma and 2 for mesothelioma. At the cut-off analysis, with a median follow-up of 8.6 months, 63 (40%) patients died, 30(19%) had a progressive disease, 31 (20%) were still receiving an immunotherapy. 25(18%) patients developed irAEs, 18(72%) before 12 weeks of treatment and 7(28%) after. 6 patients had to stop the treatment because of irAEs and 3 of them were still on immunotherapy at the cut-off analysis. Progression disease occurred in 7 patients and 9 died under treatment. Only a trend of efficacy was found between patients with irAEs and those without, with a median PFS of 13.2 vs 9.8 months (HR 1.3; p = 0,4) and a median OS of 28 vs 20 months (HR 1.4; p = 0,4). This statistically non-significant trend was found for OS between patients with an early irAEs and those without any toxicity with a median OS of 28 vs 20 months (HR 1.4; p = 0,8). No statistically difference was found between patients with early irAEs and late irAEs. Conclusions: In our study, 18% of the patients had irAEs. Patients with irAEs seemed to have better OS and PFS but no statistically difference was found. This trend is probably related to patients with late toxicity, which reflects the time of treatment and the increasing probability to develop an irAEs. In our study, early irAEs could not be considered as a reliable preemptive factor of response to immunotherapy.
Association of immune-related adverse events with immune checkpoint inhibitor efficacy in pancancer.
Authors: Ou Qiyun , Yu Yunfang , Zhong Haitao , Li Anlin , Chen Yongjian , Zhou HaiYu , Zheng Shaopeng , Huang Luyu , Yao Herui
Published: May 2019

e14087

Background: Immune-related adverse events (irAEs) have been shown to be associated with the efficacy of immune checkpoint inhibitors in patients with advanced cancer, but the reported effect sizes have varied greatly in previous trials. We did a meta-analysis to assess immune checkpoint inhibitors efficacy and further explored the correlation of irAEs with efficacy in cancer. Methods: We systematically searched database inception to January, 2019 for randomized trials of immune checkpoint inhibitor in patients with advanced cancer that had available data for overall survival (OS) and progression-free survival (PFS), and irAEs. We calculated the pooled hazard ratios (HRs) and 95% confidence intervals [CIs] using a random-effects model, and assessed the association between the irAEs and PFS or OS using coefficient of determination ( R²). The PROSPERO registry number is CRD42017075610. Results: Thirty eight trials with 19,521 patients were included. Compared with conventional therapy, anti-PD-1 or PD-L1 combined with conventional therapy significantly enhanced survival (HR = 0.62, 95% CI 0.53 to 0.72 for PFS; HR = 0.71, 95% CI 0.58 to 0.87 for OS), and anti-PD1 or PD-L1 combined with anti-CTLA4 (HR = 0.75, 95% CI 0.63 to 0.90 for PFS). Anti-CTLA4 plus conventional therapy prolonged PFS (HR = 0.80, 95% CI 0.72 to 0.89) and OS (HR = 0.80, 95% CI 0.66 to 0.96) than conventional therapy alone. Anti-PD1 or PD-L1 outperformed anti-CTLA4 on OS (HR = 0.68, 95% CI 0.57 to 0.81). Significant correlation between treatment efficacy and irAEs was only identified in pneumonitis ( R2 0.59, P = 0.026 for PFS) and diarrhea ( R2 0.22, P = 0.006 for OS). Conclusions: We recommended the concurrent use of immune checkpoint inhibitor and conventional therapy or dual immunotherapy as the most appropriate regimens for advanced cancer. Furthermore, development of pneumonitis and diarrhea were associated with survival outcome of immune checkpoint inhibitors in patients with advanced cancer.
Response rate to chemotherapy after disease progression with anti-PD-1/PD-L1 in metastatic cancer.
Authors: Al-Kadhimi Munaf , Hensing Thomas A. , Shevrin Daniel H. , Hanson Britt Erika , Campbell Nicholas Paul , Brockstein Bruce
Published: May 2019

e14088

Background: The checkpoint inhibitor (CPI) immunotherapy class of drugs is redefining how we treat cancer. The US FDA has approved CPI drugs as 1st, 2nd or salvage line after progression on conventional chemotherapy (CTX) for multiple cancers including melanoma, lung, bladder and other cancers. However, many questions remain regarding optimal treatment post-progression. Indeed, it has been noted that the patterns of response and relapse to CPI agents are quite different from those of standard cytotoxic agents and that response to CTX AFTER CPI may be different than in the de novo setting. The purpose of this retrospective analysis is to evaluate the activity (response rate (RR), response duration (DOR) and progression free survival (PFS)) of subsequent CTX after disease progression following treatment with CPI. Methods: In this analysis, patients (pts) were enrolled under an IRB approved waiver of consent. We identified pts treated with CPI agents between Jan, 2011 and Dec, 2018 at a multi-site community cancer program who received subsequent CTX as a result of disease progression (PD). We assessed the RECIST RR to subsequent therapy, DOR from onset of response, and PFS from the onset of post CPI CTX, identifying index lesions from the most recent pre-treatment anatomic scan. Results: A total of 47 cases satisfying the above criteria were found; 31 NSCLC, 8 melanoma, 1 SCLC, 1 GEJ, 1 gastric, 2 head/neck, 1 large cell neuroendocrine tumor, 2 bladder cancer. 25 pts had PD as best response to post-CPI CTX. 9 pts (19%) achieved a partial response (PR) with a median DOR of 99 days. 22 pts achieved a PR or stable disease (SD) for a clinical benefit (CB) rate of 47%. The median duration of CB was 92 days. Of the 9 patients who achieved PR, 5/6 had achieved response to CTX prior to CPI . The median PFS for the entire cohort was 97 days. Conclusions: While an expected RR could not be calculated in this heterogenous group of pts, the number and degree of responses suggests CPI possible “priming” that may enhance response to CTX. Post-CPI CTX may be of value and in this retrospective study of a heterogenous group of pts, responses may be more frequent than expected. A larger further study is warranted.
Therapeutic drug monitoring of nivolumab in clinical practice: Preliminary experience.
Authors: Sureda Manuel , Catalán-Latorre Ana , Mata Juan José , Escudero Vanesa , Brugarolas Antonio
Published: May 2019

e14089

Background: Fixed dose schemes, regardless of body weight, have been accepted by the regulatory agencies for the PD-1 targeting antibodies. Zaho X. and Ratain M. have elucidated that the mean steady state concentrations of nivolumab (N) at flat-doses of 240 mg Q2W or 480 mg Q4W were 57 µg/mL and 47 µg/mL, respectively. These levels are very similar to those observed at the dosage of 3 mg/kg Q2W. Considering the long half-life of N, its mechanism of action and the absence of correlation between exposure and response or toxicity at clinically tested doses, other schemes can be explored. Moreover, therapeutic drug monitoring (TDM) can contribute to individualize and optimize dosage. We determined serum N levels in patients with solid tumors. Methods: The PK profile of N was analyzed in 15 patients with solid tumors who received 3 mg/kg Q2W from May 2017 through January 2019. Eligible patients had non-small-cell lung cancer (n = 7), urothelial cancer (n = 1), gastric cancer (n = 1), breast cancer (n = 1), renal cell cancer (n = 1), colorectal cancer (n = 1), prostate cancer (n = 1), melanoma (n = 1) and sarcoma (n = 1). Free N serum concentrations were determined with a quantitative ELISA capable of detecting ≥ 0.3 µg/mL (Shikari Q-Nivo, Matriks Biotek, Ankara, Turkey). A total of 28 TDM were done after steady state (6th and 26th cycle). Results: For different reasons, 9 patients received N at 3, 4, 5, 6 or 7 week intervals once the steady state was reached. In these patients, a median reduction of 20.8% (6.7% - 43.0%) of the received doses was observed. Mean plasma concentrations of N observed after administration every 2 weeks was 73.5±32.5 µg/mL (n = 9). Once the steady state was reached, mean plasma concentrations at 3, 4, 5, 6 or 7 weeks, were 54.0±1.3 µg/mL (n = 2), 45.1±25.3 µg/mL (n = 7), 42.9±29.5 µg/mL (n = 5) and 24.4±11.7 µg/mL (n = 5), respectively. No statistically significant differences were observed in the serum levels of N between the dosing intervals of 3, 4 and 5 weeks and the standard regimen (Q2W) (p > 0.05). These data are similar to those described by Long G.V. et al. that compared N pharmacokinetic exposure for the 480 mg Q4W schedule simulated in 3817 patients across multiple tumor types with those for the 3 mg/kg Q2W and 240 mg Q2W schedules. Conclusions: The incorporation of the TDM of N in routine clinical practice could help to maintain a therapeutic drug plasma concentration with lower or less frequent doses, adding a financial benefit, without decreasing clinical efficacy. Further randomized trials to explore alternative dosing schemes of N, including personalization through TDM, are warranted
A retrospective cohort study of anti-PD-1 therapy combined with chemotherapy in patients with advanced biliary tract cancer.
Authors: Sun Danyang , Ma Junxun , Wang Jinliang , Han Chun , Qian Yuanyu , Chen Guangying , Li Xiaoyan , Zhang Juan , Cui Pengfei , Du Wushuang , Wu Zhaozhen , Chen Shixue , Zheng Xuan , Yue Zhichao , Song Jia , Zhao Xiaochen , Cai Shangli , HU YI
Published: May 2019

e14100

Background: Biliary tract cancer (BTC) is highly aggressive with poor prognosis and few treatment options following progression on gemcitabine-based chemotherapy. Disappointing results from clinical trials for refractory BTC highlight the need for more effective therapies. Immune checkpoint inhibitor (ICI) has been hailed as a major breakthrough for cancer treatment. However, evidence for the efficacy of immunotherapy in biliary tract cancer (BTC) is limited and unsatisfactory. KEYNOTE-158 trial has merely shown a 5.8% of overall response rate with pembrolizumab monotherapy in advanced BTCs. Thus, combining other therapies with ICIs is becoming the researching focus. Herein, we constructed a cohort to evaluate the efficacy and safety of ICIs combined with chemotherapy in advanced BTCs. Methods: Chinese BTC patients receiving PD-1 inhibitors with chemotherapy, PD-1 inhibitors monotherapy or chemotherapy alone were retrospectively analyzed. The primary outcome was overall survival (OS). The key secondary outcome were progression-free survival (PFS) and safety. Patients previously treated with any agent targeting T-cell co-stimulation or immune checkpoints were excluded. Results: The study included 77 patients (PD-1 inhibitors plus chemotherapy, n = 38; PD-1 inhibitors monotherapy, n = 20; chemotherapy, n = 19). Median OS was 14.9 months with PD-1 inhibitors plus chemotherapy, 4.1 months with PD-1 inhibitors and 6.0 months with chemotherapy, with significantly longer for anti-PD-1 combination therapy than monotherapy (HR 0.37, 95% CI 0.17-0.80, P= 0.001) or chemotherapy (HR 0.63, 95% CI 0.42-0.94, P= 0.011). Median PFS was 5.1 months with PD-1 inhibitors plus chemotherapy, 2.2 months with PD-1 inhibitors and 2.4 months with chemotherapy, with significant difference for anti-PD-1 combination therapy versus anti-PD-1 monotherapy (HR 0.59, 95% CI 0.31-1.10, P= 0.014) or chemotherapy (HR 0.61, 95% CI 0.45-0.83, P= 0.003). Grade 3 or 4 treatment-related adverse events were similar between anti-PD-1 combination group and chemotherapy group (34.2% and 36.8%). Conclusions: PD-1 inhibitors plus chemotherapy is effective and tolerable for advanced BTC.
Impact of pericardial effusion for patients receiving immune checkpoint inhibitors.
Authors: Khan Abir , Zhang Henry , Chen Christopher , Morgan Jacob , Zarifa Abdulrazzak , Shahid Marwah , Song Juhee , Naing Aung , Lopez-Mattei Juan , Durand Jean-Bernard , Kim Peter Y. , Iliescu Cezar , Palaskas Nicolas
Published: May 2019

e14121

Background: Various immune-related adverse events (IRAE) have been reported with the use of immune checkpoint inhibitors (ICI). Although a rare event, the increasing incidence of ICI related myocarditis and its reported high mortality raises concern. Cardiovascular IRAE such as pericardial effusions (PE) have been documented in case reports and case series but their clinical significance is unclear. Methods: Retrospective chart review was performed on 1075 patients receiving ICI between 2015 and 2017 with baseline echocardiograms without pericardial effusions and follow up echocardiograms at MD Anderson Cancer Center. We collected baseline characteristics, laboratory findings, echocardiograms, and dates of ICI initiation, PE development, last follow up and death. Overall survival (time from first ICI therapy to death or last follow up) was calculated. Univariate Fine-Gray regression analyses were conducted to identify variables associated with PE to account for death as a competing risk event. A p-value of less than 0.05 indicated statistical significance. Results: After initiation of ICI, 78 patients (7.3%) developed PE of which 45 patients died (58%) compared to 347 deaths (35%) out of the 997 patients without PE. The median follow-up time was 445 days. Univariate Fine-Gray analyses predicting PE demonstrated lower body surface area, lowest nadir in left ventricular ejection fraction (LVEF), higher troponin levels, lower platelet counts, absence of ectopy and hyperlipidemia, and lack of avelumab in therapy as well as a history of heart failure with preserved or reduced ejection fraction, hematologic cancer, and peripheral artery stents were significantly associated with higher incidence of PE. Conclusions: While the development of PE is an IRAE or progression of cancer itself cannot be determined, this study indicates patients receiving ICI who developed PE had higher mortality. Those with greater troponin levels and substantial decline in LVEF were shown to have a greater propensity of developing PE, suggesting the possibility of an underlying myopericarditis. If PE develops during ICI therapy, providers should consider an expedited workup and treatment of ICI related myocarditis.