bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of activating chimeric receptor on IL-15 armored NK cell on providing in vitro and in vivo antigen specific tumor response.
Authors: Chai Louis F. , Guha Prajna , Wadsworth Sarah , Gonzalez Denise , Rahman Nafees , Heatherton Kara R. , Tan Joanne B.L. , Trager James , Ghosh Chandra C. , Katz Steven C.
Published: May 2020

e15016

Background: Colorectal cancer liver metastases (CRCLM) are a major source of morbidity and mortality. Historically, curative therapy has been limited to surgical resection, but only a small fraction of patients are eligible. Cellular immunotherapy has shown promise in hematologic cancers, but challenges related to solid tumor therapy remain with optimal cell trafficking, elevated interstitial fluid pressures (IFP), and immunosuppression. We hypothesized that engineered natural killer (NK) cells expressing a natural killer group 2, member D (NKG2D) activating chimeric receptor (ACR) and membrane bound IL-15 (NKX101) would increase anti-tumor activity in vitro and in vivo utilizing our established regional delivery strategies. Methods: In vitro cytotoxicity and cytokine release of NKX101 cells or non-transduced NK cells (NT-NK) derived from the same donor were determined by co-culture systems with HCT116 cells that endogenously express NKG2D ligands. CRCLM-bearing NSG™ mice were treated with NKX101, NT-NK, or vehicle (CTRL) via portal vein (PV) for regional delivery (RD) or tail vein (TV) for systemic delivery (SD). Tumor burden (TB) was measured via tumor bioluminescence (TBL) and histopathology (HP). Flow cytometry (FC) determined the quantity of cells delivered. Student’s t-test and Mann-Whitney tests were performed for statistical comparisons. Results: NKX101 transduction efficiencies ranged between 63.5 – 75.6% across 3 separate healthy donors. EC50 values derived from a 4-hour cytotoxicity assay for NKX101 vs. NT-NK were 3-4 fold lower with the greatest difference observed at the 1:1 effector-to-target (E:T) ratio (mean percent cytotoxicity: 72% vs. 20%, p = 0.001). In vitro cytokine assessment revealed 2.0-2.6 fold increases in IFN-γ, GM-CSF, and TNF-α levels compared to NT-NK cells (p < 0.0001 across all groups). In vivo, FC showed 2.89-fold increase in cell delivery using RD vs. SD on PTD1 (n = 3, p = 0.006). TBL was improved with 5 x 106 cells via PV vs. TV (n = 6) from post-treatment day (PTD) 1-7, with greatest difference seen on PTD7 (12.9 vs. 42.6, p = 0.07). HP analysis showed reduction of TB at PTD7 with PV treatment. Conclusions: NKX101 demonstrated improvements in in vitro cytotoxicity and pro-inflammatory cytokine release. RD techniques in vivo revealed increased cell delivery and improved tumor control. Further studies are underway to confirm our initial findings and understand NKX101 cellular kinetics and susceptibility to immunosuppression in the liver, along with planned clinical evaluation in Phase 1 trials.
Dominant negative PD1 armored CART cells to induce remission in relapsed or refractory non-Hodgkin lymphoma (NHL) patients.
Authors: Pu Chengfei , Huang Liansheng , Su Yang , Ding Tianling , Xiao Xibin , Jin Lina , Cao Zhiyuan , Wu Ting , Chen Tong , Ding Luying , Zhang Xiaohong , Lan Haifeng , Wu Zhao , Xiao Lei
Published: May 2020

e15028

Background: The chimeric antigen receptor (CAR) T cell treatment has been demonstrated as an effective therapy to treat relapsed/refractory B cell malignancy. However, tumor microenvironment influences and affects the efficacy of CAR T treatment. For example, programmed death ligand 1/2 (PDL1/2) may inhibit the CAR T cells via interaction with up-regulated programmed cell death protein 1 (PD1) after T cells activation, suppressing the tumor-killing capability of the CAR T cells. Thus, blockade of the PD1-PDL1/2 interaction may enhance the anti-tumor efficacy of CAR T therapy. Methods: Here, we generated CAR T expressed an anti-CD19 CAR molecule and a dominant-negative PD1 molecule. Compared with conventional CART cells, these “armored” CART cells showed the enhanced capability of tumor-killing and more “memory-like” phenotypes after multiple-round tumor challenging. These results suggest dominant-negative PD1 molecules may protect CART cells from exhaustion in the tumor microenvironment. Results: Further, we reported the findings of a clinical trial for six relapsed or refractory B-cell non-Hodgkin lymphoma (NHLs) patients treated using our armored CAR T cells. These six patients failed multiple rounds of chemotherapy and radiotherapy. In the clinical trial, the patients were infused with autologous CAR T cells range from1×106/kg to 8×106/kg. PET/CT showed significant tumor shrinkage and SUV max declines in all six patients, and the ongoing responses were monitored. The best overall response rate (ORR)was 100%. Conclusions: The results of these six patients in the clinical trial showed that our armored CAR T cells achieved the significant anti-bulky lymphoma response while causing limited and tolerated cytokine release syndrome and central nervous system toxicity. Thus, dominant-negative PD1 molecules may increase CAR T cells persistence in patients, enhancing the efficacy of CAR T cells for treating blood cancer. Finally, dominant-negative PD1 can be used as a platform technology and may be applied to other adoptive cellular immunotherapies such as TCR-T or TIL in the treatment of solid tumors. We are continuing to monitor current patients and recruit more patients for the clinical trial.
The landscape of gene fusions and the correlation with immunotherapy biomarkers in Chinese patients with advanced solid tumor.
Authors: Liu Wenshuai , Zhou Yifan , Zhang Bei , Bai Yuezong , Wang Yueqi
Published: May 2020

e15039

Background: Due to the U.S. Food and Drug Administration approval of larotrectinib, a tumor or tissue-agnostic cancer treatment, gene fusions and fusion-driven cancer were identified as indications. Exploration of the gene fusions might be essential in both target therapy and immunotherapy in advanced solid tumor. However, the landscape of gene fusions in Chinese solid tumor patients is poorly reported. Methods: Tissue samples were obtained from 7514 Chinese patients with advanced solid tumor. Genomic alterations were identified via the next generation sequencing (NGS) with a validated commercial 381-cancer-gene panel (panel size over 0.5 MB), including 100 MSI loci. TMB was calculated according to NGS results. Statistical analysis was performed by Fisher exact test using R 3.6.1. Results: There were 162 pathologic or very like pathologic gene fusions observed in 249 (3.31%) patients, covering 30 cancer types. Top frequent fusion genes were ALK (93), RET (32), FGFR2 (26), FGFR3 (13), ROS1 (10), TMPRSS2 (10) and NTRK1 (9). Their main partner genes were EML4 (66/ 93), KIF5B (15/32), BICC1 (5/26), TACC3 (13/13), CD47 (3/10), ERG (9/10) and TPM3 (5/9), respectively. Mostly, only one fusion was detected in one patient. Three patients harbored 3 gene fusions and 35 patients harbored 2 gene fusions, among which 21 patients were observed harboring both fusion and its reciprocal fusion. In the group of patients harboring gene fusions, the prevalence of MSI-H was 4.0% (10/ 249). Especially, the prevalence was significant high (41.2%, 7/ 17) in colorectal cancer patients (P < 0.001). In MSI-H colorectal cancer patients, 4 carried NTRK1 fusions, 2 RET fusions and 1 ALK fusion. And all of them had high tumor mutation burden (TMB). As another immunotherapy response predictor, TMB was low in most solid tumor patients in this study, except for the patients harboring gene fusions involving NTRK1, NTRK2 or STK11, whose TMB-H proportion were 67%, 50% and 33%, respectively. Conclusions: Gene fusions might be associated with MSI-H. In colorectal cancer patients, gene fusions involved either NTRK1 or NTRK2 might be associated with TMB-H, which revealed a potential biomarker for both target and immunotherapy.
Peripheral cytokine as a pan-cancer predictor for immunotherapy with anti-PD-1/PD-L1 antibody.
Authors: Ji Shoujian , Chen Huan , Yang Keyan , Zhang Guanxiong , Zhang Henghui , Xu Jianming
Published: May 2020

e15044

Background: Currently, only a small proportion of cancer patients may benefit from anti-PD-1/PD-L1 immune checkpoint inhibition (ICI), suggesting an urgent need for effective biomarkers. Due to the limited accessibility and heterogeneity of the tissue samples in advanced cancer, predictors as cytokines in the peripheral immune system revealed distinct advantages. Methods: Plasma samples were collected before anti-PD-L1/PD-L1 treatment in two subsets of patients, which comprises 21 esophageal squamous cell cancer (ESCC) patients in the discovery cohort and 61 pan-cancer cases in the validation cohort. A total of 59 immunological factors including cytokines, chemokines, and checkpoints were measured by using a Luminex immunoassay kit. Moreover, tumor infiltrating lymphocytes (TILs) were analyzed using multiplex immunohistochemistry (mIHC) in a subset of tissue samples from the combined cohort. Results: In the discovery cohort of ESCC patients, multiplex Luminex profiling data revealed that soluble PD-L1 and C-C motif chemokine 5 (CCL5/RANTES) were significantly upregulated in patients with clinic benefit at baseline. We therefore tested the predictive and prognostic value of the two peripheral factors, along with their combined signature, “the 2-cytokine signature”. In specific, the signature-high subgroups displayed remarkably increased disease control rate (DCR) and prolonged survival, versus that of the lower subgroups (p < 0.05 for all comparison). More importantly, in the pan-cancer validation cohort, the three signatures exhibited a strong predictive value as well (PD-L1, AUC = 0.71; CCL5/RANTES, AUC = 0.71; the 2-cytokine signature, AUC = 0.72; p < 0.05 for all comparison). Notably, the 2-cytokine signature revealed significant stratification power for overall survival (HR = 0.431, p < 0.05) and progression free survival (HR = 0.423, p < 0.01). Intriguingly, further quantitative analysis of the local tumor microenvironment by mIHC assays revealed a positive correlation between the levels of the 2-cytokine signature and NK cell infiltration. Conclusions: A combined peripheral signature comprising CCL5/RANTES and soluble PD-L1 appears to be an effective pan-cancer biomarker to identify patients who may benefit from anti-PD-1/PD-L1 monotherapy. Further analysis indicated a link between higher peripheral signature and enrichment of NK cells in the local microenvironment. Therefore, peripheral immunological features may play an essential role in guiding patient selection for ICI immunotherapy.
Predicting the efficacy of nivolumab combined with radiation therapy by longitudinal liquid biopsy with artificial intelligence for patients with metastatic breast cancer (translational research of the KBCRN-B-002 trial).
Authors: Kawaguchi Kosuke , Takada Masahiro , Kotake Takeshi , Yoshimura Michio , Uozumi Ryuji , Kataoka Masako , Koyama Takahiko , Tokumasu Reitaro , Kato Hironori , Yoshibayashi Hiroshi , Suwa Hirofumi , Tsuji Wakako , Yamashiro Hiroyasu , Kataoka Tatsuki R , Ishiguro Hiroshi , Parida Laxmi , Morita Satoshi , Toi Masakazu ,   Kyoto Breast Cancer Research Network (KBCRN)
Published: May 2020

e15046

Background: Advances in immuno-oncology (IO), i.e., programmed cell-death protein 1 (PD-1) inhibitors, are revolutionizing cancer treatment by offering hope for a cure. However, the benefit of IO agents in metastatic breast cancer (MBC) remains limited. For immunotherapy to be successful, it is essential to understand the tumor immune contexture. Systemic immune alterations, such as the signature of peripheral blood mononuclear cells (PBMC) and cytokine expression, are one of the hallmarks of successful immunotherapy in MBC. The abscopal effect induced by radiation therapy (RT) is known to be a modulator of systemic immune alterations, and the abscopal effect is considered as a systemic anti-tumor immune response. In this study, we integrated time series multi-omics data in order to identify alteration of the immune signatures after RT combined with nivolumab, a PD-1 inhibitor, using a longitudinal liquid biopsy with artificial intelligence. Methods: This study was conducted as translational research, part of the KBCRN-B-002 trial, which is a multicenter phase Ib/II study evaluating the safety and efficacy of nivolumab in combination with RT in patients with HER2-negative MBC (UMIN: UMIN000026046). Twenty-nine patients were included in the translational analysis set. The multi-omics data included data from RNAseq, mass cytometry (CyTOF) and multiple cytokines, using PBMC, serum and plasma. We collected time series data, which covered the baseline, two weeks after starting therapy, four weeks after starting therapy and the timing of progressive disease. For integrated analysis of the multi-omics data, a machine-learning method was developed. Results: Our integrated analysis (involving a longitudinal liquid biopsy and machine-learning method) identified an apparent cluster of responder groups and alteration of the systemic immune signatures. Single-cell analysis using CyTOF results including the signature of the immune cell composition, effector immune cells and immune suppressor cells. Conclusions: Our method clustered responders well and identified candidates of the systemic immune signatures for actionable hallmarks of RT combined with IO agent by a longitudinal liquid biopsy. Clinical trial information: NCT03430479 .
Association of dynamic changes of methylated SFRP2 in ctDNA with prognosis in advanced gastric cancer.
Authors: Haijiao Yan , Ge Kele , Chen Wenyu , Mao Xizheng , Li Xiaodong , Xiao Mingzhe , Liu Wensong , Wu Jun
Published: May 2020

e15051

Background: Secreted frizzled-related protein 2 (SFRP2) is a tumor suppressor gene and its hyper methylation could cause its inactivation and promote cancer development. However, whether methylated SFRP2 (mSFRP2) in ctDNA could serve as prognostic biomarker for patients with gastric cancer has not been thoroughly studied. Methods: Stage III or IV gastric cancer patients treated with systemic chemotherapy in the Third Affiliated Hospital of Soochow University from 2015 to 2017 were included. The mSFRP2 before and during chemotherapy were dynamically detected from ctDNA by digital polymerase chain reaction-based technologies. Results: In total, 121 patients were enrolled, with 63 in stage III and 58 in stage IV. Baseline median mSFRP2 was higher in stage IV than stage III (64 VS 18 copies/ng, P < 0.001). In stage III GC, the top 50% mSFRP2 population had shorter median disease-free survival (DFS, 11.0 months VS NR; HR, 13.05; 95% CI, 3.05-55.95;) and overall survival (OS, 17.0 months VS NR; HR, 7.80; 95% CI, 1.81-33.60). Similar results were observed in stage IV GC that the median progression-free survival (PFS, 4.0 VS 7.0 months; HR, 2.74; 95% CI, 1.58-4.78) and OS (12.0 VS 16.0 months; HR, 3.14; 95% CI, 1.67-5.92) was shorter in patients with top 50% mSFRP2. During the dynamic monitor along treatment, elevated mSFPR2 was associated with worse PFS (5.0 VS 7.0 months; HR, 2.17; 95% CI, 1.25-3.76) and OS (12.0 VS 15.5 months; HR, 3.51; 95% CI, 1.94-6.35) in stage IV patients. Conclusions: Our study shows the association between SFRP2 methylation and its dynamic change and prognosis in patients with gastric cancer. Our results provide a potential biomarker in ctDNA for prognosis and dynamic monitoring in patients with gastric cancer.
Characterization of the immune tumor microenvironment of HER2-positive breast cancer following treatment with entinostat and immune checkpoint inhibition.
Authors: Roussos Torres Evanthia T. , Sidiropoulos Dimitrios N , Davis-Marcisak Emily , Kagohara Luciane Tsukamoto , Connolly Roisin M. , Stearns Vered , Jaffee Elizabeth M. , Fertig Elana J.
Published: May 2020

e15061

Background: HER2+ breast cancers are known to be less-immunogenic and associated with low response rates to immune checkpoint inhibitors (ICIs). A combination of immunosuppressive signals that prevent cytotoxic T cells from infiltrating the tumor microenvironment (TME) and, low tumor antigen expression, contribute to immunotherapy resistance in this population. Epigenetic modulators can both reexpress tumor antigens and rewire the immunosuppressive environment. We previously used a histone deacetylase inhibitor, entinostat (ENT), in combination with ICIs to reverse the immunosuppressive TME and increase tumor antigen expression in a NeuN HER2+ mouse model of breast cancer. Our results showed that ENT in combination with anti-PD-1, anti-CTLA-4, provided a significant survival benefit compared to either treatment alone. Methods: This current study employs single cell RNA-sequencing on whole tumor samples from mice treated with ICIs and entinostat to investigate the role of epigenetic inhibitors in rewiring the expression of tumor antigens and the cellular landscape of the TME. We generate single cell data over 54,000 cells from 20 tumors treated with entinostat alone or in combination with anti-PD1 and anti-CTLA4 and their combination. Results: Analysis of cells in the TME identifies consistent proportion of monocytes, macrophages, T-cells, Myeloid Derived Suppressor Cells (MDSCs) and Cancer Associated Fibroblasts (CAFs) before and after treatment. Differential expression analysis within the cell types identifies distinct subpopulations and we explore those that are either proportionally higher or lower in each treatment group. Notably, pathway analysis on differentially expressed genes of each cell type identified that combination entinostat and checkpoint treatment increased T cell activation, leukocyte proliferation, myeloid leukocyte and neutrophil migration, and decreased Wnt signaling and histone modifications in tumor cells. These results are being corroborated in patient samples from a parallel clinical trial to provide translational relevance. Conclusions: Our current work provides insights into the transcriptional network within a breast tumor after treatment with ENT+ICIs. We predict our findings will bring us closer to identifying additional therapeutic targets and ultimately improve survival rates of patients with less-immunogenic tumors.
Association of body mass index (BMI) with clinical efficacy of immune checkpoint inhibitors (ICI) in advanced cancer patients: A retrospective analysis.
Authors: Moreira Raphael Brandao , Fernandes Mauricio , Monteiro Mariana Ribeiro , Luiz Francine , Simplicio Erika , Andrade Perla de Mello , Batista Mayara , Lima Letycia , Silva Astrid , Nunez Juliana , Freitas Daniele , Araujo Luiz H. , Aguiar Pedro Nazareth
Published: May 2020

e15066

Background: Obesity is linked to an increased risk of cancer development. The excess of body fatness seems to be associated with alterations in hormonal, metabolic and inflammatory pathways, that may lead to activation of the carcinogenesis process. Previous studies suggested this obesity pro-inflammatory state could improve ICI clinical efficacy. Methods: Baseline characteristics and clinical outcomes were retrospectively collected from advanced cancer patients of any primary site, and treated with ICI in our institution. The BMI was determined for all pts and categorized into 2 groups: obese (BMI≥30) and non-obese (BMI < 30). Primary outcomes were the association of BMI category with overall survival (OS) and progression free survival (PFS) assessed by log-rank statistic, and both were stratified by sex, age, treatment agent and primary tumor site using the Cox-regression. Secondary outcome was the association of BMI with objective response rate (ORR). Results: We collected data from 448 advanced cancer pts - 192 (43%) as normal weight, 159 (36%) as overweight, 78 (17%) as obese and 19 (4%) as underweight. A total of 370 pts (83%) were included in the non-obese group (BMI < 30) and 78 (17%) patients in the obese group (BMI≥30). The majority of pts (387 - 84%) received anti-PD-1/anti-PD-L1; 128 pts (28%) were treated at 1st line and 200 pts (44%) at 2nd line. The obese group experienced longer mOS than the non-obese group - 21.8 months (95% CI NR - NR) vs. 14.9 months (95% CI 8.3 -21.5); HR = 0.82, (95% CI 0.57-1.18, P = 0.28). However, this was not statistically significant and even after stratification. The obese group had an inferior mPFS than the non-obese group - 4.7 months (95% CI 3.8- 5.7) vs. 5.3 months (95% CI 3.45-7.15); - HR = 0.99, (95% CI 0.76 -1.30), P = 0.95. There was no significative difference in mPFS and ORR according to BMI. Conclusions: Although study did not report an improved OS among high BMI pts treated with ICI, our results suggested a trend in survival benefit. The BMI should be explored as a stratification variable in the design of prospective trials with advanced cancer pts and ICI treatment.
Effect of concurrent beta-blocker use in patients receiving immune checkpoint inhibitors for advanced solid tumors.
Authors: Patel Vaibhav G. , Qin Qian , Wang Bo , Gogerly-Moragoda Mahalya , Mellgard George , Zhong Xiaobo , Parikh Anish B , Leiter Amanda , Gallagher Emily J. , Oh William K. , Galsky Matt D. , Tsao Che-Kai
Published: May 2020

e15068

Background: Stress-induced adrenergic signaling suppresses the immune system. In animal model systems, pharmacological beta-blockade stimulated CD8+ T-cell activity, and further, it improved clinical activity of immune checkpoint inhibitors (ICI) in inhibiting tumor growth. Herein, we investigate the effect of beta blockers (BB) on clinical outcomes of patients receiving ICI in advanced solid tumors. Methods: We retrospectively evaluated patients with solid tumors treated with at least 2 doses of ICI at our institution from December 2010 to April 2017. The primary outcome was disease control rate (DCR), as defined by radiographic complete response, partial response, or stable disease, by RECIST 1.1 criteria. The primary predictor was use of BB (β1-selective BB vs. no BB; non-selective BB vs no BB). The primary predictive variable was analyzed using multivariate logistic regression model controlling for several parameters including patient demographics, co-morbidities, ECOG performance status, and tumor type and location of metastases. All tests were two-sided at the significant level of 0.05. Results: We identified 298 evaluable patients with median age of 66.5 (31-95). Of these patients, 200 (67%) did not use BB, 75 (25%) used β1-selective BB, and 23 (8%) used non-selective BB. In multivariate analysis, use of β1-selective BB was significantly associated with improved DCR compared to no BB (ORR 2.43, 95% CI 1.31-4.51, P = 0.005), while use of non-selective BB was not associated with improved DCR (ORR 1.71, 95% CI 0.65-1.47, P = 0.27). Conclusions: The concurrent use of BB may enhance the clinical activity of ICI, particularly β1-selective BB. Our findings warrant further investigation to understand the interaction of β1- and β2-adrenergic signaling and antitumor immune activity, and potentially explore a combination strategy of ICI and BB.
The clinical activity and safety of anlotinib combined with anti-PD-1 antibodies in patients with advanced solid tumors.
Authors: Yuan Min , Fang Juemin , Zhu Zhongzheng , Mao Wei , Wang Hui , Liu Weixing , Qian Hong , Wu Jianguo , Guo Xianling , Xu Qing
Published: May 2020

e15081

Background: Anlotinib (AL3818) is a novel multi-target tyrosine kinase inhibitor (TKI) for tumor angiogenesis and tumor cell proliferation. Modulation of vascular endothelial growth factor-mediated immune suppression via angiogenesis inhibition may augment the activity of immune checkpoint inhibitors. We reported results from the clinical activity and safety of anlotinib combined with anti-PD-1 antibodies in patients with advanced solid tumors. Methods: 21 patients with advanced lung, gallbladder, endometrial, gastric, pancreatic, penile cancers and melanoma were treated since January 2019. Patients received a combination of anlotinib (12mg) once daily on day 1 to day 14 (21 days as a course) plus anti-PD-1 antibodies every 3 weeks until progression or unacceptable toxicity. Radiologic imaging was performed every 6 weeks for the first year of therapy. Results: Among 21 enrolled patients, 11 tumor types were represented, with lung, gallbladder, endometrial cancers and sarcoma being the most common.Most patients had received prior systemic therapy for metastatic disease (76.2%). The objective response rate (ORR) was 19.1%, including one complete responses (CR) (4.8%) and three partial responses (PR) (14.3%) and a disease control rate (DCR = CR+PR+SD) of 81.0% (17 of 21). One CR and three PRs have lasted 4, 4, 5 and 8 months, respectively. Thirteen patients (61.9%) had stable disease (SD) that lasted 1.5 to 13 months. Treatment-related adverse events occurred in 12 patients (57.1%). Three patients (14.3%) had grade 3 treatment-related adverse events. There were no grade 4 and 5 treatment-related adverse events. Grades 3 toxicities included hand-foot syndrome (n = 1) and hypertension (n = 2). Conclusions: anlotinib can be administered combined with anti-PD-1 antibodies with acceptable toxicity and promising durable antitumor efficacy that warrant further testing in a randomized trial.
Incidence and risk of colitis with programmed death-1 versus programmed death-ligand 1 inhibitors for the treatment of cancer.
Authors: Miyashita Hirotaka , Mikami Takahisa , Satoi Sera , Cruz Christina , Galsky Matt D.
Published: May 2020

e15087

Background: Programmed death 1 (PD-1) inhibitors and Programmed Death-Ligand 1 (PD-L1) inhibitors are immune checkpoint inhibitors (ICIs) approved for treatment of several different cancers. Colitis is a major immune-related adverse event associated with ICIs, but the risk of colitis with PD-1 versus PD-L1 inhibitors is not well characterized. Methods: We performed a meta-analysis for the incidence of all grade and grade 3-4 colitis with PD-1 inhibitor (nivolumab, pembrolizumab, and cemiplimab) or PD-L1 inhibitor (atezolizumab, avelumab, and durvalumab) monotherapy using a fixed effects model. We also conducted subgroup meta-analyses of non-small cell lung cancer (NSCLC) or urothelial carcinoma (UC) trials, and a network meta-analysis of randomized trials comparing PD-1 or PD-L1 inhibitors with docetaxel for NSCLC. We analyzed Food and Drug Administration Adverse Event Reporting System (FAERS) database to estimate the reporting odds ratio (ROR) of each medication, which provides the estimated relative risk most valid in spontaneous report database. Results: We identified 88 studies that met inclusion for the analysis. PD-1 inhibitors were associated with higher incidence of all grade and grade 3-4 colitis compared to PD-L1 inhibitors in the analysis of all cancer types (1.49% vs 0.83%, relative risk (RR); 1.80, 95% confidence interval (CI); 1.22-2.67 for all grade colitis, and 0.85% vs 0.34%, RR; 2.52, 95% CI; 1.46-4.37 for grade 3-4 colitis). The meta-analyses on NSCLC and UC, and the network meta-analysis on NSCLC also showed the tendency that PD-1 inhibitors are associated with higher risk of all grade and grade 3-4 colitis, though only the analysis on UC for all grade colitis showed a significant difference. (1.95% vs 0.64%, RR; 3.05, 95% CI; 1.18 - 7.88) Retrospective analysis showed ROR of 16.78 (95% CI; 15.8-17.8) for PD-1 inhibitors, and 12.93 (95% CI; 10.74-15.42) for PD-L1 inhibitors. We found that ROR of PD-1inhibitors was 1.17 (95% CI; 0.97-1.43) compared to PD-L1 inhibitors. Conclusions: Our study showed that PD-1 inhibitors have higher risk of colitis than PD-L1 inhibitors.
Risk factors for myocarditis associated with immune checkpoint inhibitors using real-world clinical data.
Authors: Jain Prantesh , Bugarin Jahir Gutierrez , Guha Avirup , Jain Chhavi , Shen Tingke , Stanevich Ilya , Margevicius Seunghee P , Fu Pingfu , Liu Fang , Nikore Vipan , Mangla Ankit , De Lima Marcos J.G. , Velcheti Vamsidhar , Barnholtz-Sloan Jill , Dowlati Afshin
Published: May 2020

e15100

Background: Immune checkpoint inhibitors (ICIs) can cause unique, high-grade immune-related adverse events. Although rare, ICI related myocarditis has the highest fatality rate (~50%). Cardiovascular monitoring is not routinely performed in patients on ICI treatment, thus risk factors remain unknown. Characterizing rare but fatal cardiac toxicities requires integration of real-world data. Methods: U.S claims data (IBM MarketScan) of over 30 million commercially insured individuals was leveraged to identify 2,687,301 cancer patients between 2011-2018. Patients ≥18 years of age treated with ICIs (targeting CTLA4 (ipilimumab) and/or the PD1 (nivolumab, pembrolizumab)/PDL1 (atezolizumab, avelumab, durvalumab) alone or in combination with ICI and/or chemotherapy were identified and followed until disenrollment. Myocarditis, comorbidities, and treatment details were identified using diagnosis and billing codes. Analyses included descriptive statistics and Cox proportional hazards regression. Results: 16,541 ICI treated cancer patients were included (median age 60; 58% male). Myocarditis was identified in 252 (1.5%) patients, majority (90%) ≥50 years old (median 63) with 12,040 person-years of follow up. 62% received anti-PD1 monotherapy, 12% anti-CTLA4, and 15% received combination treatment with other ICIs and/or chemotherapy. Most common cancer types were lung (48%), melanoma (25%), and renal cancer (14%). Cumulative incidence of myocarditis at 1 year was 2.06%; 95% CI (1.78-2.37), median onset of 80.5 days, 42% occurring within 60 days of treatment. By univariate analyses, age, cancer type, diabetes (DM), hypertension (HTN), kidney, liver disease, atrial fibrillation (AF) were related to myocarditis. Risk was lower in patients who received anti-CTLA4 monotherapy (HR: 0.490; 95% CI: 0.26-0.92; p = 0.0251). On multivariable regression analyses only age, cancer type (renal, lung cancer), comorbidities DM and liver disease were significantly associated with myocarditis (Table). Conclusions: This is the largest real-world longitudinal study for ICI associated myocarditis showing higher than reported incidence and identifiable risk factors. [Table: see text]
Thyroid dysfunction and immune checkpoint inhibitor outcomes.
Authors: von Itzstein Mitchell S. , Lu Rong , Ali Sadia , Xie Donglu , Cai Jennifer , Xie Yang , Gerber David E.
Published: May 2020

e15103

Background: Immune checkpoint inhibitors (ICI) frequently cause thyroid dysfunction. We performed a longitudinal analysis of thyroid function tests in a large, single-center cohort of patients with multiple cancer types receiving ICI. Methods: We performed a retrospective medical records review of consecutive patients treated with ICI from 1/1/2005 to 12/31/2018. We collected demographic and clinical data, including serial thyroid function tests. We compared overall survival between patients with normal and abnormal thyroid stimulating hormone (TSH) at baseline and after ICI initiation using Kaplan-Meier curves, log-rank tests, and multivariate Cox proportional hazards model. Results: A total of 910 patients were included: 63% male, 82% white, median age 67. The most common cancer types were lung (26%), kidney (18%), and melanoma (17%). ICI types were anti-PD1/L1 (78%), anti-CTLA-4 (7%), and combination ICI (15%). Normal baseline TSH and abnormal post-treatment TSH was associated with longer overall survival (median survival 26 months) compared to all other TSH permutations (median survival < 10 months) ( P< 0.001). This finding persisted after multivariate Cox regression adjustment for age, gender and cancer type (P < 0. 001), and also after sensitivity analysis censoring patients who died within 2 months after starting ICI. Conversely, abnormal TSH at baseline was associated with lower overall survival (median 8 months) compared to normal TSH at baseline (median 18 months) ( P< 0.001), which also persisted in multivariate analysis ( P< 0.001). Kidney and head and neck cancers (71% and 69%) were associated with increased development of thyroid dysfunction compared to melanoma, lung and other urological cancers (52%, 50% and 35%) ( P< 0.01). Conclusions: Although abnormal thyroid function after ICI initiation was associated with improved overall survival, pre-treatment thyroid abnormalities were associated with worse overall survival. Given the prevalence of thyroid abnormalities in the general population, further research into these observations is warranted.
Retrospective analysis of immune checkpoint inhibitor-associated myocarditis from 12 cancer centers in China.
Authors: Wang Feng , Qin Shukui , Lou Fang , Chen Feng Xiao , Shi Meiqi , Liang Xiaohua , Jiang Hua , Jiang Yu , Chen Yu , Du Yingying , Xue Jun , Zhu Hong , Ren Wei
Published: May 2020

e15130

Background: Immune checkpoint inhibitor(ICI) -associated myocarditis is rare, but it could account for a very high mortality rate. This study reviewed the occurrence of ICI-associated myocarditis in Chinese cancer patients. Methods: A retrospective analysis was made on the occurrence of ICI-associated myocarditis in cancer centers of 12 3A-grade hospitals in China from January 1, 2018 to December 31, 2019. More than 100 patients were treated with ICIs in each center. Results: A total of 2373 patients were treated with ICI alone or in combination. The incidence of ICI-associated myocarditis was 1.05% (25/2373). Of all the data elicited from 16 patients in this study, the tumor types were listed, including: melanoma, lung cancer, renal cancer, urothelial cancer, liver cancer, gastric cancer, colorectal cancer, etc. The 16 patients included 8 male and 8 female with a median age of 65 (36-80). 3 of them had coronary heart disease. The ICI drugs included nivolumab, pembrolizumab and toripalimab, camrelizumab, sintilimab, tislelizumab, atezolizumab. Among them, there were 10 cases of PD-1 inhibitor, 1 case of PD-L1 inhibitor, 5 cases of PD-1 inhibitor combined with chemotherapy or molecular targeted drug. ICI-associated myocarditis occurred in a median of 38 days (2-420) after treatment during which 81.2% (13/16) of them received ICI 1-2 infusions. The common clinical symptoms were palpitation, chest distress and dyspnea, in addition to 8 cases with asthenia, 4 cases with respiratory failure, 2 cases without symptoms. ECG abnormality accounted for 87.5% (14/16). The common abnormalities included: 6 cases of atrial premature contraction, 4 cases of ventricular premature contraction, 3 cases of sinus tachycardia, 1 case of Grade 3 atrioventricular, 1 case of complete right bundle block, and 1 case of acute myocardial infarction. 15 cases of abnormal troponin I or T were observed, followed by CK, CK-MB, MYO and BNP increased. 14 patients were treated with glucocorticoid. 6 patients died with the mortality rate 37.5%(6/16) and 66.7% (4/6) were over 70 years old. Conclusions: The incidence of ICI-associated myocarditis in Chinese patients is low, but the mortality rate is high. Regular monitoring of cardiac biomarkers and ECG is helpful for early diagnosis.
Weighing the role of concomitant medications during PD-1/PD-L1 checkpoint blockade: A preliminary analysis.
Authors: Cortellini Alessio , Mallardo Domenico , Vitale Maria Grazia , Bracarda Sergio , Macrini Serena , Di Marino Pietro , De Tursi Michele , Petragnani Nicola , Natoli Clara , Nigro Olga , Tuzi Alessandro , Patruno Leonardo Valerio , Porzio Giampiero , Cannita Katia , Fargnoli Maria Concetta , Ficorella Corrado , Ascierto Paolo Antonio
Published: May 2020

e15132

Background: The role of concomitant medications, such as steroids, antibiotics and proton pump inhibitors, during immunotherapy has already been investigated, without conclusive results. Methods: This is a multicenter retrospective study, of advanced cancer patients (any histology) treated with anti-PD-1/PD-L1 immunotherapy. Baseline concomitant medications were collected. Results: From June 2014 to November 2019, 277 consecutive patients were evaluated. Median age was 69 years; male/female ratio was 190/87. Primary tumors were: NSCLC (41.9%), melanoma (40.1%), renal cell carcinoma (11.9%) and others (6.1%). 63 patients (22.7%) had ECOG-PS ≥ 2. 120 patients (43.3%) had ≥ 2 metastatic sites. Conclusions: Cancer-related steroids administration, systemic antibiotics, proton pump inhibitors, anticoagulants, opioids, oral anti-diabetics and insulin therapy seem to significantly affect survival in patients receiving PD-1/PD-L1 inhibitors. In interpreting such data, it is important to consider the prevalent role of poor clinical condition. Our preliminary results warrant further investigation in a larger cohort of patients and in a perspective way. [Table: see text]
Comparative efficacy, safety, and tolerability of immune checkpoint inhibitors (ICIs) in cancer.
Authors: Al-Showbaki Laith , Nadler Michelle , Desnoyers Alexandra , Almugbel Fahad , Cescon David W. , Amir Eitan
Published: May 2020

e15151

Background: Multiple ICIs have been approved, and in some diseases there is a choice of more than one ICI. The comparative safety, efficacy, and tolerability are not known. Here we report on a network meta-analysis comparing different ICIs targeting PD1 or PDL1. Methods: Randomized trials (RCTs) supporting the registration of a single agent anti-PD1 or anti-PDL1 inhibitors between 2015-2019 were identified. We extracted the hazard ratio (HR) for overall survival (OS) and calculated the odds ratio (OR) for commonly reported safety and tolerability outcomes. We then performed a network meta-analysis including only disease sites in which more than one ICI has been approved. Multiple pair-wise comparisons were then performed. When more than 2 comparisons were available for a pair of ICIs these were pooled into a single estimate. Analyses were performed in Microsoft Excel and RevMan 5.3. Results: Of 16 RCTs included, 10 in non-small-cell lung cancer, 2 in melanoma, 2 in head and neck squamous cell carcinoma and 2 in urothelial cancer. There was a total of 10673 patients in the analysis. Compared to pembrolizumab, efficacy was similar for nivolumab (HR 1.06, 95% CI 0.97-1.16) and for atezolizumab (HR 1.05, 95% CI 0.93-1.20). However, avelumab appeared inferior (HR 1.29, 95% CI 1.07-1.57). Pembrolizumab showed similar odds of serious adverse events (SAEs) as nivolumab (OR 1.12, 95% CI 0.56-2.27) and atezolizumab (OR 1.05, 95% CI 0.55-2.04). However, compared to nivolumab, atezolizumab was associated with more SAEs (OR 2.14, 95% CI 1.47-3.12). Avelumab had the lowest odds of grade 3-4 adverse events compared to pembrolizumab (OR 0.42, 95% CI 0.24-0.74), nivolumab (OR 0.38, 95% CI 0.24-0.62) and atezolizumab (OR 0.21, 95% CI 0.14-0.33). Atezolizumab was associated with more grade 3-4 adverse events than nivolumab (OR 1.84, 95% CI 1.37-2.47). The odds of treatment discontinuation without progression were similar between nivolumab and atezolizumab (OR 1.20, 95% CI 0.73-2.00), but higher with pembrolizumab compared to nivolumab (OR 1.35, 95% CI 0.83-2.17) and atezolizumab (OR 2.56, 95% CI 1.29-5.00). Pembrolizumab was associated with higher OR of immune related adverse events (IRAEs) compared to nivolumab (OR 2.12, 95% CI 1.49-3.03) and atezolizumab (OR 1.63, 95% CI 1.09-2.43), while the OR of IRAEs was almost similar between nivolumab and atezolizumab. Conclusions: Pembrolizumab, nivolumab, and atezolizumab have similar efficacy. Avelumab appears efficacious. Safety and tolerability seem better with avelumab, but worse with atezolizumab and pembrolizumab.
Cancerbiome: Defining a healthy microbiome for therapeutic targeting.
Authors: Babu Hari S , Mason Robert , West Nicholas P , Gunawan Ben , Cox Amanda J , Nelson Tiffanie M , Zhang Ping , Cripps Allan W , Sanmugarajah Jasotha
Published: May 2020

e15152

Background: The gut microbiome has been shown to modify the efficacy of cancer immunotherapy. Currently, there is little understanding of how the microbiome in advanced cancer patients responding to immunotherapy compares to healthy individuals. The aim of this study was to characterise the intestinal microbiome in patients with advanced solid organ tumours that have a durable response to programmed-death-protein-1 inhibitors (PD-1) with healthy individuals. Methods: Ten patients (mean age 69 ± 11; 60% female) with metastatic melanoma, renal cell carcinoma or non-small cell lung cancer and durable response for greater than one year to anti-PD-1 antibodies and ten healthy age and sex matched individuals (mean age 69 ± 9.2; 60% female) were recruited. Clinical data and a three-day diet diary were collected, with faecal sample analysed via shallow shotgun sequencing (CoreBiome, Minneapolis, USA). Results: Duration of response to immunotherapy was 786 ± 282 days. Responders had a significantly higher body mass index (28 ± 5.5 kg/m2 v 23.3 ± 2.65 kg/m2, p = 0.005; mean ± SD) than the healthy group. There was a significantly higher intake of total fat and fibre in the healthy group. The responder group had significantly higher diversity metrics, exhibiting a greater diversity in the number (OTUs) and the richness of species than the healthy group. At the phylum level, the microbiome in the responder group was significantly abundant in proteobacteria and had a significantly lower abundance of Bacteroidetes compared to the healthy group. At the genus level, the microbiome in the responder group was significantly enriched in Desulfovibrio, Acideminococcus, Klebsiella, Enterococcus and Faecalitalea compared to Ruminococcus, Veillonella and Roseburia in the healthy group. Species that were abundantly higher in the cancer group were associated with glycolysis, the TCA cycle, sugar metabolism and amino acid metabolism. Five Kyoto Encyclopedia of Genes and Genomes (KEGG) orthologues were significantly enriched in the responder group, mostly relating to transport systems for minerals and nitrogen fixation, but also mismatch repair proteins and cell cycle activity. Conclusions: Our findings suggest that compositional and functional differences in the faecal microbiome exist between advanced cancer patients responding to immunotherapy and healthy individuals, suggesting not only potential mechanisms of durable response but also targets for future therapy.
The frequency of HPD gene mutation profile in solid tumors with PD-L1 expression positive.
Authors: Tang Sanyuan , Zhao Shunli , Liu Zhiqi , Zhao Huiping , Gao Caixia , Tian Minqi , Zhang Xing , Qi Chuang , Song Chao
Published: May 2020

e15175

Background: Program death-ligand (PD-L1) expression and tumor mutational burden (TMB) are the promising predictive biomarkers in immunotherapy for solid tumors. Immunotherapy could be harmful in patients harboring hyper-progressive disease (HPD) gene mutations. Nevertheless, the distributions of HPD gene mutation profile in patients with PD-L1 positive solid tumors especially in East Asian populations have not been well characterized yet. Methods: In this study, tumor tissues from 354 patients using 539 genes panel based on next generation sequencing were performed. Single nucleotide variants (SNVs) of DNMT3A gene and copy number variants (CNVs) of M DM2, MDM4, C CND1, F GF3, F GF4 and F GF19 genes were evaluated as HPD mutations. The protein expression of PD-L1 was divided into three groups as g1 (TC < 1%), g2 (1% ≤ TC < 50%) and g3 (TC ≥ 50%) via the percentage of positive tumor cells (TC value) identified by immunohistochemistry (IHC) method. The ratios of patients with or without HPD mutations in different PD-L1 expression groups were calculated by χ2 test using program SPSS v22.0. Results: In 354 patients with solid tumors, 33 of 354 (9.3%) were found harboring HPD mutations. The ratios of patients with HPD mutations in three PD-L1 expression groups were 8.6% in g1, 10.4 % in g2 and 8.7% in g3, respectively. Meanwhile, the ratios of patients without HPD related mutations in three PD-L1 expression groups were 91.4%, 89.6 % and 91.3%, respectively. There were no significant differences of HPD frequency between different PD-L1 expression groups via χ2 test (χ2 = 0.323, p = 0.851). Conclusions: The frequency of HPD gene mutations was not significantly heterogeneous between different PD-L1 expression groups and indicated that immunotherapy for patients with PD-L1 expression positive needed to test HPD related gene mutations. Our study provided meaningful information to the precise administration of immunotherapy in cancer clinical practice. As a retrospective study with a relatively small population, the conclusions of this study needed to be verified with a larger sample.
Multi-omic single-cell analysis of antigen-presenting compartment reveals a unique functional signature for head and neck squamous cell carcinoma.
Authors: Barber Brittany , Prlic Martin , Mair Florian , Erickson Jami
Published: May 2020

e15179

Background: Immune studies in head and neck squamous cell carcinoma (HNSCC) are lacking. Studies in the past decade have highlighted the biological significance and the distinct functional properties of immune cell subsets that are resident in non-lymphoid tissues. While tissue-resident memory T cells (TRM) have been well characterized, much less is known about the human myeloid compartment in HNSCC, which includes professional antigen-presenting cells (APCs) such as dendritic cells (DCs) and macrophages, both of which are critical for shaping the local T cell response. This is particularly relevant in the context of anti-tumor immune responses, which are currently a major focus for therapeutic intervention in HNSCC by either checkpoint inhibitory blockade or adoptive T cell therapy. Methods: A combination of multi-omic single cell RNA sequencing (sc-RNAseq) and 30-parameter fluorescent flow cytometry were used to define the APC compartment in 7 human head and neck squamous cell carcinoma (HNSCC) samples and 4 normal gingival tissue samples as references. Importantly, we performed parallel profiling of the adaptive and innate T cell compartment to elucidate the relationship between APCs and local TRM cells that have been designated as critical players for immune responses in solid tumor tissue. Results: Several novel myeloid phenotypes and an altered composition of the APC compartment in HNSCC relative to normal gingival tissues. APCs expressing pro-inflammatory cytokines such as IL-1b and IL-6 showed reduced abundance, while previously unknown APC subsets defined by the expression of a unique chemokine profile were found to infiltrate HNSCC tissue. Furthermore, our multi-omic approach allowed for profiling of the protein surface phenotype in these transcript-defined clusters, opening up avenues for future therapeutic targeting of tumor-specific antigen-presenting cells. Conclusions: A novel myeloid phenotype and APC compartment were observed in HNSCC when compared to normal gingival tissues. A multi-omic assay identified tumor-specific APCs that may represent future therapeutic targets.