bluuebunny/crossref_metadata_2025 huggingface dataset:
Survey of the immunogenomic landscape of solid tumors through clinical DNA and RNA sequencing.
Authors: Lau Denise , Chang Alan , Perera Jason , Lozac'hmeur Ariane , Bobe Alexandria , Khan Aly
Published: July 2019

153

Background: In the past decade, immunotherapy has emerged as an important new modality in cancer treatment. However, studies have shown that only a fraction of patients will experience any clinical benefit when treated with immune checkpoint blockade drugs. Given the cost and potent adverse events associated with immunotherapy, the need for effective biomarkers is clear. We sought to understand the role of key immunotherapy biomarkers, like tumor mutational burden (TMB), microsatellite instability (MSI), and PD-L1 immunohistochemistry (IHC), in the context of the greater immunogenomic landscape of solid tumors in patients. Methods: We analyzed data from a cohort of 500 patients across 10 cancer types who received the Tempus xT 595 gene targeted DNA sequencing assay and whole transcriptome sequencing assay as part of their clinical care. We determined the TMB, MSI status, and neoantigen load for each sample using the DNA sequencing data. We used the RNA expression data to evaluate immune activation and tumor infiltration by determining the expression of inflammatory gene signatures and estimating the relative proportion of key immune cell types. Results: Integrative analysis of the DNA and RNA sequencing data showed that the immunogenicity of the tumor, as measured by TMB or neoantigen load, correlates with levels of immune activation and tumor infiltration. Inflammatory immune cells, like CD8 T cells and M1 polarized macrophages, were significantly higher in TMB-high samples; while non-inflammatory immune cells, like monocytes, were significantly lower in TMB-high samples. Additionally, samples could be clustered into immunologically active “hot” tumors or immunologically silent “cold” tumors based on gene expression. The immunologically “hot” population was enriched for samples that were TMB-high, MSI-high or PD-L1 IHC positive. Conclusions: Paired next generation DNA and RNA sequencing assays allows for the identification of patients that have immunologically active tumors that lack traditional immunotherapy biomarkers. These patients represent an interesting new population who may potentially benefit from immunotherapy.
Low-dose IL-12 preconditions the tumor microenvironment to enhance the efficacy of PD-1 blockade.
Authors: Diaz-Montero C. Marcela , Ravichandran Sairekha , Pavicic Paul G. , Rayman Patricia A. , Tannenbaum Charles , Finke James , Ko Jennifer S. , Funchain Pauline , Tarhini Ahmad A.
Published: July 2019

20

Background: The immunomodulatory effects of IL-12 are well known to result in potent anti-tumor responses. However its therapeutic development has been hindered by its potential toxicity. Here we explored the impact of systemic low dose IL-12 administration as a strategy to enhance the efficacy of PD-1 blockade. Methods: Mice bearing D4M melanoma tumors were treated with anti PD-1 antibody alone or in combination with low dose IL-12 (100ng twice a week). Tumor progression was monitored, and characterization of immune cell types was performed by flow cytometry and gene expression analysis. Results: A significant reduction in tumor progression after combinatorial treatment with low dose IL-12 and anti PD-1 was observed. This synergistic effect was associated with elevated levels of intratumoral IFN-γ, iNOS, CXCL9, CXCL10, CXCL11, and perforin. Single treatment with low dose IL-12 induced a decrease in the levels of circulating neutrophils and an increase in the levels of circulating CD8+ T cells. Within the TME, low dose IL-12 treatment was associated with an increase in the frequencies of tumor infiltrating M-MDSCs expressing high levels of CXCL9. Elevated levels of CD8+ TILs were also found, which were characterized by their increased expression of PD-1 and PD-L1, as well as CD107a, CXCR3 and CD103. No signs of toxicity were noted. Conclusions: Low dose IL-12 synergizes with anti PD-1 to induce superior regression of D4M melanoma tumors. This effect was associated with an increase in the levels of molecules involved in the recruitment and effector function of CD8+ T cells. Analysis of tissues from animals treated with low dose IL-12 alone showed significant changes in the composition and phenotype of myeloid and T cells in both the tumor and blood. Expression of CXCL9 on tumor infiltrating MDSCs suggested a reversal of their immunosuppressive function to an immunopromoting one, and could explain the elevated accumulation of CD8+ TILs via enhanced CXCR3-dependent recruitment. These findings suggest that low dose IL-12 is sufficient to induce changes in the TME, with minimal toxicity,that enhance the anti-tumor effects of PD-1 blockade. A clinical study testing the safety of this combination is currently underway.
Automated flow cytometric profiling of tumor heterogeneity, tumor-infiltrating leukocyte (TIL) exhaustion, and coexpression of checkpoint receptors/ligands in patient-derived carcinomas.
Authors: Salojin Konstantin , Hauther Christine , Liu Dai , Putta Santosh , Purvis Norman , Westfall Matt
Published: July 2019

28

Background: Clinical benefits of immune checkpoint receptor (ICP-R) blockade in cancer patients can be predicted using various biomarkers such as Immune Index. However, traditional IHC approaches are lacking in sensitivity and in addressing the heterogeneity of the tumor microenvironment (TME), TIL functional status, expression of targetable ICP-R and their ligands (ICP-L), and detection of rare immune subsets within the TME. Methods: We developed a flow cytometry platform (ImmunoINTEL™) that delivers quantitative, clinically relevant information by merging these aspects of tumor biology into a single automated HTP assay comprised of multi-parameter Ab panels and automated sample/data processing procedures for immunophenotyping of blood and tissue specimens from patients with lung, breast, renal, and colorectal carcinomas. Results: Analysis of tumor specimens revealed distinct immune profiles characterized by variations in TIL makeup, differential expression of ICP-R and ICP-L (PD1/PDL1, TIGIT/CD112&CD155, Tim-3/Galectin-9, SIRPa/CD47), and changes in the functional/exhaustion status of TILs. We observed several discrete carcinoma profiles characterized by (1) an elevated Treg : CD8+GZMB+ T cell ratio, (2) high expression of ICP-L on epithelial cells and myeloid TILs, (3) enrichment for M1 macrophages (Mφ), M2 Mφ, and mixed M1/M2 phenotype Mφ (4) elevated levels of myeloid cells with suppressive phenotypes (MDSCs), (5) significant presence of myeloid and plasmacytoid dendritic cells, and (6) enrichment for mesenchymal cells. The elevated expression of several ICP-Ls on TILs and ICPs on epithelial cells suggested tumor- and TIL-intrinsic mechanisms modulating checkpoint interactions. Conclusions: The heterogeneity of TILs and ICP-R/ICP-L expression profiles across cell and tumor types can be explored in proof-of-mechanism studies and clinical trials to provide a rational for targeting distinct ICP-R/ICP-L interactions and TIL exhaustion mechanisms with immunotherapeutics, and for more refined selection of potential responders to ICP inhibitors.
Anti-PD-1 antibody cetrelimab (JNJ-63723283) in patients with advanced cancers: Updated phase I/II study results.
Authors: Rutkowski Piotr , Felip Enriqueta , Moreno Victor , Trigo Perez Jose Manuel , Calvo Aitana , Kowalski Dariusz , Cortinovis Diego , Lee James J. , Manikhas George , Plummer Elizabeth Ruth , Maio Michele , Ascierto Paolo Antonio , Vladimirov Vladimir Ivanovich , Gaffney Dana , Li Lilian Y. , Bae Kyounghwa , Greger James G. , Shin Chu Ri , Xie Hong , Calvo Emiliano
Published: July 2019

31

Background: Cetrelimab (JNJ-63723283) is an IgG4, anti-programmed cell death protein-1 (PD-1) antibody. Here we present updated results from an ongoing phase 1/2 study of cetrelimab in patients (pts) with advanced or refractory solid cancers. Methods: Part 2 of the study evaluated safety and efficacy of cetrelimab at 240 mg Q2W, a recommended phase 2 dose selected in Part 1 (Calvo JCO 2018; 36 suppl 5:58). Tumor types for Part 2 included non-small cell lung cancer (NSCLC), melanoma (MEL), bladder, renal cell, small cell lung cancer (SCLC), microsatellite-high (MSI-H)/DNA mismatch repair deficient (dMMR; locally or centrally tested) colorectal cancer (CRC) and gastric/esophageal cancer (GCA/EC). Tumor response was assessed by the investigator following RECIST v1.1. Results: As of 3 Sep 2018, 192 pts have been treated with cetrelimab from 80–800 mg Q2W and 480 mg Q4W. Median age was 60 years (23–86), and median prior regimens was 2 (1–12). Median duration of treatment was 85 days (1–561); 82 pts remain on treatment. Full receptor occupancy was maintained throughout dosing interval. Most common adverse events (AEs) were asthenia (19%), fatigue (19%), dyspnea (16%) and diarrhea (16%). Grade ≥3 AEs, regardless of causality, were reported in 45% of pts; most common were anemia (6%), dyspnea (4%), increased ALT (3%) and increased AST (3%). Observed serious AEs were dyspnea (4%), pleural effusion and intestinal obstruction (3% each). All grade and grade ≥3 immune-related AEs were reported in 30% and 7% of pts, respectively. Among response-evaluable pts (n = 156) from Parts 1 and 2, overall response rate (ORR) was 15%, with 2 complete and 22 partial responses. Half of pts had stable disease or better. ORR was 26% (7/27) in NSCLC (42% [5/12] in PD-L1+ NSCLC [≥50% by IHC]), 25% (12/49) in MEL (28% [12/43] in non-uveal MEL), 50% (1/2) in renal cancer, 8% (2/26) in MSI-H/dMMR CRC (recruited later per amendment) and 14% (2/14) in GCA/EC. No responses were observed in bladder cancer (n = 4) or SCLC (n = 10). Conclusions: The safety profile and preliminary activity of cetrelimab in immune-sensitive advanced cancers is consistent with known PD-1 inhibitors. The study is ongoing and analysis by PD-L1 status will be reported later. Clinical trial information: NCT02908906.
Tumor mutational burden (TMB) may be a promising predictive biomarker of response to PD-1/PD-L1 targeting in MSI-H colorectal cancer.
Authors: Fakih Marwan , Sandhu Jaideep Singh , Ouyang Ching , Sokol Ethan , Ross Jeffrey S. , Miller Vincent A. , Lim Dean , Chao Joseph , Catenacci Daniel V.T. , Cho May Thet , Braiteh Fadi S. , Maron Steven Brad , Chase Leah , Klempner Samuel Jacob , Ali Siraj Mahamed , Schrock Alexa Betzig
Published: July 2019

43

Background: PD-1 targeting with pembrolizumab or nivolumab leads to durable clinical benefits in patients (pts) with microsatellite instability-high (MSI-H) tumors. However, 30-35% of mCRC pts with MSI-H tumors will experience progressive disease (PD) as a best response when treated with anti-PD1 agents, highlighting the need of additional predictive biomarkers. Methods: We performed a retrospective multi-center clinical investigation to evaluate the impact of TMB, age, gender, stage at initial presentation, pattern of metastatic disease, tumor grade, and RAS/RAF status on response to anti-PD1/PD-L1 in MSI-H mCRC. TMB and MSI status were determined by hybrid capture-based next-generation sequencing (Foundation Medicine [FM]). The TMB distribution in MSI-H CRC was estimated from a large data set from FM. Results: 22 eligible MSI-H mCRC pts were identified across 5 cancer centers: 19 pts received pembrolizumab, 1 pt received nivolumab, 1 pt received nivolumab + ipilimumab, and 1 pt received durvalumab + tremelimumab. Among tested variables, TMB (as a continuous variable) showed the strongest association with an objective response (OR; p < 0.001). Also, both univariate and multivariate analyses supported that TMB serves as an independent prognostic variable in predicting progression-free survival (PFS; p < 0.001 and p < 0.01, respectively). Using log-rank statistics, the optimal predictive cut-point for TMB was estimated between 37-41 mutations/Mb to dichotomize pts into TMBhigh and TMBlow groups. All 13 pts (100%) with TMBhigh had an OR, while only 2/9 (22%) pts with TMBlow had an OR and 6/9 had PD. The median PFS for TMBhigh pts has not been reached (no progressors, median follow-up > 18 mos), while the median PFS for TMBlow pts was 2 mos. Amongst 821 MSI-H CRC cases tested at FM, the 25th, 35th, 50th and 75th percentile TMB cutoffs were 33.1, 37.4, 46.1, and 61.8 mutations/Mb, respectively. Our optimal TMB cut-point range suggests that MSI-H mCRC with the lowest 35th percentile of TMB have a low likelihood of benefit from anti-PD1. Conclusions: These TMB findings require validation in prospective trials and may guide the sequencing of PD-1 inhibitor monotherapy in MSI-H mCRC.
Analysis of colorectal cancer patients treated on ETCTN 10021: A multicenter randomized trial of combined PD-L1 and CTLA-4 inhibition with targeted low-dose or hypofractionated radiation.
Authors: Monjazeb Arta , Giobbie-Hurder Anita , Lako Ana , Tesfaye Anteneh A. , Stroiney Amanda , Gentzler Ryan D. , Jabbour Salma , Alese Olatunji B. , Rahma Osama E. , Cleary James M. , Sharon Elad , Raben David , Mamon Harvey J. , Streicher Howard , Chen Helen X. , Ahmed Mansoor , Gjini Evisa , Rodig Scott , Hodi F. Stephen , Schoenfeld Jonathan Daniel
Published: July 2019

49

Background: Pre-clinical and clinical evidence support immune effects of targeted radiation (RT) resulting in synergy with immune checkpoint therapy. However, prospective data are lacking in regards to safety, efficacy and immunologic impacts of different doses of RT given in conjunction with PD-L1 and CTLA-4 blockade. Methods: ETCTN 10021 is a multicenter randomized phase 2 study evaluating repeated low-dose fractionated RT (LDFRT) or hypofractionated RT (HFRT) in combination with PD-L1 and CTLA-4 inhibition in metastatic microsatellite-stable colorectal cancer (CRC) refractory to first-line chemotherapy, or non-small cell lung cancer progressive on prior PD-1 inhibition. The primary endpoint is objective response excluding irradiated lesions. Pre- and on-treatment biopsies were analyzed using multiplex immunofluorescence (IF) evaluating multiple immune markers. We report the prespecified analysis of the CRC cohort. Results: Twenty CRC patients were randomized, 19 of whom were treated with immunotherapy and RT, and 18 of whom were evaluable for response. Median lines of prior therapy were 4 (range 1-7). There were 16 patients with toxicity potentially related to treatment (84%), and 8 patients with possibly associated grade 3-5 toxicity (42%). Best response was stable disease in one patient with an abscopal out-of-field response who developed new lesions after HFRT and 4 cycles with decreasing overall disease burden. Correlative IF performed on 5 sample pairs revealed that HFRT, but not LDFRT, increased infiltration of CD8+, and CD8+/PD1+/Ki67+ T-cells in the RT field. Conclusions: We demonstrate the feasibility of a multicenter randomized study adding different RT regimens to PD-L1/CTLA-4 blockade. Toxicity was, in general, consistent with PD-L1/CTLA-4 inhibition with no significant RT-related toxicities noted. Although the best response of stable disease doesn’t support the use of PD-L1/CTLA-4 inhibition with HFRT or LDFRT in this population using these RT regimens and schedule, integrated biomarkers provide support that HFRT impacts the local immune microenvironment. Clinical trial information: NCT02888743.
Cell proliferation as a biomarker for response to immune checkpoint inhibitors in PD-L1 negative renal cell carcinoma.
Authors: Glenn Sean T. , Pabla Sarabjot , Zhu Jason , Labriola Matthew , Gupta Rajan , George Daniel J. , McCall Shannon , Yau Edwin , Conroy Jeffrey M. , Nesline Mary , Papanicolau-Sengos Antonios , Burgher Blake , Lenzo Felicia L. , Zhang Tian , Morrison Carl
Published: July 2019

62

Background: Cell proliferation is an important marker of survival in many tumors, and we hypothesized that this attribute could be related to response to immune checkpoint inhibitors (ICIs) in RCC. Previously we reported (SITC 2018) that moderately proliferative lung cancer have a much higher response rate than either poorly or highly proliferative tumors. Methods: 69 FFPE RCC tumor samples were evaluated by RNA-seq to measure transcript levels of 394 immune related genes. Cell proliferation was defined as the mean mRNA expression of 10 genes (BUB1, CCNB2, CDK1, CDKN3, FOXM1, KIAA0101, MAD2L1, MELK, MKI67, TOP2A) which was evaluated for association with ORR to ICIs by RECIST v1.1 criteria for both PD-L1 IHC positive and negative cases. Cell proliferation for each case was split into 3 tertiles of poorly ( < 33), moderately (33-66) and highly ( > 66) proliferative versus a reference population. Poorly and highly proliferative were grouped for comparison to moderately proliferative tumors. PD-L1 IHC was performed using DAKO 22C3 antibody and scored by FDA guidelines and considered positive if TPS ≥1% and negative if < 1%. Results: In our cohort of 69 patients, the overall ORR was 18.8. The majority, 91% of tumors were PD-L1 negative, with ORR of 14.8%, as opposed to ORR of 50% in PD-L1 positive cases. 62.2% of tumors were poorly proliferative, 8.7% were highly proliferative, and 29% were moderately proliferative. ORR in moderately proliferative tumors was 30% and 14.2% in poorly/highly proliferative tumors. In PD-L1 negative tumors the ORR in moderately proliferative tumors was 20% and 13% in poorly/highly proliferative tumors. For the 5 moderately proliferative, PD-L1 positive tumors, there were 2 PR and 1 CR, and in the 3 poorly/highly proliferative tumors there was 1 PR. Conclusions: Cell proliferation may play a crucial role in distinguishing RCC patients who may have a clinical benefit to ICI, including the important subgroup of PD-L1 negative tumors. Moderately proliferative tumors have a higher ORR than their poorly/highly counterparts.
Understanding the peripheral cellular immunome in patients with breast cancer.
Authors: Landa Karenia , Holl Eda , Frazier Victoria , Hwang Eun-Sil Shelley , Nair Smita
Published: July 2019

7

Background: Neoadjuvant chemotherapy (NAC) for breast cancer (BC) is being increasingly used in patients with stage I/II disease. Although previously reserved for patients with locally advanced disease, its use in patients with localized disease allows for higher rates of breast-conserving procedures and provides insight into tumor biology. A complete pathologic response (pCR) to NAC correlates with better clinical outcomes; sadly, many patients do not achieve pCR. The advent of immunotherapy has provided cancer patients with additional treatment options. To optimize immunotherapy in BC we must understand the peripheral cellular immunome (immune subsets and activation status) of patients as they undergo standard of care therapy (SOC). Methods: Our population includes patients with stages I-III BC undergoing SOC. Samples were collected pre- and post-NAC, post-surgery and at 2-month follow-up (FU). Results: Flow cytometry analysis for 11 patients was performed at each time-point to examine percentages of circulating immune cells (see Table). We grouped samples in 3 categories: human epidermal growth factor receptor 2 (HER2+) positive, HER2 negative (HER2-) and triple-negative (TN) tumors. 3 out of 11 patients had pCR (1 HER2+, 1 HER2-, 1 TN); they had highest percentage of circulating CD56+ NK cells during treatment course. Conclusions: We observed striking changes in the immunome of women with stage I-III BC undergoing NAC. Although our findings are preliminary, given our sample size, we observed distinct trends within each immune cell population in specific tumor receptor subtypes. These trends could serve to guide our therapies, allow for better patient selection and predict treatment response in patients. [Table: see text]
RNA-sequencing reveals immunotherapy targets in gynecological cancer.
Authors: Papanicolau-Sengos Antonios , Yen Ting-Tai , Dressman Devin , DePietro Paul , Pabla Sarabjot , Nesline Mary , Conroy Jeffrey M. , Glenn Sean T. , Lenzo Felicia L. , Odunsi Kunle , Wang Tian-Li , Morrison Carl
Published: July 2019

8

Background: We performed microsatellite instability testing and expression immune profiling of endometrioid and serous carcinomas to identify immunotherapeutic targets and histologic attribute correlates. Methods: Microsatellite instability and RNA-seq of 395 immune-related genes were performed in 37 endometrioid and 53 serous carcinomas. Each gene was ranked against a reference population and subsequently compared to a separate clinical database reference of diverse neoplasms to perform Wilcoxon ranked sum test comparisons. Benjamin-Hochberg corrected p-values are reported. Results: VTCN1, IDO1, LAG3, and components of the mTOR/AKT1 pathway were overexpressed in both endometrioid and serous carcinomas compared to the clinical database population. CD276 and NT5E were uniquely overexpressed in the endometrioid set (Table). In the endometrioid set ADGRE5 was overexpressed in endometrioid primaries when compared to their metastatic counterparts. Serous metastases relatively overexpressed HLA-DPA1 compared to their primary counterparts. Ten of 26 endometrioid cancers with available microsatellite instability status were microsatellite unstable. All serous carcinomas were microsatellite stable. There was no correlation between microsatellite instability status and expression of any gene in either endometrioid or serous cancers. Conclusions: We identified high RNA-expression of VTCN1, IDO1, CD276, and LAG3 in endometrioid and serous carcinomas while NT5E (ADORA2A ligand) was found to be uniquely upregulated in endometrioid carcinomas. These markers may play a role in immune suppression in gynecological cancers and are potential immunotherapeutic targets. The upregulation of ADGRE5 in primary endometrioid cancers and upregulation of HLA-DPA1 in metastatic serous cancers suggests immunologic differences which may be relevant to the formation of metastatic disease.
Real-world characterization of patients with cancer admitted with immune-related adverse events (irAEs).
Authors: Eng Lawson , Chen RuiQui , Smith Elliot Charles , Chan Sze Wah Samuel , Hueniken Katrina , Brown M. Catherine , Majeed Habeeb , Ross Kendra , Gray Diana , Xu Wei , Hogg David , Sridhar Srikala S. , Sacher Adrian G. , Leighl Natasha B. , Krzyzanowska Monika K. , Liu Geoffrey , Butler Marcus O.
Published: July 2019

82

Background: Immune checkpoint inhibitors (ICI) are improving the care of cancer patients. Despite being better tolerated than chemotherapy, there is a risk of developing irAEs which may require hospitalization. Although ICI and irAEs are well studied in clinical trials, there is a paucity of studies characterizing the care patterns for real-world irAEs hospitalizations. Methods: A single centre retrospective chart review (Princess Margaret Cancer Centre, Toronto, ON) identified patients receiving standard of care ICI (2012-2017) hospitalized for irAEs. For hospitalizations, clinico-pathological, investigation and treatment details were collected. Descriptive statistics helped to characterize hospitalizations. Results: Among 697 patients (266 lung, 381 melanoma and 50 genitourinary (GU)) on ICI, 8% (14 lung, 41 melanoma and 2 GU) had at least 1 irAE (range 1-4) hospitalization for a total of 69 hospitalizations. Average length of stay was 12 days (range 1-105). Among hospitalized patients, median age was 60; 63% were male; 29% received ipilimumab monotherapy, 28% pembrolizumab, 22% nivolumab and 22% received combination ICI. The most common irAEs were colitis (52%), pneumonitis (20%), hepatitis (10%) and CNS disease (demyelination, hypophysis) (9%). Cases were admitted directly from clinic (39%), emergency rooms (29%), urgent care clinic (18%) or transferred from another hospital (13%). Most patients (72%) were admitted to oncology; 28% to general medicine. Endoscopy was performed in 21% of admissions with 60% showing evidence of irAE; biopsies were obtained in 16% of admissions and 73% had evidence of irAE. Subspecialty services were involved in 60% of admissions. Most patients received steroids (94%); 17% received Infliximab. While age did not impact length of stay (p = 0.63), patients admitted to oncology had longer admissions compared to general medicine (14 vs 6 days, p = 0.009). Conclusions: irAEs occur at similar rates in the real-world compared to clinical trials. There is significant heterogeneity in the care patterns for irAEs. Patients admitted to oncology had longer average lengths of stay. Further characterizing irAE can help to develop quality indicators that may improve irAE outcomes.
Comparison of care patterns for hospitalized immune-related adverse events (irAEs) between melanoma patients on combination immune checkpoint inhibitor (ICI) therapy versus ICI monotherapy.
Authors: Chen RuiQui , Smith Elliot Charles , Chan Sze Wah Samuel , Hueniken Katrina , Brown M. Catherine , Majeed Habeeb , Ross Kendra , Gray Diana , Xu Wei , Hogg David , Sridhar Srikala S. , Sacher Adrian G. , Leighl Natasha B. , Krzyzanowska Monika K. , Butler Marcus O. , Liu Geoffrey , Eng Lawson
Published: July 2019

85

Background: Prior clinical trials in melanoma have demonstrated higher rates of irAEs from combination ICI therapy compared to monotherapy. However, this has not been well studied in the real-world where patients often have greater co-morbidities and less organ reserve. We aim to compare irAEs hospitalizations for melanoma patients on combination vs monotherapy ICIs. Methods: We performed a single centre retrospective chart review (Princess Margaret Cancer Centre, Toronto, ON) for all melanoma patients receiving ICI as standard of care (2012-2017) admitted with irAEs. Data collected include demographics, investigations, management and outcomes of hospitalizations. Descriptive analyses were performed to characterize hospitalizations and compare between ICI combination vs monotherapy groups. Results: Among 381 melanoma patients identified on standard of care ICI, 41 (11%) were admitted for irAE. Among those admitted, 10% received monotherapy with nivolumab, 22% pembrolizumab, 39% ipilimumab and 29% combination ICI. Admission rates were higher among patients receiving combination ICI compared to monotherapy (20% vs 8% p = 0.003). Prevalence of the most common irAEs were similar between combination and monotherapy groups: colitis (58% vs 59%), pneumonitis (8% vs 14%) and hepatitis (8% vs 10%). Less than half received invasive diagnostic tests (i.e, endoscopy) (42% combination vs 35% monotherapy, p = 0.50) with 3 (60%) and 5 (50%) confirming irAEs, respectively. Rates of infliximab use were similar between the combination and monotherapy group (25% vs 21%, p = 0.70). Average length of stay was shorter for patients on combination ICI compared to monotherapy (5 days vs 15 days, p = 0.08). irAE readmission rates were similar between patients receiving combination ICI compared to monotherapy (20% vs 17%, p = 0.65). Conclusions: Despite higher admission rates among patients receiving combination ICI, there was a trend towards shorter hospitalizations. Other outcomes including diagnoses, investigations and management were not significantly different between patients receiving combination vs ICI monotherapy.
Patient reported toxicities: Development and validation of patient-reported symptom measure for lung cancer patients receiving immunotherapy.
Authors: Shaw Sandra S. , Jim Heather S.L. , Eisel Sarah , Hoogland Aasha , LeDuc David , Dicker Adam P.
Published: July 2019

93

Background: There is increasing clinical and research interest in patient-reported outcomes (PROs) which provide unique and complementary information to provider-rated adverse events. While several studies have been published of PROs in lung cancer patients receiving immune checkpoint blockade, to our knowledge all have focused on PROs collected as part of a clinical trial. This interim analysis describes PROs outside the context of a clinical trial. Methods: The Addario Lung Cancer Foundation (ALCF) international patient registry was used to collect patient-reported clinical and PRO information. Patients who reported current or past treatment with an FDA-approved immune checkpoint inhibitor were asked to complete a second survey of symptomatic toxicities of these therapies. Patients rated 40 symptoms on a five-point scale. The Charlson Comorbidity Index and Functional Assessment of Cancer Therapy General (FACT-G) were administered to assess comorbidities and quality of life, respectively. Results: A total of 116 patients (mean age 61, 75% female) who reported treatment with nivolumab (52%) or pembrolizumab (47%) were included in analyses. The majority of patients (70%) had been treated for 6 months or less. The most commonly reported symptoms were fatigue (72%), aching joints (52%), aching muscles (35%), insomnia (34%), back pain (30%), itching (27%), bone pain (26%), and skin dryness (25%). A total of 26% of patients had experienced a treatment delay, 10% had been to the emergency room, and 6% had been hospitalized due to toxicity. Participants reported a mean score of 75.88 (SD=17.59) on the FACT-G, significantly lower than previously-published normative data for cancer patients. Conclusions: This study is among the first to evaluate patient-reported toxicities of immune checkpoint inhibitor outside the context of a clinical trial. Results from this interim analysis indicate patient reported toxicities of immune checkpoint inhibitors are common in lung cancer patients. Additional research is needed to better understand the longitudinal course of symptomatic toxicities. Acknowledgements: ALCF, IASLC, American Lung Association.
Effect of concomitant medications on overall survival in patients with cancer undergoing immunotherapy.
Authors: Spakowicz Daniel , Husain Marium , Tinoco Gabriel , Patel Sandip H. , Burkart Jarred Thomas , Verschraegen Claire F. , Kendra Kari Lynn , Hoffman Sarah , Philippon Jennifer , Quiroga Dionisia Marie , Otterson Gregory Alan , Owen Dwight Hall
Published: July 2019

94

Background: The response to Immunotherapy (IO) is known to be affected by concomitant medications including corticosteroids and antibiotics. We evaluated the medication history of patients undergoing IO to explore other medications that affect overall survival and to estimate the relative impact of each medication when given in combination. Methods: A retrospective review of patients with advanced cancer who received IO from 2011 to 2017 at the Ohio State University was performed with IRB approval. Data were extracted from the medical record, including medication history 180 days around the start of IO therapy. Data were collected in a REDCap database. Overall Survival (OS) was calculated from the initiation of IO. Cox Proportional-Hazards models were used and evaluated by log-rank test at alpha = 0.05. All calculations were performed using the survival and survminer packages in R. Results: Patients who received antibiotics or corticosteroids had decreased OS (p = 0.019 and p = 0.043, respectively) across several cancer types. Medications that were not significantly associated with OS included statins (p = 0.38), proton pump inhibitors (p = 0.94), H2 blockers (p = 0.27) and NSAIDS (p = 0.46). A total of 159 patients had complete data for all medications suitable for modeling relative effects. 149 (94%) of patients received antibiotics within 180 days of IO and 19 (12%) received both corticosteroids and antibiotics. The combination of corticosteroids and antibiotics had lower median OS than antibiotics alone or neither medication (p < 0.0018). A Cox Proportional Hazards model of antibiotics and corticosteroids, controlling for age, BMI and ECOG performance status, showed antibiotics, age and BMI to be significant predictors. Conclusions: Antibiotics and corticosteroids near the start of IO reduced overall survival, and the combination reduced the median overall survival further. However, a combined model that controlled for age, BMI and ECOG showed antibiotics, age and BMI to have a significant effect on OS. Though preliminary, these results suggest that antibiotics and corticosteroids may be affecting OS in the context of IO through overlapping pathways.
Randomized phase II trial of patient-specific dendritic cell vaccines loaded with autologous tumor antigens versus autologous monocytes in patients with primary advanced ovarian cancer.
Authors: Dillman Robert O. , Abaid Lisa , Hsieh Candace , Langford Christopher , Nistor Gabriel I.
Published: July 2019

TPS10

Background: With standard debulking surgery and combination chemotherapy (adjuvant ± neoadjuvant) the 5-year survival for women with newly diagnosed advanced epithelial ovarian cancer (stage III or IV) is less than 40%. After completion of primary therapy there is an opportunity to introduce an immunotherapy modality in an effort to improve long-term survival. In patients with metastatic melanoma, patient-specific vaccines consisting of autologous dendritic cells (DC) loaded with autologous tumor antigens (ATA) derived from a short-term autologous tumor cell line were associated with minimal toxicity and a 5-year survival of 50% in a single arm trial, and more than doubled median survival (43 vs. 20 months) in a randomized trial. Newly diagnosed patients with ovarian cancer might benefit from addition of such patient-specific therapeutic vaccines (DC-ATA) to standard therapy. Methods: This is a double-blind, 2:1 randomized trial comparing adjunctive treatment with DC-ATA to autologous monocytes (MC) in patients with newly diagnosed stage III or IV epithelial cancer of the ovary, fallopian tube, or peritoneum. Patients eligible for randomization are those who have completed or discontinued standard primary therapy, have a Karnofsky performance status ≥70, have an autologous tumor cell line, and have a monocyte product from which DC can be derived. The tumor cell line is derived from fresh tumor; MC are derived from leukapheresis, and MC are converted to DC by incubation with GM-CSF and IL-4. Patients are stratified by whether there is no evidence of disease at completion of primary therapy, and then are randomized, typically 6 to 7 months after tumor collection. Treatment can begin about 4 weeks from randomization. The trial has been open at a single site since mid-November 2017; the first tumor was collected in December. Appropriate tumor samples have been submitted from 11 patients and all 11 have resulted in cell lines. The first patient was randomized in May 2018. As of October 2018 four patients had been randomized and all four had started treatment. Additional clinical sites are being initiated. Clinical trial information: NCT02033616.
Preoperative PD1 checkpoint blockade and receptor activator of NFkB ligand (RANKL) inhibition in non-small cell lung cancer (NSCLC) (POPCORN).
Authors: Ahern Elizabeth Stephanie , Cubitt Annette , Ballard Emma , Teng Michele W.L. , Dougall William C. , Smyth Mark J. , Hughes Brett Gordon Maxwell
Published: July 2019

TPS129

Background: Preclinical studies indicate Receptor Activator of NF-κB Ligand (RANKL) blockade improves anti-tumor efficacy of immune checkpoint blockade (ICB). Clinical trials combining denosumab (anti-RANKL mAb) with ICB are underway in various cancers although the hypothesized mechanism of action of such combinations remains incomplete. RANKL and its receptor, RANK, are frequently expressed in NSCLC (tumor and immune cells). Denosumab demonstrated survival advantage over bisphosphonate in metastatic NSCLC (mNSCLC) to bone; a recent retrospective case series suggests a relationship between concurrent ICB and denosumab duration and survival in mNSCLC. Neoadjuvant nivolumab recently showed encouraging pathologic response rates in resectable NSCLC; neoadjuvant trials lend themselves to translational research. Methods: POPCORN is a multicenter phase 1b/2 study to determine the mechanism of action, activity and safety of neoadjuvant nivolumab plus denosumab versus nivolumab alone. 30 patients with resectable stage 1A (tumor > 2cm) – 3A NSCLC will be randomized 1:1 to two arms (Table). Exclusion criteria include uncontrolled autoimmune disease, steroid contraindications, and unhealed dental disease. Tumor tissue at baseline, surgery and relapse, and peripheral blood at various timepoints (including on-therapy) will be collected. The primary endpoint is to define pharmacodynamic correlates of the two arms through investigations including T-cell receptor clonality, RNA/transcription profile changes (tumor and peripheral blood), and expression of tumor/immune markers of interest via multiplex immunohistochemistry, compared between groups. Secondary endpoints include pathologic response rates, toxicity, R0 resection, and PFS/OS (exploratory). Statistical analysis will be primarily descriptive on the intention-to-treat population. The trial is sponsored by Metro North Hospital and Health Service (Queensland, Australia) with funding from AMGEN, Inc. Clinical trial information: ACTRN12618001121257. [Table: see text]
A pilot study of pembrolizumab in combination with decitabine and hypofractionated index lesion radiation in pediatric and young adult patients with relapsed and refractory solid tumors or lymphoma.
Authors: Turpin Brian , Vatner Ralph
Published: July 2019

TPS25

Background: A potential limitation to the use of immune checkpoint inhibitors in younger patients with immune-resistant histologies is related to low tumor associated antigen expression and an immunosuppressive microenvironment. Low dose decitabine, as an inhibitor of DNA methyltransferase, can unrepress immunogenic cancer testes antigen expression, while hypofractionated radiation promotes infiltration of immune effector cells, stimulation of toll-like receptors on dendritic cells, and induction of type I interferons and other cytokines. As induced PD-L1 expression may also result, we hypothesize that decitabine, radiation, and the PD-1 inhibitor, pembrolizumab, will be synergistic. Here, we aim to verify the safety and preliminary activity of the combination. Correlative studies include an investigation of changes in antigen expression, the kinetics of immune effector and regulatory cell phenotype and function, and microbiome. Methods: Treatment program: Every 28 day cycle, patients receive 10 mg/m2 IV decitabine on days 1-5 and 2 mg/m2 (max dose 200 mg) IV pembrolizumab on day 8. Hypofractionated radiation (8 Gy x 3) to one or more lesion(s) is given on days 5-7 of the second cycle only. Adult patients may consent to optional biopsy of an irradiated lesion. Beyond cycle 3, patients may undergo elective surgery of one or more lesions. Patients remain on therapy for 27 cycles, absent progression by irRECIST or unacceptable toxicity. Patient eligibility: Patients 12 months to 40 years with available archived tissue may be considered, and must have adequate organ function including an absolute neutrophil count ≥ 750/mm3 and platelet count ≥ 75,000/mm3. Patients may have stable central nervous system metastases. Patients previously treated with radiotherapy may be eligible. Patients previously treated with PD-1 inhibitor therapy may be eligible, unless treated for an immune related adverse event. Current enrollment: This trial has been open to enrollment since February of 2018. No dose limiting toxicities have been observed in 2 patients evaluable for toxicity. Clinical trial information: NCT03445858.
Genetic Deletion of Esr1 in the Mouse Preoptic Area Disrupts the LH Surge and Estrous Cyclicity
Authors: Porteous Robert , Herbison Allan E
Published: July 2019

Estrogen receptor α (ESR1) is critical for the generation of the preovulatory LH surge. Experiments in rodents have indicated a role for neurons located in the anteroventral periventricular area and preoptic periventricular nucleus [termed the rostral periventricular area of the third ventricle (RP3V)] in surge generation. In the current study, we aimed to examine whether ESR1 expressed by RP3V neurons was necessary for the LH surge. The estrous cycles of mice with estrogen receptor α (Esr1) exon 3 flanked by LoxP sites (Esr1 flox) and controls were monitored before and after bilateral stereotactic injection of adeno-associated virus encoding Cre recombinase into the RP3V. This resulted in 84% and 72% decreases in ESR1-immunoreactive cell numbers in the anteroventral periventricular area and preoptic periventricular nucleus, respectively, with no changes in the arcuate nucleus. Beginning three weeks after the adeno-associated virus injection, Esr1 flox mice began to show a loss of estrous cyclicity going, primarily, into constant estrus. Wild-type mice and Esr1 flox mice with injections outside the RP3V or unilateral ablations of ESR1 continued to exhibit normal estrous cycles. Mice were then gonadectomized and given an estradiol replacement regimen to generate the LH surge. This resulted in an absence of cFOS expression in GnRH neurons (1 ± 1% vs 28 ± 4% of GnRH neurons; P < 0.01) and markedly reduced LH surge levels (2.5 ± 0.6 vs 9.1 ± 1.0 ng/mL; P < 0.01) in Esr1 flox mice compared with controls. These results demonstrate that neurons expressing ESR1 within the RP3V are critical for the generation of the LH surge and estrous cyclicity in the mouse.
Hydroxylated long-chain acylcarnitines are biomarkers of mitochondrial myopathy
Authors: Vissing Christoffer Rasmus , Duno Morten , Wibrand Flemming , Christensen Mette , Vissing John
Published: July 2019

Context

Plasma acylcarnitines are biomarkers of beta-oxidation and are useful in diagnosing several inborn errors of metabolism but has never been systematically investigated in patients with mitochondrial myopathy.

Objective

We hypothesized that acylcarnitines can also be biomarkers of mitochondrial myopathy and sought to investigate the prevalence and pattern of elevated acylcarnitines.

Design

The study was a prospective cohort study of patients with confirmed mitochondrial myopathy followed at Copenhagen Neuromuscular Center, Rigshospitalet, Copenhagen, Denmark

Patients

We included 35 patients (44±15 years, 15 women) with mitochondrial myopathy caused by single, large-scale deletions of mt-DNA (n=17), pathogenic variants in mt-tRNA (n=13) or in proteins of the respiratory chain complexes (n=5).

Concentrations of 35 acylcarnitines were measured using ultra-high-performance liquid-chromatography and tandem mass-spectrometry. Findings were compared to muscle mutation load in all patients, and to respiratory chain activity in 26 patients.

Main outcome measures

Prevalence of elevated concentrations of acylcarnitines related to acyl-CoA dehydrogenases in patients with mitochondrial myopathy and relation to geno-/phenotypes.

Results

In total, 27 (77%) patients had elevated concentrations of acylcarnitines related to acyl-CoA dehydrogenases. Elevated concentrations of seven acylcarnitine species were significantly more common in patients compared to a control cohort of> 900 individuals, and a specific pattern involving hydroxylated long-chain acylcarnitines occurred in 22 (63%) patients. Severity of derangements was correlated with muscle mutation load and geno-/phenotypes.

Conclusion

In conclusion, elevated concentrations of acylcarnitines is common in patients with mitochondrial myopathy and shows a specific pattern affecting hydroxylated long-chain acylcarnitines, which can have implications for future diagnostic work-up of patients.
Impact of Anesthetics, Analgesics, and Perioperative Blood Transfusion in Pediatric Cancer Patients: A Comprehensive Review of the Literature
Authors: Cata Juan P. , Owusu-Agyemang Pascal , Kapoor Ravish , Lonnqvist Per-Arne
Published: July 2019

Cancer is the leading cause of death by disease in developed countries. Children and adolescents with cancer need surgical interventions (ie, biopsy or major surgery) to diagnose, treat, or palliate their malignancies. Surgery is a period of high vulnerability because it stimulates the release of inflammatory mediators, catecholamines, and angiogenesis activators, which coincides with a period of immunosuppression. Thus, during and after surgery, dormant tumors or micrometastasis (ie, minimal residual disease) can grow and become clinically relevant metastasis. Anesthetics (ie, volatile agents, dexmedetomidine, and ketamine) and analgesics (ie, opioids) may also contribute to the growth of minimal residual disease or disease progression. For instance, volatile anesthetics have been implicated in immunosuppression and direct stimulation of cancer cell survival and proliferation. Contrarily, propofol has shown in vitro anticancer effects. In addition, perioperative blood transfusions are not uncommon in children undergoing cancer surgery. In adults, an association between perioperative blood transfusions and cancer progression has been described for some malignancies. Transfusion-related immunomodulation is one of the mechanisms by which blood transfusions can promote cancer progression. Other mechanisms include inflammation and the infusion of growth factors. In the present review, we discuss different aspects of tumorigenesis, metastasis, angiogenesis, the immune system, and the current studies about the impact of anesthetics, analgesics, and perioperative blood transfusions on pediatric cancer progression.
A Question of Personal Status
Authors: Hyndman-Rizk Nelia
Published: July 2019

Amid an enduring political deadlock in Parliament, the first civil marriage contracted in Lebanon in 2013 received significant media coverage in a country where the personal status law of eighteen recognized religious sects governs marriage. This case study examines the debate on civil marriage reform and the implications for women’s rights in Lebanon. For advocates, the recognition of civil marriage legalizes interreligious marriages, strengthens secular citizenship, shifts the jurisdiction of marriage from religious to civil law, and ensures women’s rights. Opponents, meanwhile, fear the loss of religious autonomy, the transformation of self-identification in Lebanon from sect to nation, and the destabilization of the confessional system. To date, civil marriage reform has been incremental, given clerical and social opposition, but the winds of change are blowing as couples increasingly take matters into their own hands to reform Lebanon’s system of personal status from the ground up.
Improving the Diagnosis of Nonfunctional Overreaching and Overtraining Syndrome
Authors: BUYSE LUK , DECROIX LIESELOT , TIMMERMANS NIELS , BARBÉ KURT , VERRELST RUTH , MEEUSEN ROMAIN
Published: July 2019

Introduction

This study aimed to simplify and optimize the distinction between nonfunctional overreaching (NFO) and overtraining syndrome (OTS) by developing a multivariate approach (discriminant analysis [DA]) including hormonal and psychological changes measured during the Training Optimization (TOP) test.

Methods

Sensitivity of previously defined cutoff values for hypothalamic–pituitary–adrenal axis hormonal changes were recalculated on a larger database (n = 100). Discriminant analysis including hormonal and psychological variables measured during the TOP test was used to discriminate between NFO and OTS and predict the diagnosis of new cases.

Results

Adrenocorticotrophic hormone (ACTH) and prolactin (PRL) responses to the second exercise test were most sensitive to NFO and OTS. Cutoff values for ACTH and PRL response to the second test (NFO > cutoff value (200%) > OTS), showed a sensitivity of 67% for ACTH and 93% for PRL in case of OTS and 74% for both ACTH and PRL in case of NFO. A DA including hormonal and psychological changes measured during the TOP test, resulted in the accurate diagnosis of NFO and OTS with 98% sensitivity. The ACTH and PRL responses to the first and second exercise tests and feeling of fatigue were the most discriminating variables.

Conclusions

The ACTH and PRL responses during the TOP test are the most sensitive markers to discriminate between NFO and OTS. Discriminant analysis including hormonal and psychological responses during the TOP test, can be used to optimize the diagnosis of NFO and OTS.