bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pilot trial treating recurrent GBM patients with precision medicine regimens.
Authors: Clarke Jennifer Leigh , Solomon David , Oberheim Bush Nancy Ann , Grabowsky Jennifer A. , Kline Cassie , Kroetz Deanna L. , Taylor Jennie Webster , Villanueva-Meyer Javier , Molinaro Annette , Gibson David , Tedesco Meghan , Rabbitt Jane E , Rodriguez Almaraz Eduardo , Schulte Jessica , Buerki Robin Arthur , Hervey-Jumper Shawn L. , Aghi Manish K. , Berger Mitchel S. , Chang Edward , Chang Susan Marina 
Published: June 2021

2045 Background: Recurrence of GBM after initial treatment with surgery, radiation, and chemotherapy is nearly universal. Salvage therapies have limited efficacy with median overall survival (OS) of approximately 9 months and 6-month-progression-free survival (PFS-6) of 10-25% for both targeted and traditional therapies. Given GBM’s molecular heterogeneity, targeting a single molecular abnormality in isolation has consistently failed as a strategy, and precision combination approaches are needed. Methods: The primary objective was to demonstrate the feasibility of implementing a personalized drug regimen for patients (pts) with surgically resectable recurrent GBM within 35 days of surgery. Secondary objectives included safety and efficacy. Eligible pts signed consent before surgery, and tumor tissue was analyzed using the CLIA-approved “UCSF500” next-generation sequencing panel with paired tumor/germline sequencing. A specialized genomic tumor board made individualized treatment recommendations incorporating sequencing results of the recurrent tumor and clinical history for each pt, using up to 4 FDA-approved drugs in combination (all drugs provided by study). Correlative studies will be reported separately. Results: 19 pts signed consent and 16 pts had surgery on trial, 1 with pathology showing treatment effect only. The remaining 15 pts were all genetically profiled and successfully started their individualized treatment within 35 days of surgery, meeting the primary feasibility endpoint. Conclusions: Implementation of an individualized treatment regimen was feasible in a timely fashion in surgically resectable recurrent GBM pts, with encouraging preliminary efficacy results. Further investigation is warranted, both to validate efficacy and to streamline this approach in larger pt populations. Clinical trial information: NCT03681028. [Table: see text]
Health-related quality of life for glioblastoma short and long-term survivors receiving treatment with TTfields.
Authors: Palmer Joshua David , Chuang Po-Ya , Chavez Gordon , Wang Bruce CM , Proescholdt Christina 
Published: June 2021

2055 Background: The aim of this study was to administer the first large-scale, international survey eliciting real-world patient-reported quality-of-life (QoL) for patients with newly diagnosed and long-term glioblastoma (GBM) currently receiving treatment with TTFields. Methods: A survey was designed and mailed to 2,815 patients actively using TTFields for treatment of GBM in the United States (US, n = 2,182) and Europe (EU, n = 633). The survey included 1) demographic information, 2) patient-reported clinical information and 3) EuroQol’s EQ-5D-5L and EQ visual analogue scale (EQ-VAS) surveys. Univariate and multivariate analyses were performed on five dimensions (mobility, self-care, usual activity, pain/discomfort, anxiety/depression) of the EQ-5D-5L and EQ-VAS to understand the impact of patient demographics and clinical characteristics on QOL. Results: A total of 1,106 patients were included (39.3% response rate) with 782 and 324 responses in the US and EU, respectively. The median time from diagnosis was 14 mos (range, 0-301 mos) and ≥24 mos in 28.4% of patients. Patients were mostly male (62.3%) with a mean age of 58.5 (SD = 12.5) and 69.3% had stable disease. Mean EQ-VAS was 68.2 for all patients and was significantly higher for those with > 15 months since diagnosis compared to < 15 months since diagnosis (p = 0.008). There were significantly fewer problems reported on self-care ( p = 0.04) and usual activity ( p = 0.007) in patients with a longer time since diagnosis in the univariate analysis. In the multivariate analysis, patients with a longer time since diagnosis reported significantly better EQ-VAS ( p = 0.04). The effect size in the multivariate analysis for time since diagnosis on EQ-VAS was higher in the progressed subgroup ( p = 0.17) compared to the broader sample (0.08). The EQ-VAS and all five dimensions including mobility, self-care, usual activity, pain/discomfort, and anxiety/depression were improved for stable patients compared to progressed patients in the univariate and multivariate analyses. However, when stratified by progression status, progressed patients with longer time from diagnosis had significantly fewer reported problems with mobility ( p = 0.04), self-care ( p = 0.004) and usual activity ( p = 0.008), and significantly better self-rated health status ( p = 0.02). Conclusions: GBM survivors receiving TTFields reported significantly improved health status over time since diagnosis. Long-term survival with TTFields does not have a detriment in patient reported quality of life, in fact with longer time from diagnosis QOL significantly improves. This is true for patients with stable and progressed disease. Future prospective clinical trials are needed to further study the impact of our treatment and tumor progression on patient QOL.
Phase I study of ruxolitinib with radiation and temozolomide in patients with newly diagnosed grade III gliomas and glioblastoma.
Authors: Rauf Yasmeen , Hufsey Rachel , Robinson Kathy , Suh John H. , Chao Samuel T. , Murphy Erin Sennett , Yu Jennifer S. , Peereboom David M. , Ahluwalia Manmeet Singh , Wei Wei 
Published: June 2021

2060 Background: Ruxolitinib is a novel, potent, and selective inhibitor of JAK1 (Janus kinase 1) and JAK2 with modest to marked selectivity against TYK2 (tyrosine kinase 2) and JAK3, respectively. Ruxolitinib interferes with the signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function. JAK signaling involves recruitment of signal transducers and activators of transcription (STATs) to cytokine receptors, activation, and subsequent localization of STATs to the nucleus leading to modulation of gene expression. Dysregulation of the JAK/STAT pathway has been associated with several types of cancer and increased proliferation and survival of malignant cells. Methods: Newly diagnosed patients with unmethylated MGMT Glioblastoma or grade III glioma were recruited to Arm 1. Every patient received ruxolitinib and 60 Gy radiation for 6 weeks over 6 weeks (2Gy x 30). The dose of Ruxolitinib was administered given the 3+3 design. Level 1 or starting dose was 10 mg twice daily, level 2 was 15 mg twice daily, level 3 was 20 mg twice daily and level -1 was 5 mg twice daily. Arm 2 was started once safe dose was established for Arm 1 for each dose level. Patients with methylated MGMT glioblastoma or grade III glioma were eligible for Arm 2. Every patient received ruxolitinib + radiation x 60 Gy + daily temozolomide at 75 mg/m2 for 6 weeks over 6 weeks. Overall survival (OS) and progression-free survival (PFS) were estimate by Kaplan-Meier method and compared using log rank test. Results: 45 patients had survival data, 25 patients were Arm I and 20 arm II. The median OS and PFS were 18.2 (95% CI: 3.6-NA) months for Arm 1 and were not reached for Arm 2. OS and PFS Rate at 1 year was 61% (95% CI: 43-85%) and 51% (35-76%) for Arm 1, and 95% (85-100%) for Arm 2 (p = 0.01 and p = 0.002), respectively. Conclusions: Patients that received ruxolitinib + radiation x 60 Gy + daily temozolomide at 75 mg/m2 for 6 weeks over 6 weeks (Arm 2) had significantly better PFS and OS than those that received ruxolitinib + radiation x 60 Gy alone. Clinical trial information: NCT03514069.
Predictive value of lymphocyte immunophenotyping (LIP) in primary central nervous system lymphoma (PCNSL).
Authors: Berthelot Axel , Boucard Celine , Petrirena Gregorio , Campello Chantal , Chinot Olivier L. , Tabouret Emeline 
Published: June 2021

2063 Background: Immunity plays an important role in PCNSL development. PCNSL predictive factors need to be improved. Objective: to evaluate the characteristics and predictive value of blood LIP in PCNSL patients. Methods: we prospectively analyzed blood LIP in all newly PCNSL referred to our institution between December 2013 and January 2020. LIP analysis was performed before rituximab and chemotherapy administration. The clinical, radiological, histological, biological and treatment data were retrospectively collected. Results: fifty-three patients were included with a median age of 69.7 (range 21.7-87.5). Median KPS was 60 (range 30-100). All patients presented with cerebral involvement, 13 (25%) with cerebrospinal fluid extension and 8 (15%) with ocular extension. Thirty-four patients (62%) benefited of steroid treatment at the time of LIP. Patients characteristics did not differ depending on steroid intake. Forty-eight patients (95%) benefited of polychemotherapy with high-dose methotrexate as first line treatment. We observed three (6%) lymphoproliferative syndromes on the LIP and 33 patients (64%) presented with one or several lymphopenias: 21 (40%), 24 (46%) and 9 (17%) NK, T and B lymphopenias respectively. Only 11 patients (21%) had normal LIP. Median CD4/CD8 ratio was 2.11 (range 0.54-9.11). This ratio was normal, low or high in 27%, 28% and 44% of patients respectively. The presence of steroids did not impact LIP results, including CD4 (p = 0.475) or CD8 (p = 0.726) rates and CD4/CD8 ratio (p = 0.727). Complete or partial responses, stable and progressive disease (PD) were observed in 24 (50%), 10 (21%), 4 (8%), and 10 (21%) patients respectively. CD4/CD8 ratio tended to be different between refractory (PD patients) and non-refractory patients (p = 0.077). A ROC curve analysis was performed with an AUC of 0.684 allowing the selection of a CD4/CD8 ratio cutoff of 1.97 with a sensibility, specificity, positive predictive value, and negative predictive value to identify refractory patients of 90%, 55%, 35% and 95% respectively. Median progression-free survival (PFS) and overall survival (OS) were 14.7 (95%CI: 6.5-22.9) and 43.2 (95%CI: 21.6-64.9) months, respectively. In multivariate analyses, adjusted by KPS, a CD4/CD8 ratio > 1.97 was associated with poor PFS (p = 0.043, HR = 3.32 [1.02-4.88]) and tended to be associated with worse OS (p = 0.064). Conclusions: LIP at baseline may predict refractory disease and exhibits a prognostic value in PCNSL patients.
Pan cancer analysis of the intra-tumoral microbiome’s correlation with racial disparities.
Authors: Li Wei Tse , Uzelac Matthew , Chakladar Jaideep , Wong Lindsay M. , Gnanasekar Aditi , Lee Abby C. , John Daniel , Lopez Jay Patrick , Ongkeko Weg M. 
Published: June 2021

2519 Background: Microbiome composition can influence cancer development and is moderated by diet, hygiene, sanitation, and other environmental variables. For example, a Mediterranean diet could increase breast Lactobacillus abundance, while the gut microbiome changes dramatically with fructose intake. Recent studies have revealed correlations between microbial abundance and racial disparities in cancer. Given these reports, it is critical to examine whether environmental influences on the microbiome contribute to racial disparities in cancer incidence and prognosis. Methods: We examined the intra-tumoral microbiome in the lungs, breasts, bladder, colon, rectum, cervix, head and neck, prostate, and pancreas (n = 4,169). Raw tumor RNA sequencing data were downloaded from The Cancer Genome Atlas (TCGA) and aligned to bacterial genomes. Microbial abundance was correlated to race, ethnicity, and prognostic variables (Kruskal-Wallis test or Cox regression, p< 0.05). Results: We identified several microbes correlated with racial disparities for breast and bladder cancer, two microbes for lung squamous cell carcinoma, and one microbe for colon cancer. For breast cancer, African Americans have the highest mortality rate, followed by white Americans and Asian Americans. We found that four microbes, all under the order Burkholderiales, were positively correlated with poor prognosis and were most abundant in African Americans and least abundant in Asian Americans. Therefore, increased abundance of these microbes may contribute to the observed mortality differences between races. For bladder cancer, Asian Americans have the lowest incidence and mortality rates. Seven microbes, including two Geobacillus, two Pseudomonas, and two Burkholderiales, positively correlate with good prognosis and are upregulated in Asian Americans. High Pseudomonas fluorescens abundance is positively correlated with decreased risk of death (HR: 0.57, 95% CI: 0.38-0.85). High abundance of the Burkholderiales R. pickettii (HR: 0.62, 95% CI: 0.42-0.92) and V. paradoxus (HR: 0.59, 95% CI: 0.36-0.98) also exhibit the same trend. Geobacillus and Pseudomonas are both present in food, while Burkholderiales can cause nosocomial infections and are altered by diet. Conclusions: Our study is the most comprehensive to date investigating racial differences in the intra-tumoral microbiome. Our data serve as a starting point for exploring whether environmental influence of microbial abundance contributes to racial disparities in cancer.
CAR-T cells to deliver engineered peptide antigens and reprogram antigen specific T cell responses against solid tumors.
Authors: Lee Daniel , Minn Andy J , Johnson Lexus R 
Published: June 2021

2530 Background: Neoantigen depleted malignancies such as colorectal cancer demonstrate primary resistance to immune checkpoint blockade, and solid tumors in general have shown resistance to chimeric antigen receptor (CAR) T cell therapy. However, CAR-T cells have been shown to be capable of delivering various therapeutic molecules in a targeted fashion to the tumor microenvironment, in some cases through extracellular vesicles (EVs). In vivo studies have shown that the presentation of foreign viral peptides by solid tumors can reprogram bystander virus-specific cytotoxic T cells (CTLs) against tumor cells. In this study, we demonstrate that CAR-T cells can deliver engineered peptide antigens to solid tumors, leading to presentation on tumor cells and anti-tumor response. Methods: Second generation CAR-T cells (41BB endodomain) targeting human CD19 (19BBz) or human mesothelin (M5BBz) were generated via retroviral and lentiviral transduction respectively. CAR-T cells were engineered to co-express peptides such as SIINFEKL of ovalbumin and NLVPMVATV of CMV pp65 among others. Peptides were isolated from EVs via ultracentrifugation. For in vivo studies, C57BL/6 or NSG mice were injected on the flank with relevant tumors and treated with peptide-CAR-T cells. In vitro studies utilized flow cytometry and xCELLigence killing assays. Results: Murine 19BBz CAR-T cells expressing the SIINFEKL peptide of ovalbumin (ova-19BBz) were found to transfer SIINFEKL peptide to tumor cells via EVs in vitro and in vivo, leading to peptide presentation on MHC-I of tumor cells. This resulted in significantly delayed tumor growth in tumor bearing mice transfused with OT-I T cells to mimic an existing antigen specific T cell pool. We expanded on these findings by isolating EVs from human M5BBz CAR-T cells expressing CMV viral peptides. Peptide-CAR-T EVs were co-cultured with human ovarian cancer cells to assess presentation to Jurkat T cells. Finally, we utilized primary human T cells from CMV+ healthy donors to assess the clinical feasibility of our peptide delivery approach. Conclusions: CAR-T cells can be engineered to deliver peptides to tumor cells for presentation and subsequent targeting by antigen specific CTLs. This represents a novel strategy for the treatment of non-immunogenic tumors.
A single-arm phase Ib study of multiple target cytotoxic T-lymphocyte (MCTL) in combination with toripalimab as second-line therapy in advanced non-small cell lung cancer (NSCLC).
Authors: Ren Xiubao , Zhang Weihong 
Published: June 2021

2535 Background: Anti-PD-1/ PD-L1 (programmed cell-death 1) mAb treatment has been approved in the US and in Europe as second-line treatment for advanced NSCLC because of the good tolerance and efficacy in comparison with docetaxel. Unfortunately, The objective response rate is only around 20%. Multiple Target Cytotoxic T-lymphocyte (MCTL) cells can restore the antitumor immunity to improve patient outcome. Combining MCTL cells with anti-PD-1 mAb may strengthen the results as second-line treatment in patients with advanced NSCLC. (NCT04193098). Methods: This is a single-center, open-label, phase 1b trial of combination MCTL cells with toripalimab (anti-PD-1 mAb)as second-line treatment for advanced NSCLC. Systemic therapy patients received toripalimab every 3 weeks for 12 cycles and received MCTL cells every 3 weeks for 9 cycles, then toripalimab and MCTL cells for maintenance therapy until disease progression or unacceptable toxicity. Results: From June 2019 to October 2020, 14 pts aged 43-70 years (median age 59 years) were enrolled. The squamous/non-squamous ratio was 50%/50%. 8 (57.1%) were men, 13(92.8%) were ECOG PS=0-1, 5 (35.7%) had pleural effusion, and 3 (21.4%) had bone metastases. Among 13 evaluable pts, the ORR and DCR were 38.4% and 71.4%, At the time of data cutoff, the median DOR was not reached (range 8.25m-NA), the median PFS was 399 days (range 192d-NA), and the median OS were not mature. Adverse events (AEs) occurred in 5 (38.4%), No grade≥3 AEs events occurred. Immune-related AEs were thyroid hypofunction (3, 23%) and weak (2, 15.4%). Biomarkers which correlated with efficacy and AEs are being analyzed. Conclusions: Multiple Target Cytotoxic T-lymphocyte (MCTL) in combination with toripalimab as second-line treatment for advanced NSCLC because of the well tolerated and encouraging efficacy. Further studies are warranted to confirm these results. Research Sponsor: Tianjin Medical University Cancer Institute and Hospital. Clinical trial information: NCT04193098.
A 4-chemokine signature to predict intermediate immunogenicity in homologous recombination repair deficient tumors.
Authors: Romero Joan Miguel , Wang Yifan , Pacis Alain , Denroche Robert Edward , Jang Gun Ho , Grunwald Barbara , Gallinger Steven , Zogopoulos George 
Published: June 2021

2546 Background: Treatment responses to immune checkpoint blockade (ICB) associate with T cell tumor inflammation. Tumors with mismatch repair deficiency display an inflammatory tumor phenotype and respond to ICB. Similarly, tumors with homologous recombination repair deficiency (HR-d) may be primed for ICB treatment. We have previously shown that a panel of 4 chemokines identifies a subclass of pancreatic cancer with markers of T cell-inflammation. Here, we evaluated this 4-chemokine signature in cancer types with HR-d molecular subclasses. Methods: We combined paired transcriptomes and genomic data of breast (n = 699), ovarian (n = 174) and prostate (n = 457) cancers from the Cancer Genome Atlas and tumor-enriched pancreas cancers (n = 121) to evaluate the 4-chemokine signature in HR-d vs. HR-proficient tumors across these 4 cancers. Metrics of antitumor immunity were also compared. Results: Across tumor types, elevated expression of the 4-chemokine signature (chemokine-hi) associated with transcriptional hallmarks of a T cell-mediated antitumor response, including antigen presenting cell stimulation, antigen presentation, and T cell activity. In tumors with a predominant COSMIC signature 3, which associates with HR-d, the 4-chemokine signature predicted intermediate levels of T cell-inflammation. Conclusions: These data suggest that 1) the 4-chemokine signature may be a clinically relevant biomarker in identifying subclasses of tumours responsive to immunotherapies, and that 2) HR-d tumors harbor intermediate immunogenicity. Correlation of treatment responses to immunotherapies with the 4-chemokine signature is needed validate its predictive value as a biomarker for treatment stratification with immunotherapies.[Table: see text]
Risk of immunosuppression and hospitalization after checkpoint inhibitor therapy in patients with cancer and radiation therapy.
Authors: Lee Kate E , Bender David Andrew , Spina Catherine S. , Hyde Brigham , Faye Adam S , Cheng Simon 
Published: June 2021

2588 Background: Immune checkpoint inhibitors (ICIs) are potent new cancer therapies but can cause serious immune-related adverse events. Radiation therapy (RT) also induces systemic immunologic effects, and data on the interaction and safety of combining ICIs and RT are limited. Methods: In this retrospective cohort study using a large medical claims database from 2010 to 2017, we ascertained the risk of immunosuppressive steroid therapy as well as the risk of hospitalization within 180 days of treatment with an ICI in patients with diagnoses of malignant melanoma or lung cancer. Patients were stratified by use of RT within 30 days before and after ICI therapy. ICIs included pembrolizumab, nivolumab, and ipilimumab, while immunosuppressive agents included oral prednisone and intravenous methylprednisolone. Results: 2020 patients (218 with RT, 1802 without RT) met inclusion criteria for prednisone analysis, while 3519 patients (361 with RT, 3158 without RT) met inclusion criteria for all other analyses. On univariable analysis, RT was not associated with need for prednisone or methylprednisolone (RR 1.2, 95%CI 0.8-1.9 and RR 1.2, 95%CI 0.7-2.1 respectively). When assessing hospitalization, RT was significantly associated with hospitalization following ICI therapy for certain cancer/drug combinations (RR 1.4, 95%CI 1.2-1.6, p<0.001 for lung cancer/PD-1 inhibitors, RR 2.0, 95%CI 1.0-3.5, p=0.03 for melanoma/ipilimumab). Conclusions: In patients treated with ICIs, receiving RT was not associated with a higher risk of requiring immunosuppressive steroid therapy as compared to not receiving RT. However, in those with ICIs, RT was associated with a higher risk of hospitalization as compared to no RT, though this may be a result of underlying differences in patent severity (more severe disease may require ICI and RT).[Table: see text]