bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety, efficacy, and immunogenicity of autologous tumor lysate-pulsed dendritic cell vaccination therapy after resection of stage IIA (T2N0, T3N0) esophageal cancer: A phase I trial.
Authors: Sato Yasuyoshi , Matsushita Hirokazu , Mori Kazuhiko , Kakimi Kazuhiro , Seto Yasuyuki 
Published: November 2019

153 Background: Immunotherapy using active immunization of tumor associated antigens has been expected to improve the prognosis of malignant tumor patients. We conducted a phase I trial to investigate safety and efficacy of autologous tumor lysate-pulsed dendritic cell (DC) vaccination therapy after resection for esophageal cancer. Methods: Patients (pts) with stage IIA (T2N0 or T3N0, UICC TNM classification 6th edition) esophageal cancer after curative (R0) resection, ECOG PS 0-2, 20 years or more and adequate organ function were eligible. We used tumor lysate for DC vaccines; the lysates potentially contain mutated proteins or neoantigens derived from somatic mutations in each patient's tumor. Patients received DC vaccines (more than 5.0×106 cells) 6 times every 2 weeks. Primary endpoint was safety and secondary endpoint were efficacy including recurrence rate and immunological responses. Results: A total of 11 pts (median age: 71 years) were enrolled until the trial stopped on March 31, 2016, because standard of therapy for objective patients had changed. No treatment related adverse events of grade 3 or 4 were reported. Recurrence rate within 2 years were 18% (n=2). We performed whole-exome sequence of tumors and adjacent normal tissues with 5 pts, and identified mutated peptide derived from their tumor specific missense mutations. To examine immune responses against those predicted candidate neoepitopes, we immunized HLA-A2 transgenic mice (HHD-II mice) with the synthesized peptides from the 2 pts harboring HLA-A2. Conclusions: This study showed that autologous tumor lysate-pulsed DC vaccination therapy is safe and have expectation of recurrence risk reduction after resection of T2N0 or T3N0 esophageal cancer. Clinical trial information: UMIN000002837.
Immunological changes following intraperitoneal administration of a formulated IL-12 plasmid in combination with standard neoadjuvant chemotherapy in patients with newly diagnosed advanced stage ovarian cancer.
Authors: Anwer Khursheed , Matsuzaki Junko , Bshara Wiam , Lugade Amit , Omilian Angela , Thaker Premal H. , Bradley William Hampton , Leath Charles A. , Gunderson Camille Catherine , Fewell Jason , Borys Nicholas , Musso Lauren , Odunsi Kunle 
Published: November 2019

156 Background: The translational component of a Phase I study of weekly intraperitoneal GEN-1, an IL-12 plasmid formulated with polyethyleneglycol-polyethyleneimine cholesterol lipopolymer, in combination with dose-dense weekly taxane (T) and carboplatinum (C) every 3 weeks in newly diagnosed epithelial ovarian, fallopian tube, or primary peritoneal cancer (EOC) patients undergoing neoadjuvant therapy (NAC). Our hypothesis is that the GEN-1 plus NAC treatment will reprogram the tumor immune microenvironment towards a potent antitumor immune response. Methods: Patients received GEN-1 at escalating dose levels from 36 mg/m2, 47 mg/m2, 61 mg/m2, to 79 mg/m2weekly for 8 treatments with concurrent T/C. Tumor samples collected at time of diagnostic laparoscopy and interval debulking (IDB). Blood and peritoneal ascites were collected before and after treatment. The immunological analysis included frequency of immune cell populations and cytokine levels in tumor, blood, and peritoneal ascites and cell-specific mRNA expression profile. Results: The preliminary results obtained from first two cohorts show that GEN-1 may be enhancing post-treatment changes in immune cell populations including an increase in cytotoxic CD8+ T-cells and decrease in immunosuppressive FoxP3+ T-reg cells in tumor at IDB. The CD8:Foxp3 ratio appeared to be skewing beneficially towards more cytotoxic T lymphocyte and away from suppressive cells in most patients. The analysis of circulating immune cells 21 days after first GEN-1 treatment showed a decrease in circulating CD123+ plasmacytoid dendritic cells, but no change in CD11c+ myeloid dendritic cells. There were no major changes in the frequency of circulating T-cells. Additional analyses from this study are in progress. Conclusions: Based on preliminary analyses of cohorts 1 & 2 samples analyzed, the treatment of EOC patients with GEN-1 and NAC has resulted in favorable immunological responses. Updated results to be presented at meeting. Clinical trial information: NCT02480374.
Oncolytic viruses: New era in cancer therapy.
Authors: Rasmy A. , A. Amal 
Published: November 2019

161 Background: Modern technology has afforded the human race with a new treatment for cancer using immunotherapy, and the Oncolytic Viruses (OVs) represent a new class of this type of therapeutic agent. Targeted therapy of cancer using OVs has generated much interest over the past few years in light of the limited efficacy and side effects of standard cancer therapeutics for advanced disease. Methods: By definition, OVs are a type of virus that infect and lyse cancer cells, but healthy cells are left intact. OVs can occur naturally or can be synthesized in the laboratory through the alteration of other viruses. The OVs immunotherapy treats cancer patients by using native or genetically modified viruses that selectively replicate within tumor cells. The mechanisms of action are not entirely understood but are likely dependent on viral replication within transformed cells, induction of primary cell death, interaction with tumor cell antiviral elements, and initiation of innate and adaptive anti-tumor immunity. Results: On 27 October 2016, the FDA approved the first genetically engineered virus called talimogene laherparepvec (T-VEC or Imlygic) to treat advanced melanoma. A treatment course with Imlygic consists of injections into the melanoma lesions. After the first injection, a second one is administered after three weeks, then additional doses every two weeks for at least six months. Conclusions: The OVs immunotherapy is a highly promising approach and introduces a new class of drugs for treating cancer patients particularly in combination approach. Additional studies are required to learn more about the mechanism of action and to understand how this new class of drug can improve the prognosis of cancer patients. As continuing work is being done to improve the OVs that are currently available, new viral species are also emerging and are worth exploring.
CD70 as a critical mediator of tumor progression and immunosuppression in gliomas.
Authors: Yang Changlin , Ge Haitao , Jin Linchun , Wang Qiong J. , Yang James C. , Long Yu , Chang Yifan(Emily) , Drake Jeffrey , Mu Luyan , Sayour Elias Joseph , De leon Gabriel , Kubilis Paul , Kresak Jesse , Lu Dunyue , Kong Yingjun , Hu Li , Sun Jiahang , Mitchell Duane Anthony , Lin Zhiguo , Huang Jianping 
Published: November 2019

18 Background: For malignant gliomas, current treatment modalities are rarely curative, necessitating development of novel therapies. Cancer immunotherapy has represented one of the most promising new treatment strategies for patients with gliomas based on the evidence that patients with brain tumors are able to mount immune responses against the autologous tumors. However, very few tumor specific targets have been discovered in this malignancy. Thus, identifying clinical useful targets for immunotherapeutic approaches is desperately needed. Methods: CD70 expression was tested from primary GBM and low grade gliomas patient tissues. CD70 gene expression and clinical outcomes were culled from TCGA datasets. CD70 inducing CD8 T cells death was performed by flowcytometry. Results: We demonstrate that CD70, a member of the TNF ligand family, was constitutively overexpressed by primary IDH-wild-type LGG and GBMs with mesenchymal gene signatures. Elevated CD70 expression was also found in recurrent tumors and correlated with tumor progression and poor survival outcome in LGGs and GBMs. CD70 was shown to be directly involved in tumor-chemokine production and associated with sustained T regulatory cells in tumor. Importantly, CD70 played a role inducing CD8+T- specific cell death via engagement of the EREG-EGFR axis in glioma. Conclusions: CD70 is a multi-pronged modulator of immunosuppression in gliomas and enhances tumor progression.
Diagnostic accuracy of molecular tumor profiling in determining the tissue of origin in adult patients with cancer of unknown primary: A meta-analysis.
Authors: Inocencio Rowena Torres , Kesari Kavitha , Smith Susan 
Published: November 2019

20 Background: Appropriate cancer treatment requires determination of the primary site of origin. The standard of care for diagnosing Cancer of unknown primary (CUP) based on the 2016 NCCN Guidelines is a comprehensive clinical work-up including biopsy and immunohistochemistry (IHC). However, IHC was able to identify a primary tumor in only 25% of CUP. Molecular tumor profiling (MTP) validation studies demonstrated sensitivities of 74-89% and specificities of 95-99%. Only a few studies with small sample sizes using MTP to diagnose the primary in CUP have been performed yielding variable results. This study aims to evaluate the diagnostic accuracy of MTP in determining the tissue of origin in adult patients with CUP. Methods: Literature search included articles published in any language indexed in MEDLINE and Cochrane. A Google Scholar search and a review of all published articles’ references were performed. Unpublished studies and abstracts from conference proceedings were also reviewed. Studies involving adult patients with CUP who underwent both MTP and clinical evaluation with IHC were identified. Articles were included if they had primary data sufficient to calculate both sensitivity and specificity. Methodological qualities of the included studies were evaluated using the QUADAS-2 tool. Data was analyzed using Review Manager 5.3 and MetaDiSc 1.4. Results: Seven studies with 549 patients were analyzed. MTP was found to have a pooled sensitivity of 89% (95% CI 0.85-0.92)and pooled specificity of 74% (95% CI 0.67-0.80)with pooled positive and negative likelihood ratios of 2.97 (95% CI 1.17-7.63) and 0.20 (95% CI 0.07-0.51), respectively. Area under the curve was measured to be 0.9107. Conclusions: This meta-analysis suggests that MTP could be useful in determining the tissue of origin in adult patients with CUP. With an area under the curve of 0.9107, it is an excellent diagnostic test. The results showed considerable heterogeneity as expected in meta-analyses of diagnostic test accuracy. In this case, it may be due to variability among the MTP assays used which may reflect different cutoffs.
Prognostic value of CD8+ tumor-infiltrating lymphocyte density and PD-L1 expression in tumor cells in thymic epithelial tumors.
Authors: Katsuya Yuki , Horinouchi Hidehito , Goto Yasushi , Kanda Shintaro , Fujiwara Yutaka , Nokihara Hiroshi , Yamamoto Noboru , Watanabe Shun-ichi , Motoi Noriko , Ohe Yuichiro 
Published: November 2019

21 Background: The prognostic significance of CD8+ tumor-infiltrating lymphocytes (TILs) in thymic epithelial tumors (TETs; thymoma [TM] and thymic carcinoma [TC]) is unknown. We examined whether the density of CD8+ TILs and the PD-L1 expression level in TETs were correlated with patient outcome. Methods: Immunohistochemistry and a semi-automated software quantification analysis were used to examine formalin-fixed paraffin-embedded specimens from patients with TET who had been treated with chemotherapy. The density of CD8+ TILs was evaluated at two representative sites: within the tumor nest (intratumoral CD8), and at the invasive margin (stromal CD8, if evaluable). The average density of CD8+ TILs was used as the cut-off value, while an H-score of 5% was used as the cut-off for PD-L1 expression. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Univariate and multivariate Cox regression analyses were performed to evaluate prognostic factors. Results: Twenty-six patients (TM/TC 9/17) were evaluated. A high intratumoral CD8 density was correlated with a superior outcome in terms of both PFS (median, 7.6 vs 27.7 months; P = 0.002) and OS (median, 54.3 months vs not reached; P = 0.022) among the patients with TM, and a similar tendency was seen among the patients with TC, although the correlations were not statistically significant. PD-L1 expression was not significantly correlated with patient outcome in the TM and TC groups. Univariate and multivariate analyses demonstrated that a high intratumoral CD8 density was a significant predictive factor for PFS (Hazard ratio, 0.25 [95%CI 0.08–0.75]; P = 0.014) and OS (Hazard ratio, 0.06 [95%CI 0.007–0.44]; P= 0.006), whereas PD-L1 expression was not. The tendency for a change in the intratumoral CD8 density in pre/post-chemotherapy TM specimens was not consistent. The proportion of stromal CD8 density to intratumoral CD8 density in the TC specimens was not correlated with survival. Conclusions: A high intratumoral CD8 density had a positive prognostic impact for patients with TETs, especially those with TMs. The impact of this immune-related factor should be validated in a larger cohort.
Neutrophil lymphocyte ratio (NLR) as a predictor of outcomes with immune checkpoint inhibitor (ICI) therapy in genitourinary cancer and melanoma.
Authors: Jeyakumar Ghayathri , Bumma Naresh , Kim SeongHo , Landry Craig , Weise Amy , Flaherty Lawrence E. , Heath Elisabeth I. , Silski Cynthia , Zechar Erich , Vaishampayan Ulka N. 
Published: November 2019

37 Background: Immunotherapy, such as PD-1 and PD L1, has been recently approved in melanoma and genitourinary cancers (GU) such as renal cell carcinoma and urothelial carcinoma. There is an unmet need to determine factors predictive of response, to guide therapeutic selection in these cancers. We evaluated NLR (ratio of absolute values of neutrophils to lymphocytes) as predictors of response, progression free survival (PFS) and overall survival (OS) in patients treated with PD1 or PD L1 inhibitors. We extrapolated from renal cell data with NLR and used a value of 4 as cutoff. Other known prognostic clinical factors assessed were age, race, and smoking status. Methods: Regulatory approval was obtained. A retrospective chart review of melanoma and genitourinary cancer patients at Karmanos Cancer Institute, treated with ICI was conducted. Data were collected on demographics, smoking status, pretherapy NLR, and post 4 doses of ICI. Association with clinical outcomes (response rate, PFS and OS) was conducted by univariable and multivariable analyses. A log-rank test was used to compare PFS and OS. Results: 143 pts, (59 GU and 84 Melanoma) were evaluated with median age of 61yrs (range, 24-87). 11 pts (19%) and 5 (6%) were African American (AA) in GU and melanoma respectively. 61 pts (43%) were smokers in total. Pretherapy NLR<4 and ≥4 was seen in 97(68%) and 46 (32%) pts. The table summarizes the results of the analysis. Conclusions: Pretherapy NLR ≥4 was a statistically significant predictor of shorter PFS and OS with ICI therapy in GU and melanoma cancers. NLR is an easily applicable predictive factor, however validation of this observation is required in a larger sample size. [Table: see text]
The pan-cancer, pan-biomarker landscape for precision immuno-oncology.
Authors: McLeod Howard L. , Berglund Anders E. , Yao Jiqiang , Avedon Melissa , Teer Jamie K. 
Published: November 2019

43 Background: Precision medicine has the opportunity to also change medical practice. However, there are many cancer treatments for which there are few tools for individualized selection based on patient-specific attributes. This is especially the case for the immune check point inhibitors, where a subset of patients receive almost unimaginable benefit, there is a significant incidence of severe, life threatening, and persistent autoimmune oriented toxicities, and the financial burden is real for patients. At least 3 distinct predictive immunooncology biomarkers (IOMark) have been proposed. This includes tumor mutation analysis, expression of PD-L1, and tumor-specific t cell subset (Weber Predictor). However, there is little data on the intrapatient relationship of these putative response markers. Methods: Analysis of individual patient IOMark status was determined in TCGA patients that had cancers for which immunotherapy is FDA approved (n = 2039; bladder, colorectal, kidney, lung, melanoma, stomach). Patients were categorized as putative high/low predicted responders for each biomarker [neoantigen burden (whole exome cutpoint = 225), PD-L1 (median), Weber predictor (upper 50% for each of CD8/Ki67/EOMES)]. Results: A high neoantigen burden was detected in 1%-60% of the tumors (median 31%; range kidney to melanoma). There was less variance for high PD-L1 (26%-78%, median 49%; colorectal to lung). The Weber predictor ranged from 2% to 41% (kidney to stomach). A subset of each cancer type were positive for each of the response markers (0% to 12%; median 6%; renal to stomach). There is not a high association between the IOMarks. Conclusions: Immuno-oncology is in need of robust IOMark, to allow more informed patient treatment. Analysis of the currently most promising IOMarks show high variation across tumor types and within tumor types. Only a subset of patients has high response predicted for all 3 IOMarks. The IOMarks are independent and identify distinct patient features.
Total tumor burden as predictive tool of response and survival of patients with metastatic melanoma treated with nivolumab.
Authors: Barros e Silva Milton Jose , Salgado Boneti Bianca , de Moares Rafael 
Published: November 2019

48 Background: Nivolumab (NIVO) has shown increased results either in objective response rate (ORR), progression free survival (PFS) and overall survival (OS), which have completely changed the treatment of patients with metastatic melanoma (MM). Tools to guide selection of patients are absent. Methods: This is a retrospective, observational, single-center study. The TBT was calculated considering the sum of the largest diameter of all measurable lesions and the smallest diameter of lymph nodes affected. Results: 54 patients with histologiacally confirmed MM were included in the protocol (OCT/14-may/16). Patients had a median age of 61 years (22-86 years), 58% were male, and 73% of tumor were located in the skin. 42% had ECOG 1, 72% had M1c, and 36% had LDH over the upper limit of normality (ULN). 34% had the mutation of the BRAF (half of them treated with IBRAF). About 75% had no prior benefit with anti-CTLA4 and 21% of the population had brain metastases. The median follow-up was 11.1 months and the median NIVO doses was 10 cycles. The ORR was 30.2% and the clinical benefit rate was 54.7%. The median PFS was 6.89 months (95% CI 1.12 to 12.6 months) and OS was not reached. TBT being < or > the median impact on OS with HR 4.5 (95% CI 1.22 to 16.9; p = 0.024). Once again, there was a statistically significant difference in terms of PFS and OS when related to pooled TBT ≤ or > 200 mm. The PFSm was 9.4 months (95% CI NR) for TBT ≤ 200 and 2.6 months ( 95% CI 1.9 to 3.2 months) to TBT > 200, with a HR: 2.64 (95% CI 1.03 to 6.74; p = 0.042). OSm regarding TBT ≤ 200 was not reached and was 2.6 months (95% CI 2.0 to 3.2 months) to TBT > 200, with RH:8.9 (95% CI 2.56 to 30.9; p = 0.001). According to the Fisher's exact test analysis, there is a significant association between LDH > ULN and pooled TBT > 200, with p = 0.023. Also, a relation between grouped TBT ( ≤ 200 or > 200) and the type of response seemed to be significant, with p = 0.021. Conclusions: The results of our study are very consistent with current medical literature. In our study, high TBT was associated with less response rates and both less OS and PFS rates.
Single-cell cytokine profiling of tumor-infiltrating T cells to measure patient responses to anti-PD-1 therapy.
Authors: Mackay Sean , Flynn Brianna , Morse Kevin , Paczkowski Patrick , Bacchiocchi Antonella , Fan Rong , Halaban Ruth , Zhou Jing 
Published: November 2019

49 Background: Functional alteration of tumor-infiltrating T lymphocytes (TILs) may serve as a predictor for clinical outcome in cancer patients receiving immunotherapy.To evaluate TILs function unleashed by anti-PD-1 blocking, we employed a single-cell technology integrated with automated bioinformatics to simultaneously measure 17 cytokines secreted by single TILs, permitting the full spectrum delineation of anti-tumor T cell functions in patients with metastatic melanoma. Methods: TILs were enriched from biopsied melanoma tissues digested with enzymes, stimulated with anti-CD3 at 37°C, 5% CO2 for 24 hrs and loaded into a single-cell barcode chip (SCBC) containing ~12000 microchambers. Each chamber (~1.2 nl) was pre-patterned with a complete copy of a 17-plex antibody array. Cells on the SCBC were imaged and incubated for 16 hrs at 37°C, 5% CO2; single-cell cytokine signals were captured with a microarray scanner. The polyfunctional expression (2+ cytokines per cell) of single TILs was evaluated across 4 groups: Effector (Granzyme B, IFN-γ, MIP-1α, Perforin, TNF-α), Stimulatory (GM-CSF, IL-2, IL-5, IL-8, IL-9), Regulatory (IL-4, IL-10, IL-13, IL-22), and Inflammatory (IL-6, IL-17A, MCP-1). Results: Single-cell TILs analysis revealed significant increase of polyfunctional cytokines in patients who responded to anti-PD-1 therapy, compared to those resistant to therapy or in the control group. It was further revealed that the major contributions to enhanced polyfunctional strength are dominated by effector and stimulatory cytokines – both associated with anti-tumor immunity. Notably, TILs of patients responding to therapy exhibited polyfunctional secretions containing a subset of cells co-secreting Granzyme B, IFN- γ, MIP-1 α, and IL-8, which upon further validation is potentially a biomarker to predict clinical outcome of melanoma patients treated by checkpoint immunotherapy. Conclusions: Single-cell multiplexed cytokine profiling is capable of dissecting the full spectrum of immune functions associated with anti-tumor T cell immunity and more accurately measuring the function of TILs for predicting the response of patients receiving anti-PD-1 blocking therapy.