bluuebunny/crossref_metadata_2025_split huggingface dataset:
A radiosensitivity gene signature and PD-L1 status to predict clinical outcome of patients with invasive breast carcinoma in the cancer genome atlas (TCGA) dataset.
Authors: Kim In Ah , Jang Bum Sup 
Published: November 2019

54 Background: A radiosensitivity gene signature that included 31 genes was identified using microarray data from NCI-60 cancer cells; however, this has not been validated in independent datasets for breast cancer patients. We investigated the link between the radiosensitivity gene signature and programmed cell death ligand 1 (PD-L1) status and clinical outcome to identify a group of patients that would possibly receive clinical benefit of radiotherapy (RT) combined with anti-PD1/PD-L1 therapy. Methods: We validated the identified gene signature related to radiosensitivity and analyzed the PD-L1 status of invasive breast cancer in The Cancer Genome Atlas (TCGA) dataset using bioinformatic tools. To validate the gene signature, 1,065 patients (or samples) were selected and divided into two clusters using a consensus clustering algorithm based on their radiosensitive (RS) or radioresistant (RR) designation according to their prognosis. Patients were also stratified as PD-L1-high or PD-L1-low based on the median value of CD274 mRNA expression level as surrogates of PD-L1. The relationship between the RS/RR groups and PD-L1 status was also assessed. The prognostic value was evaluated by Kaplan-Meier analysis and Cox proportional hazard models. Results: Patents assigned to the RS group had better 5-year recurrence-free survival (RFS) rate than patients in the RR group by univariate analysis (89% vs. 75%, p = 0.017) only when treated with RT. The RS group was independently associated with the PD-L1-high group, and CD274 mRNA expression was significantly higher in the RS group (p<0.001) than the RR group. In the PD-L1-high group, the RS group had better 5-year RFS rate compared to the RR group (89% vs. 72%, p = 0.015), and this difference was also significant by Cox-hazard proportional analysis. Conclusions: The radiosensitivity gene signature and PD-L1 status were important factors for prediction of the clinical outcome of RT in patients with invasive breast cancer and may be used for selecting patients who will benefit from RT combined with anti-PD1/PDL1 therapy.
Correlation of circulating PD-L2 levels with outcomes of therapy with the anti-PD-1 antibody pembrolizumab (P) in patients (pts) with advanced soft tissue sarcomas (STS): Biomarker analysis of SARC028.
Authors: Burgess Melissa Amber , Roszik Jason , Van Tine Brian Andrew , Hu James , Schuetze Scott , D'Angelo Sandra P. , Attia Steven , Priebat Dennis A. , Okuno Scott H. , Riedel Richard F. , Davis Lara Emily , Movva Sujana , Reed Damon R. , Baker Laurence H. , Reinke Denise K. , Maki Robert G. , Patel Shreyaskumar , Tawbi Hussein Abdul-Hassan , Butterfield Lisa Helene 
Published: November 2019

60 Background: The activity of the anti-PD-1 antibody P in pts with advanced STS was evaluated in a prospective multicenter Phase II study conducted by the Sarcoma Alliance for Research through Collaboration (SARC). SARC028 enrolled 40 patients with advanced soft tissue sarcoma. Pembro had an ORR of 19% and PFS rate at 12 weeks of 55%, suggesting clinical activity. We investigated biomarkers of response to P. Methods: The primary endpoint was Objective Response Rate (ORR) by RECIST 1.1. Secondary endpoints included progression-free survival (PFS), overall survival, and biomarkers of response in blood and tumor. Pre- and on-treatment biopsies were required and obtained from over 90% and 72% of pts respectively. Serum was obtained from all pts at baseline and at multiple time points on therapy (pre-, week 8, and every 12 weeks). Sera were examined for candidate circulating biomarkers by Affymetrix Luminex platform array, including PD-L2. To determine whether there is a statistically significant difference between different conditions, we used Mann-Whitney and two-tailed t tests. Log-rank p-values in Kaplan-Meier survival analyses were calculated using the "survival" R package. Results: Forty pts with STS were enrolled into 4 cohorts (10 each) based on histological subtype including undifferentiated pleomorphic sarcoma (UPS), dedifferentiated liposarcoma (LPS), synovial sarcoma (SS), and leiomyosarcoma (LMS). 4 pts with UPS, 2 pts with LPS, and one pt with SS achieved a response. Six of seven responses were durable at the time of this analysis. Circulating levels at baseline or after therapy of PD-1, PD-L1, 4-1BB, IDO, BTLA, CTLA-4, LAG-3, and TIM-3 did not correlate with outcome. However, pre-treatment and week 8 PD-L2 levels correlated best with clinical outcome: high PD-L2 levels were associated with better PFS (p=0.019) in STS. Conclusions: P has clinical activity in specific histologic subtypes of STS, namely UPS and LPS. Pre-treatment circulating PD-L2 levels correlated with progression-free survival and is a novel and promising predictor of improved clinical outcome of PD-1 therapy in STS.
Response to nivolumab in radiation induced, BRCA-2 N372H variant, programed death ligand-1 negative, pleomorphic undifferentiated sarcoma.
Authors: Foster Yevgeniya Gora , Cecchini Michael , Slater Dennis , Neumeister Veronique , Walther Zenta , Husain Zain , Judson Benjamin , Deshpande Hari Anant 
Published: November 2019

61 Background: Early results from recent studies using immune checkpoint blockade targeting programmed death 1 (PD-1) have suggested that pleomorphic undifferentiated sarcomas may have response rates of over 40%. As of now predictive biomarkers for response and resistance have been incompletely characterized. Methods: A 58-year-old man who received radiation for a head and neck squamous cell cancer, developed a radiation-induced undifferentiated pleomorphic sarcoma (UPS) in his neck in 2014. His sarcoma was resected but recurred in 2015. He received adjuvant radiation after surgical debulking in September 2015 and was found on radiation simulation scan to have new widespread metastatic disease involving liver, lung, and bone. He started treatment on nivolumab in November 2015 and has had a sustained near complete response in all lesions. Results: All sites had a near complete response to nivolumab treatment. Pre treatment tissue analysis revealed no mutations or amplifications in 134 cancer-related genes, on the Oncomine Assay (Life Technologies, Inc.). Normal tissue was noted to be heterozygous for BRCA2 N372H, while the allelic fraction of the 372H variant in the tumor was found to be 85%. Programmed death ligand-1 (PDL-1) immunohistochemistry staining of the tumor tissue was negative. Tumor infiltrating lymphocytes were not noted in the tumor tissue specimen. Conclusions: This patient exhibited a near complete response to all sites of disease, with remaining PET avidity in a single hilar node. The role of the BRCA2 variant and radiation just prior to starting nivolumab is unknown. BRCA2 N372H is a common single nucleotide polymorphism (SNP) in the population with a minor allele frequency of 0.25. Although the effect of the 372H variant on BRCA2 protein structure is predicted to be minimal, population studies have suggested a slightly increased risk of breast and ovarian cancer in homozygotes. It is possible that the radiation treatment to the site of recurrence in the head and neck, resulted in an abscopal effect enhancing the therapeutic effect of nivolumab therapy. Additional testing on his tissue is being done to further investigate the response.
Pattern of tumor-infiltrating lymphocytes (TILs) and PD-L1 expression in primary and metastatic epithelial ovarian cancer (EOC).
Authors: Mesnage Soizick Jeanne Lynette , Auguste Aurelie , Genestie Catherine , Dunant Ariane , Pain Erwann , Drusch Francoise , Gouy Sebastien , Morice Philippe , Bentivegna Enrica , Lhomme Catherine , Pautier Patricia , Michels Judith , Le Formal Audrey , Cheaib Bianca , Adam Julien , Leary Alexandra 
Published: November 2019

64 Background: Tumour immune response plays a critical role in progression and prognosis of EOC, however patterns of TILs and PD-L1 expression in primary and metastatic disease remain poorly described. Methods: Patients treated with neoadjuvant chemotherapy (NACT) for advanced EOC, between 2002-2014, and available sequential tumours (pre-NACT, post-NACT, or relapse) were retrospectively identified. Stromal TILs (sTILs) were evaluated according to the International TILs Working Group 2014 (Salgado 2015) on whole sections, and scored as a percentage of stromal area. Immune cell PD-L1 expression was evaluated by immunohistochemistry (E1L3N clone, Cell Signaling) in a smaller number of tumours. Cutoffs for analysis were: high sTILs ≥50%, PD-L1 positivity ≥5% membranous staining. Results: Among a total of 236 tumour samples from 150 patients (110 pre-NACT, 111 post-NACT, and 15 relapse tumours) median sTILs levels was significantly higher in metastatic tumours ( n=151) compared with primary tumours ( n=85) (median 30, IQR 10-50 vs. 15, IQR 5-30, p=0.0004). Among diagnostic samples, median sTILs level was 20 (IQR 10-45, n=85) in metastatic tumours compared with 10 (IQR 5-20, n =25) in primary tumours ( p=0064). Similarly in post-NACT samples, median sTILs level was 40 (IQR 15-60, n=51) in metastatic tumours compared with 20 (IQR 6.25-30, n=60) in primary tumours ( p=0026). Among relapse samples median sTILs level was 30 (IQR 10-50, n=15). Among all available samples ( n=97) PD-L1 positivity was detected in 33% (9/30) of primary and 50% (34/68) of metastatic tumours (Fisher’s exact test OR 2.3, 95%CI 0.94-5.4, p =0.08). Conclusions: In patients with EOC there is increased lymphocytic infiltration in both synchronous metastatic disease at diagnosis, and metachronous metastatic disease at relapse, compared with the primary tumour. This suggests increased immunogenicity as disease progresses. Furthermore, there is a trend towards upregulation of the PD-L1 immune checkpoint with disease progression.
Blood eosinophil counts as predictive marker in advanced melanoma patients treated with anti-PD1 therapies.
Authors: Gaba Lydia , Victoria Iván , Aya Francisco , Ruiz Gustavo , Pineda Estela , Reig Òscar , Fernandez-Martinez Aranzazu , Prat Aleix , Arance Ana 
Published: November 2019

66 Background: Anti-PD1 antibodies (Abs) Nivolumab (Nivo) and Pembrolizumab (Pembro) have both demonstrated to improve the overall survival (OS) in patients (pts) with advanced or metastatic melanoma (MM) in the first line setting. We previously reported that an increase in absolute eosinophil counts (AEC) of 100/mm3 over baseline at week 3 and an AEC > 400/mm3 at week 12 during anti-PD1 treatment (tmt) might identify pts with MM most likely to experience long-term disease control (1). AEC could serve as an important marker allowing the detection of those patients who may benefit from the therapy with anti-PD1 Abs. Methods: This retrospective observational study included pts with MM who received anti-PD1 tmt in a single institution. The objective was to identify whether an increase over the upper limit of normal AEC (>400/mm3) at any time during the tmt could predict better outcomes. Blood tests were performed before every tmt administration. Progression free survival (PFS) and OS were evaluated. Descriptive statistics were used to analyze patient baseline characteristics. PFS and OS were estimated by the Kaplan-Meier method. Results: From March 2013 to February 2016, 50 pts were treated with anti-PD1 Abs (39 pts with Pembro and 11 pts with Nivo). Median age was 58 years (33-84). 72% had received previous systemic tmt for MM, 64% had stage M1c disease, and 50% had elevated LDH levels. BRAF V600 mutations were observed in 34%. The median time to increase AEC > 400/mm2 was 42 (14-196) days. Pts who experienced an increase > 400/mm3 at 12 weeks demonstrated better outcomes in terms of PFS (21,9 [95% CI: 11,1-32,6] vs. 7,5 [95% CI: 4,3-10,7] months, p=0.017) and OS (38,0 [95% CI: 30,8-45,1] vs. 20,5 [95% CI: 15,7-25,3] months, p=0.025) compared with those who did not. Moreover, according to our previous results, pts with an increase of at least 100/mm3 in AEC over the baseline at 12 weeks also showed better OS (32,5 [95% CI: 26,3-38,8] vs. 16,3 [95% CI: 11,1-21,6] months, p=0.008). Conclusions: An increase in AEC of 100/mm3 over baseline and an absolute AEC > 400/mm3 at week 12 during anti-PD1 tmt might identify pts with MM most likely to experience clinical benefit with anti-PD1 Abs which could be relevant for pts management.
Correlation between dysthyroidism and efficacy in patients treated with anti PD-1 or anti PDL-1 agents.
Authors: Signorelli Diego , Cona Maria Silvia , Vitali Milena , Lo Russo Giuseppe , Proto Claudia , Imbimbo Martina , Zilembo Nicoletta , Platania Marco , Del Vecchio Michele , Seregni Ettore , Garassino Marina C , Di Nicola Massimo A. , De Braud Filippo G. 
Published: November 2019

67 Background: Immune checkpoints inhibitors have clearly improved patients’outcomes in different tumors, but definitive predictive biomarkers are still missing. Since thyroiditis have been reported, we have evaluated whether clinical responses are more frequent in patients who underwent anti PD-1 or anti PDL-1 agents and experienced dysthyroidism. Methods: We retrospectively evaluated 135 metastatic solid tumor patients, treated at our Institute with anti PD-1/PDL-1 antibodies since 2013. Thyroid toxicity was defined according to CTCAE version 4.0 and disease control (DC: CR+PR+SD) was chosen as efficacy endpoint. Correlation between dysthyroidism and DC rate was assessed by Fisher’s exact test. Results: Of 135 patients, 76 (56.3%) were treated by anti PD-1 and 59 (43.7%) by anti PDL-1 agents. Population was heterogeneous, including patients from the 1st to the 9th line of therapy, affected by the following cancers: 57 (42.2%) NSCLC, 18 (13.3%) melanoma, 13 (9.6%) RCC, 7 (5.2%) bladder and urothelial, 6 (4.5%) mesothelioma, 5 (3.7%) SCLC, 5 (3.7%) sarcoma, 5 (3.7%) biliary tract, 5 (3.7%) head and neck, 3 (2.2%) gastric, 3 (2.2%) colon, 2 (1.5%) Merkel cells and one each for thyroid, HCC, ovary, cervix, anal carcinoma and germ cells tumor. Median follow up was 8.6 months. Best responses were: 5 CR, 30 PR, 51 SD and 49 PD; 86 (63.7%) patients achieved DC. Overall, 38 patients developed dysthyroidism (subclinical, G1, G2 hypo/hyperthyroidism): 18/76 (23.7%) in anti PD-1, 20/59 (33.9%) in anti PDL-1 group; 31/38 (81.6%) of them achieved DC. The median time of dysthyroidism appearance was the 6th cycle of therapy (range 1st-22th). Of 97 patients who did not develop thyroid toxicity, 55 (56.7%) achieved DC. Dysthyroidism significantly correlated with DC rate (p=0.009). Conclusions: We found a significant correlation between dysthyroidism and clinical responses in solid tumor metastatic patients treated by anti PD-1 or anti PDL-1 antibodies. Our observation suggests that evaluation of thyroid function should be regularly performed during therapy with these agents. These retrospective findings must be confirmed in a prospective trial powered to see whether thyroid dysfunction is a surrogate marker of response.
In situ vaccination with local radiation and intratumoral immunocytokine to elicit a tumor-specific memory B-cell response.
Authors: Baniel Claire , Hank Jacquelyn A , Guy Emily I. , Gillies Stephen D , Korman Alan J. , Loibner Hans , Rakhmilevich Alexander L. , Harari Paul M. , Sondel Paul M. , Morris Zachary Scott 
Published: November 2019

69 Background: In a murine melanoma (MEL) model, we reported an in situ vaccination response to combined radiation (RT) and intra-tumor (IT) injection of anti-GD2 hu14.18-IL2 immunocytokine (IC). This treatment resulted in 71% complete regression of 5-week (~ 200mm3) tumors, a memory T cell response, and augmented response to systemic anti-CTLA-4 antibody (mAb) checkpoint blockade. We hypothesized that mice rendered disease-free (DF) by RT, IT-IC, and anti-CTLA-4 mAb might also exhibit a memory B cell response. Methods: C57BL/6 mice were implanted with 2x106 syngeneic, GD2+ B78 MEL cells and tumors developed for 5 weeks. Mice were treated with 12 Gy RT to this tumor followed by 5 daily IT injections of hu14.18-IL2 d6-10 after RT and IP injection of anti-CTLA-4 d3, 6, and 9 after RT. DF mice and naïve controls were challenged by subcutaneous implantation with 2x106 B78 MEL cells. Peripheral blood was collected from mice before and after B78 challenge and serum was evaluated for presence of tumor-specific mAbs using flow cytometry and ELISA. Results: Seventy-three percent of mice were rendered DF by treatment with RT, IT-hu14.18-IL2, and anti-CTLA-4. All of these (13/13) rejected a rechallange B78 implantation > 1 year later (range d378 – 511), whereas no naïve mice rejected B78 implantation (0/66). IgG from serum of DF mice bound selectively to B78 and parental GD2- B16 MEL cells and the level of this mAb response appeared to increase modestly d14 after B78 challenge. In naïve mice, a modest increase in tumor-specific mAb was identified between non-tumor implanted mice and d35 post-implantation mice (bearing tumors > 200mm3), however this level remained ~ 5 fold below that observed in DF mice prior to B78 rechallenge. In contrast, no appreciable mAb response was observed for unrelated syngeneic GD2+ Panc02 pancreatic tumor cells in serum of DF or naïve mice. Conclusions: We report an endogenous anti-tumor IgG humoral response in DF mice > 1 year after treatment with RT, IT-IC, and anti-CTLA-4 mAb, concurrent with demonstration of long lasting immune protection from re-challenge. Studies are underway to determine whether this response is involved in the therapeutic efficacy of this in situ vaccination regimen.
The landscape of the tumor-infiltrating B cell and its association with T-cell and tumor microenvironment in human cancers.
Authors: Chae Young Kwang , Bae William Han , Choi Yeonjoo , Kim Young Suk , Anker Jonathan Forrest , Giles Francis J. 
Published: November 2019

76 Background: Compared to recent advances in our knowledge of T cell biology with success of immunotherapy, little progress has been made in understanding of the effects of B cells in tumor microenvironment and their interactions with T cells. Preclinical studies reported that B cells may have immune suppressive roles in tumor microenvironment via induction of T cell exhaustion. However, this association has not been shown in human tissues. We explored the landscape of tumor infiltrating B and T cells and their association with tumor microenvironment in various human cancers for which the FDA approved the use of immune checkpoint inhibitors. Methods: Expression patterns for 812 immune related genes from the TCGA database were utilized to define tumor infiltrating cells in 2951 patients with bladder urothelial carcinoma, renal clear cell carcinoma, skin cutaneous melanoma, lung squamous cell carcinoma, lung adenocarcinoma, and head and neck squamous cell carcinoma. Odds ratios (ORs) of the numbers of tumors with versus without activated B cell infiltration by the presence of activated CD8T cell infiltration were calculated. Results: Immune landscape of the six human cancers showed a consistent inverse association between tumor infiltrating activated B and CD8 T cells (OR = 0.18, p < 0.001). B cell infiltration was associated with increased expressions of immune checkpoints PD-L1, PD-1 and CTLA-4 and regulatory cytokines TGF-β, IL-10 and IL-35, which are known to be secreted by regulatory B cells. Angiogenic markers, such as angiopoietins, VEGF, MMP-9, CXCL10, CXCL11 and Tie2, showed differential expression patterns between B cell high and low groups. Conclusions: This is the first study that reports the inverse association between tumor infiltrating B and CD8 T cells in human tissues. The strong associations between B cell infiltration and increased expressions of suppressive cytokines and immune checkpoints suggest regulatory B cells may play a role in the T cell suppression in tumor microenvironment. Our results implicate that depleting B cells, leading to possible disinhibition of T cell activation, may be a future therapeutic option in potentiating T cell mediated immunity.
Clonality of T-cell repertoire in the tumor microenvironment (TME) and peripheral blood of metastatic melanoma patients treated with CTLA4 blockade and interferon-α (IFN).
Authors: Tarhini Ahmad A. , Agha Aya , Rahman Zahra , Benzeno Sharon , Yusko Erik , Vallabhaneni Priyanka 
Published: November 2019

9 Background: Patients with metastatic melanoma were treated with tremelimumab and IFN in a previously reported study (Tarhini. J Clin Oncol. 2012). Clonality of T-cell repertoire was analyzed in terms of clinical response both in TME and in peripheral blood. Methods: Patients received tremelimumab 15 mg/kg I.V. every 12 weeks. High dose IFN (HDI) was administered concurrently. Responses were assessed by RECIST as complete (CR) or partial (PR), stable disease (SD) or progression (PD). T-cell receptor beta chain (TCRB) repertoire was immunosequenced in peripheral blood mononuclear cells (PBMC) (N=33 patients) and tumor (N=18) utilizing Adaptive Biotechnologies immunoSEQ platform to determine repertoire clonality and T-cell fractions at pre-treatment (tumor, PBMC), one month (PBMC), and 3 months (PBMC). The clonality metric quantitates, the extent of mono- or oligo-clonal expansion by measuring the shape of the clone frequency distribution. Values range from 0 to 1; values approaching 1 indicate a nearly monoclonal population. Results: In pretreatment TME, T-cell clonality was significantly (p = 0.0008) different and greater in patients who achieved disease control (CR, PR, SD) versus those with PD. Further, there was a significant (p = 0.044) difference between the increased TCR fraction in TME in responders (CR, PR) and non-responders (SD, PD). There was a trend towards association between pretreatment TME T-cell clonality and overall survival (OS) (p = 0.24) and progression free survival (PFS) (p = 0.18) not reaching significance. Within the circulation (PBMC), no significant associations were found by examining the pretreatment samples. However, early on-treatment (day 29) there was significant association and decrease in T-cell clonality and OS (p = 0.005) and PFS (p = 0.003). Conclusions: T-cell clonality in the TME pretreatment is a promising biomarker of immunotherapeutic benefit in our study. While baseline PBMC clonality was not associated with clinical benefit, early on-treatment (day 29) was significantly associated. These findings require validation in an independent cohort and exploration in relation to other immunotherapeutics. Clinical trial information: NCT00610857.