bluuebunny/crossref_metadata_2025_split huggingface dataset:
iRGD in combination with IL-2 reprograms tumor immunosuppression.
Authors: Botta Gregory P. , De Mendoza Tatiana Hurtado , Jarvelainen Harri , Ruoslahti Erkki 
Published: July 2019

55 Background: Fibrotic solid tumors have lagged in immunotherapy efficacy. Although breast cancer (BC) shows modest single-agent activity, pancreatic ductal adenocarcinoma (PDAC) immunotherapy has repeatedly failed in clinical trials. A protective desmoplastic, inflammatory reaction encapsulates BC and PDAC where it can make up to 80% of the tumor microenvironment (TME). Reports in BC and PDAC patients and mouse models suggest that tumoricidal effector CD8+ T-cells are indeed present, yet suppressed by regulatory CD4+/CD25+/FoxP3+ T-cells (Tregs) and myeloid cells. Long-term PDAC and BC survivors harbor CD8+ T-cells by immunohistochemistry (IHC), and although inactivated (CD107a-), they are not terminally exhausted (PD-1low). Further, when CD8+ T-cells were found in large quantities within a treatment-naïve biopsy, that patient had an increased overall survival. We hypothesize that low doses of the T-cell proliferative cytokine IL-2 can class switch the TME T-cells if specifically concentrated within the tumor by the stroma-penetrating peptide iRGD. Methods: Subcutaneous BC tumors (4T1) and PDAC (KPC ) tumors were formed in immunocompetent mouse models. Mice were treated with either vehicle, iRGD, IL-2, or both in combination. Tumors were preserved for IHC or enzymatically digested for FACS. CD45+ live cells were fluorescently labeled for effector T-cells (CD4+/CD44+ or CD8+/CD44+), Tregs (CD4+/CD25+/FoxP3+), or cytotoxic T-cells (CD8+/CD44+/Granzyme B+/IL-2+). Results: Versus normal controls, tumors from BC and PDAC both showed a subsequent increase in bulk CD3+ T-cells within the tumor microenvironment (14.3% ± 5 vs. 27.6% ± 8). A significant increase in CD3+ T-cells within all tumors (10%) occured with iRGD only, IL-2 only, or iRGD + IL-2 treatment. Whereas sub-populations of T-cells in the iRGD only and IL-2 only treatment groups was overwhelming composed of Tregs (5%) at CD4/Treg and CD8/Treg ratios of 1.75 and 0.5 respectively, the combination of iRGD + IL-2 shifted the T-cell sub-populations away from Tregs (1.5%) and towards increased CD4/Treg and CD8/Treg ratios (4 and 12 respectively). Conclusions: The combination of iRGD + IL-2 is capable of reprogramming the immunosuppressive Treg tumor microenvironment, increasing effector CD4+ and CD8+ T-cells.
Differences in immune tumor microenvironment between primary and metastatic castration-resistant prostate cancer.
Authors: Yang Yuanquan , Zhang Yali , Wang Jianmin , Krolewski John , Levine Ellis Glenn , Mohler James , Chatta Gurkamal S. , Kalinski Pawel 
Published: July 2019

58 Background: Androgen deprivation therapy (ADT)-induced immunosuppression has been described in animal models as contributing to castration-resistant prostate cancer (CRPC) development, but the clinical relevance of these observations has not been established. In this study, we compared the immune tumor microenvironment (iTME) of primary prostate cancer (PPC) versus metastatic CRPC (mCRPC). Methods: Genomic and clinically annotated data were obtained of PPC and mCRPC from the TCGA provisional and SU2C/PCF databases. Patients without RNA-seq data were excluded. 22 iTME cell subsets were estimated using CIBERSORT LM22 algorithm. Relative cell proportions and gene expression in log-transformed FPKM were compared using Wilcoxon tests. Results: 499 PPC and 118 mCRPC were studied. Compared to PPC, mCRPC had higher percentage of M2 macrophages (24.6% vs. 10.2%, p<0.0001). High M2 in mCRPC was associated with 2.5-, 6- and 19.5-fold increases in IL-10, VEGFA and ARG1 mRNA levels, respectively (p<0.0001). T- cell exhaustion markers, LAG3 and CD160, were upregulated in mCRPC by 43.2% and 266.7% (p<0.0001). Although CD8 T-cells were higher in mCRPC, the CD8/M2 ratio was lower (1.1 vs. 1.5, p=0.002). Prior use of abiraterone or enzalutamide in the mCRPC cohort (n=54) did not alter iTME cell fractions compared to AR antagonist naïve mCRPC. The detailed iTME comparisons were listed in Table. Conclusions: Our data indicate the development of tumor-favoring iTME in the course of progression to mCRPC while on ADT. The iTME is characterized by increased M2 macrophage infiltration that may provide a novel and important therapeutic target. [Table: see text]
Role for immune checkpoint blockade in BRCA2-mutant prostate cancer.
Authors: Panda Anshuman , Stein Mark N. , Riedlinger Gregory , Bhanot Gyan , Ganesan Shridar 
Published: July 2019

59 Background: Except for rare cases with microsatellite instability, prostate cancer has low mutation burden and low response rate to immune checkpoint blockade (ICB). Genomic correlates of response to ICB in microsatellite stable (MSS) prostate cancer are currently unknown. Here we describe an exceptional response to ICB in BRCA2-mutant prostate cancer and explore immunologic features of BRCA-mutant tumors. Methods: A patient with BRCA2-mutant MSS prostate cancer who progressed on PARP inhibitor therapy was treated with pembrolizumab. Another 8 cases of BRCA2-mutant prostate cancer were evaluated for lymphocyte infiltration and PD-L1 expression by a pathologist. The Cancer Genome Atlas (TCGA) dataset was used to evaluate BRCA-mutant tumors from multiple histology. Presence of putative pathogenic mutations in BRCA1/2 were tested for association with mRNA levels of CD8+ T cell marker ( CD8A), immune checkpoint genes (in PD-1, CTLA-4 pathways), and expression of endogenous retroviruses (ERV). Markers of homologous recombination (HR) defects, namely number of Signature 3 mutations and large ( > 3bp) indels, were also analyzed. Results: Initial patient with BRCA2-mutant MSS prostate cancer had a rapid and ongoing response to pembrolizumab. Analysis of local cohort will be presented. In the TCGA prostate cancer dataset, BRCA2-mutant tumors showed significant overexpression of CD8A, PD-1 and CTLA-4 pathway genes, and ERV3-2. Similar results were observed in BRCA1-mutant (but not BRCA2-mutant) ER+ HER2− breast cancer, but not in BRCA-mutant triple-negative breast and ovarian cancer. Analyses of HR defect markers corroborated these observations. Conclusions: BRCA-mutation accompanied by ERV3-2 overexpression, observed in BRCA2-mutant prostate and BRCA1-mutant ER+ HER2− breast cancer, is associated with CD8+ T cell infiltration and checkpoint pathway upregulation. The effect of BRCA1/2 mutation on immunogenicity may be very tissue and/or cell-of-origin specific, with different cancer types having different levels of immune activation. The association between ERV expression and BRCA2-mutation in prostate cancer requires further investigation. BRCA2-mutant prostate cancers are a class of MSS tumors that may be sensitive to ICB.
Cell proliferation as a biomarker for response to immune checkpoint inhibitors in highly inflamed renal cell carcinoma.
Authors: Pabla Sarabjot , Zhu Jason , Labriola Matthew , Gupta Rajan , George Daniel J. , McCall Shannon , Yau Edwin , Conroy Jeffrey M. , Glenn Sean T. , Nesline Mary , Papanicolau-Sengos Antonios , Burgher Blake , Lenzo Felicia L. , Zhang Tian , Morrison Carl 
Published: July 2019

61 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 in RCC. Previously we reported (SITC 2018) moderately proliferative lung cancer has a much higher response rate than either poorly or highly proliferative tumors. Methods: 69 FFPE tumor samples of RCC were evaluated by RNA-seq to measure transcript levels of 394 immune related genes, including 10 related to cell proliferation (BUB1, CCNB2, CDK1, CDKN3, FOXM1, KIAA0101, MAD2L1, MELK, MKI67, TOP2A). Cell proliferation, defined as the mean mRNA expression of these 10 genes 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 compared to a reference population. Poorly and highly proliferative were grouped for comparison to moderately proliferative tumors. Tumors were inflamed or non-inflamed based upon RNA‐seq analysis of CD8 compared to a reference population of more than 500 cases of multiple tumors. Non-inflamed, or immune desert tumors, defined as the lower 25th percentile of rank for CD8+ T-cells, and greater than 75th percentile of rank as inflamed. Results: In our cohort of 69 patient the overall ORR was 18.8%. 15.9% of tumors were non-inflamed with an ORR of 9.1%. For 36.2% inflamed tumor the ORR was 32%. For cell proliferation 62.2% were poorly proliferative, 8.7% were highly proliferative, and 29% were moderately. ORR in moderately proliferative tumors was 30% versus 14.2% in poorly/highly proliferative tumors. In inflamed tumors, ORR in moderately proliferative tumors was 37.5% as opposed to 17.6% in poorly/highly proliferative tumors. In 11 non-inflamed tumors, there was only one responder, which was a poorly/highly proliferative tumor. 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 inflamed tumors. Moderately proliferative tumors have a higher ORR than their poorly/highly counterparts.
Evaluation of tumor microenvironment and biomarkers of immune checkpoint inhibitor (ICI) response in metastatic renal cell carcinoma (mRCC).
Authors: Zhu Jason , Pabla Sarabjot , Labriola Matthew , Gupta Rajan T. , McCall Shannon , George Daniel J. , Dressman Devin , Glenn Sean T. , Nesline Mary , George Saby , Morrison Carl , Zhang Tian 
Published: July 2019

63 Background: ICIs are now standard of care for mRCC; however, there are few biomarkers to predict ICI response. Recent data from atezolizumab/bevacizumab trials in mRCC suggest tumors with high Teffhigh/PD-L1+ are more likely to respond to ICI. Here, we use this Teff gene panel as well as other markers of inflammation in the tumor microenvironment to correlate with ICI responses. Methods: This multicenter study evaluated 69 pts with mRCC treated with ICIs. FFPE tumor samples were evaluated by RNA sequencing to measure transcript levels of genes related Teff status. Teff status was defined as the mRNA expression of 17 genes (CD8, CD27, IFNG, GZMA, GZMB, PRF1, EOMES, CXCL9, CXCL10, CXCL11, CD274, CTLA4, FOXP3, TIGIT, IDO1, PSMB9, TAP1), with Teffhigh/low separated at the median. PD-L1 positivity was defined as ≥1% TPS based on Dako 22C3 IHC assay, and TMB high as > 10 mutations per megabase. Inflamed tumors were defined as CD8 expression in the top 75th percentile compared to a large reference population of multiple tumor types. Best responses to ICI was determined by an expert radiologist using RECIST 1.1 criteria. Inflamed tumor status, Teff gene expression, PD-L1 positive, and TMB were associated with disease control (DC, defined as CR, PR, or stable disease). DC comparisons were tested using a chi-squared test with Yates’s continuity correction. Results: DC was 63% (5/8) amongst PD-L1 positive pts and 52% (31/60) in PD-L1 negative patients (p = 0.84). Only 2 pts were TMB high. The majority of mRCC tumors (97%, 67/69) were TMB low. 6-month DC in TMB high tumors was 50% (1/2) and 49.3% (33/67) in TMB low tumors (p = 1.0). 36 pts were classified as Teffhigh and 33 patients were classified as Tefflow. 6-month DC was 61% (22/36) in the Teffhigh cohort and 36% (12/33) in the Tefflow cohort (p = 0.069). 6-month DC was 64% of inflamed tumors (16/25) vs 41% of non-inflamed tumors (18/44) (p = 0.111). Conclusions: TMB high and PD-L1 expression do not reliably predict for DC in pts with mRCC. Utilizing a gene signature score may better predict ICI response.
Effect of age and gender on expression levels of markers of immune cell infiltration and immune checkpoint pathways in patients with muscle-invasive transitional cell carcinoma of the bladder: A retrospective study of 50 patients treated with radical cystectomy.
Authors: Alanee Shaheen Riadh , Holland Bradley , Delfino Kristin , Dynda Danuta 
Published: July 2019

65 Background: Older age and female gender have been associated with worse outcomes in patients with muscle invasive bladder cancer undergoing radical cystectomy. Reduced immune response has been implicated in disease metastasis and worse survival. The objective of our study was to determine the expression patterns of various cellular proteins active in immune pathways in bladder cancer patients, and assess the correlation between age, gender, and expression of these immune markers. Methods: Tissue samples were obtained from equally distributed male/female patients with/without lymph node metastasis on final pathology after undergoing radical cystectomy for transitional cell carcinoma (TCC) of the bladder from 2009-2011 (n = 50). Immunohistochemistry (IHC) for CD3, CD4, CD8, LAG3, CD56, TIM3, PD-1 and PD-L1 were performed and scored by a single pathologist (scoring was on 0 to 100% scale). Statistical analyses investigated association between age, gender, lymph node metastasis, and IHC results. Results: Mean age at surgery was 67 yrs (range 50 to 78 yrs); all patients were Caucasians. Statistical analyses showed no association between patients' age, gender, and the expression of any of the immune markers (p > 0.05). Similarly, the staining scores for the immune markers were not noted to be correlated with LN metastasis. Correlation between stains showed a negative correlation between CD56 and PD-L1 (-0.286, p = 0.047) and between PD-1 and PD-L1 (-0.381, p = 0.007). Conclusions: Although age and female gender have been associated with worse outcomes in bladder cancer, this association may be independent of the immune pathways active in the disease. Increased expression of PD-L1 is associated significantly with suppression of anti-tumor natural killer cells in the transitional cell carcinoma of the bladder.
Efficacy of first-line immune checkpoint inhibitors in patients with sarcomatoid and/or rhabdoid (S/R) metastatic renal cell carcinoma (mRCC).
Authors: Bakouny Ziad , Abou Alaiwi Sarah , Nassar Amin , Steinharter John A. , Wei Xiao X. , McGregor Bradley Alexander , Harshman Lauren Christine , Choueiri Toni K. 
Published: July 2019

66 Background: Patients with mRCC with S/R components tend to have a poor prognosis with few therapeutic options available. Recent data suggest that immune checkpoint inhibitor (ICI)-based therapies may be especially effective for these patients. Our aim was to evaluate the efficacy of ICI-based therapies in patients with S/R mRCC. Methods: We retrospectively assessed objective response rate (ORR), progression free survival (PFS) & overall survival (OS) of patients with S/R mRCC treated at our institution with first-line ICI-based therapies and compared these to those of patients treated with first-line non-ICI-based therapies. Univariable and multivariable (adjusted for IMDC group) Cox and logistic regressions were performed. Results: 92 patients (70 S, 9 R, and 13 S&R) patients were included, of which 74 with a clear-cell component. For all patients (regardless of therapy), 74 (80.4%) patients experienced a PFS event (progression or death) and 52 (56.5%) died at 25.3 months (m) median follow-up. Overall median PFS was 5.3 m (95% CI= 3.4–7.2) and 24 m OS rate was 39.5% (27.4–51.7). Out of 78 patients in whom response was evaluable, ORR was 30.8% (20.4–41.2). Patients treated with ICI-based therapies had significantly better ORR, PFS, and OS on multivariable analysis (table). Conclusions: mRCC patients with S/R components have significantly better ORR, PFS, and OS with first-line ICI-based compared to non-ICI-based therapies. These data support the use of ICI-based therapies for patients with S/R mRCC. [Table: see text]
Factors associated with severity of immune checkpoint inhibitor gastroenterocolitis requiring hospitalization in melanoma patients.
Authors: Hughes Michael Sang , Zheng Hui , Zubiri Leyre , Dougan Michael , Allen Ian Matthew , Molina Gabriel , Lumish Melissa , Mooradian Megan , Reynolds Kerry Lynn 
Published: July 2019

81 Background: Immune checkpoint inhibitors (ICIs) have resulted in a subset of patients experiencing durable responses in solid and liquid malignancies. ICIs can be associated with adverse events, including gastroenterocolitis (GEC), that require immunosuppression and even hospitalization. Currently, no data determine the severity of patients hospitalized for ICI-related GEC. Our primary objective was to identify candidate surrogate endpoints that may predict the severity of ICI-related GEC; our secondary objective was to identify predictors of glucocorticoid (GC) response. Methods: In a retrospective cohort study, we identified melanoma patients who developed ICI-related GEC requiring hospitalization at Massachusetts General Hospital between 6/1/11 and 12/31/17. We extracted clinical, laboratory, radiographic, and pathological data; linear regression was used to estimate trends. Additional subgroup analyses were performed. Results: 69/1842 (3.7%) melanoma patients treated with ICI developed GEC requiring hospitalization (total 98 admissions). Mean age was 64 +/- 13; 42 (61%) were male. Readmission rate was 21/69 (30.4%); 6/21 (28.6%) required multiple readmissions. 90/98 (92%) were confirmed by histopathologic examination. 26/69 (37.7%) responded to GCs; 43/69 (62.3%) required second-line immunosuppression (e.g. TNFi) and/or operative intervention. ECOG PS (at initial ICI administration) was associated with response of GEC to GCs (p = 0.04). Lymphocyte count (p = 0.03), % lymphocyte count (p = 0.02), and LDH (p = 0.004) on admission were independently associated with GEC requiring second-line immunosuppression. Conclusions: Admissions for ICI-related GEC are infrequent, but they are associated with a high readmission rate and the need for second-line immunosuppression. We show that high ECOG PS at time of ICI administration may be a predictor of GC response in ICI-related GEC requiring hospitalization. We also propose that low % lymphocyte count and high LDH may serve as clinical biomarkers of severity in ICI-related GEC requiring hospitalization. Our findings suggest the need for further research and validation of these proposed biomarkers.
Multisystem immune-related adverse events from anti-PD-1/PD-L1 in patients with lung cancer: Incidence, clinical patterns, management, and outcomes.
Authors: Shankar Bairavi , Zhang Jiajia , Barasa Durrant , Forde Patrick M. , Feliciano Josephine Louella , Marrone Kristen , Kelly Ronan Joseph , Ettinger David S. , Hann Christine L. , Brahmer Julie R. , Naidoo Jarushka 
Published: July 2019

84 Background: Anti-PD-1/PD-L1 immune checkpoint inhibitors (ICIs) for cancer may cause immune-related adverse events (irAEs). Large clinical trials and meta-analyses have identified the spectrum of single organ-specific irAEs that may occur with these agents. However, patients treated with these agents may develop irAEs involving multiple organ systems. The prevalence and clinical patterns of multi-system irAEs and their management have yet to be elucidated. Methods: Patients with lung cancer treated with either PD-1/PD-L1 monotherapy or PD-1/PD-L1-based combinations at Johns Hopkins Hospital were identified. Clinical, radiologic and pathologic data were stored in an IRB-approved database. irAEs were identified through retrospective chart review and confirmed by a multidisciplinary team. Multi-system irAEs were defined as irAEs in +1 organ system. Patients with multi-system irAEs, their clinical patterns, management and outcomes were identified. Results: 319 patients were identified (NSCLC: 299, 93.7%; SCLC: 20, 6.3%) and received treatment with either PD-1/PD-L1 monotherapy (197, 61.8%) or combinations (122, 38.2%: + chemotherapy = 42; +immunotherapy = 41; +other = 39). Of these patients, 77 (24.1%) developed 1 irAE, and 16 (5%) developed multi-system irAEs (2 irAEs: 14; 3 irAEs: 2). The most common irAEs were pneumonitis (42, 13.2%), dermatitis (11, 3.4%), and hypothyroidism (9, 2.8%). The most common multi-system irAEs was pneumonitis/dermatitis (3, 3.9%). Patients who developed dermatitis, colitis, or hypothyroidism were most likely to develop multi-system irAEs (all p < 0.05). Management and outcome data for individual and multi-system irAEs will be presented. Conclusions: Patients treated with ICIs may develop multi-system irAEs. In the first report of this clinical entity, we identified that 5% of lung cancer patients treated with PD-1/PD-L1 developed multi-system irAEs, and that those who developed dermatitis, colitis, or hypothyroidism were most likely to develop multi-system events. These data have important implications for interdisciplinary patient management in the era of cancer immunotherapy.
Preliminary study into the impact of immunotherapy on patterns of care and healthcare service utilization in stage IV non-small cell lung cancer in a tertiary hospital setting.
Authors: Guo Xiao Yue , Gunawan Ben , Sanmugarajah Jasotha 
Published: July 2019

92 Background: The advent of immunotherapy for Non-Small Cell Lung Cancer (NSCLC) has dramatically altered cancer care. There is increasing clinical evidence to support immunotherapy improving disease-free progression and survivorship. However, there is limited data on how this impacts healthcare in terms of service utilization. Methods: We conducted a retrospective study on patients newly diagnosed with Stage IV NSCLC at a tertiary referral hospital with a large catchment area in Australia. Data was collected for the years 2013 (pre-immunotherapy) and 2016 (immunotherapy in use) to investigate the impact of immunotherapy on treatment patterns, survivorship and healthcare service utilisation. A total of 62 patients were included in the study with equal numbers in both cohorts. Results: Preliminary analysis indicates that since the introduction of immunotherapy in NSCLC treatment protocols, there has been a trend towards improved survivorship. There was a 19% increase in the number of patients surviving to 12 months in the 2016 cohort compared with 2013 cohort patients. Median survival was 6 months and 8 months for 2013 and 2016 cohorts respectively. There was a significantly greater burden of visits to outpatient clinics and treatment day units in the 2016 cohort. We also found fewer Emergency Department presentations and hospital admissions in the 2016 cohort compared with their 2013 counterparts. Conclusions: In conclusion, our study demonstrates increasing healthcare utilisation in ambulatory cancer services with decreased Emergency presentations and hospital admissions following the introduction of immunotherapy for patients with advanced NSCLC. Although this preliminary study suggested important trends, our sample size was small and these effects need to be confirmed in a larger cohort. [Table: see text]