bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cardiovascular complications of immune checkpoint inhibitor therapy.
Authors: Master Samip R. , Robinson Arelis , Mills Glenn Morris , Mansour Richard P 
Published: May 2019

2568 Background: Cardiac toxicity has largely been underestimated toxicity of checkpoint inhibitors. There have been several cases of myocarditis and fatal heart failure reported in patients treated with checkpoint inhibitors. We did a retrospective analysis of data of adverse effects of drugs that has been made available to public by the FDA. Methods: The FDA has made the data on adverse effects of various treatments available to general public through the FDA Adverse Events Reports System (FAERS) public dashboard. We investigated the cardiac toxicities of various immune check point inhibitor therapies available at FDERS for the years 2017-2018. Results: The reviewed the reported side effects of pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab and ipilimumab from FDA data. A total of 36,848 toxicities from immunotherapies were reported. Out of that, 2316(6.2 %) were cardio toxicities and 816 were fatal. The most common cardiac complications were as follows: myocarditis (15%), atrial fibrillation (13%), pericardial disease including pericardial effusion (13%), cardiac failure (17%) and coronary artery disease (19%). Approximately 50%, 43%, 40% 22% and 15 % of cases with myocarditis, ischemic heart disease, cardiac failure, atrial fibrillation and pericardia disease were fatal. Conclusions: Out of the reported cases of adverse reaction to check point inhibitor, 6.2% were cardio toxicities. 35% of cardio toxicities were fatal. Half of the cases who developed myocarditis died. There was no statistical difference in rate of cardiotoxicities caused by PD1, PDL1 or CTLA 4 inhibitors.
Immunomodulation by HDAC inhibition: Results from a phase Ib study with vorinostat and pembrolizumab in metastatic urothelial, renal, and prostate carcinoma patients.
Authors: Pili Roberto , Quinn David I. , Albany Costantine , Adra Nabil , Logan Theodore F. , Greenspan Andrew , Budka Justin , Damayanti Nur , Green Mark A , Fletcher James W. , Tann Mark , Edwards Sara I , Burney Heather , Liu Hao , Hahn Noah M. 
Published: May 2019

2572 Background: Immunosuppressive factors such as regulatory T cells (Tregs) and myeloid-derived suppressive cells (MDSCs) limit the efficacy of immunotherapies. Histone deacetylase (HDAC) inhibitors have been shown to have immunomodulatory effects. We have previously reported that HDAC inhibitors have synergistic antitumor effects in combination with PD-1 inhibition in tumor models by inhibiting the function of Tregs and MDSCs. Thus, we conducted a Phase Ib clinical study with the HDAC inhibitor vorinostat and the PD-1 inhibitor pembrolizumab in patients (pts) with metastatic urothelial, renal and prostate carcinoma. Methods: The primary objective was to evaluate the safety and tolerability of this combination strategy. The phase I portion consisted of two dose levels of vorinostat (100 and 200 mg, PO daily 2 weeks ON and one week OFF) and a fixed, standard dose of pembrolizumab (200 mg IV every 21 days). Patients were assigned to three cohorts: Cohort A (previously treated, anti-PD1/PD-L1 naïve urothelial and renal cancer pts = 15), Cohort B (previously treated, anti-PD1/PD-L1 resistant urothelial and renal cancer pts = 14), and Cohort C (prostate cancer pts = 14). Results: Dose levels 1 (4 enrolled, 3 evaluable) and 2 (4 enrolled, 3 evaluable) were completed without DLTs and 200 mg was the Phase II recommended dose for vorinostat. The most common resolved grade 3/4 toxicities were acute kidney injury (n = 1), anemia (n = 1), diarrhea (n = 1), and hypothyroidism (n = 1) in the dose expansion cohorts. We have enrolled 43 pts (37 evaluable) in the dose expansion cohorts. For Cohort A, B, and C the median PFS were 2.8 months, 5.2 months, and 3.5 months. Two PR were observed including the dose escalation phase. Two PCA pts have achieved undetectable PSA. We have performed several correlative studies including flow cytometry and gene expression analysis on peripheral blood mononuclear cells, PDL-1 staining and PSMA PET scans in a subset of pts. Conclusions: The results from this phase Ib suggest that the combination of vorinostat and pembrolizumab is relatively well tolerated and may be active in a subset of immune checkpoint resistant UC/RCC pts and immune checkpoint naïve PCA pts. Clinical trial information: NCT02619253.
Immune-mediated colitis after resumption of immune checkpoint inhibitor therapy.
Authors: Abu-Sbeih Hamzah , Ali Faisal , Naqash Abdul Rafeh , Owen Dwight Hall , Patel Sandip H. , Otterson Gregory Alan , Kendra Kari Lynn , Ricciuti Biagio , Chiari Rita , Giglio Andrea De , Sleiman Joseph , Funchain Pauline , Beatriz Wills , Zhang Jiajia , Naidoo Jarushka , Philpott Jessica , Gao Jianjun , Subudhi Sumit Kumar , Wang Yinghong 
Published: May 2019

2577 Background: Immune checkpoint inhibitor (ICI) therapy is often suspended because of immune-mediated diarrhea and colitis (IMDC). We examined the recurrence rate and risk factors for IMDC after ICI resumption. Methods: This retrospective multicenter study examined patients who resumed ICI therapy after improvement of IMDC between 1/2010 and 11/2018. Univariate and multivariate logistic regression analyses assessed the association of clinical covariates and IMDC recurrence. Results: Of the 167 patients in our analysis, 32 resumed an anti-CTLA-4 agent and 135 an anti-PD-1/L1 agent. The median duration from IMDC to restart of ICI treatment was 49 days (IQR, 23-136). IMDC recurred in 57 (34%) patients overall (44% of those resuming an anti–CTLA-4 and 32% resuming an anti–PD-1/L1 agent); 47 of these patients (82%) required immunosuppressive therapy for recurrent IMDC (Table). The median duration from ICI resumption to IMDC recurrence was 53 days (IQR 22-138). On multivariate logistic regression, patients who received anti-PD-1/L1 therapy at initial IMDC had a higher risk of IMDC recurrence (odds ratio [OR], 3.45, 95%CI, 1.59-7.69; P<0.01). Risk of IMDC recurrence was higher for patients who required immunosuppression for initial IMDC (OR, 3.22; 95%CI, 1.08-9.62; P=0.02) or had longer duration of IMDC symptoms in the initial episode (OR, 1.01; 95%CI, 1.00-1.03; P=0.03). Risk of IMDC recurrence was lower for those who resumed anti–PD-1/L1 therapy than for those who resumed anti–CTLA-4 therapy (OR, 0.30; 95%CI, 0.11-0.81; P=0.02). Conclusions: One-third of patients who resumed ICI treatment after IMDC experienced recurrent IMDC. IMDC recurrence was less frequent after resumption of anti–PD-1/L1 than after anti–CTLA-4. Characteristics of recurrent IMDC based on resumed ICI therapy. [Table: see text]
High prevalence of IBD-associated genetic variants in patients (pts) with immune checkpoint inhibitor (ICI) enteritis/colitis.
Authors: Grover Shilpa , Srivastava Amitabh , Friedman Sonia , Buchbinder Elizabeth Iannotti , Hodi F. Stephen , Rahma Osama E. 
Published: May 2019

2582 Background: Colitis is a frequent toxicity of ICI therapy but there is paucity of data on risk factors. Specific serological markers and genetic polymorphisms have been associated with inflammatory bowel disease (IBD) (ulcerative colitis, Crohn’s disease). However, the prevalence of these markers in pts with ICI colitis is unknown. We performed a pilot study to determine the prevalence of IBD-associated genetic and serologic biomarkers in pts with ICI colitis. Methods: Cancer pts with histologically confirmed ICI enteritis/colitis and no history of IBD underwent commercial IBD panel testing. The panel included 4 genetic markers ( ATG16L1, NXK2–3, ECM1, STAT3), 8 serological markers (anti-A4-Fla2, anti-A4-FlaX, anti-CBir1, anti-OmpC, ASCAIgA, ASCA-IgG, pANCA, ANCA), and 5 inflammatory markers (vascular endothelial growth factor [VEGF], intracellular adhesion molecule 1[ICAM-1], vascular cell adhesion molecule 1 [VCAM-1], C-reactive protein, serum amyloid A [SAA]). Clinical testing on serum samples was performed by Prometheus Laboratories (San Diego, CA). Results: Of 15 cancer pts with biopsy confirmed ICI colitis, 10 (67%) were homozygous for 1 or more of 4 genetic markers. The remaining 5 pts were all heterozygous for two or more of the genetic markers. One or more serologic markers associated with IBD were elevated in 7/15 (47%) pts. Serum reactivity was noted for ASCA-IgA (1/15, 7%), ASCA-IgG (1/15, 7%), anti-OmpC (3/15, 20%), anti-CBR IgG (2/15, 13%), anti-A4-FlaX (1/15, 7%), and ANCA (2/15, 13%). One or more inflammatory markers were elevated in 13/15 (88%) pts. Elevations in VEGF, VCAM-1, ICAM-1, and SAA were noted in 2 (13%), 8 (53%), 8 (53%), and 11 (73%) pts, respectively. Only 6 (40%) pts had elevations in CRP levels despite the presence of active inflammation on biopsy. The IBD panel was reported as being consistent with Crohn’s disease in 2 pts, ulcerative colitis in 1 pt and inconclusive for type but consistent with IBD in 1 pt. Conclusions: In this pilot study, all patients with ICI colitis, were either homozygous or heterozygous for two or more high risk IBD alleles. If validated, such testing may prospectively identify pts at risk for developing ICI colitis.
Overcoming genetically based resistance mechanisms to PD-1 blockade.
Authors: Torrejon Davis Yuri , Abril-Rodriguez Gabriel , Tsoi Jennifer , Champhekar Ameya , Kalbasi Anusha , Campbell Katie Marie , Parisi Giulia , Puig-Saus Cristina , Cheung-Lau Gardenia , Wohlwender Tom , Berent-Maoz Beata , Grasso Catherine , Comin-Anduix Begoña , Hu-Lieskovan Siwen , Ribas Antoni 
Published: May 2019

2584 Background: Mechanism-based strategies to overcome resistance to anti-PD1 therapy are urgently needed. Using CRISPR/Cas9 genome editing tools, we developed acquired resistant models through JAK1/2 and B2M loss of function (LoF) mutations in human melanoma cell lines and in the murine MC38 colon carcinoma, known for high mutational load and good response to anti-PD-1. We hypothesized that the downstream activation of the IFN-receptor pathway or the activation of natural killer (NK) cells would overcome this resistance. Methods: We studied signaling changes in four human cell lines (parental and LoFs) exposed to IFN-gamma using RNAseq. In addition, we analyzed the in-vivo antitumor activity in MC38 variants with anti-PD1 and characterized the tumor microenvironment using mass cytometry (CyTOF). Finally, we tested strategies to overcome resistance mechanisms with SD-101 (TLR-9 agonist) and bempegaldesleukin (NKTR-214, CD-122 biased agonist) with the extent of CD8 and NK1.1 depletion. Results: RNAseq differential gene expression analysis showed that the IFN-gamma induced increased expression of antigen presenting machinery, IFN-gamma signaling and chemokines (CXCL9/10) was lost in JAK1/2-LoF human melanoma cell lines. The significant antitumor activity of anti-PD-1 against MC38 parental cell line was lost in JAK1/2 and B2M LoF sublines, and CyTOF analysis revealed that anti-PD-1 therapy was unable to increase tumor CD8+ T-effectors in these LoF tumors. The intratumoral administration of SD-101 (50 μg/injection q4dx3wks) was able to overcome local resistance even in non-injected sites in JAK1/2 and IFNAR-type-I LoF tumors, and systemic administration of bempegaldesleukin (0.8 mg/kg, q9dx2, i.v.) was able to overcome resistance in B2M LoF with significantly increased survival (Table). Depletion studies showed complete abrogation of anti-tumor response with anti-NK1.1 in JAK1 LoF and B2M LoF, and partial abrogation with anti-NK1.1 or anti-CD8 in JAK2 LoF tumors. Conclusions: Even in the extreme setting of genetic resistance to PD-1 blockade by JAK1/2 LoF, resistance can be overcome by SD-101, a TLR9 agonist, while resistance of B2M LoF can be overcome by bempegaldesleukin (NKTR-214), a CD-122 biased agonist. Our findings support the testing of these rational mechanistic strategies in patients with a-PD1 resistance. [Table: see text]
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 , George Saby , Morrison Carl , Zhang Tian 
Published: May 2019

2595 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 two gene panels as well as other inflammation markers in the tumor microenvironment to correlate with ICI responses. Methods: This multicenter study evaluated 86 patients (pts) with mRCC treated with ICIs. FFPE tumor samples were evaluated by RNA sequencing for Teff status. Two gene panels were analyzed: a Teff Gene Panel (CD8, CD27, IFNG, GZMA, GZMB, PRF1, EOMES, CXCL9, CXCL10, CXCL11, CD274, CTLA4, FOXP3, TIGIT, IDO1, PSMB9, TAP1) and a 5-Gene panel (FOXP3, CCR4, KLRK1, ITK, and TIGIT) based on the gene expression pattern of tumors in our cohort. Objective response rates (ORRs, defined as CRs and PRs) were correlated with PD-L1 status (positivity was defined as ≥1% TPS based on Dako 22C3 IHC assay), and TMB (0-10, 10-20, ≥20 mut/Mb), and tumor inflammation (high CD8 expression compared to a large reference population). Best responses to ICI was determined by an expert radiologist using RECIST 1.1 criteria. Inflamed tumor status, Teff gene panel, 5-gene panel, PD-L1 status, and TMB were associated with ORR and tested using a chi-squared test with Yates’s continuity correction. Results: ORR was 50% (4/8) for PD-L1 positive pts and 14% (9/65) for PD-L1 negative pts (p = 0.042). The majority of tumors (95%, 82/86) had TMB < 10 mut/mb. 43 pts (50%) were classified as Teffhigh and 43 pts were classified as Tefflow. ORR was 23% (10/43) in the Teffhigh cohort and 12% (5/43) in the Tefflow cohort (p = 0.256). ORR was 31% (14/45) in the 5-Gene high cohort and 2% (1/41) in the 5-Gene low cohort (p = 0.001). Conclusions: TMB and tumor inflammation based on CD8 did not reliably predict for objective responses in this study of mRCC pts treated with ICIs. Gene expression signatures provide a more comprehensive evaluation of the tumor microenvironment and may lead to better predictive biomarkers for ICI response than individual biomarkers such as PD-L1, TMB, or CD8 expression.
Dynamic changes of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lactate dehydrogenase (LDH) during treatment with immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC).
Authors: Russo Alessandro , Franchina Tindara , Ricciardi Giuseppina , Battaglia Alessandra , Schifano Silvia , Schifilliti Maurizio , Scimone Antonino , Toscano Giuseppe , Zanghì Mariangela , Adamo Vincenzo 
Published: May 2019

2596 Background: ICIs have revolutionized the therapeutic landscape of NSCLC. However, with the exception of PD-L1 expression, predictive biomarkers are lacking. The aim of this study was to evaluate the dynamic changes of some markers of inflammation over time and the outcome of NSCLC patients (pts) treated with nivolumab (N) or pembrolizumab (P). Methods: All consecutive NSCLC pts treated with N or P between Aug. 2015-Dec. 2018 were analyzed. Laboratory results were collected at baseline, 6 weeks (6-wk), and 12 weeks (12-wk) and correlated with the outcome. NLR and PLR were defined as absolute neutrophil and platelet count divided by lymphocyte count, respectively. NLR ≥5, PLR ≥200, and LDH levels ≥ upper normal limit were considered high. Overall survival (OS) was defined as time from ICI start to death and Progression Free Survival (PFS) as time from treatment start to progression disease or death for any cause. OS and PFS curves were estimated using the Kaplan–Meier method and compared with the log-rank test. Results: We included 71 consecutive NSCLC pts treated with either N (75%) or P (25%). Baseline characteristics: median age 69 years (range 46-80), sex male 76%, squamous histology in 39%. PD-L1 expression (39/71): < 1% in 20%, 1-49% in 45%, and ≥50% in 35%. NLR ≥5 was associated with lower PFS and OS, with an increased predictive value over time ( p =0.01 and p =0.009 at baseline; p =0.007 and p <0.001 at 6-wk; p <0.001 and p <0.001 at 12-wk, respectively). PLR ≥200 at baseline and 12-wk was significantly associated with shorter OS ( p =0.05 and p =0.004, respectively), but no in terms of PFS at all the three time points. Finally, LDH ≥UNL at baseline was associated with shorter PFS and OS ( p =0.02 and p =0.03), as well as a reduction of LDH levels at 12-wk compared with baseline values ( p =0.006 and p =0.004). Conclusions: Baseline evaluation of NLR, PLR and LDH levels is significantly associated with outcome in NSCLC treated with single agent ICIs. Moreover, dynamic changes of LDH levels at 12 weeks significantly predicted outcome. These easy to determine parameters may have a place in the selection process of pts candidate for immunotherapy.
A dose-finding study of the SMAC mimetic Debio 1143 when given in combination with avelumab to patients with advanced solid malignancies.
Authors: Juergens Rosalyn A. , Chu Quincy S. , Renouf Daniel John , Laurie Scott Andrew , Purcea Daniela , McWhirter Elaine , Arndt Diane , Gelmon Karen A. , Hilton John , Gavillet Bruno , Ellis Peter Michael , Sawyer Michael B. , Kollmannsberger Christian K. , Andrews Wright Natalie , Rouits Elisabeth , Brichory Frank , Vuagniaux Gregoire , Szyldergemajn Sergio A. , Goss Glenwood 
Published: May 2019

2599 Background: Second mitochondria-derived activator of caspase (SMAC) mimetics regulate apoptosis and modulate NFκB signaling which drives the expression of genes involved in immune and inflammatory responses. In patient (pt) tumors, Debio 1143 increased PD-1/PD-L1 expression and tumor infiltrating lymphocytes. In pre-clinical models, it synergizes in vitro and in vivo with PD1/PD-L1 checkpoint inhibitors (CPIs). Methods: In a phase I study, using a mCRM model, avelumab (10 mg/kg i.v. on D1&15 q4w) was combined with escalating doses of Debio 1143 (100 mg/d to 250 mg/d orally, D1-10 & D15-24 q4w) to define the RP2D. Consenting adult pts with advanced solid tumors, normal organ function, and PS-ECOG = 0-1 were eligible provided none received prior CPI. Dose-limiting toxicities (DLTs), efficacy, safety, PK, PD and biomarkers were assessed. Results: As of DEC’18, 16 pts were treated; M/F: 8/8; ECOG = 0 in 6 (38%); median age = 58 (28-79); 5 pts had NSCLC, 2 MPM, 2 ovarian and 7 had other tumors (n = 1 each). Common AEs were: nausea (69%); fatigue (62%); vomiting (50%); cough, dyspnea, myalgia (44% each); diarrhea, anorexia (38% each); pruritus and constipation (31% each). These were generally grade 1-2, occasionally grade 3. One pt had a DLT at 250 mg/d dose: a grade 3 AST/ALT increase. No treatment-related AEs grade 4 or higher occurred. No dose-relationships for laboratory abnormalities were observed, except for ALT/AST increases, which at 200 mg/d were all grade 1 and asymptomatic. Maximal tolerated dose was not reached and there were no dose reductions. In 15 evaluable pts, 1 PR (NSCLC) and 5 SD (RECIST v1.1) were observed. Tumor shrinkage > 15% was seen in 2 other NSCLC pts. PK showed high interpatient variability and dose-proportional increase. TNFα and IFNγ peaked in plasma following Debio 1143 dose on D1 after 8 hrs, and on D17/22, in a dose-proportional manner. Four pts developed anti-avelumab antibodies. Conclusions: Debio 1143 at 200 mg/d can be safely combined with avelumab. Toxicity was predictable and mild. Clinical activity was observed in NSCLC pts. PK was linear; no drug interaction was suspected. PD and biomarker analysis is ongoing. Expansion at this RP2D is ongoing in NSCLC. Clinical trial information: NCT03270176.
First-in-human (FIH) trial evaluating immune activation and safety of PIN- 2 administered intravenously to patients with advanced solid tumors.
Authors: Bier Colin , Millward Michael , Kotasek Dusan , Gorelick Kenneth J , Goldberg Joshua Brian 
Published: May 2019

2600 Background: Innate immunity is an integral component necessary to initiate systemic anti-tumor immunity in patients with progressive malignancy. PIN-2 is a novel immunomodulating agent derivatized from a transactivator (Tat) protein that stimulates innate immunity in vivo by promoting differentiation of peripheral blood monocytes into activated APC’s linking the innate and adaptive immune systems resulting in endogenous T-cell priming against a multitude of tumor associated antigens unique to the individual. Methods: A FIH clinical trial was conducted in patients (pts) with extensively pretreated solid tumors to evaluate the pharmacodynamics (PD) and safety of PIN-2. 8 pts (2 men), mean age 62.7 (±7.9) years, and a median of 4.5 prior treatment lines, were enrolled in 2 Australian centers. 2 pts received 1 cycle of treatment and 6 received 2 cycles. Pts were given 300 µg of PIN-2 IV 3 times/wk for 2 wks followed by a 1 wk rest period. A 2nd cycle of treatment was offered based on pt and investigator preference. Plasma was collected at 6 and 24H post-infusion 1 to evaluate immune activation. Th1 cytokines (TNF-α, IFN-γ, IL-12, CSF-2) were analyzed to assess PD activity. Results: A significant increase in TNF-α was seen 6H following PIN-2 infusion (p = 0.0142), demonstrating rapid onset of immune activation. There were no clear changes in the other parameters evaluated. PIN-2 was rapidly cleared from plasma, with mean T1/2 = 24.0 (8.07) min, Tmax = 1.06 (0.665) min, Cmax= 77,500 (61,600) pg/mL, and AUC0-inf = 690,000 (493,000) pg•min/mL. 3 pts discontinued treatment, 2 for adverse events (1 gr 2 infusion reaction, 1 unrelated SAE of abdominal pain) and 1 for disease progression on day 12. Treatment related AEs were grade 1 and 2, and readily managed. There was a single unrelated gr 3 event (anemia) and no AEs > gr3. 2 pts developed anti-drug antibodies; however, these did not result in changes in the immuno-PD profile. Conclusions: PIN-2 was generally well tolerated with an acceptable safety profile. PIN-2 caused an early increase in TNF-α, consistent with PD activity predicted by preclinical data. Further study alone and in combination with other agents in pts with advanced solid tumors is warranted. Clinical trial information: ACTRN12617001597381.