bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human leukocyte antigen expression in paired primary lung lesions and brain metastases in non-small cell lung cancer.
Authors: Failing Jarrett , Aubry Marie-Christine , Mansfield Aaron Scott 
Published: February 2020

43 Background: Human leukocyte antigens (HLA) are crucial for cytotoxic T cell responses to cancer. Loss of HLA expression is a mechanism of tumor immune escape and may contribute to resistance to immunotherapy. In patients with non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors we have observed discordant responses between brain metastases and extracranial disease and reported on differential PD-L1 expression and clonal T cell infiltration between paired primary lung lesions and brain metastases. In this project we sought to evaluate whether HLA expression was retained in metastatic NSCLC. Methods: Adult patients with paired primary NSCLC and brain metastases were identified from our institution’s tissue registry. HLA-A cell membrane expression on tumor cells was determined by immunohistochemistry with an anti-HLA-A antibody. Tumors with greater than 10% HLA expression were considered positive. Agreement statistics (κ) and Fisher’s exact test were used for analysis. Results: 51 patients with paired primary NSCLC and brain lesions were identified. The median HLA expression was 20% in the primary tumors (IQR 0-65%) and 10% in the brain metastases (IQR 5-40%). 27 primary tumors and 24 brain metastases were positive for HLA expression. There was disagreement in HLA positivity between paired lesions in 11 patients (22%, 95% CI 12-35%)(κ = 0.57, 95% CI 0.35-0.79)(p = 0.0001). There was no significant difference in the time between the primary tumor and brain metastasis resections in patients with HLA expression disagreement compared to those with HLA expression agreement. None of the patients received immune checkpoint inhibitors for treatment of these lesions. Conclusions: We found significant differences in HLA-A expression on tumor cells in nearly one quarter of paired primary lung cancers and brain metastases. Differences in HLA expression may help explain the discrepancies in response to immune checkpoint inhibitors at different sites of disease and warrants further study.
Metastatic melanoma patient outcomes since introduction of immune checkpoint inhibitors in England between 2014 and 2018.
Authors: Corrie Philippa Gail , Chao David , Board Ruth , Sarah Lawton , Smittenaar Rebecca 
Published: February 2020

55 Background: Population-based research provides real world information about prescribing trends, as well as benefits and harms associated with new interventions first evaluated in randomized clinical trials (RCTs). The national health service in England has comprehensive databases which we used to track prescribing of checkpoint inhibitors (CPIs) approved for 1st line use in metastatic melanoma and determine patient outcomes associated with survival and treatment toxicity. Methods: National Cancer Registration and Analysis Services (NCRAS) datasets were used to identify metastatic melanoma patients (pts) prescribed 1st line CPIs and calculate survival outcomes. The HES (Hospital Episode Statistics) database was used to identify emergency attendances and emergency hospital admissions. Results: 5465 melanoma pts were registered between April ‘14 and March ‘18. 2322 pts received 1st line CPIs: 1174 pembrolizumab (pem), 724 ipilimumab (ipi), 52 nivolumab (nivo), 372 ipinivo. Prescribing reflected national access, with ipi starting in July ‘14 and dropping rapidly on approval of pem in Nov ’15. Ipinivo prescriptions increased annually since July ’16. There was good 3yr OS concordance with RCT outcomes for ipinivo (56%), nivo (51%), pembro (40%) and ipi (32%). Pts treated with ipinivo were significantly younger (88% vs 49% <70 years, P<0.001) and fitter (60% vs 38% ECOG PS 0, P<0.0001) than pts treated with antiPD1. 30-day mortality from last SACT was 3.8% for ipinivo, 9.1% for antiPD1 and 9.4% for ipi. 30-day rates of emergency hospital admissions/A&E emergency attendances from the earliest SACT and last SACT treatment dates were significantly higher for ipinivo (37%/16% and 55%/19%) compared with antiPD1 (17%/8% and 29%/14%) and ipi (24%/9% and 40%/15%), P<0.01. 25% of ipinivo-, 4% of antiPD1- and 15% of ipi-treated pts had a hospital admission for colitis. Conclusions: This largest real world dataset demonstrated rapid uptake of CPIs and survival outcomes similar to RCTs. Use of emergency services varied by regimen, with colitis dominating hospitalization after ipi+/-nivo. Pt selection appeared to differ for different regimens, the consequences of which warrant further research.
Association of antibiotic exposure with overall survival and colitis in patients with stage III and IV melanoma receiving immune checkpoint inhibitors.
Authors: Chu Brian , Mohiuddin Jahan J. , Facciabene Andrea , Wang Xingmei , Doucette Abigail , Zheng Cathy , Xu Wei , Amaravadi Ravi K. , Karakousis Giorgos C. , Mitchell Tara C. , Maity Amit , Schuchter Lynn Mara , Lukens John Nicholas 
Published: February 2020

56 Background: Recent studies suggest that changes in the gut microbiome modulate response to cancer treatment, including immune checkpoint inhibitors (ICI). Broad-spectrum antibiotics (Abx) are known to cause significant dysbiosis. We hypothesize that recent Abx exposure worsens outcomes in patients (pts) with stage III/IV melanoma (MM) receiving ICI. Methods: We identified MM pts treated with ICI from our institutional database. All received their first ICI between 2004-2019. Antibiotic exposure was defined as receipt of Abx within 3 months prior to the first infusion of ICI. The primary outcome was overall survival (OS) and the secondary outcome was immune-mediated colitis requiring intravenous (IV) steroids. Stage III and IV pts were analyzed separately for the primary analysis. Results: Of 568 pts in our database, 20% received Abx within the 3 months prior to ICI. 36% of pts had stage III disease and 26% of pts were treated with either adjuvant or neoadjuvant ICI. 1.6% of pts died of causes other than MM. The Abx+ and Abx- groups were balanced in terms of stage, race, age, sex, BRAF status, LDH, prior systemic therapies, and class of ICI received. Only 4 pts were hospitalized due to the infection prompting the Abx, and no pts died due to the infection. In the Stage IV group, Abx+ pts had worse OS on MV analysis (HR 1.6, 95% CI 1.1-2.2). Stage III Abx+ also had worse OS (HR 2.8, 95% CI 1.3-5.9). In a sensitivity analysis excluding pts who received IV Abx or were admitted due to infection, survival was still worse for Abx+ pts (HR 1.7, 95% CI 1.2-2.4). In a Fine-Grey competing risk MV model, Abx+ had a higher rate of immune-mediated colitis requiring IV steroids (HR 2.1, 95% CI 1.02-4.5). Conclusions: In MM pts treated with ICI, receipt of Abx within 3 months prior to ICI initiation was associated with decreased OS and increased colitis. Future research should include prospective studies to better define the risk/benefit profile of antibiotics in close proximity to ICI. [Table: see text]
Immune adverse events (irAEs) with adjuvant ipilimumab in melanoma, use of hormone replacement and immunosuppressants, and association with outcome: E1609 study analysis.
Authors: Tarhini Ahmad A. , Lee Sandra J. , Kang Ni , Hodi F. Stephen , Rao Uma N. M. , Cohen Gary Irvin , Flaherty Lawrence E. , Petrella Teresa M. , Sondak Vernon K. , Kirkwood John M. 
Published: February 2020

60 Background: E1609 evaluated adjuvant ipilimumab at 3 mg/kg (ipi3) and 10 mg/kg (ipi10) versus high-dose interferon-α (HDI). In-depth analysis of irAEs and the use of immunosuppressants and hormone replacement may provide important lessons for management and future research. Methods: E1609 enrolled 1670 adult pts with resected cutaneous melanoma (AJCC7 IIIB, IIIC, M1a, M1b); Table. We investigated the characteristics of irAEs, corticosteroid, immunosuppressant and hormone use on the ipi arms and association with outcome. Stratified log-rank test was used and since most irAEs were observed within 3 months of initiating ipi, a 3-month landmark adjustment analysis was conducted. Results: The rates of corticosteroid, immunosuppressant and hormone use by treatment are summarized in Table and none had a significant association with RFS or OS. Significant association between occurrence of grade 1-4 irAEs (vs. no AE) and RFS was observed [5-year RFS: 0.49, 95% CI: (0.45, 0.52) compared to 0.41, 95% CI: (0.31, 0.50); landmark p=0.010]. Occurrence of grade 1-2 irAEs appeared to have a stronger association with RFS [5-years RFS: 0.52, 95% CI: (0.47, 0.56) compared to 0.41, 95% CI: (0.31,0.50) with no AE; p=0.006] and a trend towards improved OS [5-year OS: 0.75, 95%CI:( 0.71, 0.79) compared to 0.67, 95% CI: (0.56, 0.75) with no AE; p=0.064]. Among specific irAEs, rash was most significantly associated with RFS (p = 0.004 and 0.002) and OS (p = 0.007 and 0.003) for grade 1-4 and grade 1-2, respectively, followed by endocrinopathies, and weaker associations seen with other AEs. Conclusions: Adjuvant therapy with ipi is associated with significant irAEs that appear to be related to the immune mechanism of action. Corticosteroids and immunosuppressants were not shown to negatively affect the clinical outcomes. Predictors of irAE risk and understanding the underlying mechanisms are a major gap and are currently actively being investigated. Clinical trial information: NCT01274338. [Table: see text]
Interim results from a phase Ib/II study of pepinemab in combination with avelumab in advanced NSCLC patients following progression on prior systemic and/or anti-PDx therapies.
Authors: Shafique Michael Rahman , Fisher Terrence Lee , Evans Elizabeth E. , Leonard John E. , Pastore Desa Rae Electa , Mallow Crystal L. , Smith Ernest , Schröder Andreas , Chin Kevin M. , Beck J. Thaddeus , Baumgart Megan Ann , Govindan Ramaswamy , Gabrail Nashat Y. , Sanborn Rachel E. , Spira Alexander I. , Seetharamu Nagashree , Lou Yanyan , Mansfield Aaron Scott , Goldman Jonathan Wade , Zauderer Maurice 
Published: February 2020

75 Background: Despite progress of immune checkpoint therapies, many cases of non-small cell lung cancer (NSCLC) are refractory or acquire resistance to current therapies. Antibody blockade of semaphorin 4D (SEMA4D, CD100) can overcome resistance mechanisms of immune exclusion and myeloid suppression. Importantly, combinations of anti-SEMA4D with various immunotherapies enhanced T cell infiltration and activity, as well as durable tumor regression in preclinical models. Pepinemab (VX15/2503) is a first-in-class humanized monoclonal antibody targeting SEMA4D. Methods: The CLASSICAL-Lung clinical trial (NCT03268057) evaluates the combination of pepinemab with anti-PD-L1 antibody avelumab to couple beneficial modifications of the immune microenvironment via pepinemab with immune activation via checkpoint inhibition. This ongoing study evaluates the safety, tolerability and efficacy of the combination in patients with advanced (stage IIIB/IV) NSCLC, including immunotherapy-naïve (ION) patients and patients whose tumors progressed during or following immunotherapy (IOF). Results: The combination was well tolerated with no major safety signals identified. Among 29 evaluable IOF patients, two experienced confirmed partial response (PR) with 63% and 52% tumor reduction on study following acquired resistance to prior treatment with pembrolizumab, 15 additional patients experienced stable disease, and at least 5 patients with durable clinical benefit of ≥ 23 weeks. Among 21 evaluable ION patients, 5 experienced PR, clinical benefit ≥ 1 year was observed in 3 patients, and Disease Control Rate was 81%. Analysis of pre- and on-treatment biopsies demonstrated increased CD8+ T cell density correlating with response, reduction or elimination of tumor in 11/13 biopsies from subjects with PR or SD. Conclusions: Interim analysis suggests the combination of pepinemab plus avelumab is well tolerated and shows initial clinical signals of antitumor activity. Updated clinical response data (minimum of 6 mo. follow-up), as well as additional immunophenotyping of both inflammatory and suppressive myeloid cells will be presented. Clinical trial information: NCT03268057.
Intratumoral administration of DNA-damaging chemotherapy-treated tumor cells to enhance therapeutic benefit of systemic immune checkpoint blockade in mouse cancer models.
Authors: Sriram Ganapathy , Milling Lauren , Chen Jung-Kuei , Abraham Wuhbet , Irvine Darrell J. , Yaffe Michael B. 
Published: February 2020

77 Background: Immune checkpoint inhibition or ICI (antibodies to PD-1 and CTLA4), has shown promise in the treatment of some tumor types, especially in inducing durable remissions in advanced stage cancer patients. However, the majority of patients do not respond to ICI. Identifying combinations to enhance response to ICI is an urgent medical need. Methods: Murine tumor cell lines B16-Ova and MC-38-Ova were treated with DNA-damaging chemotherapeutic drugs, co-cultured with primary murine bone marrow derived dendritic cells (BMDC) followed by addition of OT-1 CD8+ T-cells and flow cytometric analysis of IFN-γ+ CD8+ T-cells. Mice bearing B16-Ova or MC-38 flank tumors were injected intra-tumorally with ex vivo chemotherapy-treated B16-Ova cells with or without systemic ICI. Tumor cross-sectional area was measured using calipers. Intra-tumoral DC and circulating H2-Kb/SIINFEKL-specific CD8+ T-cells were analyzed by flow cytometry. Results: Etoposide and mitoxantrone-treated B16-Ova and MC-38-Ova tumor cells, when co-cultured with BMDC, efficiently promote IFN- γ induction in OT-1 CD8+ T-cells. This was abrogated by co-treatment of tumor cells with Necrostatin-1 but not ZVAD-FMK. Intra-tumoral injection of ex vivo etoposide-treated tumor cells, with systemic ICI, increases the numbers of intra-tumoral CD103+ DC, the frequency of circulating H2-Kb/SIINFEKL-specific CD8+ T-cells and significantly improves survival. The tumor cell vaccine/systemic ICI combination, but not ICI alone, induced complete tumor regressions in a subset of mice. This is abrogated in BATF3-deficient mice. Conclusions: Etoposide and mitoxantrone-treated tumor cells efficiently promote BMDC-mediated CD8+ T-cell priming, in a tumor cell RIPK1 activity-dependent but caspase-independent manner. Intra-tumoral administration of the DNA-damage induced tumor cell vaccine in vivo, in combination with systemic ICI, enhances anti-tumor CD8+ T-cell responses, tumor-free and overall survival, and anti-tumor immunological memory. This enhancement in therapeutic efficacy is dependent on BATF3+ DC in vivo.
Phase I results of the phase I/II study of pembrolizumab in combination with binimetinib in patients with unresectable locally advanced or metastatic triple-negative breast cancer.
Authors: Chumsri Saranya , Polley Mei-Yin , Mathur Pulkit , Reis Aline , Tenner Kathleen S. , Weidner Morgan , Advani Pooja , Moreno-Aspitia Alvaro , Perez Edith A. , Knutson Keith L. 
Published: February 2020

78 Background: Previous study demonstrated that activation of RAS/MAPK pathway is associated with reduced tumor infiltrating lymphocytes and poor response to neoadjuvant chemotherapy in triple negative breast cancer (TNBC). Further study showed that inhibition of MAPK pathway with a MEK inhibitor is synergistic with anti-PD1/PD-L1 therapies. Methods: Patients with unresectable locally advanced or metastatic TNBC with ≤ 3 prior lines of therapy without prior anti-PD-1/PD-L1/PD-L2 therapies were enrolled. Treatment was started with a 2-week run in period with single agent binimetinib. Dose level 0 was binimetinib at 45 mg oral twice daily continuously and dose level -1 was 30 mg twice daily. Pembrolizumab was given at a fixed dose of 200 mg every 3 weeks at both dose levels. Phase I study was based on the standard 3+3 design. Results: A total of 12 patients were enrolled and treated in the phase 1. Five patients were enrolled at dose level 0, 1 patient withdrew prior to treatment and 1 patient was not evaluable for dose limiting toxicity (DLT). Among 3 evaluable patients, 2 patients experienced DLT with grade 3 flank pain and ALT abnormality. Additional 8 patients were enrolled at dose level -1. Out of 6 evaluable patients for DLT, there was 1 DLT observed with grade 3 AST and ALT abnormality. However, this particular patient had liver metastasis with grade 1 AST and ALT abnormality at baseline and her liver function test (LFT) normalized in 3 weeks after treatment discontinuation and oral prednisone. Other grade 1-2 common AEs included rash, LFT increase, abdominal pain, mucositis, nausea, cardiac troponin T increase without EKG change. The efficacy data will be presented at the meeting after the phase II interim analysis. Conclusions: Pembrolizumab in combination with binimetinib at 30 mg twice daily appears to be safe based on the initial cohort. Phase II part is currently ongoing with binimetinib 30 mg twice daily and pembrolizumab 200 mg every 3 weeks with a total of 23 patients planned where the safety and efficacy of this combination will be further evaluated. Clinical trial information: NCT03106415.
Quantification of dose dependence and frequency of checkpoint inhibitor immune-mediated adverse events: A Bayesian model-based meta-analysis.
Authors: Shulgin Boris , Kosinsky Yuri , Smirnova Alexandra , Helmlinger Gabriel , Peskov Kirill 
Published: February 2020

83 Background: Immune checkpoint inhibitors (ICIs) are associated with immune-mediated adverse events (imAEs). The objective of this study was to use a Bayesian model-based meta-analysis to quantify dose dependence and compare imAE frequencies for PD-1, PD-L1 and CTLA-4 inhibitor monotherapies and their combinations. Methods: We searched PubMed, TrialTrove, ASCO and ESMO databases and retrieved relevant ICI safety data. In order to quantitatively compare safety across doses and drugs against a given target, we converted the various dose regimens used into drug exposures derived from pharmacokinetic models; we also normalized exposures by the corresponding drug potency. We performed a Bayesian meta-analysis for Grades 3&4 of treatment related (trAE) and immune-mediated (imAE) adverse events. Results: A total of 149 articles were identified, covering 35,559 patients in 197 dosing cohorts treated with ICI therapies. For PD-1 and PD-L1 inhibitor monotherapies, no dose dependence of AEs was found; Grades 3&4 trAE rates for anti PD-L1 vs. anti PD-1 were, respectively, 12% and 15%. The AE rates for the different ICI drugs and organ classes were estimated. Dose dependence was found for anti CTLA-4 monotherapies, for total trAEs of Grades 3/4, gastrointestinal and hepatic imAEs. Dose dependence was found and quantified for anti CTLA-4 in combination with anti PD-1 with respect to total trAEs of Grades 3/4 trAEs and imAEs per gastrointestinal and hepatic organ groups. We found that combination of anti PD-L1 agents with anti CTLA-4 exhibited lower AE rates, as compared to anti PD-1 combined with anti CTLA-4. Conclusions: We introduced a novel meta-analysis methodology and used it to quantify and compare AE rates across ICI agents. Significant AE rate dose dependencies were observed for CTLA-4 inhibitors, either as monotherapy or used in combinations. Patients naive to anti-cancer therapies exhibited higher AE rates vs. previously treated patients. AE rates for CTLA-4 + PD-1 inhibitor combination regimens were supra-additive vs. the respective monotherapies. AE rates for anti PD-L1 agents were lower vs. anti PD-1, both in monotherapy and combinations with CTLA-4.
Interferons alpha and gamma with monocytes as a therapeutic strategy for ovarian cancer.
Authors: Annunziata Christina M. , Duemler Anna , Ning Franklin 
Published: February 2020

9 Background: In the presence of pro-inflammatory cytokines, monocytes are cytotoxic to tumor cells. We previously showed that monocytes stimulated with interferon alpha and gamma result in synergistic killing of ovarian cancer cells in vitro. Here we better characterize monocyte differentiation and their ability to induce cell death through co-culture experiments with spheroids and in mouse xenografts. Methods: OVCAR8 cells were grown in ultra-low attachment conditions for three days before being co-cultured with human monocytes as well as interferon gamma and interferon alpha. Monocytes and OVCAR8s were assayed by flow cytometry for markers of differentiation and viability, respectively. Mouse studies were performed to confirm the viability of human monocytes stimulated with interferon alpha and gamma within the peritoneal cavity seventy-two hours after injection. Subsequent mouse experiments analyzed monocyte differentiation towards M1 or M2 phenotypes by flow cytometry with or without exposure to tumor cells and/or interferons. Results: OVCAR8 spheroids showed decreased viability in the presence of monocytes combined with interferon. We show that monocytes also express a hybrid M1/M2 phenotype when stimulated to IFN and exposed to tumor cells. In mice, monocytes demonstrated a unique differentiation towards both M1 and M2 macrophages as well as plasmacytoid and classic DCs. Various immune cell subsets also differed when comparing peritoneal washes versus tissue digests. Mouse survival studies are ongoing. Conclusions: Monocytes with the combination of interferons alpha and gamma are effective at killing ovarian cancer cells in laboratory models. Phenotypic analyses show a novel pattern of differentiation markers. Our ongoing clinical trial with these agents will incorporate similar studies to correlate monocyte differentiation with anti-tumor activity.
Identifying strategies to address obstacles to optimal integration of cancer immunotherapies in the community.
Authors: Shivakumar Latha , Weldon Christine B. , McBride Ali , Puzanov Igor , Riemer Joanne , Zibelman Matthew R. , Boehmer Leigh 
Published: February 2020

96 Background: Evolving indications for immuno-oncology (IO) therapies in cancer pose a significant challenge to community clinicians around the practical issues that must be addressed to implement these therapies safely and effectively. The Association of Community Cancer Centers (ACCC) initiated a quality improvement (QI) research study to assess the impact of educational interventions targeting the multidisciplinary cancer care team on evidence-based integration of IO therapy. Methods: The QI study collected baseline data from 100 patients initiating IO therapy between Dec 2017-Apr 2018 at two community cancer centers on co-morbidities, immune-related adverse events (irAEs), laboratory tests, ER visits and hospitalizations, patient education, and adherence. The advisory committee analyzed this data to identify practice gaps and designed educational interventions to address these gaps. After clinicians at both centers completed the educational interventions, data was collected from 100 patients initiating IO therapy between Jan 2019-Apr2019 and compared using Fisher’s exact test. We also conducted staff surveys before and after participating in the interventions. Results: Offering ACCC-created IO wallet cards to patients was a recommended intervention but only one site adopted this. The site that used the wallet cards had a statistically significant reduction in hospitalization rates compared to the other site (38% vs 70%, p = 0.0024). Respondents to the practice surveys reported an increase in handing out patient education materials following participation in the interventions. They also reported an improved understanding of strategies to manage patients with co-morbidities, management of irAEs, patient education and engagement, interprofessional communication, and coordination with non-oncology specialists. Conclusions: Community cancer center directed educational interventions are feasible and may improve clinician understanding, comfort, and attitudes with the integration of emerging IO agents. Administering wallet cards to patients at the beginning of IO therapy may decrease the risk of hospitalization and warrants further investigation in larger studies.