bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immune-related adverse events (IrAE) of elderly patients (pts) receiving PD-1 or PDL-1 inhibitors (PDIs) in a community-oncology setting: The experience at Kaiser Permanente California.
Authors: Truong Thach-Giao , Yamamoto Christopher , Chiu Timothy , Niu Fang , Spence Michele M. , Chan Jim , Cooper Robert Michael , Moon Helen , Hui Rita L. 
Published: February 2018

124 Background: Checkpoint inhibitors (CI) are rapidly changing the treatment (Tx) landscape across multiple cancers. They have brought with them a new set of immune-related toxicities and complications . Currently, our knowledge of irAEs has been largely informed by clinical trials enrolling younger and fitter pts. In this study, we report the experience of our large community practice, where many elderly pts of diverse backgrounds received PDIs. Methods: We conducted a retrospective cohort study, including pts who were ≥65 years old (yo) and had received PDIs between FDA approval in 2014 and September 2016, with follow-up through December 2016. Through data-mining of our electronic medical record, we evaluated the incidence of irAE and Tx outcomes, stratified by age, ethnicity, gender, co-morbidity index, and tumor subtype. Results: There were 776 pts included in the analysis. 58% were male and 29% were non-Caucasian. 83% were ages 65 to 79 yo and 17% were ≥80 yo (range 80-94 yo). 28 % of pts had a CCI > 5. Over 55% received PDIs for non-small cell lung cancer (NSCLC), followed by 12% for melanoma. 65-79 yo pts experienced similar incidence of irAE compared to pts ≥80 yo (14% vs 18%, p = 0.26). Notably, incidence was similar for gastrointestinal, pulmonary, and endocrine toxicity, though pts ≥80 yo experienced higher incidence of dermatologic toxicity (p = 0.01). Pts 65-79 yo received PDIs for median 3.3 months (mos), while pts ≥80 yo were on Tx for median 2.8 mos.The rate of irAE that resulted in health care utilization were noted in 15% of pts. Time to onset of irAE was similar between the 2 age groups (p = 0.40). Unadjusted hazard ratio (HR) for survival at the end of study was similar for pts 65-79 yo and ≥80 yo who had melanoma (HR = 0.99, p = 0.97) or NSCLC (HR = 1.32, p = 0.12). Conclusions: This is the first report of Tx outcomes with PDI use in elderly pts in a real-world setting. We found irAE rates and Tx outcomes to be similar for pts age 65-79 yo and those ≥ 80 yo. With rising cancer incidence among an ageing population, it is important for the oncology community to understand how CI therapy affects older pt groups to improve their cancer outcomes.
Inpatient admissions related to immune-related adverse effects (irAE) among patients treated with immune checkpoint inhibitors for advanced malignancy: A tsunami is coming, but are we ready?
Authors: Reynolds Kerry Lynn , Cohen Justine Vanessa , Durbin Sienna , Thomas Molly , Dougan Michael , Martinson Holly S , Faje Alex , Guidon Amanda , Channick Colleen , Chen Steven T , Lo Jennifer , Schoenfeld Sara , Sise Meghan , Leaf Rebecca , Neilan Tomas G , Awadalla Magid , Long Aidan , Sullivan Ryan J. , Bardia Aditya 
Published: February 2018

127 Background: Disruption of the immune system with immune checkpoint inhibitors can result in a multitude of immune-related adverse effects (irAE). While irAEs have been well-reported in clinical trials, the impact and magnitude of irAE’s in the real-world, particularly inpatient is unclear. Methods: Data was collected on patients with advanced malignancy who experienced a suspected irAE needing admission to an academic hospital (Feb 2011 to June 2017). Each case was reviewed comprehensively by minimum of two reviewers, including one sub-specialist. In addition, oncologists at our institution were surveyed regarding their confidence about managing patients with irAEs. Results: Over a span of 6 years, there were 343 hospitalizations for suspected irAEs and the majority (65%; N = 223) were confirmed irAEs that required treatment with immunosuppression or therapy stopped as result. The mean length of stay was 6.3 days (range 1 to 31 days), readmission rate for another irAE event 25%, total readmission rate 61.7%, and inpatient mortality 8%. The most common irAEs were enterocolitis (43.9%), pulmonary (16%), hepatic (15%), neurological (8.9%), endocrinopathies (7.1%), rheumatological (4%), dermatological (3%), cardiovascular (3%), renal (1.8%), and allergy (1.3%). Over the past 5 years, there was a significant increase in admissions due to irAEs (admissions in 2016 vs 2011, odds ratio = 3.07; p < 0.01). The Cancer Center survey (N = 26) revealed majority of oncologists do not feel very comfortable managing irAEs, and 48% felt that irAE complications should be managed on a different service. Conclusions: irAEs from immune checkpoint inhibitors can result in prolonged hospitalizations, high rate of readmissions, and mortality. The number of patients admitted due to irAEs has significantly increased by more than three-fold in the recent years, but majority of oncologists do not feel very comfortable managing irAEs. Consequently, there is a critical need for coordinated multidisciplinary approach, comprehensive provider education, and translational research program for early detection and intervention.
Survey analysis: Assessing the needs of immunotherapy patients, caregivers, and health care providers.
Authors: Aspiras Anabella , Power Nicholas James , Gonzalo Maria Belen 
Published: February 2018

135 Background: As the use of cancer immunotherapy increases, unique challenges emerge for both patients undergoing immunotherapy and the clinical staff who care for them. To better understand these challenges, the Cancer Support Community (CSC) conducted surveys of patients, caregivers, and healthcare staff (e.g. oncologists, nurses, social workers) at nine oncology centers across the country. Methods: Needs assessments were conducted through paper and online surveys between August and September, 2017. The analysis is based upon a cross-sectional survey of adult (18 years old and older) cancer patients, caregivers, and healthcare providers. 93 healthcare providers, 65 patients, and 21 caregivers completed the survey. Descriptive statistics and statistical analyses were performed using SPSS Version 24; analyses of association used a significance level of .05. Results: Findings from this analysis yielded important provider perspectives and illustrated targeted areas of patient and caregiver concern. Of note, while only about one-third of patients and caregivers (31% and 38%, respectively) indicated that it was important to understand the science of immunotherapy, nearly half of healthcare providers (46%) reported that educational resources should go “quite a bit” in-depth into immunotherapy science. Also, although caregivers reported greater difficulty finding information about immunotherapy, the majority of both patients (55%) and caregivers (85%) identified managing treatment-related side effects as their foremost education need. Conclusions: CSC’s analysis revealed valuable insights in both clinical care and patient education. Needs assessment results will inform the development and implementation of Immunotherapy & Me, a CSC pilot program to determine whether layering in patient education and care-management tools leads to improved patient and clinical outcomes. CSC’s needs assessments conclude that for both patients and providers, treatment-related side effects are top-of-mind. This underscores the importance of developing turnkey resources to help patients and healthcare providers manage immunotherapy-related side effects – an express goal of the Immunotherapy & Me pilot.
Association of the T-cell receptor landscape with survival in non-small cell lung cancer.
Authors: Reuben Alexandre , Gittelman Rachel , Zhang Jiexin , Quek Kelly , Vence Luis M , Behrens Carmen , Chen Runzhe , Fujimoto Junya , Chow Chi-Wan , Wu Xifeng , Allison James Patrick , Sharma Padmanee , Zhang Jianhua , Lee J. Jack , Sepesi Boris , Gibbons Don Lynn , Heymach John , Futreal Andrew , Wistuba Ignacio Ivan , Zhang Jianjun ,   ICON-PROSPECT Team
Published: February 2018

140 Background: Non-small cell lung cancer (NSCLC) is characterized by a high mutational load. Accordingly, it is also among the tumor types which respond best to immune checkpoint blockade, likely through its ability to enhance the anti-tumor T cell response. However, the lung is constantly exposed to the outside environment, which may result in a continuous state of inflammation targeting pathogens rather than tumor cells. Therefore, a greater understanding of the T cell receptor (TCR) landscape and phenotypes across normal lung and tumor is warranted. Methods: Here, we performed sequencing of the CDR3 variable region of the beta chain of the TCR as well as whole exome sequencing on peripheral blood, normal lung and tumor in 235 NSCLC patients. We further analyzed the immune microenvironment by Cytometry by Time-of-Flight (CyTOF) in 10 NSCLC patients with paired normal lung and tumor. Results: Comparison of the TCR repertoire showed 9% (up to 15%) of T cells were shared between normal lung and tumor, though the most dominant were generally shared (up to 95%). Interestingly, T cell clonality was higher in the normal lung than tumor in almost all patients (89%, p < 0.0001) suggesting potential differences in the ongoing immune response in different regions of the lung. A substantial number of non-synonymous exonic mutations (NSEM) were detected in tumors (average = 566 NSEM) but also in the normal lung (average = 156 NSEM), with many shared (up to 45.6%). CyTOF confirmed marked differences in the immune microenvironment, including higher frequency of VISTA+ antigen-presenting cells in the tumor (p = 0.04). Finally, analysis of clinicopathological attributes revealed a greater T cell diversity in the periphery in patients with increased overall survival (OS, p = 0.001), while patients with a more similar normal lung/tumor T cell repertoire showed decreased OS (p = 0.028). Conclusions: These results suggest that a substantial proportion of infiltrating T cells in NSCLC tumors may be lung-resident T cells associated with response to environmental factors. However, normal lung and NSCLC tumors carry T cells of distinct phenotypes, which highlights differences in the ongoing antigenic response within the lung.
Response and adverse events to chemotherapy after prior checkpoint inhibition in lung cancer.
Authors: Judd Julia , Ramamurthy Chethan , Handorf Elizabeth , Borghaei Hossein , Zibelman Matthew R. , Geynisman Daniel M. , Bauman Jessica Ruth 
Published: February 2018

170 Background: Historically, responses to chemotherapy beyond the first line for lung cancer range from 5-10%. The effect of antecedent immunotherapy on the response and reaction to chemotherapy is not well-established, but the immunomodulatory effects of many chemotherapy agents may lead to synergistic effects including both improved responses and unique toxicities. Methods: We reviewed the charts of patients at our institution who received at least one dose of an anti-PD-1 agent (aPD-1) as monotherapy prior to June 1, 2017. Patients with a diagnosis of non-small cell lung cancer or small cell lung cancer who received subsequent chemotherapy were included for analysis. Charts were assessed for response to aPD-1, occurrence of immune-related adverse event (irAE) on aPD1, type of post-aPD-1 (PaPD-1) chemotherapy, PaPD-1 best response to chemotherapy, and occurrence of irAE during PaPD-1 chemotherapy. irAEs were assessed based on treating physician diagnoses. We tested the association between response and treatment characteristics using Fisher’s exact and Wilcoxon rank-sum tests. Results: A total of 40 patients met criteria for inclusion. Histology was NSCLC in 38 (95%) and SCLC in 2 (5%). Median age was 68 and mean number of lines of therapy prior to aPD-1 was 2.00 (95% CI, 1.72-2.28). PaPD-1 chemotherapies included paclitaxel (15%), docetaxel (28%), gemcitabine (23%), docetaxel-ramucirumab (7.5%), pemetrexed (2.5%) and platinum doublet (15%). The disease control rate to PaPD-1 chemotherapy was 35% and the ORR was 15% (0 complete responses, 6 partial responses). The response to PaPD-1 was not higher in taxane-containing regimens than in non-taxane-containing regimens (16% v. 13%, p = 0.99). Four (10%) patients were diagnosed with an irAE during their receipt of PaPD-1 chemotherapy. These PaPD-1 irAEs included dermatitis, colitis, and pneumonitis that responded to steroid therapy and occurred on various chemotherapy agents (gemcitabine, paclitaxel, docetaxel). Conclusions: In lung cancer, the response to chemotherapy beyond first line may be modestly higher when administered after aPD-1 therapy. Immune-related adverse events can occur during chemotherapy administered after aPD-1 therapy has been stopped.
Treatment with PD-1 inhibitors in NSCLC beyond disease progression: Impact on symptoms and cost.
Authors: Moskovitz Mor Tal , Matthews Priscilla M , Pavel Alexandra M , Xu Wei , Bradbury Penelope Ann , Liu Geoffrey , Shepherd Frances A. , Leighl Natasha B. 
Published: February 2018

174 Background: Immunotherapy with PD-1 axis inhibitors has become standard of care in the treatment of patients with advanced non-small cell lung cancer (NSCLC), with improved survival and less toxicity than chemotherapy. Response patterns to PD-1 axis inhibitors can be unconventional, including pseudoprogression. Identifying disease progression using RECIST has been challenging. We explored treatment past progression (TPP) with PD-1 inhibitors and its impact on patient symptoms and costs. Methods: Retrospective analysis of consecutive patients with advanced NSCLC that received single agent PD-1 inhibitors at the Princess Margaret Cancer Centre (PMH) between 2013 and 2017. Patient symptom burden was assessed by Edmonton Symptom Assessment Scale (ESAS) at outpatient clinic visits. Drug acquisition costs were calculated using hospital-based costs for the agents used and both actual and fixed dosing recommendations. Results: The study cohort included 89 patients with advanced NSCLC. Median age was 62, half were female and 75% had adenocarcinoma. Most, 70%, developed disease progression during treatment, 19% stopped due to toxicity. Twenty-one patients received TPP (23% of entire cohort, 34% of those with progression). Demographic characteristics except age and baseline symptom scores were similar between groups. Younger patients (p = 0.046), those with lower symptom burden upon RECIST progression (mean ESAS 14.7 vs. 27.2 non-TPP, p = 0.013) and greater symptom improvement from baseline (mean ESAS change -11.7 vs. -2.3 non-TPP, p = 0.11) were more likely to receive TPP. During TPP, only 1 patient achieved tumor response. TPP represented 29% of total treatment costs. This did not vary significantly between weight- based and fixed dosing. However, the costs of treatment of the entire cohort was 23% higher using fixed dosing compared to weight-based. Conclusions: : Treatment with immunotherapy beyond RECIST progression is common in advanced lung cancer, although patient benefit is rare. This can lead to substantial expenditure without clear value for most patients. Better methods for detecting early failure of immunotherapy in advanced NSCLC are needed, to allow patients to switch to more active treatment.
Effect of STING agonist on tumor immune microenvironment of non-inflamed lung cancer and efficacy of immune checkpoint blockade.
Authors: Chon Hongjae 
Published: February 2018

178 Background: Cancer immunotherapy targeting immune checkpoints are now emerging as a promising therapeutic strategy in various tumors. However, the treatment of T cell non-inflamed tumor which lacks intratumoral T cell infiltrates are still major clinical hurdle. Therefore, drugs that target signaling pathways to increase T cell infiltration in non-inflamed tumor microenvironment (TME) should be investigated. In this study, we aimed to explore the therapeutic potential of STING agonist in murine model of non-small cell lung cancer to overcome immunotherapy resistance. Methods: C57BL/6 mice, which are 6 to 8 weeks of age, were used for the experiment. Mice were injected with Lewis lung carcinoma cells on the right flank. STING agonist (cGAMP) was injected intratumorally. CD8+ and CD31+ cells were detected using immunofluorescence (IF) staining. Gene expressions of tumor microenvironment were analyzed by NanoString RNA sequencing. Flow cytometry (FACS) was performed to detect CD8+, CD4+, Treg and myeloid cell population. Tumor growths were evaluated in combination with anti-PD1 and STING agonist treatment. Results: Local injection of STING agonist effectively delayed tumor growth of LLC. STING agonist increased intratumoral CD8+ T cells and vascular disruption. Expressions of inhibitory checkpoint molecules (PD-1, PD-L1), cytokines (IFN), CD8+ and CD4+ T cells were increased, which showed that anti-cancer immune responses were augmented. Combination treatment of anti-PD-1 antibody and STING agonist synergistically decreased tumor growth. Conclusions: In this study, STING agonist was shown to delay tumor growth and remodel tumor microenvironment in non-inflamed lung carcinoma model. Combination therapy of STING agonist and immune checkpoint inhibitors (ICI) targeting PD-1 synergistically suppressed the growth of lung cancer which is resistant to ICI monotherapy. Collectively, our findings demonstrated that localized STING therapy effectively sensitizes non-inflamed lung cancer to systemic ICI treatment and induces a maximal anti-cancer immune response.
MHC-II expression to drive a unique pattern of adaptive resistance to antitumor immunity through receptor checkpoint engagement.
Authors: Balko Justin M. , Johnson Douglas Buckner , Wang Daniel Ying , Ericsson-Gonzalez Paula , Nixon Mellissa , Salgado Roberto , Sanchez Violeta , Schreeder Daniel , Kim Ju Young , Bordeaux Jennifer , Sanders Melinda , Davis Randall S. 
Published: February 2018

180 Background: Anti-PD-1 therapy is effective in many cancers, but tumor-intrinsic factors governing response and resistance are largely unknown. MHC-II (HLA-DR) expression on tumor cells can predict response to anti-PD-1. Thus, we sought to determine the molecular features of MHC-II+ tumors in the evolution of anti-PD-1 response. Methods: We performed RNA-seq on 58 anti-PD-1 treated melanoma and lung tumors, including a subset of matched specimens prior to treatment and at acquired resistance. We performed immunohistochemistry (IHC) for immunologic markers, including HLA-DR on tumor cells. In triple-negative breast cancers (TNBC; n = 103), we performed IHC and/or quantitative immunofluorescence (QIF) for LAG3, PD-L1, CD4, CD8, Fc-receptor-like 6 (FCRL6), and granzyme B (GZMB). QIF images were assessed by Automated Quantitative Analysis (AQUA). To determine the functional effect of MHC-II on tumor cells, we generated isogenic MHC-II+ mouse tumors and assessed immune responsiveness and efficacy of checkpoint inhibition. Results: We identified unique inflammatory signatures in HLA-DR+ tumors, correlating with enhanced pre-treatment CD4+ and CD8+ tumor-infiltrating lymphocytes (TILs) and response to anti-PD-1. LAG3+ and FCRL6+ TILs were enriched in HLA-DR+ tumors. LAG3 and FCRL6, known inhibitory receptors which bind MHC-II, were elevated at anti-PD-1 resistance. Similarly, in > 100 TNBCs, HLA-DR+ tumor cells associated with increased CD4+ and CD8+ TILs and enhanced LAG3+ and FCRL6+ TILs. Further, presence of MHC-II-suppressing (LAG3+/FCRL6+) TILs associated with decreased GZMB+ CD8+ T cells, suggesting suppressed cytotoxicity. In mice, enforced expression of MHC-II on tumor cells enhanced CD4-enhanced anti-tumor immunity but was thwarted by LAG3+ TIL recruitment. Combined anti-LAG3 and anti-PD-1 therapy was selectively effective in MHC-II+ tumors. Conclusions: MHC-II+ tumors are immunologically active and may circumvent anti-tumor immunity by targeting MHC-II antigen presentation via recruitment of MHC-II-suppressing TILs. MHC-II expression may be useful to stratify patients to anti-PD-1/anti-LAG3 and eventually, anti-PD-1/anti-FCRL6 combinations.
Outcomes of immunotherapy in advanced melanoma in relation to age.
Authors: Joshi Krishna Prasad , Atwal Dinesh , Ravilla Rahul , Tao Jun , Su Joseph , Makhoul Issam , Hutchins Laura Fulper , Mahmoud Fade A. 
Published: February 2018

187 Background: Older age is a risk feature in melanoma. Elderly are more likely to have immunosenescence, which could help melanoma cells escape immune surveillance. Hence, there is a belief that elderly people cannot mount a potent immune response to checkpoint inhibitors (CPI) to fully eliminate melanoma. The objective of the study was to investigate age-related differences in the time to progression (TTP), overall survival (OS), and immunotherapy related adverse events (irAEs) among patients with metastatic melanoma who received CPI. Methods: We retrospectively identified patients with stage IV melanoma who received at least 1 dose of ipilimumab, pembrolizumab, nivolumab, or combined ipilimumab and nivolumab. Demographics, pathologic, and clinical characteristics were obtained. Immune-related response criteria were utilized to define responses. Results: Sixty patients were included; 29 were less than 65 years old and 31 were 65 years or older. No significant differences, when adjusted for gender, type of melanoma and presence of brain metastasis, in TTP [HR 0.79; 95% CI (0.371.70); p = 0.46] and OS [Hazard ratio (HR) 0.75; 95% CI (0.31-1.82); P = 0.491] was observed between the < 65 and ≥65 year-old groups who received CPI for metastatic melanoma. Overall irAEs in two groups was comparable with 62% in the younger patients and 45% in the older patients (P = 0.19). Thirty responders had a median age of 66.9 (54.3-73.3 years old) and 30 non-responders had a median age of 62.7 (54-69.1 years old). Non-responders, regardless of age, were more likely to have BRAF mutated melanomas (53.3% vs. 27.6%; P = 0.04) and less likely to have irAEs (40% vs. 66.7%; P = 0.04) than responders. Conclusions: No difference in TTP, OS or irAEs was observed between the elderly and the young patients who received CPI for metastatic melanoma. In general, responders had higher irAEs and less BRAF mutated melanomas than non-responders.