bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analysis of colorectal cancer patients treated on ETCTN 10021: A multicenter randomized trial of combined PD-L1 and CTLA-4 inhibition with targeted low-dose or hypofractionated radiation.
Authors: Monjazeb Arta , Giobbie-Hurder Anita , Lako Ana , Tesfaye Anteneh A. , Stroiney Amanda , Gentzler Ryan D. , Jabbour Salma , Alese Olatunji B. , Rahma Osama E. , Cleary James M. , Sharon Elad , Raben David , Mamon Harvey J. , Streicher Howard , Chen Helen X. , Ahmed Mansoor , Gjini Evisa , Rodig Scott , Hodi F. Stephen , Schoenfeld Jonathan Daniel 
Published: July 2019

49 Background: Pre-clinical and clinical evidence support immune effects of targeted radiation (RT) resulting in synergy with immune checkpoint therapy. However, prospective data are lacking in regards to safety, efficacy and immunologic impacts of different doses of RT given in conjunction with PD-L1 and CTLA-4 blockade. Methods: ETCTN 10021 is a multicenter randomized phase 2 study evaluating repeated low-dose fractionated RT (LDFRT) or hypofractionated RT (HFRT) in combination with PD-L1 and CTLA-4 inhibition in metastatic microsatellite-stable colorectal cancer (CRC) refractory to first-line chemotherapy, or non-small cell lung cancer progressive on prior PD-1 inhibition. The primary endpoint is objective response excluding irradiated lesions. Pre- and on-treatment biopsies were analyzed using multiplex immunofluorescence (IF) evaluating multiple immune markers. We report the prespecified analysis of the CRC cohort. Results: Twenty CRC patients were randomized, 19 of whom were treated with immunotherapy and RT, and 18 of whom were evaluable for response. Median lines of prior therapy were 4 (range 1-7). There were 16 patients with toxicity potentially related to treatment (84%), and 8 patients with possibly associated grade 3-5 toxicity (42%). Best response was stable disease in one patient with an abscopal out-of-field response who developed new lesions after HFRT and 4 cycles with decreasing overall disease burden. Correlative IF performed on 5 sample pairs revealed that HFRT, but not LDFRT, increased infiltration of CD8+, and CD8+/PD1+/Ki67+ T-cells in the RT field. Conclusions: We demonstrate the feasibility of a multicenter randomized study adding different RT regimens to PD-L1/CTLA-4 blockade. Toxicity was, in general, consistent with PD-L1/CTLA-4 inhibition with no significant RT-related toxicities noted. Although the best response of stable disease doesn’t support the use of PD-L1/CTLA-4 inhibition with HFRT or LDFRT in this population using these RT regimens and schedule, integrated biomarkers provide support that HFRT impacts the local immune microenvironment. Clinical trial information: NCT02888743.
Cell proliferation as a biomarker for response to immune checkpoint inhibitors in PD-L1 negative renal cell carcinoma.
Authors: Glenn Sean T. , Pabla Sarabjot , Zhu Jason , Labriola Matthew , Gupta Rajan , George Daniel J. , McCall Shannon , Yau Edwin , Conroy Jeffrey M. , Nesline Mary , Papanicolau-Sengos Antonios , Burgher Blake , Lenzo Felicia L. , Zhang Tian , Morrison Carl 
Published: July 2019

62 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 (ICIs) in RCC. Previously we reported (SITC 2018) that moderately proliferative lung cancer have a much higher response rate than either poorly or highly proliferative tumors. Methods: 69 FFPE RCC tumor samples were evaluated by RNA-seq to measure transcript levels of 394 immune related genes. Cell proliferation was defined as the mean mRNA expression of 10 genes (BUB1, CCNB2, CDK1, CDKN3, FOXM1, KIAA0101, MAD2L1, MELK, MKI67, TOP2A) which 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 versus a reference population. Poorly and highly proliferative were grouped for comparison to moderately proliferative tumors. PD-L1 IHC was performed using DAKO 22C3 antibody and scored by FDA guidelines and considered positive if TPS ≥1% and negative if < 1%. Results: In our cohort of 69 patients, the overall ORR was 18.8. The majority, 91% of tumors were PD-L1 negative, with ORR of 14.8%, as opposed to ORR of 50% in PD-L1 positive cases. 62.2% of tumors were poorly proliferative, 8.7% were highly proliferative, and 29% were moderately proliferative. ORR in moderately proliferative tumors was 30% and 14.2% in poorly/highly proliferative tumors. In PD-L1 negative tumors the ORR in moderately proliferative tumors was 20% and 13% in poorly/highly proliferative tumors. For the 5 moderately proliferative, PD-L1 positive tumors, there were 2 PR and 1 CR, and in the 3 poorly/highly proliferative tumors there was 1 PR. 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 PD-L1 negative tumors. Moderately proliferative tumors have a higher ORR than their poorly/highly counterparts.
Understanding the peripheral cellular immunome in patients with breast cancer.
Authors: Landa Karenia , Holl Eda , Frazier Victoria , Hwang Eun-Sil Shelley , Nair Smita 
Published: July 2019

7 Background: Neoadjuvant chemotherapy (NAC) for breast cancer (BC) is being increasingly used in patients with stage I/II disease. Although previously reserved for patients with locally advanced disease, its use in patients with localized disease allows for higher rates of breast-conserving procedures and provides insight into tumor biology. A complete pathologic response (pCR) to NAC correlates with better clinical outcomes; sadly, many patients do not achieve pCR. The advent of immunotherapy has provided cancer patients with additional treatment options. To optimize immunotherapy in BC we must understand the peripheral cellular immunome (immune subsets and activation status) of patients as they undergo standard of care therapy (SOC). Methods: Our population includes patients with stages I-III BC undergoing SOC. Samples were collected pre- and post-NAC, post-surgery and at 2-month follow-up (FU). Results: Flow cytometry analysis for 11 patients was performed at each time-point to examine percentages of circulating immune cells (see Table). We grouped samples in 3 categories: human epidermal growth factor receptor 2 (HER2+) positive, HER2 negative (HER2-) and triple-negative (TN) tumors. 3 out of 11 patients had pCR (1 HER2+, 1 HER2-, 1 TN); they had highest percentage of circulating CD56+ NK cells during treatment course. Conclusions: We observed striking changes in the immunome of women with stage I-III BC undergoing NAC. Although our findings are preliminary, given our sample size, we observed distinct trends within each immune cell population in specific tumor receptor subtypes. These trends could serve to guide our therapies, allow for better patient selection and predict treatment response in patients. [Table: see text]
RNA-sequencing reveals immunotherapy targets in gynecological cancer.
Authors: Papanicolau-Sengos Antonios , Yen Ting-Tai , Dressman Devin , DePietro Paul , Pabla Sarabjot , Nesline Mary , Conroy Jeffrey M. , Glenn Sean T. , Lenzo Felicia L. , Odunsi Kunle , Wang Tian-Li , Morrison Carl 
Published: July 2019

8 Background: We performed microsatellite instability testing and expression immune profiling of endometrioid and serous carcinomas to identify immunotherapeutic targets and histologic attribute correlates. Methods: Microsatellite instability and RNA-seq of 395 immune-related genes were performed in 37 endometrioid and 53 serous carcinomas. Each gene was ranked against a reference population and subsequently compared to a separate clinical database reference of diverse neoplasms to perform Wilcoxon ranked sum test comparisons. Benjamin-Hochberg corrected p-values are reported. Results: VTCN1, IDO1, LAG3, and components of the mTOR/AKT1 pathway were overexpressed in both endometrioid and serous carcinomas compared to the clinical database population. CD276 and NT5E were uniquely overexpressed in the endometrioid set (Table). In the endometrioid set ADGRE5 was overexpressed in endometrioid primaries when compared to their metastatic counterparts. Serous metastases relatively overexpressed HLA-DPA1 compared to their primary counterparts. Ten of 26 endometrioid cancers with available microsatellite instability status were microsatellite unstable. All serous carcinomas were microsatellite stable. There was no correlation between microsatellite instability status and expression of any gene in either endometrioid or serous cancers. Conclusions: We identified high RNA-expression of VTCN1, IDO1, CD276, and LAG3 in endometrioid and serous carcinomas while NT5E (ADORA2A ligand) was found to be uniquely upregulated in endometrioid carcinomas. These markers may play a role in immune suppression in gynecological cancers and are potential immunotherapeutic targets. The upregulation of ADGRE5 in primary endometrioid cancers and upregulation of HLA-DPA1 in metastatic serous cancers suggests immunologic differences which may be relevant to the formation of metastatic disease.
Real-world characterization of patients with cancer admitted with immune-related adverse events (irAEs).
Authors: Eng Lawson , Chen RuiQui , Smith Elliot Charles , Chan Sze Wah Samuel , Hueniken Katrina , Brown M. Catherine , Majeed Habeeb , Ross Kendra , Gray Diana , Xu Wei , Hogg David , Sridhar Srikala S. , Sacher Adrian G. , Leighl Natasha B. , Krzyzanowska Monika K. , Liu Geoffrey , Butler Marcus O. 
Published: July 2019

82 Background: Immune checkpoint inhibitors (ICI) are improving the care of cancer patients. Despite being better tolerated than chemotherapy, there is a risk of developing irAEs which may require hospitalization. Although ICI and irAEs are well studied in clinical trials, there is a paucity of studies characterizing the care patterns for real-world irAEs hospitalizations. Methods: A single centre retrospective chart review (Princess Margaret Cancer Centre, Toronto, ON) identified patients receiving standard of care ICI (2012-2017) hospitalized for irAEs. For hospitalizations, clinico-pathological, investigation and treatment details were collected. Descriptive statistics helped to characterize hospitalizations. Results: Among 697 patients (266 lung, 381 melanoma and 50 genitourinary (GU)) on ICI, 8% (14 lung, 41 melanoma and 2 GU) had at least 1 irAE (range 1-4) hospitalization for a total of 69 hospitalizations. Average length of stay was 12 days (range 1-105). Among hospitalized patients, median age was 60; 63% were male; 29% received ipilimumab monotherapy, 28% pembrolizumab, 22% nivolumab and 22% received combination ICI. The most common irAEs were colitis (52%), pneumonitis (20%), hepatitis (10%) and CNS disease (demyelination, hypophysis) (9%). Cases were admitted directly from clinic (39%), emergency rooms (29%), urgent care clinic (18%) or transferred from another hospital (13%). Most patients (72%) were admitted to oncology; 28% to general medicine. Endoscopy was performed in 21% of admissions with 60% showing evidence of irAE; biopsies were obtained in 16% of admissions and 73% had evidence of irAE. Subspecialty services were involved in 60% of admissions. Most patients received steroids (94%); 17% received Infliximab. While age did not impact length of stay (p = 0.63), patients admitted to oncology had longer admissions compared to general medicine (14 vs 6 days, p = 0.009). Conclusions: irAEs occur at similar rates in the real-world compared to clinical trials. There is significant heterogeneity in the care patterns for irAEs. Patients admitted to oncology had longer average lengths of stay. Further characterizing irAE can help to develop quality indicators that may improve irAE outcomes.
Comparison of care patterns for hospitalized immune-related adverse events (irAEs) between melanoma patients on combination immune checkpoint inhibitor (ICI) therapy versus ICI monotherapy.
Authors: Chen RuiQui , Smith Elliot Charles , Chan Sze Wah Samuel , Hueniken Katrina , Brown M. Catherine , Majeed Habeeb , Ross Kendra , Gray Diana , Xu Wei , Hogg David , Sridhar Srikala S. , Sacher Adrian G. , Leighl Natasha B. , Krzyzanowska Monika K. , Butler Marcus O. , Liu Geoffrey , Eng Lawson 
Published: July 2019

85 Background: Prior clinical trials in melanoma have demonstrated higher rates of irAEs from combination ICI therapy compared to monotherapy. However, this has not been well studied in the real-world where patients often have greater co-morbidities and less organ reserve. We aim to compare irAEs hospitalizations for melanoma patients on combination vs monotherapy ICIs. Methods: We performed a single centre retrospective chart review (Princess Margaret Cancer Centre, Toronto, ON) for all melanoma patients receiving ICI as standard of care (2012-2017) admitted with irAEs. Data collected include demographics, investigations, management and outcomes of hospitalizations. Descriptive analyses were performed to characterize hospitalizations and compare between ICI combination vs monotherapy groups. Results: Among 381 melanoma patients identified on standard of care ICI, 41 (11%) were admitted for irAE. Among those admitted, 10% received monotherapy with nivolumab, 22% pembrolizumab, 39% ipilimumab and 29% combination ICI. Admission rates were higher among patients receiving combination ICI compared to monotherapy (20% vs 8% p = 0.003). Prevalence of the most common irAEs were similar between combination and monotherapy groups: colitis (58% vs 59%), pneumonitis (8% vs 14%) and hepatitis (8% vs 10%). Less than half received invasive diagnostic tests (i.e, endoscopy) (42% combination vs 35% monotherapy, p = 0.50) with 3 (60%) and 5 (50%) confirming irAEs, respectively. Rates of infliximab use were similar between the combination and monotherapy group (25% vs 21%, p = 0.70). Average length of stay was shorter for patients on combination ICI compared to monotherapy (5 days vs 15 days, p = 0.08). irAE readmission rates were similar between patients receiving combination ICI compared to monotherapy (20% vs 17%, p = 0.65). Conclusions: Despite higher admission rates among patients receiving combination ICI, there was a trend towards shorter hospitalizations. Other outcomes including diagnoses, investigations and management were not significantly different between patients receiving combination vs ICI monotherapy.
Patient reported toxicities: Development and validation of patient-reported symptom measure for lung cancer patients receiving immunotherapy.
Authors: Shaw Sandra S. , Jim Heather S.L. , Eisel Sarah , Hoogland Aasha , LeDuc David , Dicker Adam P. 
Published: July 2019

93 Background: There is increasing clinical and research interest in patient-reported outcomes (PROs) which provide unique and complementary information to provider-rated adverse events. While several studies have been published of PROs in lung cancer patients receiving immune checkpoint blockade, to our knowledge all have focused on PROs collected as part of a clinical trial. This interim analysis describes PROs outside the context of a clinical trial. Methods: The Addario Lung Cancer Foundation (ALCF) international patient registry was used to collect patient-reported clinical and PRO information. Patients who reported current or past treatment with an FDA-approved immune checkpoint inhibitor were asked to complete a second survey of symptomatic toxicities of these therapies. Patients rated 40 symptoms on a five-point scale. The Charlson Comorbidity Index and Functional Assessment of Cancer Therapy General (FACT-G) were administered to assess comorbidities and quality of life, respectively. Results: A total of 116 patients (mean age 61, 75% female) who reported treatment with nivolumab (52%) or pembrolizumab (47%) were included in analyses. The majority of patients (70%) had been treated for 6 months or less. The most commonly reported symptoms were fatigue (72%), aching joints (52%), aching muscles (35%), insomnia (34%), back pain (30%), itching (27%), bone pain (26%), and skin dryness (25%). A total of 26% of patients had experienced a treatment delay, 10% had been to the emergency room, and 6% had been hospitalized due to toxicity. Participants reported a mean score of 75.88 (SD=17.59) on the FACT-G, significantly lower than previously-published normative data for cancer patients. Conclusions: This study is among the first to evaluate patient-reported toxicities of immune checkpoint inhibitor outside the context of a clinical trial. Results from this interim analysis indicate patient reported toxicities of immune checkpoint inhibitors are common in lung cancer patients. Additional research is needed to better understand the longitudinal course of symptomatic toxicities. Acknowledgements: ALCF, IASLC, American Lung Association.
Effect of concomitant medications on overall survival in patients with cancer undergoing immunotherapy.
Authors: Spakowicz Daniel , Husain Marium , Tinoco Gabriel , Patel Sandip H. , Burkart Jarred Thomas , Verschraegen Claire F. , Kendra Kari Lynn , Hoffman Sarah , Philippon Jennifer , Quiroga Dionisia Marie , Otterson Gregory Alan , Owen Dwight Hall 
Published: July 2019

94 Background: The response to Immunotherapy (IO) is known to be affected by concomitant medications including corticosteroids and antibiotics. We evaluated the medication history of patients undergoing IO to explore other medications that affect overall survival and to estimate the relative impact of each medication when given in combination. Methods: A retrospective review of patients with advanced cancer who received IO from 2011 to 2017 at the Ohio State University was performed with IRB approval. Data were extracted from the medical record, including medication history 180 days around the start of IO therapy. Data were collected in a REDCap database. Overall Survival (OS) was calculated from the initiation of IO. Cox Proportional-Hazards models were used and evaluated by log-rank test at alpha = 0.05. All calculations were performed using the survival and survminer packages in R. Results: Patients who received antibiotics or corticosteroids had decreased OS (p = 0.019 and p = 0.043, respectively) across several cancer types. Medications that were not significantly associated with OS included statins (p = 0.38), proton pump inhibitors (p = 0.94), H2 blockers (p = 0.27) and NSAIDS (p = 0.46). A total of 159 patients had complete data for all medications suitable for modeling relative effects. 149 (94%) of patients received antibiotics within 180 days of IO and 19 (12%) received both corticosteroids and antibiotics. The combination of corticosteroids and antibiotics had lower median OS than antibiotics alone or neither medication (p < 0.0018). A Cox Proportional Hazards model of antibiotics and corticosteroids, controlling for age, BMI and ECOG performance status, showed antibiotics, age and BMI to be significant predictors. Conclusions: Antibiotics and corticosteroids near the start of IO reduced overall survival, and the combination reduced the median overall survival further. However, a combined model that controlled for age, BMI and ECOG showed antibiotics, age and BMI to have a significant effect on OS. Though preliminary, these results suggest that antibiotics and corticosteroids may be affecting OS in the context of IO through overlapping pathways.
Randomized phase II trial of patient-specific dendritic cell vaccines loaded with autologous tumor antigens versus autologous monocytes in patients with primary advanced ovarian cancer.
Authors: Dillman Robert O. , Abaid Lisa , Hsieh Candace , Langford Christopher , Nistor Gabriel I. 
Published: July 2019

TPS10 Background: With standard debulking surgery and combination chemotherapy (adjuvant ± neoadjuvant) the 5-year survival for women with newly diagnosed advanced epithelial ovarian cancer (stage III or IV) is less than 40%. After completion of primary therapy there is an opportunity to introduce an immunotherapy modality in an effort to improve long-term survival. In patients with metastatic melanoma, patient-specific vaccines consisting of autologous dendritic cells (DC) loaded with autologous tumor antigens (ATA) derived from a short-term autologous tumor cell line were associated with minimal toxicity and a 5-year survival of 50% in a single arm trial, and more than doubled median survival (43 vs. 20 months) in a randomized trial. Newly diagnosed patients with ovarian cancer might benefit from addition of such patient-specific therapeutic vaccines (DC-ATA) to standard therapy. Methods: This is a double-blind, 2:1 randomized trial comparing adjunctive treatment with DC-ATA to autologous monocytes (MC) in patients with newly diagnosed stage III or IV epithelial cancer of the ovary, fallopian tube, or peritoneum. Patients eligible for randomization are those who have completed or discontinued standard primary therapy, have a Karnofsky performance status ≥70, have an autologous tumor cell line, and have a monocyte product from which DC can be derived. The tumor cell line is derived from fresh tumor; MC are derived from leukapheresis, and MC are converted to DC by incubation with GM-CSF and IL-4. Patients are stratified by whether there is no evidence of disease at completion of primary therapy, and then are randomized, typically 6 to 7 months after tumor collection. Treatment can begin about 4 weeks from randomization. The trial has been open at a single site since mid-November 2017; the first tumor was collected in December. Appropriate tumor samples have been submitted from 11 patients and all 11 have resulted in cell lines. The first patient was randomized in May 2018. As of October 2018 four patients had been randomized and all four had started treatment. Additional clinical sites are being initiated. Clinical trial information: NCT02033616.