bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modification of intrinsic ovarian cancer tumor factors by Wnt-pathway agents influences macrophage recruitment and activity.
Authors: Dholakia Jhalak , Scalise Carly Bess , Katre Ashwini A. , Arend Rebecca Christian 
Published: June 2021

e14514 Background: The Wnt/B-catenin pathway is associated with a “cold” phenotype in the gynecologic malignancy tumor microenvironment (TME), resulting in immunosuppression. Research is limited regarding this pathway’s effects on TME myeloid cell populations. We aimed to characterize the impact of Wnt pathway modulation on macrophage activity in ovarian cancer. Methods: Syngeneic murine models harboring ID8 parental (ID8par) tumors were treated with DKN-01 and CGX-1321 as single agents or in sequence (DKN-01 followed by CGX-1321.) Flow cytometry analyses were performed on harvested omenta and blood. Ascites from 10 high grade serous epithelial ovarian cancer patients were treated with DKN-01 (Wnt activator) or CGX-1321 (Wnt inhibitor) for 48 hours; multiplex cytokine array was performed to determine changes in cytokine/chemokine expression. Lastly, we performed co-culture analyses on the effects of ID8par and ID8p53-/- isolated cell media on murine macrophage (RAW264.7) activity. Results: In the ID8par model, sequential DKN-01/CGX-1321 resulted in the greatest macrophage influx into the TME. CGX-1321 monotherapy increased the M2:M1 macrophage ratio (pro-tumor) while DKN-01 monotherapy resulted in decreased M2:M1 ratio (anti-tumor.) In human ascites, DKN-01 increased macrophage colony stimulating factor (M-CSF) expression. Of note, ascites from a patient harboring a p53 mutation demonstrated an increase in M1 polarization cytokines IFNy and TNFa in response to DKN-01; CGX-1321 treatment resulted in increased M2 polarization cytokines IL-4 and IL-13. In co-culture analysis, ID8par isolated media increased RAW264.7 migration and polarization towards an M2 phenotype; ID8p53-/- isolated media polarized towards an M1 phenotype. Conclusions: Macrophage activity influences immune responses and tumor behavior. For example, M2 macrophages are pro-tumor and can enhance tumor growth and immune evasion. In our studies, we demonstrated that macrophage recruitment and polarization (M1 vs M2) are influenced by genetic alterations that can be modified by treatment. The ID8par model positively influenced M2 macrophage activity; ID8p53-/- cells positively influenced M1 macrophage activity. Importantly, DKN-01 treatment reverses the M2-dominant phenotype in ID8par model towards M1. These results suggest that p53 mutation and/or DKN-01 treatment in ovarian cancer influences M1 anti-tumor macrophage activity, and posits a novel targetable pathway. Further studies should investigate Wnt/B-catenin modulation on macrophage activity for immunotherapy in gynecologic malignancies.
Immune effector cell therapies in oncology: A systematic analysis and forecast from ClinicalTrials.gov.
Authors: Forero-Forero Jose Vicente , Garcia-Robledo Juan Esteban , Castro-Martinez Daniela A. , Moreno Eider Felipe , Diaz Paula Andrea Lengerke , Booth Natalie , Castro Januario E. 
Published: June 2021

e14516 Background: IEC are arguably the most promising therapy in oncology, and FDA approvals for CAR T cells are a testament to their real potential. This has led to a great growth of clinical trials (CT), making the evaluation of their associated data increasingly challenging. To facilitate this process, we performed a systematic review of ClinicalTrials.gov focused on IEC therapies in oncology. We performed an analysis of the CT data and forecast trends for 2025. Methods: CT registries were retrieved from ClinicalTrials.gov with a systematic search query. We included CT registered between 1993-2020, which used IEC-based therapies in oncology. Statistical analysis using descriptive and inferential methods allowed us to identify trends and establish forecasts. Results: We identified 938 registrations of IEC-CTs in oncology, and 51% of those were active. The most common IEC type was CAR T (51%), followed by NK (15%), TCR T (8%), TIL (8%), and CIK (3%). 69% of IEC-CTs were aimed at a specific target vs. 31% that lack that specificity. The number of annual CAR T-CTs continue to increase, and we forecast 320 registrations during 2025. Since 2018, the number of CTs using unmodified T cells and TIL has increased (largely due to metastatic melanoma studies). NK cells CTs represent 8% of all registrations, and by 2025 we anticipate that >150 NK-based CTs will be registered per year, a number similar to CAR T-CTs registered during 2020. IEC-CTs based on allogeneic sources represent 18% of all registrations and are expected to grow 2.5 fold in the next 5 years. In solid tumors, the most common IEC-CTs are based on Non-CAR studies, while in hem-malignancies 76% of CTs are CAR T. Only one solid tumor, CAR T-CT, has reached phase 2/3, while 7 CIK-CTs were used to target various organ tumors. Conclusions: IEC-CTs continue to grow exponentially and represent an active field of clinical research in oncology. Allogeneic and NK-CTs increase rapidly and are among the most promising IEC-CTs. A rising proportion of CTs in solid tumors are using CIK and TIL rather than CAR T-cells, which are more popular for treating hem-malignancies. This is a direct reflection of the challenges associated with CAR T infiltration and persistence in solid tumors. Our analyses indicate that annual IEC-CTs registrations will double by 2025. We anticipate the increase in cellular therapy options will demand an organized response, including adequate logistical planning and policy implementation in response to the landscape changes in clinical oncology during the upcoming years.[Table: see text]
Systemic and local inflammation characteristics in patients with cancer after lung transplantation.
Authors: Steindl Ariane , Nackenhorst Maja , Puhr Hannah Christina , Marhold Maximilian , Sinn Katharina , Hoetzenecker Konrad , Hoda Mir Alireza , Preusser Matthias , Berghoff Anna Sophie 
Published: June 2021

e14527 Background: Immune suppressive treatment is associated with an increased cancer risk due to its negative impact on immunosurveillance. We analyzed the association of immune suppressive treatment with the inflammatory tumor microenvironment and systemic inflammation parameters in patients with solid cancers after lung transplantation. Methods: Systemic inflammation was measured by neutrophil-to-lymphocyte ratio (NLR), leucocyte-to-lymphocyte ratio (LLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR) and CRP/albumin ratio (CRP/Alb) and analyzed at time of lung transplantation and time of tumor diagnosis. In tumor samples, the expression of tumor infiltrating lymphocytes (TIL) including CD3, CD8, CD45RO and PD-L1 using the Ventana Benchmark Ultra system for immunohistochemistry were investigated. Automated tissue analyses were performed for CD3, CD8 and CD45RO TIL (Definiens software). PD-L1 expression was determined by using the combined positive score (CPS). Results: 28 patients with cancer (10 lung cancer, 4 colorectal cancer, 2 renal cell carcinoma, 2 gastric cancer, 2 pancreatic cancer, 2 head&neck tumor, and others) were included in the study. Median time from transplantation to cancer diagnosis was 45 months (range 29-61). 57% (16/28) experienced a period of transplant rejection between transplantation and tumor diagnosis. Therefore, 25% (7/28) of the patients received intensified immunosuppression up to 8 weeks before tumor diagnosis. Median density of CD3+TIL was 5742 cells/ mm2 (range 3,203-8,429), median density of CD8+TIL was 6,363 cells/ mm2 (range 3,643-8,190), median density of CD45RO TIL was 72 cells/ mm2 (range 4-635) and median expression of PD-L1 was 60 (range 5-100) in tumor samples. No statistically significant changes in systemic inflammation were observed from time of transplantation to time of tumor diagnosis (p>0.05; Wilcoxon Signed-Rank Test). Furthermore, a history of transplant rejection before tumor diagnosis was not statistically significant associated with changes in TIL densities or systemic inflammation parameters (p>0.05; Mann Whitney U test). Conclusions: An activated local inflammatory tumor microenvironment as well as stable systemic inflammation characteristics were observed in our cohort. These results support the further development of immunotherapy as treatment approach also in cancer patients under immunosuppression after lung transplantation.[Table: see text]
Personalized DNA neoantigen vaccine in combination with plasmid IL-12 for the treatment of a patient with anaplastic astrocytoma.
Authors: Johanns Tanner Michael , Perales-Puchalt Alfredo , Stupp Roger , Berger Mitchel , Gillanders William E. , Miller Chris , Hundal Jasreet , McLellan Michael D. , Goedegebuure S. Peter , Rochestie Sarah , Cooch Neil , Peters Joann , Dunn Gavin P. , Sardesai Niranjan 
Published: June 2021

e14561 Background: Tumor neoantigens are epitopes derived from tumor-specific mutations that may be incorporated in personalized vaccines to prime T cell responses. DNA vaccines delivered with electroporation have recently shown strong CD8 and CD4 T cell responses in clinical trials. In preclinical studies, DNA-encoded neoantigen vaccines have shown induction of CD8 T cells against 50% of predicted high affinity epitopes with the ability to impact tumor growth. Methods: Two resection samples from a patient with IDH+ MGMT-methylated anaplastic astrocytoma were subject to whole exome and transcriptome sequencing. Epitopes derived from 27 neoantigens and 3 shared tumor-associated antigens were prioritized and included in a personalized vaccine. The patient was treated with surgery, radiotherapy and temozolomide starting June 2018 and received the first dose of the personalized vaccine in June 2019 under a compassionate use single patient IND application with the FDA. Results: As of February 10, 2021, the patient has received 10 doses of the DNA personalized vaccine. No serious adverse events have been reported. Related adverse events are limited to grade 1 injection site reactions. The patient remains progression-free 32 months after surgery and 20 months after starting vaccination. Three weeks following the third dose, a hyperintense image on the tumor bed was identified, which disappeared on the following MRI, 2 weeks following dose 5, being catalogued as pseudo progression. Ex vivo ELISpot have identified T cell responses to 21/30 epitopes (70%), including 18/27 (67%) neoantigens and 3/3 (100%) shared antigens. Flow cytometry analysis has determined that T cell responses are 92.3% CD8 and 69.2% CD4 (30.8% CD8 only; 61.5% both CD8 and CD4; and 7.7% CD4 only). Conclusions: This compassionate use treatment in an adjuvant setting demonstrates manufacturing feasibility, safety, tolerability, immunogenicity, and suggests potential for persistent clinical response of DNA encoded personalized vaccines. The data supports further investigation of DNA-encoded personalized vaccines into newly diagnosed high-grade gliomas.
Immune-related adverse events associated with immune-checkpoint inhibitors therapy in Mexican patients: Experience at a single center.
Authors: Gonzalez Espinoza Iván Romarico Romarico , Cortés Escobar Neil , Chiquillo-Domínguez Mariana , Juárez Salazar Gabriela , Garibay Diaz Julio Cesar , Gozalishvili Boncheva Anna , Acosta Ponce De León Eric , Sánchez Sosa Sergio , Ibarra Fernández Rebeca , Miguel Cruz Enrique , Sabaté Fernández Mónica , García Reyna Juan Carlos , Aguilar Priego José Manuel , Domínguez Peregrina Alfredo , Tobón Helú Giovanni , Cordero Vargas Carlos , Gonzalez Blanco María de Jesús , Aguilar Carmen , Arroyo Kuribreña José Carlos , Vizcarra Ramos Feliciano de Jesús 
Published: June 2021

e14580 Background: The use of immune-checkpoint inhibitors (ICIs) for solid malignancies is rapidly rising, and many new agents and treatment combinations are in development. However, ICIs have a unique side-effect profile of immune-related adverse events (irAEs) compared with chemotherapeutic agents or targeted therapies. The aim of this work was to describe the irAEs in diverse types of malignant tumors using real-world data. Methods: This is a retrospective and descriptive study of patients with diverse types of advanced malignancies treated with immunotherapy at Centro Oncológico Integral of the Hospital Ángeles in Puebla, México; during the period 2016-2020. Data about the primary neoplasm, ICIs, irAEs, organ system affected, grade and treatment was collected. Clinical and laboratory parameters were obtained by reviewing medical records. Results: A total of 117 patients were included, median age of 65 years, of which 63.2% were male and 36.8% were female. The most frequent neoplasms treated with ICIs were: lung (27.4%), kidney (16.2%), melanoma (12.8%), hepatocellular (9.4%), breast (8.5%), non-melanoma skin cancer (6.0%), mesothelioma (4.3%) and other tumors (15.3%). 39.3% of the patients had no metastases, 41.9% had metastases to at least 1 or 2 sites, and 18.8% to 3 or more sites. The types of ICIs were: nivolumab (35.0%), pembrolizumab (28.2%), atezolizumab (23.9%), ipilimumab + nivolumab (12.0%) and durvalumab (0.9%). The most frequent irAEs were: gastrointestinal (61.5%), neurologic (46.2%), pulmonary (38.5%), metabolic (32.5%) and hematologic (29.1%). 39.3% of the irAEs were reported as grade 1, 31.6% as grade 2, 14.5% as grade 3 and 2.6% as grade 4. Conclusions: Our work shows the incidence of irAEs in a poorly studied population and provides new data that complement that reported by other works, however, further prospective studies are necessary.[Table: see text]
Venous thromboembolism in patients on check point inhibitors.
Authors: Giri Upama , Yu Xiao , Resnick Karen , Larsen Travis , In Gino Kim 
Published: June 2021

e14582 Background: Checkpoint inhibition (CPI) therapy, including PD-1/PD-L1 and CTLA-4 inhibition strategies, has significantly improved the prognosis for patients with advanced malignancies. Anticancer treatments like chemotherapy and antiangiogenic agents are associated with higher rate of cancer associated thrombosis. However, the association of CPI with venous thromboembolism (VTE) is not well established. Methods: We conducted a retrospective cohort study of patients with advanced malignancy who were started on CPI between 2016 and 2019 at a tertiary care medical center in Southern California. We used descriptive statistics to describe the occurrence of VTE. Logistic regression was used to identify factors that had a significant impact on occurrence of VTE. Results: The cohort comprised 240 patients with median age of 60 years (range 27-96) at initiation of CPI and majority of the patients were males (57%). 45% were Hispanic, followed by Asian (19%), Caucasian (18%) and African American (8%). 80% had metastatic disease and the most common indication for use of CPI was lung cancer (20%), followed by gynecological malignancies (19%) including ovarian, endometrial and cervical cancer, melanoma (15%) and genitourinary malignancies (15%) including renal and urothelial cancer. The most used agent was nivolumab (68%) followed by pembrolizumab (25%), with most patients receiving single agent CPI (94%). Combination CPI and CPI with other agents including chemotherapy or targeted therapy was given to 3% and 4% respectively. The incidence of VTE was 10% (24/240) – pulmonary embolism (5), upper extremity deep vein thrombosis (5), lower extremity deep vein thrombosis (10) and visceral vein thrombosis (4). Patients were also stratified by Khorana score (KS) based on laboratory values and body mass indices at initiation of CPI (median score 1, range 0-4). VTEs occurred in patients on nivolumab in 8.02% of cases and in 18.2% of cases for pembrolizumab. VTEs occurred in 7.04% of patients with initial KS 0; 8.33%, KS 1; 17.5%, KS 2; and 15.4%, KS 3. Logistic regression analysis using a significance level of p < 0.05 showed no significant association between occurrence of VTE and age, sex, race, type of cancer or Khorana score. Conclusions: In our study, VTE risk in patients receiving CPI was similar to that with other systemic therapy. Further larger studies are needed to assess clinical significance of these findings, stratify for risk factors, and account for dose-dependence.
Corticosteroid use and its impact on the efficacy of immunotherapy in multiple tumor types.
Authors: Nelson Blessie Elizabeth , Greiner Benjamin , Hong Angelina , Tipton Shelby , Lee Marissa , Dixon Andre , Venkatesan Rohit 
Published: June 2021

e14583 Background: Studies have suggested that concurrent corticosteroid use may decrease the efficacy of immunotherapy for cancer treatment, however, the data remains limited. The purpose of this study is to expand upon the previous literature to analyze the outcomes of patients with the following cancer sites: renal cell, lung, melanoma, urothelial, head and neck, hepatocellular, or breast cancer who received immunotherapy and steroids concurrently. Our primary objective was to analyze the overall survival (OS) and objective response rate (ORR) of patients receiving immunotherapy with corticosteroids compared to immunotherapy alone. Methods: A retrospective cohort study was conducted of patients receiving immunotherapy plus corticosteroids compared to immunotherapy alone using University of Texas Medical Branch patients. Patients receiving nivolumab, pembrolizumab, atezolizumab, ipilimumab, durvalumab, or avelumab between January 1, 2012-August 2020 with one of the following cancers were included in the analysis: Renal cell carcinoma, lung carcinoma, melanoma, urothelial carcinoma, head and neck carcinoma, hepatocellular carcinoma, and breast cancer carcinoma. The resulting sample was then separated into two arms. The experimental sample received any of the following steroids either as part of their therapeutic regimen or for symptom management and within 30 days of immunotherapy initiation or at any time during the immunotherapy regimen: dexamethasone, prednisone, methylprednisolone, or hydrocortisone. The control did not receive steroids within 30 days of initiation or during the course of their immunotherapy regimen. Weibull regression models were then constructed to compute hazard ratios for OS at 6 months, 12 months, and 3 years. ORR - complete and partial response, stable disease, and disease progression - between the two arms was assessed using a chi-squared test. Results: Two hundred and sixty patients met inclusion criteria. Of this, 164 received corticosteroids. Our sample was primarily male (70.38%), white (66.54%), and had 0-1 comorbidities (83.08%), lung cancer (45%), and metastases (81.92%). There was no significant difference between the two arms regarding sex, age, number of comorbidities, ECOG score, cancer type, or race. There was no statistically significant difference in OS between the experimental and control arm at 6 months (HR: 1.01; 95%CI 0.63-1.62), 12 months (1.02; 95% CI 0.69-1.51), or 3 years (1.06; 95% CI 0.79-1.42). There was no significant difference in ORR at 6 months between the two arms (2 = 6.3, p=0.178). Conclusions: There was no statistically significant difference in OS or PFS between the two study arms. This study suggests that corticosteroid use does not affect immunotherapy efficacy as previous literature suggests. Larger studies are needed to assess the impact of corticosteroids on immunotherapy efficacy in patients with cancer.
Prediction of clinical efficacy by plasma concentration of apatinib in patients with solid tumor.
Authors: He Hongtao , Wang Lixing , Huang Guanglei , Liu Rongfeng , Yuan Meng , Xing Penghui , Shan Baoen , Shi Jian 
Published: June 2021

e15000 Background: To explore the correlation between plasma concentration of apatinib and clinical efficacy. Methods: 42 patients were enrolled. Plasma specimens of all patients were collected. At 7:40 am, fasting blood was drawn as plasma trough concentration (Ctrough). At 8 am, apatinib mesylate (APA-M, 250mg qd) was orally administrated. At 11 am, venous blood was drawn as plasma peak concentration (Cpeak). Each patient has Ctrough and Cpeak samples. A total of 84 plasma samples were obtained. The concentration of APA-M in plasma was determined by UPLC-MS/MS. Results: 1) 42 patients were evaluable. Treatment response was assessed by RECIST1.1. 2 patients achieved complete response (CR), 16 partial response (PR), 12 stable disease (SD) (tumor shrinks), 5 SD (tumor enlargement), 7 progressive disease (PD). Objective response rate (ORR) was 42.9% (18/42) and disease control rate (DCR) was 83.3% (35/42). 2) On day 1 and 456 after oral APA-M from different patients, median trough concentration (Ctrough median) was 264.38 ng/ml (1.18 ng/ml-918 ng/ml), and median peak concentration (Cpeak median) was 543.61 ng/ml (71.11 ng/ml-1609.4 ng/ml), respectively. 3) The Ctrough median in patients with CR, PR and SD (tumor shrinks) was significantly higher than that SD (tumor enlargement) and PD ( P＜0.05). There was significantly difference between CR and PR with SD (tumor shrinks) ( P＜0.05). But there was no significantly difference between CR and PR ( P＞0.05). (Table) 4) The Cpeak median in patients with CR, PR, SD (tumor enlargement) and PD was significantly higher than that SD (tumor shrinks) ( P＜0.05). But there was no significantly difference between CR and PR with SD (tumor enlargement) ( P＞0.05). (Table). Conclusions: The plasma Ctrough of Apatinib can predict the clinical efficacy of patients with solid tumor. Perspective clinical studies with adequate sample size are required to validate our results. [Table: see text]