bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preliminary safety and pharmacodynamic (PD) activity of XmAb20717, a PD-1 x CTLA-4 bispecific antibody, in a phase I dose escalation study of patients with selected advanced solid tumors.
Authors: Hickingbottom Barbara , Clynes Raphael , Desjarlais John , Li Caiyan , Ding Ying 
Published: May 2020

e15001 Background: Interim safety and PD data from an ongoing first-in-human, multi-center, open-label dose escalation study of XmAb20717 (XmAb20717-01; NCT03517488) are reported here. The primary objectives were to determine safety, tolerability, and the MTD and/or recommended doses (RDs). Secondary objectives included preliminary anti-tumor activity and PK/PD. Methods: A 3+3 dose escalation design was used to establish an MTD/RD(s) for infusions on Days 1 and 15 of each 28-day cycle. DLT evaluation was based on Cycle 1 through Day 28. Patients with selected solid tumors (in indications both with and without approved checkpoint therapy) who have exhausted standard of care are eligible. Results: As of 05FEB 2020, 34 patients were treated in cohorts 1-6 at fixed doses of 0.15 to 10 mg/kg. Patients had a median age of 57 years (range 32-81), a median time since initial diagnosis of 42 months (range 3 -313), and a median of 4 prior systemic therapies (range 0-9). 68% of patients had a TNM stage of III/IV, and 68% had been exposed to checkpoint therapy. XmAb20717 treatment was generally well tolerated through the highest dose cohort tested. Overall rates of Gr3/4 immune-related AEs occurred in 8 (24%) patients including elevations of transaminases 3 (9%), rash 2 (6%), lipase and amylase 1 (3%, without clinical symptoms or radiographic evidence of pancreatitis), lipase (alone) 1 (3%), pruritus 1 (3%), hyperglycaemia 1 (3%), arthritis 1 (3%) and colitis 1 (3%), all reversible. Responses were evaluated based on RECIST 1.1 criteria, and there was 1 CR reported (melanoma, progressed on prior pembrolizumab) at 10 mg/kg (highest dose level). Dose-dependent pharmacodynamic activity consistent with dual PD-1/CTLA-4 blockade was noted, namely a proliferative burst of both CD8 and CD4 T cells and induction of IFN-inducible chemokines (Table). Conclusions: XmAb20717 is generally safe and has demonstrated PD activity in heavily pretreated patients with selected advanced solid tumors. Dose escalation continues. Clinical trial information: NCT03517488 . [Table: see text]
A novel CSF-1R neutralizing antibody, DCB-AB21, as a potential therapeutics for tumors.
Authors: HO Chen-Hsuan , Liao Chu-Bin , Kai Yu , Yang Tze-Ping , Lai Sze-Liang , Chien Yin-Chieh 
Published: May 2020

e15006 Background: Tumor-associated macrophages (TAMs) represent the major cell components of immune infiltrate in solid tumors, and it has been reported that high TAMs density is associated with poor clinical prognosis. Within the tumor microenvironment, TAMs rely on signaling through colony stimulating factor 1 receptor (CSF-1R)/CSF-1 axis for various tumor promoting processes such as tumor growth, drug resistance, angiogenesis, and metastasis. Therefore, decrease of TAMs density in tumors through CSF-1R inhibition is considered an attractive therapeutic target for drug development. Methods: DCB-AB21 was screened from immunized mouse hybridoma clones. ELISA-based and flow cytometry-based affinity screening is performed and then the growth inhibition test by cell-based CSF-1-dependent cell line were further used as antibody screening assay. Results: A novel anti-CSF-1R monoclonal antibody DCB-AB21 which specifically binds to CSF-1R and inhibits CSF-1R downstream signaling. Our results showed DCB-AB21 can block the CSF-1 and IL-34-induced cell proliferation. Potent inhibition of CSF-1R-dependent signaling was observed in the Ba/F3 CSF-1R driven model cells, and in human THP-1 leukemia monocytic cell lines. Humanization engineering further improves this antibody’s affinity and anti-proliferative efficacy. The discovery of novel binding epitope of DCB-AB21 differentiates itself from the current CSF-1R targeting antibodies testing in clinical trials. In vivo efficacy of DCB-AB21 showed AB21 alone has moderate anti-cancer activity and it further potentiate anti-PD-1’s efficacy. Conclusions: These data demonstrate that DCB-AB21 can potently inhibit CSF-1R in cellular contexts and in vivo model, and has the potential to induce a phenotypic effect on macrophages. These data suggest that DCB-AB21 is a promising new agent with possibility to combine with immune checkpoint inhibitors to relief macrophage-dependent immune suppression and would yield clinical benefit.
Profiling antigen specificity concurrently with protein and mRNA quantification using high throughput single-cell multiomics reveal surprising similarities between bystander and tumor specific CD8+ tumor-infiltrating lymphocytes (TILs) in renal cell carcinoma (RCC).
Authors: Tyznik Aaron , Simoni Yannick , Li Shamin , Zhuang Summer , Newell Evan 
Published: May 2020

e15014 Background: Recently, using human colorectal and lung cancer, we showed that CD8+ T cells infiltrating tumor tissue (TILs) are not only specific for tumor antigens, but are also composed of CD8+ TILs specific for cancer unrelated epitopes – called bystander – such as HCMV, EBV or flu epitopes. We also showed that the surface marker CD39 can be useful for discriminating bystander (CD39−) from tumor-specific (CD39+) CD8+ TILs (Simoni et al, Nature, 2018). Methods: Here, our aim was to test these findings in human Renal cell Carcinoma (RCC) and to better understand the biology of these bystander CD8+ TILs. Results: Surprisingly, our primary CYTOF analyses showed heterogeneity within bystander CD8 TILs that possess various phenotypes including effector (CD45RO+), memory (CD45RO+ CCR7+), Trm (CD69+ CD103+/–), and senescent (CD57+ KLRG1+) cell features. Using targeted mRNA single-cell sequencing combined with BD AbSeq assay, we analyzed sorted CD8+ TILs from RCC patients and identified bystander CD8+ TILs using oligo-tagged tetramers. Gene signature analysis of these different subsets revealed transcriptomic similarities with the tumor-specific CD8+ TILs. Conclusions: Our data provide a comprehensive perspective of cancer unrelated CD8+ TILs in RCC and suggest functional roles for these cells in tumor immune responses, which could lead to new diagnostic and therapeutic strategies.
Analysis of the efficacy of CIK therapy in adjuvant treatment of colorectal cancer.
Authors: Guo Rui , Piao Haiyan , Shi Gang , Zhang Guirong , Zhang Rui 
Published: May 2020

e15022 Background: In the past decade, cell-based immunotherapy has been reported to improve the clinical outcomes by altering tumor immune responses, improving prognosis and overall survival rates in cancer patients.This retrospective study aimed to evaluate the efficacy of cytokine-induced killer (CIK) cell infusion as an adjuvant therapy in patients with colorectal cancer. Methods: A total of 370 patients with colorectal cancer admitted to Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Insititute from March 2013 to April 2015 were retrospectively analyzed.All patients were treated with surgery for primary lesions, and then adjuvant chemotherapy was determined according to the guidelines. Among these patients, 201 patients received CIK therapy (CIK group),while the other 169 patients who had similar demographic and clinical characteristics did not receive a CIK cell infusion therapy (non-CIK group). Then we followed up these patients. Data were analyzed by Kaplan-Meier. Results: Our results showed that the 1,3,5-year overall survival (OS) rate for the CIK group versus the non-CIK group was 98.46 versus 93.61%, 85.4 versus 71.61%, 79.39 versus 67.9%, respectively. The OS was significantly longer in CIK group than in non-CIK group (P = 0.009). Meanwell, the OS of stage II and III colorectal cancer was significant in CIK group than in non-CIK group (P = 0.02 and 0.02). But the OS was not significant in Stage I and IV colorectal cancer (P = 0.347 and 0.285). We analyzed the patients between chemotherapy plus CIK therapy group and chemotherapy only group. We find that the OS has significant difference in two groups (P < 0.001). Conclusions: CIK therapy can improve the efficacy of adjuvant therapy in patients with colorectal cancer. But multicenter, large-sample randomized controlled trials are still needed to confirm it.
CoupledCAR technology for treating thyroid cancer.
Authors: Xiao Lei , Liu Xingchen , Zhou Keshu , Liu Yu , Huang Yong , Pu Chengfei , Cao Zhiyuan , Lu Cheng , Hang Yang , Huang Xi , Shen Xiaogang , Song Yongping , Liu Renbin , Wu Zhao 
Published: May 2020

e15027 Background: Significant challenges restrict CAR-T cell therapy to treat solid tumors. Methods: Here, we generated CAR-T cells using a novel CoupledCAR technology. Specifically, we engineered CoupledCAR T cells with lentiviral vectors encoding an anti-thyroid stimulating hormone receptor (TSHR) CAR molecule, and anti-TSHR CAR-T cells showed anti-tumor activities in vitro and in vivo experiments. Further, we treated refractory/relapsed post-thyroidectomy thyroid cancer patients using anti-TSHR CoupledCAR T cells, and observed the rapid expansion of CAR-T cells and the enhanced killing of tumor cells. Results: Both patients achieved PR (Partial Response). Patient Profile: Patient 1 Male, 64Y, Papillary Thyroid Carcinoma. In May 2017, thyroid cancer was diagnosed, bilateral total thyroidectomy, and right cervical lymph node functional dissection were performed in June, followed by iodine 131 isotope therapy. In December 2018, bilateral multiple cervical lymph nodes were enlarged. In February 2019, right neck lymphadenectomy was performed. Patient 2 Female, 60Y, Thyroid Carcinoma. In Aug 2013, a "double lobectomy of the thyroid gland” was performed. From Oct 2013 to Jan 2014, she received iodine 131 isotope therapy. In Sep 2014, she was diagnosed with iodine-resistant thyroid cancer. In 2016, 5 cycles of chemotherapy were performed. In Mar 2019, multiple metastases in both lungs and multiple enlarged lymph nodes were observed. Observations and Results: Patient 1: One month after infusion (M1), the patient was evaluated as PR: lymph node metastasis became undetectable and the size of the thoracic paratracheal tumor nodules decreased significantly. Three months after infusion (M3), the patient was evaluated as having a durable response, and the tumor tissue was substantially smaller than M1. Patient 2: M1, the patient was evaluated as PR (Partial Response): the tumor volume in the right lower lobe of the lung was reduced by approximately 67.51% (decreased from 65*55mm to 42*39mm). Three months after infusion (M3), compared with that before, the tumor volume was reduced by approximately 73.54% and SUV max value decreased from 14.9 to 2.8, therefore, the patient was evaluated as nCR (near complete remission). Conclusions: We show that TSHR is a good target for treating thyroid cancer, and our anti-TSHR CoupledCAR T cells are safe and effective for treating thyroid cancer. Recruitment is ongoing to evaluate the safety and efficacy of our CoupledCAR T cells. Further, since our CoupledCAR technology is a platform technology, we are developing it to treat other solid tumors using different target markers.
Predictive value of circulating B cells and T cell subsets in melanoma patients treated with neoadjuvant ipilimumab and interferon.
Authors: Khunger Arjun , Sarikonda Ghanashyam , Tsau Jenn , Alfonso Zeni , Gao Jane , Pahuja Anil , Laing Christian , Kim Ju Young , Bordeaux Jennifer , Vaupel Christine , Dakappagari Naveen , Tangri Shabnam , Tarhini Ahmad A. 
Published: May 2020

e15036 Background: Patients with locally/regionally advanced melanoma were treated on a clinical trial with a neoadjuvant combination of ipilimumab (ipi) and high dose IFNα2b (HDI) (Tarhini et al, JITC 2018). In this study, immune cell composition in peripheral blood samples collected at various time points was measured to determine any correlation with clinical outcomes and investigate the immune modulating effect of the combination therapy. Methods: Patients were randomized to neoadjuvant ipi at 3 mg/kg or 10 mg/kg, both given in combination with HDI. Tumor radiologic responses were designated as complete (CR), partial (PR), stable disease (SD) or disease progression (PD). Pathologic complete response (pCR) was defined as absence of viable tumor on histologic assessment. Peripheral blood mononuclear cells (PBMC) from treated patients (N = 28) were tested at baseline (before initiating ipi-HDI), then at 6-weeks, 3-months and 12-months (following neoadjuvant ipi-HDI). High complexity (14-color) flow cytometry analysis was performed to detect key immunological biomarkers including myeloid derived suppressor cells (MDSCs), B cells, regulatory T cells (Tregs), PD-1 and TIM3 expression on T-cells, and differentiation of T-cells into Th1, Th2 or Th17 phenotype at different time points during systemic immunotherapy. Statistical significance was determined using R-package employing Kruskal’s test. Results: Lower levels of peripheral Tregs (p = 0.02), MDSCs (p = 0.05), and CD4 effector memory cells (p = 0.04) at 3-months post treatment correlated with radiologic response. In addition, lower change from baseline at 3 months in CD4/CD8 ratio (p = 0.04), levels of Tregs (p = 0.01) and CD4 effector memory cells (p = 0.02) was associated with radiologic response. Patients exhibiting pCR had significantly lower Tregs (p = 0.04) at 6-months post treatment and significantly higher CD8 central memory cells at both 3 months (p = 0.04) and 12 month time-points (p = 0.01) as compared to patients without pCR. Finally, patients without pCR had significantly lower change from baseline in CD19 B cells at 6 months (p = 0.01) and 12 months (p = 0.04) as compared to patients with pCR. Conclusions: Our data demonstrates that the levels of immunosuppressive cells including Tregs and MDSCs in periphery are negatively associated with response. Higher levels of CD8 memory cells and B cells on-treatment are associated with clinical benefit.
The validity and predictive value of blood-based biomarkers in prediction of response in the treatment of non-small cell lung cancer: A systematic review.
Authors: IJzerman Maarten J. , van Delft Freek Anne , Koffijberg Hendrik , Retel Valesca P. , van den Heuvel Michel 
Published: May 2020

e15053 Background: With the introduction of targeted therapies and immunotherapy, molecular diagnostics gained a more profound role in the management of non-small cell lung cancer (NSCLC). Currently, tissue biopsies (TB) are used as primary source for molecular testing and generally require an invasive procedure. The introduction of liquid biopsies (LB) not only decreases patient burden, but it also allows for more frequent testing. Which might be of value in the monitoring of treatment response. This study aimed to systematically search for studies reporting on the use of LB, the correlation between LB and TB, and finally the predictive value in the management of NSCLC. Methods: A systematic literature search was performed using Scopus and PubMed, including results published in English after 01-01-2014. Articles were included when 1) describing the predictive value of a LB with regard to overall and/or progression-free survival, or 2) describing the validity of a marker by comparing LBs to TBs regarding sensitivity, specificity, or concordance. Results: 1705 articles were identified in the search, 1323 articles were excluded after title and abstract screening, leaving 382 articles for full-text evaluation. Of the 137 articles included after full-text evaluation, 78 articles described the validity, and 65 articles described the predictive value of LBs. In studies describing the predictive value of LBs, the majority of articles reported on the predictive value of biomarkers in relation to targeted therapies (n = 31). In studies describing the validity of LBs, the majority of studies report on EGFR mutations including, exon 19 deletion (n = 23) and L858R (n = 26). Looking at the validity of LBs, we saw a large variation in reported sensitivity (range 20-100%), specificity (range 30-100%), and concordance (range 40-99%). Conclusions: Although a variety of blood-based biomarkers has been investigated, most studies have limited their evaluation to sensitivity and specificity of liquid biopsies to determine EGFR mutation status compared to tissue and the subsequent targeting of EGFR tyrosine kinase inhibitors based on the mutation status found in LBs of NSCLC patients. The first adoption of LBs in practice is expected to involve the detection of EGFR mutations by LB analysis in addition to TBs.
Application of PD-1/PD-L1 immune checkpoint inhibitors treating lung cancer in Yerevan Armenia: Two-center experience.
Authors: Karapetyan Nune , Zohrabyan Davit , Arakelyan Jemma , Harutyunyan Lilit , Bardakhchyan Samvel , Avagyan Armen , Safaryan Satenik , Harutyunyan Martin , Safaryan Liana 
Published: May 2020

e15058 Background: Over the past few years PD-1/PD-L1 pathway blockade through immune checkpoint inhibitors appeared to be an effective treatment approach in advanced lung cancer. The current study aims to investigate the utilization of immunotherapy for lung cancer management purposes in Armenia. Methods: For this retrospective, hospital-based cohort study census sampling method was approached. Data was collected on all the patients who were diagnosed with stage III and IV lung cancer and passed treatment in the departments of Adult Solid Tumors in Hematology Center after prof. Yeolyan and Institute of Surgery after Mikaelyan from 01.05.2019 till 12.01.2020. The time period was selected based on the initiation of PD-L1 testing in Armenia. The prevalence of non-small cell (NSCLC) and small cell (SCLC) lung cancer was calculated. The patients’ PD-L1 testing performance, subsequent immunotherapy utilization, and developed adverse effects were evaluated. Results: According to the hospital-based data, during the mentioned time period 60 patients diagnosed with stage III and IV lung cancer received treatment in the two units. In the cohort, the patients’ median age was 65,5 years (range 46 – 88). The male-to-female ratio was 5.6. The prevalence of NSCLC and SCLC was 61.7% and 28.3% respectively. At the time of follow-up on 10.02.2020, 74.4% of NSCLC patients and 64.7% of SCLC patients were alive. Of the 43 NSCLC subjects, only 11 were checked for the PD-L1 status. Among them, 7 were determined to be PD-L1 positive and 5 of them received immunotherapy. For SCLC patients PD-L1 status wasn’t checked. Of 17 SCLC patients, only one has received immunotherapy. Overall only one case of immunotherapy related adverse effect was observed (severe rash and pruritus). At the time of follow-up, one of the six patients who underwent immunotherapy was dead. Conclusions: The presented data demonstrate a lack of PD-L1 test performance and underutilization of immunotherapy treatment. In the future, it is recommended to perform a nationwide study on the current topic to assess the immune checkpoint inhibitors impact on the survival rates of advanced lung cancer patients.
Real-world usage and outcomes for patients treated with immune checkpoint inhibitors across multiple treatment indications in the Veterans Affairs system.
Authors: La Jennifer , Cheng David , Do Nhan , Brophy Mary T. , Fillmore Nathanael , Tuck David P. 
Published: May 2020

e15063 Background: Increasingly broad patient groups are being treated with immune checkpoint inhibitors (ICIs) in clinical practice, but few studies have assessed their usage and outcomes in large, comprehensive real-world cohorts. In this study, we identified patients who received ICI therapy through April 2019 in the Veterans Affairs (VA) system. We described patient characteristics and assessed survival outcomes for patients across multiple treatment indications based on the cancer type and line of therapy. Methods: We conducted a retrospective analysis using electronic health record data captured from VA facilities nationwide. Patients treated with ICI were identified based on pharmacy and orders records. The associated cancer type and line of therapy (first line 1L or later line 2L+) was ascertained based on data on patients’ treatment history, administrative codes, and VA cancer registry records. The distribution of time from ICI treatment initiation to death was separately assessed by treatment indication using Kaplan-Meier estimates. Results: We identified 13,276 patients treated with ICI. The mean age was 69 years old. A majority of patients were male (97.2%) and white (76.9%), and a substantial minority were African-American (16.9%). Among patients treated with ICI for an identifiable cancer type, the most common cancer types included non-small lung cancer (NSCLC; 47.2%), melanoma (22.2%), renal cell carcinoma (RCC; 6.7%), squamous cell carcinoma of the head and neck (SCCHN; 10.4%), and urothelial cancer (6.4%). For major treatment indications, VA patients generally exhibited lower rates of survival than those reported in many ICI clinical trials, but the results are more comparable to those in trials among a subgroup of non-frail patients. Conclusions: This study describes ICI utilization and outcomes across multiple tumor types in a real-world population at the VA. The results offer evidence on the utilization and performance of ICIs in a real-world population. In addition, this work establishes a platform for further analyses of ICI outcomes in real-world practice at the VA. [Table: see text]
Changing paradigm in oncology clinical trials: Cox-TEL—Adjustment made ready for early crossover and tail tale.
Authors: Lin Emily Pei-Ying , Hsu Chih-Yuan , Yang Pan-Chyr , Shyr Yu 
Published: May 2020

e15067 Background: Approvals of immune checkpoint inhibitors (ICI) were made based on positive clinical trial results analyzed by the Cox proportional hazards (PH) model. With ICI data, however, long tails and early crossover in survival curves, which violate the Cox PH assumption, can lead to misinterpretation of clinical significance of findings. Here we introduce the Cox-TEL and show the differences of study results before and after Cox-TEL adjustment using KEYNOTE 042 and 045 as examples. Methods: Cox-TEL is built on the mathematical foundation of Taylor expansion. As an easily implemented alternative of PH cure model, it not only infers associations between survival probabilities of the two study arms among patients without long-term survival (poor-responders), but also estimates differences in proportion (DP) between arms among patients in the long-tail segment of the survival curve (true-responders). Results: In KEYNOTE 042, the Cox-TEL HRs for death were statistically insignificant across all subgroups. The trend of DP, on the other hand, is positively related to that of PD-L1 TPS and inverted related to that of Cox HR when the PD-L1 ≥50% cohort is covered. In KEYNOTE 045, the Cox-TEL HRs suggested that for the poor-responders, pembrolizumab did not do better than chemotherapy in terms of overall survival (OS) and might do harm to the patients in terms of progression-free survival (PFS). For the true-responders, DPs of OS and PFS were both statistically significant (Table). Conclusions: Our data demonstrated the biases derived from insufficient data analyses and strengthened the necessity of analytic model revisits in the new oncology era of which cure for advanced cancers is no longer impossible. [Table: see text]