bluuebunny/crossref_metadata_2025_split huggingface dataset:
Racial differences in development of immune-related adverse events.
Authors: Bhandari Shruti , Kumar Rohit , Nice Laura , Cheema Anmol , Kloecker Goetz H. 
Published: May 2020

e15148 Background: Immune-related adverse events (irAEs) due to immune checkpoint inhibitors (ICIs) are caused by non-specific immune system activation and develop in 30-70% of patients. The goal of this study is to examine the association of race with the development of irAEs secondary to ICIs as autoimmune diseases generally exhibit racial differences. Methods: A retrospective chart review was done using University of Louisville pharmacy database. Patients with solid cancers who received ICIs between Jan 2016 to June 2019 were included. IrAEs were identified through the review of electronic medical records. Descriptive analysis evaluated the incidence and severity of irAEs. Multivariable logistic regression was used to calculate standardized incidence of irAEs among Whites and African Americans. Results: A total of 476 patients were included in this study. The mean age was 61 years, 57% were males and 89.7% were whites. A majority of patients had melanoma (50%). The remainder of the dataset included lung (33.4%), gastrointestinal (7.4%), head & neck (4.8%), breast (2.5%) and genitourinary (1.9%) cancers. ICIs included single agent anti-PD-1 (74.8%), single agent anti-PD-L1 (9.4%), combination anti-CTLA-4 with anti-PD-1 (7.1%). Some patients were also treated with > 1 ICI as subsequent therapy (8.6%). Overall, the rate of irAEs was 44.3% with 33.8% grade 1-2 and 12.4% grade 3-4 irAEs. There was no difference in development of any grade irAEs in Whites as compared to African Americans after adjusting for age, sex, cancer type and ICIs (44.3% vs 44.2%; OR: 0.99, 95% CI: 0.50 – 1.97; p = 0.99). There was also no difference in development of grade 3-4 irAEs in whites as compared to African Americans (12.8% vs 14.5%; OR: 1.16, 95% CI: 0.43 – 3.12; p = 0.75). Conclusions: In this study, we found no racial difference in the development of irAEs between Whites and African Americans. This is in contrast to general autoimmune diseases which exhibit racial differences with higher prevalence among African Americans compared to Whites. We will continue to accrue patients to this study as larger sample size is needed to confirm these findings.
Personalized multimodality therapy (ICT) with immune checkpoint inhibitors (ICI), chemotherapy (CT), and targeted treatment (TT), in advanced/refractory cancer.
Authors: Salem Philip A. , Jabboury Khaled W. , Wheeler Thomas M. , Stenoien Randall 
Published: May 2020

e15150 Background: Therapy for advanced/refractory malignancies is associated with poor prognosis. The combination of ICI and CT has been shown in lung and several other cancers to be superior to CT alone. Since ICI, CT, and TT have a convergent efficacy with divergent toxicity, the combination was evaluated in the treatment of these diseases. Initial evaluation was reported in JCO. 2019 37.15 suppl. e14254. Methods: Treatment was highly personalized and based on diagnosis, prior therapy, and eligibility for TT. Genomic profiling was done to determine TT. ICI included pembrolizumab in 14, nivolumab in 8, and atezolizumab in 2. Chemotherapy was given in 28-day cycles. 23 received multiple agents. 17 received platinum, 11 taxanes. TT included erlotinib in 6, bevacizumab in 6, cetuximab in 2, everolimus 2, and 8 received others. From 04/2016 to 12/2019, 24 patients, median (M) age 62 (27-78) received ICT; 15 females, 9 males. Tumor type: lung 9, pancreas 4, colon 2, glioblastoma multiforme 2, melanoma 2, stomach 1, cervix 1, cholangiocarcinoma 1, thymoma 1, Hodgkin's lymphoma 1. 18 patients had prior therapy, M2 (1-11), of them 6 had ICI and 5 TT. Response evaluation was based on PET scan. Tumor regression occurred after the first cycle. Results: All patients responded. 12 (50%) achieved CR, M14 months (3-32+); 11 (45.8%) had PR, M5+ months (1+ - 20+); and 1 minor response 1+ month. CR + PR was 95.8%. All 3 patients with lung cancer and metastases to brain, achieved CR in brain. Of 3 patients with advanced gastrointestinal cancer, 2 achieved CR and 1 achieved more than 95% reduction in disease. Tolerance was reasonable. No unexpected side effects were noted. Adverse events were primarily hematologic and febrile events/infection. Conclusions: Personalized ICT combination in advanced/refractory and diverse cancer diagnoses is associated with more than 95% response rate. In particular, it was effective in primary and metastatic CNS disease.
Characterizing toxicities, body composition, and health-related quality of life (HRQoL) among long-term survivors treated with anti-PD-1.
Authors: Patrinely James Randall , Young Arissa Caroline , Quach Henry , Williams Grant Richard , Ye Fei , Fan Run , Horn Leora , Beckermann Kathryn Eby , Gillaspie Erin Alexis , Sosman Jeffrey Alan , Friedman Debra L. , Moslehi Javid J , Johnson Douglas Buckner 
Published: May 2020

e15158 Background: Anti-PD-1 agents produce durable responses in many cancers. However, the long-term impact of PD-1 blockade in terms of chronic toxicities, medical comorbidities, and HRQoL are not well-defined. Methods: We assessed 217 patients (pts) who received anti-PD-1 for melanoma, renal cell carcinoma or non-small cell lung carcinoma, with survival of > 2 years after treatment. Pt and tumor characteristics, immune related adverse events (irAEs), cardiometabolic parameters, body composition measurements (BCM), and HRQoL outcomes were tracked. Results: Median overall survival (OS) was not reached; 33 (15.2%) died during follow-up primarily from progressive cancer (n = 28). Acute irAEs developed during treatment in 65% of pts, 45.2% were grade 1/2, 35.5% required steroids, and most commonly presented with dermatitis (18.4%), thyroiditis (12.9%), or arthritis (9.7%). At last follow up, most pts were ECOG 0 (38%) or 1 (41%). There was no difference in blood pressure, glucose, or weight from baseline to 2 years after treatment initiation. BCM showed increased adiposity (140.1 vs. 144 cm2/m2, p = 0.05), skeletal muscle mass (47.05 vs. 47.72 cm2/m2, p = 0.03), and skeletal muscle gauge (1653.9 vs. 1671 AU, p = 0.04). The most common chronic irAEs at last follow-up included hypothyroidism (10.6%), arthritis (3.2%), adrenal insufficiency (3.2%), neuropathy (2.8%), pneumonitis (1.8%), and type 1 diabetes (0.8%). No pts died from chronic irAEs although one pt had fatal CNS radiation necrosis (with unknown contribution of ICI). Chronic irAEs were more common in pts treated with ipilimumab/nivolumab (49%) vs. those with monotherapy (26%). New comorbidities included type 2 diabetes (6.5%) and hypertension (6.0%). HRQoL at 2 years compared favorably to cancer and general populations, although younger age (p < 0.01) and need for subsequent therapy (p = 0.03) were associated with worse HRQoL using Functional Assessment of Cancer-General questionnaire (FACT-G). Acute irAEs were associated with worse National Comprehensive Cancer Network distress scores (p = 0.019). Conclusions: Durable responses to anti-PD-1 therapy and favorable HRQoL outcomes are encouraging in this long-term survivor population. Chronic irAEs may be more common than previously thought although no clear chronic adverse cardiometabolic effects were observed.
Predicting overall survival (OS) and overall response (OR) following durvalumab treatment in patients with multiple cancer types using a hybrid modeling strategy.
Authors: Chen Ting , Zheng Yanan , Roskos Lorin , Mager Donald E 
Published: May 2020

e15161 Background: This study aimed to predict OS/OR and identify key predictors in patients with diverse cancer types treated with durvalumab, a PD-L1 targeting monoclonal antibody, using a hybrid modeling strategy that combines population pharmacodynamic (PD) modeling and machine learning (ML) algorithms. Methods: Individual longitudinal tumor size measurements and OS/OR data were available for 855 patients who received durvalumab therapy (10 mg/kg Q2W or 20 mg/kg Q4W; NCT01693562). Nine cancer types included non-small cell lung cancer (NSCLC), bladder cancer (BC), microsatellite instability-high (MSI-H) cancer, hepatocellular carcinoma (HCC), squamous cell carcinoma of the head and neck (SCCHN), gastroesophageal cancer (GEC), ovarian cancer (OC), pancreatic adenocarcinoma (PDAC) and triple-negative breast cancer (TNBC). A tumor kinetic model was developed to characterize diverse temporal profiles using a population-based modeling approach. Individual estimated tumor kinetic model parameters and patient demographic/physiological factors were used as inputs for predicting OS/OR using several ML approaches. Results: The final tumor kinetic model with liver metastasis (LM), neutrophil/lymphocyte ratio (NLR), tumor size at baseline (TBSL) and cancer types as covariates characterized the temporal tumor size data well. HCC and MSI-H cancer have the slowest tumor growth rate constant (kg), while GEC, SCCHN and TNBC have the fastest kg. BC, NSCLC and OC have the highest tumor killing rate constant. The most important predictors of OS identified by ML approach were tumor kinetic parameters (kg, fraction of drug-sensitive cells, time-delay in immune response), along with baseline disease factors, including hemoglobin (HGBBL), albumin (ALB), and NLR. Decision tree-based algorithms showed the best performance in predicting OR with accuracy above 90%. In addition to tumor kinetic parameters, PD-L1 expression on tumor cells (TC) and ALB were the most important predictors of OR. Conclusions: A combined population PD/ML approach showed good predictions of OS/OR in patients with different cancer types treated with durvalumab. LM, NLR,TBSL and cancer types were found to be important factors for tumor kinetics. In addition to tumor kinetic parameters, HGBBL, ALB, and NLR were found to be important predictors of OS, and TC and ALB were found to be important predictors of OR. These findings could provide a guidance on patient selection in future clinical trials.
Nivolumab versus the standard of care for cancer therapy: A meta-analysis of 6 CHECKMATE trials comparing overall survival.
Authors: Al-Obaidi Ammar , Parker Nathaniel , Truong Quoc Van 
Published: May 2020

e15165 Background: Nivolumab (N) is an antineoplastic agent approved for multiple different tumor origins as well as tumor agnostic based on MSI status. Thus, understanding the tumor characteristics most predictive of response is essential. Living meta-analysis provides a method to continuously assimilate emerging trials. In this study, we created a living meta-analysis to compare the effect of N on overall survival (OS). Methods: Meta-analysis was conducted according to the PRISMA guidelines. PubMed and Cochrane databases, and conference abstracts (e.g. ASCO, ESMO), were searched for phase III CHECKMATE RCT’s that reported OS among cancer patients receiving N. Results: Six phase III trials involving 3,342 patients (1,826 in N arms) treated for 4 different types of cancer were retrieved. Median follow up was 12.1 months [range: 5.1-25.2]. Improved efficacy and safety were observed in all N arms compared to control groups (22.8% ORR; 17.4% grade 3-5 AE vs 15.1% ORR; 51% grade 4-5 AE). Treatment was N alone, SOC chemo, and N + chemo in four (33%), six (50%), and two (16%) arms, respectively. Primary endpoints were OS in the first-line setting in 50% of all arms. Excluding one RCT due to insufficient survival data, the mean median OS was 11.1 [95% CI: 7.5-14.4] vs 8.7 [95% CI: 5.1-13.2] months in the total populations for all N and control arms, respectively. N improved OS when used in any cancer type, setting, or therapy for advanced refractory or chemo-naive cancer patients. Also, efficacy of N was improved with PD-L1% (Table). Conclusions: Among all trials, N was associated with improved OS. Additional meta-analysis is ongoing with R software (version 3.3.3; R Fdn.). Random-effects models will be used to compare OS. Heterogeneity will be assessed with Cochrane Q-statistic and quantified with I2test via subgroup analyses for cancer type, setting, therapy, and PD-L1%. [Table: see text]
Distribution of PD-L1 expression level across major tumor types.
Authors: Xu Shun , Tian Minqi , Zhang Xing , Qi Chuang , Song Chao 
Published: May 2020

e15176 Background: Programmed death-ligand (PD-L1) expression is an efficacy predictive biomarker in cancer immunotherapy. PD-1/PD-L1 axis can restore the host immunity against malignancies causing durable tumor remissions, and thus the level of PD-L1 protein expression is of critical clinical significance. However, the knowledge of PD-L1 expression level of patients with different malignancies is still inadequate understanding. Methods: Based on the percentage of positive tumor cells (TC value) identified by immunohistochemistry (IHC) method, the protein expression of PD-L1 was divided into three groups as g1 (TC < 1%), g2 (1% ≤ TC < 50%) and g3 (TC ≥ 50%). The expressions of PD-L1 from 1772 patients with malignancies across eight types including 133 patients with liver cancer, 35 patients with bile duct cancer, 94 patients with gastric cancer, 146 patients with colorectal cancer, 48 patients with pancreatic cancer, 76 patients with melanoma cancer, 33 patients with glioma and 1207 patients with lung cancer cases were made. The relationships between cancer types and PD-L1 expression were calculated via χ2 test using SPSS v22.0. Results: The ratios of PD-L1 expression in three groups (g1, g2 and g3, respectively) across eight cancer types were 67.7, 30.8 and 1.5% in liver cancer, 65.7, 28.6 and 5.7% in bile duct cancer, 77.7, 20.2 and 2.1% in gastric cancer, 81.5, 18.5 and 0% in colorectal cancer, 64.6, 31.2 and 4.2% in pancreatic cancer, 50.5, 35.7 and 13.8% in melanoma, 30.3, 63.1 and 6.6% in glioma and 55.9, 34.0, 10.1% in lung cancer, respectively. Significant correlation between the PD-L1 expression and cancer types were found (χ2 = 140.543, Cramer’s V coefficient = 0.199, p = 5.53×10−23). The expression of PD-L1 in patients with lung cancer tended to be distributed in g3, in patients with melanoma tended to be distributed in g2, and in patients with gastric cancer, glioma, and colorectal cancer tended to be distributed in g1. Conclusions: Our study suggested the protein expression of PD-L1 was significantly heterogeneous among various cancer types and offered new references for cancer-specific characters of PD-L1 expression. As a retrospective study with a relatively small population, the conclusions of this study needed to be verified with a larger sample.
The potential target of double negative T cells in cancer immunotherapy.
Authors: Okamura Kazumi , Nagayama Satoshi , Tate Tomohiro , Kiyotani Kazuma , Nakamura Yusuke 
Published: May 2020

e15180 Background: Double negative T cell (DNT) is defined by the expression of CD3 (or TCRαβ) with the absence of CD4, CD8 and iNKT cell markers. DNTs account for 1-3% of the total peripheral lymphocytes. Although healthy donor cells derived allogeneic DNTs were reported to have anti-tumor effects in several cancer models, the function of DNTs in tumor microenvironment is not well understood. In this study, we aim to characterize DNTs in cancer tissues and lymph nodes of colorectal cancer patients including their immunological functions. Methods: A total of 14 colorectal cancer tissues and regional lymph nodes were collected and examined for the proportion and the immunological functions of DNTs by FACS analysis. Results: DNTs, which were defined in this study as TCRαβ positive with CD4-, CD8- and CD56- T cells, were detected in colorectal cancer tissues. DNT cells account for more than 5% of TCRαβ-positive populations in 12 cases and out of which 7 cases were more than 20% observed in this study. In all of these 7 cases, DNT cells were also found to be higher in the tumor tissues than in non-metastatic lymph nodes. In addition to colorectal cancer, DNTs were found to be more than 5% of TCRαβ-positive populations in cancer tissues in 3 out of the 6 cases of ovarian and uterine cancer cases.To further evaluate the potential immunological functions of DNTs, expression of cell membrane protein markers were evaluated. CD3ε expression was down regulated in almost all of the DNTs. The CD107a expression of DNTs were higher than that of CD8+ T cells in tumor tissues. When co-culturing DNTs with tumor cells, CD107a expression of DNTs was significantly upregulated. Notably, the intracellular production of perforin and granzyme B were lower than CD8+ T cells. Fas-L expression were found to be higher on DNT cells compared to other T cell populations, suggesting DNT might possess cytotoxic activity in the tumor microenvironment. It is known that upregulation of Fas expression is caused by T cell activation and subsequently induces T cell apoptosis. The upregulation of Fas expression was also observed in DNT cells from non-metastatic lymph nodes. In contrast, Fas expression of DNT cells in tumor tissues was observed to be lower than CD4+ or CD8+ T cells, suggesting that DNT could escape from apoptosis. This downregulation of Fas expression was speculated to be one of the reasons for the accumulation of DNTs in tumor tissues. Conclusions: Although the function of DNTs was still not well elucidated, the accumulation of DNT cells in tumor microenvironment suggests DNTs could be a potential target for cancer immunotherapy.
Effect of idronoxil combined with cisplatin on refractory immune responses in nasopharyngeal carcinoma.
Authors: Kam Ngar-Woon , Lee Victor Ho-Fun , Hung Tae Yang Desmond , Yim Man Kim , Tsao George , Laczka Olivier , Delebecque Frederic , Wilkinson John , Kwong Dora LW 
Published: May 2020

e15186 Background: Nasopharyngeal carcinoma (NPC) is endemic in Southern China. Although it is both radio-and chemo-sensitive, resistance to these treatments remains a major problem for successful management of NPC. The main characteristic of a cancer cell is its resistance to undergo apoptosis; therefore, reversing this resistance may represent the best approach for the treatment of cancer. Additionally, NPC is well-known to be heavily infiltrated by lymphocytes and constitute a unique but poorly defined tumor microenvironment (TME). We aimed at delineating and defining the contribution of idronoxil (IDX) in restoring sensitivity to apoptosis and potentially modulating the immune microenvironment of NPC. Methods: The IC50 of cisplatin (Cis) and IDX from 2D and 3D spheroid cultures of four NPC cancer cell lines (C666, C17, and the paired NPC43 EBV-positive and EBV-negative cell lines) were evaluated. The migration and proliferation of cells treated with IDX and/or Cis were investigated by Transwell and XTT, respectively. Cell phenotype and migratory analyses were measured by flow cytometry on Cis/IDX-pretreated NPC cell lines cocultured with HLA-matched PBMC. Results: IDX and Cis inhibited NPC migration and cell proliferation (IC50 for IDX in 2D and 3D was 2µM; IC50 for Cis in 2D and 3D: was 0.6µM and 1.4µM, respectively). A dose-dependent induction of apoptosis in NPC cell lines by IDX was observed [early apoptotic cells (Annexin V+/PI- at 1µM); late apoptotic cells (Annexin V+/PI+ at 2µM), and necrotic cells (Annexin V-/PI+, at 4µM) were distinguished]. Intriguingly, IDX increased the migratory potential of PBMC towards tumor cells in both 2D and 3D spheroid cultures. Finally, IDX, but not Cis, facilitated the migration of CD8+ T cells toward tumor cells by 3.5-fold (p < 0.05) as well as promoted the expansion of proliferative CD8+ T cells (increased by ~2.8-fold) with degranulation activities (~1.3-fold and 3-fold increase in surface CD107a and intracellular granzyme B expression, respectively) in the cocultures. Conclusions: IDX was shown to induce apoptosis in NPC cells while inhibiting their migration and proliferation. Moreover, the ability of IDX to modulate T cell populations indicates the drug’s potential to enhance the efficacy of current chemotherapy treatments in NPC by upregulating cellular trafficking to the cancer cell.
Immunological functional study by use of the chemotherapy drug plus immunologic hapten like penicillin on the fibrosis of local tumor inflammatory reaction and the immunity of tumor-bearing mice.
Authors: Li Bian , Chen Dong , Han Yan , Zhang Jian , Zheng Guoqin , Wu Yanfei , Fu Qiang , Yu Baofa ,   Shandong Baofa Cancer Therapeutics, Inc.
Published: May 2020

e15196 Background: Observe the antitumor effect of intratumoral injection of chemotherapy drugs or combined with immune adjuvant on Balb/c and c57 tumor bearing mice and the local inflammatory response, fibrosis and immune effect of tumor. Methods: H22 ascites tumor was inoculated in the armpit of BABL / c mice left forelimb to establish subcutaneous solid tumor model of liver cancer, B16 melanoma tumor filtrate was inoculated in the armpit of C57 mice left forelimb to establish subcutaneous solid tumor model of melanoma. The mice were randomly divided into DNP control group, penicillin control group, I group, II group, III group, IV group, V group, VI group, DOX control group, PYM control group, BLM control group and control group when the longest tumor diameter was about 5-8mm. On the first day of the experiment, the mice in each group were injected with corresponding of different group drugs. Three mice in each group were killed on day 1, day 4 and day 7 respectively and then the tumors were taken The C57 mice were used for immunohistochemistry BABL/c mice to detect the content changes of various fibroproliferative, inflammatory and immune related factors. Results: I group: The expression of COL1A1, CD4, IL12A, TGFB1, elastin, NFkB, COX 2, CD11c, CD8 and TNFa in group I was higher than that in other factors at day 1. After 4 and 7 days of administration, all factors decreased significantly; The results of C57 Mouse immunohistochemistry showed that the expression of CD4, cd11bc, Foxp3 in tumor tissue of group V was significantly increased on the first day after administration, and the expression of CD4, CD8, CD86, CD11bc in tumor tissue of group V was significantly increased on the seventh day. Conclusions: The results of immunohistochemistry and PCR showed that the content of fibroproliferative, inflammatory and immune factors in tumor tissue changed significantly after administration og intratumoral injection of combination drugs and penicillin with H2O2. All the above results has showed that chemotherapy drug and hapten was released in the tumor through H2O2 and induced the inflammatory reaction inside tumor (including various fiber proliferation and tumor growth inhibition) as well as the systemic immune response, this also is called abscopal effect.