bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase I, pharmacokinetic (PK), and preliminary efficacy assessment of ALD518, a humanized anti-IL-6 antibody, in patients with advanced cancer
Authors: Clarke S. J. , Smith J. T. , Gebbie C. , Sweeney C. , Olszewski N. 
Published: August 2020

3025 Background: ALD518 is a humanized anti-IL-6 antibody being developed for the treatment of cancer cachexia and fatigue. The primary objective of the study was to determine the safety of ALD518. Methods: 9 patients (pts) with advanced cancer, ECOG 0–2, and C-reactive protein (CRP) >10mg/L were enrolled. Pts were assigned to 1 of 3 dose-escalating cohorts (n=3/cohort). ALD518 was given as a single i.v. infusion of 80mg, 160mg, or 320mg. Pts were followed up for 12 weeks. Data included lab safety tests (LSTs), vital signs, ECGs, adverse events, hand grip strength (HGS), FACIT-F, PK and C-reactive protein (CRP). Results: 9 pts were evaluable for dose limiting toxicity (DLT) assessment at week 4 and 5/9 pts completed all visits. Of the 4 pts who failed to complete every visit; 3 were withdrawn due to progressive disease and 1 to be treated with chemotherapy. There were no DLTs or infusion reactions. There were 4 SAEs: 3 disease progressions and 1 sepsis secondary to a blocked biliary stent. There were no grade 3/4 toxicities. Changes in LSTs, CRP, HGS and FACIT-F fatigue subscale (pooled ITT analysis) are shown (Table). Conclusions: ALD518 given to pts with advanced cancer was safe and well tolerated. ALD518 reversed fatigue, increased hemoglobin and albumin, and there was a trend to increased HGS. There was a mild decrease in platelet count that remained stable throughout the study. [Table: see text] [Table: see text]
Biomarkers associated with clinical outcome in advanced non-small cell lung cancer patients treated with TG4010
Authors: Acres B. , Quoix E. , Ramlau R. , Lacoste G. , Marie Bastien B. , Tavernaro A. , Bettinger S. , Bizouarne N. , Limacher J. M. , Bonnefoy J. Y. 
Published: August 2020

3027 Background: TG4010 is a targeted immunotherapy product. It was tested in combination with first-line chemotherapy in a randomized, controlled, multicenter phase II study in patients with advanced non small cell lung cancer (NSCLC) (ASCO 2008- Abstract No 8023) Methods: In addition to clinical endpoints, immune parameters were tested. Blood samples were drawn prior to therapy (day1) as well as at day 43 (after 6 injections of TG4010). Lymphocyte populations were assessed by 5-color flow cytometry. Plasma samples were tested for biochemical markers using multi-analyte profile technology. Results: Out of the 148 patients enrolled in the study, 138 were evaluable for immunological analyses. Baseline characteristics were similar in both arms. Day 1 blood samples show: i) a correlation between lower levels of inflammation-associated plasma proteins and a longer median survival in Arm 1 (TG4010 + chemotherapy) (p< 0.001); ii) an improved clinical outcome with TG4010 in patients having normal levels of lymphocytes with an activated NK phenotype. Day 43 blood samples show: i) an association between higher levels of activated T lymphocytes and longer patient survival in Arm 1 (p < 0.05). No such association was observed in patients in Arm 2 (chemotherapy alone); ii) a longer survival for patients with higher levels of Interferon γ in Arm 1 than in Arm 2 (p=0.0001). Patients in both Arm 1 and Arm 2 showed specific binding of MUC1 tetramers to circulating CD8+ lymphocytes. No significant association between either treatment arm or clinical outcome and MUC1 tetramer binding was detected. Conclusions: These results identify the level of activated NK cells at baseline as a predictive biomarker for selection of patients to be treated with TG4010. Biomarker data including Interferon γ support a Th1 dependent pathway of activity for TG4010. [Table: see text] [Table: see text]
The antitumor effects of CIK cells combined with docetaxel against drug-resistant lung adenocarcinoma cell line SPC-A1/DTX in vitro and in vivo
Authors: Pengying L. , Longbang C. , Xiang H. 
Published: August 2020

3039 Background: Cytokine-induced killer (CIK) cells transfer is now being considered the most promising adoptive cellular therapy strategy. Multidrug resistance (MDR) phenomenon is a major hindrance to the successful chemotherapy of cancer. In this study, the anti-tumor activity of CIK cells combined with docetaxel (DTX) against multidrug resistance SPC-A1/DTX cell line was evaluated in vitro and in vivo. Methods: MTT assay was employed to evaluate the cytotoxic activity of DTX, CIK cells, and DTX plused CIK cells against SPC-A1/DTX cells in vitro. In vivo assay, SPC-A1/DTX cells were injected to nude mice subcutaneously to establish tumor-bearing mice model. On the 14th day, normal saline, docetaxel, CIK cells, and CIK cells combined with docetaxel were administered intraperitoneally respectively. All the nude mice were sacrificed at day 15 after treatment and the tumor were weight out. Results: MTT assay showed that CIK cells possessed a higher antitumor cytotoxic activity against SPC-A1/DTX cells than SPC-A1 cells in vitro (p <0.05). The synergetic anti-tumor activity positively correlated with the E:T ratio and the concertration of docetaxel. The animal data also suggested that CIK cells combined with DTX had a stronger suppressive effect on the tumor growth in vivo. Conclusions: CIK cells plused with docetaxel demonstrated a prominent augmentation of anti-tumor activity against MDR lung adenocarcinoma cell lines both in vitro and in vivo. No significant financial relationships to disclose.
Association of sTNF-R1 and the development of treatment-related symptoms in patients undergoing concurrent chemoradiation therapy for colorectal or esophageal cancer
Authors: Wang X. S. , Williams L. A. , Johnson V. E. , Mao L. , Krishnan S. , Liao Z. , Mobley G. , Cleeland C. S. 
Published: August 2020

3041 Background: Cancer-treatment-induced dysregulation of proinflammatory cytokines may be a common mechanism underlying the development of symptom burden (e.g., pain, fatigue, distress, and disturbed sleep) during concurrent chemoradiation therapy (CXRT). Methods: Patients undergoing CXRT for locally advanced colorectal or esophageal cancer (N=97) reported symptoms weekly via the M. D. Anderson Symptom Inventory (MDASI). Serum samples were tested weekly during therapy for changes in concentration levels of inflammatory cytokines (interleukin [IL]-6, IL-8, IL-10, IL-1 receptor antagonist [IL-1RA], vascular endothelial growth factor [VEGF], and soluble tumor necrosis factor receptor type 1 [sTNF-R1]) via enzyme-linked immunosorbent assay (ELISA). Symptom responses were modeled using longitudinal ordinal probit regression functions that included these serum cytokine values, along with age, cancer type, prechemotherapy status, and race (non-Hispanic white vs. others), as explanatory variables. Results: The severity of multiple symptoms significantly increased at week 4 and peaked around the end of CXRT (weeks 5–7). We found that an increase in the serum level of sTNF-R1 was significantly associated with an increase in the severity of 14 of the 16 MDASI symptoms individually over the course of CXRT, as well as with each of the 6 interference items (all p<.001). Even when week of observation was added as a variable to account for concurrent systematic trends in symptom reports and cytokine levels, sTNF-R1 retained a significant positive association with 14 of 16 symptoms, and IL-6 also showed a significant positive association with 6 of 16 symptoms. Conclusions: Longitudinal analysis identified temporal associations between increases in level of serum sTNF-R1 (and, to a lesser degree, IL-6) and the development of multiple symptoms in patients undergoing CXRT for colorectal and esophageal cancer. The results may be indicative of these cytokines as potential intervention targets of reducing aggressive chemoradiation-induced symptom burden. No significant financial relationships to disclose.
Radiation dose-benefit analysis of hematopoietic stem cell grafting for tolerence induction across MHC barriers in living related donor renal allograft recipients
Authors: Shankar V. , Haritha C. , Trivedi H. L. , Vanikar A. , Modi P. M. , Shah P. , Shah V. 
Published: August 2020

3044 Background: Donor specific immunologic tolerance protects an allograft from chronic rejection and allows discontinuation of chronic immunosuppressive therapy. Ahmedabad-tolerance induction protocol (A-TIP) allows grafting in living related donor (LRD) renal allograft recipients with persistent low-level MLHC. Present study aims to define of the ideal radiation dose needed for tolerance induction in patients undergoing A-TIP. Methods: 210 consecutive end stage renal disease patients recruited between May '05 through Mar '07 underwent renal transplantation (RTx) following A-TIP and negative Lymphocytotoxicity cross match (LCM). A-TIP includes (a) 2 DLI's (b) low intensity conditioning, and (c) HSC grafting.The conditioning regimen included fractionated low dose target specific radiation, cyclosporine, cyclophosphamide, anti T-cell a.b and treosulfan. All patients underwent subtotal lymphoid irradiation (STLI) targeting spleen, abdominal, iliac and inguinal lymph nodes, thoraco-lumbar vertebra and 75% of pelvis. Patients were randomized into 3 groups of 70 each: STLI 600, STLI 800, STLI 1000, corresponding to doses of 600cgy, 800cgy and 1000cgy delivered conventionally using 6MV/15MV photons. Unfractionated HSC procured from donor BM was administered into portal circulation, within 24 hours of achieving CD4+/CD8+ T cell count ≤ 10% of baseline. Donor specific cytotoxic antibodies were eliminated before RTx. Immunosuppression (ISp) was withdrawn 3–6 mo after RTx for patients with consistently positive chimerism. Tolerance - Robust (R), Prope (P) and Metastable (M) is defined as RT: Stable allograft function (fn.) for >100 days without ISp; PT: Early adequate, stable grafts fn. with no rejection episodes on minimum ISp; MT: Adequate graft fn. on ISp with single episode of steroid responsive ac. rejection. Results: See Table. Conclusions: The safe and effective dose for tolerance induction in LRD renal transplantation is 1000 cGy. [Table: see text] No significant financial relationships to disclose.
Population pharmacokinetics (PK) of tremelimumab in patients (pts) with melanoma
Authors: Kang D. , Wang E. , Wang D. , Amantea M. , Hsyu P. 
Published: August 2020

3048 Background: Tremelimumab is a fully human monoclonal antibody targeted against CTLA4, a protein on T cells critical for regulating T-cell activities, which is under development for treatment of various cancers, including melanoma. Population PK analysis was conducted using concentration-time data from 450 pts, most with melanoma or solid tumors, enrolled in four phase I or II studies that evaluated PK, tolerability, and efficacy of single-agent tremelimumab. Methods: Tremelimumab was administered intravenously either as single dose or multiple doses every 4 or 12 weeks; doses varied between 0.01 and 15 mg/kg. PK was determined using nonlinear mixed-effect modeling implemented in NONMEM VI. Baseline characteristics, including body weight, ECOG score, age, sex, serum creatinine, AST, ALT, and bilirubin, and formulation effects were investigated as potential factors affecting PK. Tremelimumab plasma concentrations were determined using a sensitive, specific, validated ELISA assay. Results: A two-compartment linear model adequately described tremelimumab concentration-time data; an additive residual error model was employed on log-transformed data. Initial and terminal half-lives were 2.5 days and 22 days, respectively. Estimated parameter values were: 0.0109 L/hr for CL (clearance), 3.72 L for V1 (central volume of distribution), 0.0172 L/hr for Q (intercompartment clearance), and 3.31 L for V2 (peripheral volume of distribution). Females had 29.6% smaller V2 compared with males. Both CL and central V1 increased with weight. An ECOG score of ≥1 showed 20.2% increase in CL compared with a score of 0. New commercial formulation decreased CL by 18.5%. The model-predicted area under concentration-time curve value in females was 13.3% greater than males (p=0.5). None of the other covariates tested significantly affected PK. Furthermore, tremelimumab was tolerated in most pts at all doses tested. Conclusions: PK of tremelimumab were shown to be affected by weight, baseline ECOG score, and formulation. However, no effects other than weight were considered clinically significant enough to warrant treatment regimen change. Further investigation of PK-response relationships is warranted. [Table: see text]
Relationship between pharmacokinetics and safety of tremelimumab in patients with melanoma
Authors: Wang E. , Kang D. , Wang D. , Bulanhagui C. , Hsyu P. 
Published: August 2020

3049 Background: Tremelimumab is a fully human anti-CTLA4 monoclonal antibody that has antitumor activity in some patients with advanced melanoma. The most common adverse event associated with tremelimumab is diarrhea/colitis. This analysis investigated the relationship between pharmacokinetics (PK) and diarrhea or colitis in 450 patients enrolled in four phase I or II clinical studies. Methods: PK parameters including AUC during the first 90 days (AUC90), Cmax, concentration at day 29 (C29), and AUC of concentration >30 μg/mL (AUCG30) of tremelimumab were determined using nonlinear mixed-effect modeling. Severity and frequency of diarrhea and colitis during the 90 days after the first dose were considered in relation to each individual PK parameter. Frequency of diarrhea was further analyzed by logistic regression analysis. Frequencies of diarrhea and colitis were combined for logistic analysis. Results: The PK/safety analysis included 450 patients (445 with advanced melanoma). In this analysis, the severity of diarrhea and colitis appeared to be independent of PK (AUC90, Cmax, C29, and AUCG30) of tremelimumab. Although frequency of diarrhea was positively related to AUC (AUC or AUCG30), Cmax, and C29, AUC appeared to be best correlated to frequency of diarrhea. Logistic regression analysis of change in AUC on probability of having diarrhea indicated that the frequency of diarrhea increased initially with increasing AUC, but reached a plateau quickly at approximately AUC value of 50,000 μg × hr/mL (20th percentile). Results of the combined diarrhea and colitis analysis were similar to those of diarrhea alone. Conclusions: Severity of diarrhea and colitis is independent of AUC in patients with melanoma treated with tremelimumab. Frequency of diarrhea and colitis initially increases with increasing AUC, but plateaus quickly. [Table: see text]
A prospective observational clinical study involving an alternative cancer treatment, psorinum therapy, in treating stomach, gallbladder, pancreas, and liver cancers
Authors: Chatterjee A. , Bhattacharya S. , Chatterjee A. K. , Biswas J. , Mukhopadhyay B. 
Published: August 2020

3050 Background: The prospective observational clinical study was conducted to know the efficacy of an alternative cancer treatment, ‘psorinum therapy,‘ in treating liver, gall bladder, pancreatic, and stomach cancers. The primary outcome measures of the study were (1) to assess the radiological tumor response; (2) to assess how many participants survived at least 1 year, 2 years, 3 years, 4 years, and finally, 5 years after the beginning of the study. The secondary outcome measure of the study was to assess the side effects of the investigational anti-cancer drug (psorinum) if any. Methods: The drug psorinum (an alcoholic extract of scabies, scrub, slough, and pus cells) was administered orally at 0.01ml-0.02 ml/Kg body weight as a single dose in empty stomach per day and ongoing to all the participants along with allopathic and homeopathic supportive cares. Results: 158 histopathology or cytopathology proved participants (42 of stomach, 40 of gallbladder, 44 of pancreas, and 32 of liver cancers) were included in the final analysis at the end of the study. According to the AJCC/UICC TNM staging system, 7 (4.43%) of them diagnosed at stage II, 39 (24.68%) of them diagnosed at late stage II or early stage III and 112 (70.87%) of them diagnosed at late stage III or stage IV. According to the RECIST criteria, complete tumor response occurred in 28 (17.72%) cases and partial tumor response occurred in 56 (35.44%) cases. 126 (79.75%) of them survived at least 1 year, 99 (62.66%) of them survived at least 2 years, 87 (55.06%) of them survived at least 3 years, 76 (48.10%) of them survived at least 4 years, and 62 (39.24%) of them survived at least 5 years. These participants did not receive any other conventional or investigational cancer treatments. The participants report no side effects from the drug psorinum. Conclusions: Psorinum therapy is effective in treating stomach, gallbladder, pancreas, and liver cancers. Double-blinded randomized controlled clinical trial should be done for further investigation of this alternative cancer treatment. No significant financial relationships to disclose.
Long-term safety of BLP25 liposome vaccine (L-BLP25) in patients (pts) with stage IIIB/IV non-small cell lung cancer (NSCLC)
Authors: Butts C. , Anderson H. , Maksymiuk A. , Vergidis D. , Soulières D. , Cormier Y. , Davis M. , Marshall E. , Falk M. , Goss G. 
Published: August 2020

3055 Background: The BLP25 liposome vaccine (L-BLP25, Stimuvax) is an investigational innovative therapeutic cancer vaccine incorporating immunoadjuvant monophosphoryl lipid A and synthetic MUC1 lipopeptide in a liposomal delivery system. In an open-label phase IIb study in 171 pts with stage IIIB/IV NSCLC randomized to best supportive care (BSC) alone (n=83) or BSC + L-BLP25 (1000 μg lipopeptide) (n=88), L-BLP25 pts received weekly vaccinations for 8 weeks (wks) and could continue maintenance vaccinations every 6 wks from wk 13. Results were encouraging (Butts et al, JCO 2005) and a remarkable number of pts received prolonged treatment (tmt). As a result a global phase III study (START) has been initiated. Methods: Safety results for 16 pts from the phase IIb study treated for ≥2 years with L-BLP25 are reported. Results: In these 16 pts (median age 57.5 years, ECOG PS: 0 in 5/16 [31%] and 1 in 11/16 [69%]), there were more females (56% vs 44% [9/16 vs 76/171]) and locoregional stage IIIB disease at entry (81% vs 38% [13/16 vs 65/171]) vs the phase IIb study population. Pts received L-BLP25 for 2.0–7.7 years and 10 pts were treated for >5 years. Compliance with tmt was good: almost all (96%) maintenance vaccinations were given every 6 wks according to the tmt schedule. L-BLP25 was well tolerated: the most common tmt-emergent adverse events (TEAEs) were cough (n=12, 75%), fatigue (n=12, 75%), and dyspnea (n=11, 69%). The pattern of TEAEs did not change significantly over time and there was no rise in the incidence of TEAEs with increasing time on tmt. Among the most common TEAEs in years 1, 2, and >2 were nausea (44, 19, and 38%), fatigue (56, 18, and 38%), chest pain (38, 31, and 31%), and cough (38, 25, and 31%). Twelve pts (75%) had tmt-related TEAEs (grade 1/2 in 11/12 pts [92%] and grade 3 in 1/12 [8%]): the most common were injection-site reactions. The occurrence of tmt-related TEAEs decreased with increasing tmt duration. There was no evidence of any TEAEs related to autoimmunity. Analysis of laboratory data did not indicate any long-term renal, liver, or other toxicity. Conclusions: Long-term use of L-BLP25 was without any identifiable safety issues. In particular, there was no evidence of autoimmune reactions with prolonged use. [Table: see text]
Antitumor activity of patient-derived renal cell carcinoma cells fused with allogeneic dendritic cells: In vitro results and clinical responses
Authors: Xia J. , Zhou J. 
Published: August 2020

3056 Background: Renal cell carcinoma (RCC) has been shown to be highly susceptible to immune-based treatment strategies. Methods: In the present study, patient-derived tumor cells were fused with allogeneic dendritic cells (DC) to elicit antitumor activity against RCC. DC from HLA-A2+ healthy donors were fused with primary RCC cells from 10 patients. Phenotype of fusion cells was characterized by flow cytometer and confocal microscopy. In vitro, T-cell proliferation, IFN-γ secretion, and cytotocic T lymphocytes (CTL) activity elicited by allogeneic DC/RCC fusion cells were assessed. Clinically, 10 patients were vaccinated with allogeneic DC/RCC fusion vaccine. The adverse effects and toxicity were observed. The clinical response was evaluated by CT scans. Results: After fusion, the created hybrids expressed both tumor-associated antigen and DC-derived molecules and could stimulate the proliferation and IFN-γ secretion of T-cells as well as elicit strong CTL activity against RCC cells in vitro. In vivo, neither serious adverse effects nor signs of autoimmune disease were observed after vaccination therapy. Percentage of T lymphocyte subsets in peripheral blood of patients was increased significantly. One of 10 patients exhibited a partial response with regression of lung metastases. Six patients showed stable disease with stabilization of previously progressive disease (follow-up 1.5 year). Conclusions: The data suggest that allogeneic DC/RCC fusion vaccine is safe and can elicit immunological responses in patients with RCC. No significant financial relationships to disclose.
Analysis of immunological and clinical data resulting from four phase I and II trials of MVA-5T4 in colorectal cancer patients
Authors: Harrop R. , Shingler W. H. , Goonewardena M. , de Belin J. , Kelleher M. , Drury N. , Treasure P. , Naylor S. 
Published: August 2020

3058 Background: The attenuated vaccinia virus MVA has been engineered to deliver the tumor antigen 5T4 (MVA-5T4; TroVax). 5T4 is a surface glycoprotein expressed by most solid tumors. MVA-5T4 has been tested in one phase I/II and three phase II clinical trials in colorectal cancer patients. All trials demonstrated that MVA-5T4 was well tolerated when administered alone (1 trial), as adjuvant/neoadjuvant to surgery (1 trial), or in combination with chemotherapy (FOLFOX or FOLFIRI; 2 trials). We have now collated data from all four trials, determined the incidence of immune responses across trials, and looked for associations with improved survival. Methods: Patients with histologically proven CRC were recruited to 4 independent trials in which 3 to 6 vaccinations of MVA-5T4 were scheduled to be administered either as a monotherapy, as adjuvant/neoadjuvant to surgery for respectable liver metastases or alongside treatment with FOLFIRI or FOLFOX. Antibody responses specific for 5T4 and MVA were monitored by ELISA. Survival data were collated from each hospital site. Immunological and survival data were analyzed using proportional hazards regression adjusting for age and gender. Results: Survival and immunological response data were available for 73 patients (median age 63), who received a median of 5 MVA-5T4 vaccinations (range 1–6). Of 69 patients tested for antibody responses post-vaccination (4 patients had no post-vaccination blood sample available), 54 (78%) and 65 (94%) showed positive responses for 5T4 and MVA respectively. Exploratory analyses demonstrated significant associations between immune responses and overall survival across trials. Indeed, a Cox proportional hazards model showed that a doubling in the geometric mean 5T4 antibody titre (injections 1 to 3) was associated with a 19.9% reduction in relative risk, adjusted for age and gender (p<1%). Conclusions: MVA-5T4 induced 5T4-specific immune responses in the majority of patients. Although the studies described here were uncontrolled, there were encouraging signs of activity which associated with the presence of 5T4-specific immune responses. [Table: see text]