tbuckley/cabot-search huggingface dataset:
Pre-clinical development of TNB-383B, a fully human T-cell engaging bispecific antibody targeting BCMA for the treatment of multiple myeloma.
Authors: Ben Buelow, Priya Choudry, Starlynn Clarke, Kevin Dang, Laura Davison, Shelley Force Aldred, Katherine Harris, Payal Pratap, Duy Pham, Udaya Rangaswamy, Ute Schellenberger, Nina Shah, Nathan Trinklein, Harshad Ugamraj, Arun Wiita, Wim Van Schooten
Journal: Journal of Clinical Oncology (2018)

8034 Background: T-cell redirecting therapies such as CAR-T cells and T-cell engaging bispecific antibodies (T-BsAb) targeting B Cell Maturation Antigen (BCMA) have been highly efficacious against relapsed/refractory myeloma (MM) in early phase clinical studies. However, strongly pan-T cell activating T-BsAbs have also been shown to overstimulate T cells, inducing toxicity and possibly decreasing efficacy. We have developed TNB-383B, a fully human BCMA-specific T-BsAb incorporating a low-activating αCD3 that preferentially activates effector over regulatory T cells. TNB-383B mediates T-cell killing of MM in vitro, ex vivo and in vivo but stimulates minimal cytokine release. Methods: In vitro and ex vivo efficacy studies included T-cell activation by cytokine- and tumor cell kill by calcein-release assays and/or flow cytometry. In vivo efficacy of the molecules was evaluated in NSG mice harboring myeloma cells and human PBMCs. Pharmacokinetics and tolerability were assessed in Cynomolgus. Results: TNB-383B showed T-cell activation and tumor-cell cytotoxicity in vitro and ex vivo, with markedly reduced cytokine production even at doses that showed maximum tumor cell lysis as compared to a positive control T-BsAb. In vivo, TNB-383B reduced tumor load and increased survival. TNB-383B had a T1/2 of ~13-16 days in Cyno, consistent with an IgG4 Ab. Conclusions: Our results suggest that TNB-383B may have a favorable toxicity profile with comparable or possibly improved efficacy compared to T-BsAbs that incorporate strong, pan T-cell activating anti-CD3 moieties in the treatment of MM.
<i>In silico</i> approach to inhibit the checkpoint protein PD-1by the monoclonal antibody nivolumab.
Authors: E.L. Albuquerque, Ana Beatriz M.L.A. Tavares, J.X. Lima-Neto, U.L. Fulco
Journal: Journal of Clinical Oncology (2018)

e15089 Background: Immunotherapy is nowadays an important active area of cancer research. In particular, the use of checkpoint inhibitors, such as the programmed cell death receptor PD-1, are being considered an important novel therapeutic approach. It binds to PD-L1, a protein found on some cells, to avoid the T cell activation. Monoclonal antibodies, like nivolumab, can block this binding and boost the immune response, leading to an efficient treatment of some cancers. Methods: We investigated the nivolumab recognition surface on PD-1 under a quantum mechanics point of view. It supplies enough information at the binding interface that substantially contribute to the affinity and specificity between the receptor and the therapeutic antibody, taking into account the crystallographic structure of the drug in complex with the extracellular domain of human PD-1. Afterwards, a fragmentation scheme based on the molecular fractionation with conjugate caps (MFCC) method was performed, together with an optimization procedure using a parametrization tool for organic molecules. Results: The interaction energy between each PD-1 molecule and the drug was calculated considering any significant attractive and repulsive drug’s amino acid residues. Although it was observed few repulsive interactions, the attractive ones were predominant, pointing out to a strong inhibition of the PD-1 receptor. The nivolumab recognition surface on PD-1 was found to be filled with intermolecular direct and water-mediated hydrogen bonds, non-conventional hydrogen bonds, salt bridges, and hydrophobic contacts. Conclusions: We have presented a quantum mechanics description of the Nivolumab/PD-1 complex at a molecular level, providing an accurate electronic and interaction pattern of the amino-acid residues. Our computational method is a simple and efficient alternative to unveil the drug's amino-acids residues that play the most important role on the binding affinity of the receptor-ligand complex. Considering the small cost/benefit of the operation, our approach, not only in clinical oncology but also in pharmaceutical medicine in general, is an important initial step toward the development of efficient cancer pharmaceutical drugs.
Development of the Princess Margaret Immune Oncology Prognostic Index (PM-IPI): A novel prognostic score for patients (pts) treated in immune oncology (IO) phase I (P1) trials.
Authors: Daphne Day, Anthony M. Joshua, Lisa Wang, Albiruni R. Razak, Aaron Richard Hansen, Natasha B. Leighl, Marcus O. Butler, Anna Spreafico, Lillian L. Siu, Philippe L. Bedard
Journal: Journal of Clinical Oncology (2016)

3058 Background: Several previously published scores prognosticate survival for pts treated in cytotoxic and molecularly targeted P1 trials. IO is rapidly evolving in early drug development with unique response patterns and survival outcomes. Our aims were to develop a prognostic index for IO P1 trials, compare its performance with previously published P1 scores, and evaluate associations with IO treatment outcomes. Methods: We included 192 consecutive advanced solid tumor pts treated at Princess Margaret Cancer Centre from Aug 2012 to Aug 2015 in 13 IO P1 trials, targeting immune checkpoint and/or co-stimulatory molecules. Ten clinical factors were tested in univariate survival analysis. Multivariate analysis (MVA) was used to develop the PM-IPI. The ability of the PM-IPI to predict overall survival (OS), progression-free survival (PFS), 90-day mortality (90DM) and overall response rate (ORR) was compared with previously published P1 prognostic scores. Results: Median age was 58 y and 81% of pts had at least 1 prior systemic therapy (range 0-8). The most common tumor sites include melanoma (27%), lung (20%), urological (11%), head and neck (10%) and gastrointestinal (9%). Median PFS and OS were 13.4 and 73.6 wk respectively and 90DM was 16%. ORR was 20% by RECIST 1.1 or immune-related response criteria (irRECIST). In MVA, ECOG PS > / = 1 (HR 3.2, p < 0.001), no. of metastatic sites > 2 (HR 2.0, p = 0.003) and albumin < lower limit of normal (HR 1.8, p = 0.007) were independent prognostic factors; comprising the PM-IPI. Pts with a score of 2-3 compared to pts with a score of 0-1 had significantly shorter OS (HR 3.4, p < 0.001), PFS (HR 2.3, p < 0.001), higher 90DM (OR 8.1, p < 0.001) and lower ORR (OR 0.4, p = 0.019). Additionally, the PM-IPI performed better than previously published P1 prognostic scores (Table). Conclusions: The PM-IPI prognosticates for survival and is associated with ORR and PFS in pts treated in IO P1 trials. Validation of this novel prognostic score in a large external cohort is ongoing. PM-IPI Royal Marsden Index Hammersmith Score Nijmegen Score OS C- index 0.71 0.65 0.59 0.59 PFS 0.66 0.63 0.58 0.58 90DM AUC 0.75 0.69 0.70 0.68 ORR 0.64 0.59 0.56 0.58
Diagnostic performance of thyroid multimodal-imaging comprehensive risk stratification scoring (TMC-RSS) system in characterising thyroid nodules.
Authors: Abhishek Mahajan, Richa Vaish, Supreeta Arya, Nilesh Sable, Shilpa Pande, Peter Paul, Shubhada Kane, Devendra Chaukar, Pankaj Chaturvedi, P. S. Pai, Gouri Pantvaidya, Meenakshi Thakur, Anil D'Cruz
Journal: Journal of Clinical Oncology (2017)

e17588 Background: A univocal ultrasound (US) classification system for characterising thyroid nodules is still lacking. The aim was to create an algorithm (TMC-RSS) using US features in combination with Color Doppler (CD), TIRADS, elastography (ES) and test its diagnostic performance. Methods: Analysis of prospectively collected data over 10 months. All studies were performed on single equipment using standard US protocol with TIRADS scoring. Gold standard was pathology. 340 nodules in 260 patients of which 316 nodules included for final analysis. 148 (46.8%) benign and 168 (53.2%) Malignant. TMC-RSS Multiple Logistic Regression Model. Malignant characteristics:Plus (+) 3 points for: ES score 3/4, malignant nodes. (+) 1 point for: Taller than wider, microcalcification, hypoechogenicity, solid composition, ill-defined margins, central +/- peripheral vascularity. (+) 0.5 point for: irregular halo, size &gt; 1 cm. Benign characteristics:Minus (-) 3 points for: Purely cystic, ES score-1; (-) 1 point for: spongiform, comet tail artefact, complete halo. (-) 0.5 point for: peripheral vascularity. Final TMC-RSS Score calculated by addition of all the points. Results: Mean age was 47.3 yrs. Mean size was 2.3 +/- 1.5 cm. Diagnostic performance of combined US, ES, TIRADS and CD (sensitivity: 96%, specificity: 95%, PPV: 95%, NPV: 96%, kappa: 0.911) was significantly higher (p &lt; .001) than either combination of US, TIRADS, ES, CD. On multivariate analysis all US features except taller than wider were independent predictor of malignancy (p &lt; .01). TMC-RSS Model had 90% sensitivity, 89% specificity and 91% accuracy for characterising nodules. On the ROC curve the cut-off for best performance of TMC-RSS score was 5.75. The cumulative risk of malignancy based on TMC-RSS score was 2.4% for score &lt; 3, 18% for score ≥ 3 - &lt; 6 and 80% for score ≥ 6. Conclusions: The proposed TMC-RSS is easy-to-use, robust, reproducible and provides higher degree of confidence to a non-expert radiologist. It can be the first step in standardization of reporting lexicon to allow effective communication between the radiologists, pathologists, and clinicians; helping avoid unnecessary interventions.
Circulating AR copy number and outcome to enzalutamide in patients with metastatic castration-resistant prostate cancer after docetaxel.
Authors: Samanta Salvi, Valentina Casadio, Vincenza Conteduca, Cristian Lolli, Giorgia Gurioli, Filippo Martignano, Giuseppe Schepisi, Sara Testoni, Emanuela Scarpi, Dino Amadori, Daniele Calistri, Gerhardt Attard, Ugo De Giorgi
Journal: Journal of Clinical Oncology (2016)

e16583 Background: Enzalutamide is a new anti-androgen with a great affinity for androgen receptor (AR). We aimed at identifying circulating AR copy number (CN) gain as non-invasive biomarker for outcome prediction to enzalutamide. Methods: Fifty-nine castration-resistant prostate cancer (CRPC) patients (pts) treated with enzalutamide 160 mg daily after docetaxel were evaluated. Twenty-eight of 59 (47%) pts previously received abiraterone. AR CN was evaluated in the serum collected before the start of treatment with real-time PCR with TaqMan assays and digital PCR analysis. Progressive disease was defined on the basis of Prostate Cancer Working Group 2 criteria. Univariate and multivariate Cox regression models addressed potential predictors of progression-free survival (PFS) and overall survival (OS). Results: AR CN gain was found in 21 of 59 (36%) pts. Median baseline PSA, alkaline phosphatase and LDH levels were higher in the AR CN gained group (p= 0.007, p= 0.003, p= 0.0009, respectively). A PSA decline ≥ 50% was reported in 4 of 21 (19%) pts with AR CN gain and 14 of 38 (37%) without AR CN gain (p= 0.260). The median PFS of pts with AR CN gain was 2.4 months (95% CI: 1.9-3.2) vs. 4.0 months (95% CI: 3.0-6.5) of those with no AR CN gain (p= 0.0004). The median OS of pts with AR CN gain was 6.1 months (95% CI: 3.4-8.6) vs. 14.1 months (95% CI: 8.2-20.5) of those with no AR CN gain (p= 0.0003). Univariate analysis showed a significant impact on PFS and OS for previous abiraterone, PSA decline ≥ 50%, and AR CN. At multivariate analysis, only PSA decline ≥ 50%, and AR CN showed a significant association with PFS (p =0.003 and p= 0.0006, respectively) and OS (p= 0.002 and p= 0.019, respectively). Conclusions: Detection of circulating AR CN gain is a potentially promising non-invasive biomarker for outcome prediction to enzalutamide treatment in CRPC pts.
Single-center experience with nutrition intervention on patients with advanced colorectal cancer undergoing chemotherapy.
Authors: Jin-Xiang Lin, Heng-Ying Fang, Zhan-Hong Chen, Meng-Qi Duan, Qu Lin
Journal: Journal of Clinical Oncology (2016)

e21615 Background: Enteral nutrition in advanced colorectal carcinoma patients with palliative chemotherapy is performed to prolong survival, alleviate tumor-associated symptoms, and maintain or improve health-related quality of life (HRQOL). The aim of the study is to observe the effect of nutrition specialist nurse-led intervention on patients with advanced colorectal cancer undergoing chemotherapy. Methods: A total of 60 patients were recruited. They were randomized into an intervention group(30 patients) and a control group (30 patients). The intervention group accepted the nutrition specialist nurse-led intervention during the whole chemotherapy, including assessment of dietary habits, nutrition and chemotherapy related gastrointestinal reactions, personalized recipe consistent with assessment results, and telephone follow-up every 2 weeks. The control group was treated with conventional diet guidance. Body weight, serum prealbumin, serum albumin and quality of life measured by EORTC Quality of Life Questionnaire-C30 were acquired at baseline, 6 months and after intervention. Results: Compared with baseline, the values of serum prealbumin, serum albumin and QLQ-C30 were improved in the intervention group (169.17±69.18 VS 240.30±59.21, p = 0.000; 37.39±4.89 VS 41.62±2.64, p = 0.000; 54.17±11.74 VS 78.11±13.58, p = 0.000; respectively), and the values of body weight, serum prealbumin and serum albumin but QLQ-C30 were not improved in the control group. Compared with control group, the intervention group exhibited significant differences in improvements in QLQ-C30 (23.94±19.30 VS 9.72±13.33, p = 0.002) Conclusions: Nutrition specialist nurse-led intervention can improve the nutritional status and quality of life of patients with advanced colorectal cancer undergoing chemotherapy.
Cost-effectiveness of prophylactic antibiotics to prevent pneumonia in patients treated with chemoradiotherapy (CRT) for locally advanced head and neck carcinoma (LAHNC).
Authors: Janneke Ham, Chantal Driessen, Mathijs P Hendriks, W. Edward Fiets, Bas Kreike, Ann Hoeben, Marije Slingerland, Claudia van Opstal, Bart-Jan Kullberg, Eddy MM Adang, Johannes Kaanders, Winette T.A. Van Der Graaf, Carla M.L.- Van Herpen
Journal: Journal of Clinical Oncology (2017)

6075 Background: Recently, we reported about a prospective randomized study (PANTAP-study) investigating the effect of prophylactic antibiotics in LAHNC pts treated with CRT. We did not show a reduction in pneumonias, but did find a significant decrease in the number of hospitalizations. Detailed quality of life (QoL) results have been reported elsewhere. Now we present the results of the cost-effectiveness analysis. Methods: A multicenter study was performed in LAHNC pts treated with CRT, i.e.cisplatin weekly or 3-weekly combined with radiotherapy for 42 or 49 days. The standard treatment group (STG) received no prophylactic antibiotics; the intervention group (IG) received prophylactic antibiotics, i.e. amoxicillin/clavulanic acid, from day 29 until 14 days after completion of CRT. QoL questionnaires, including EQ-5D, QLQ-C30, EORTC Head&amp;Neck35 and PSSHN, were taken before start of CRT, before start of antibiotics, at the end of CRT and at the end of follow up. Costs of hospitalization, prophylactic antibiotics, pain medication and anti-emetics were taken into account for the cost-effectiveness analysis. Results: A total of 94 pts were randomized; 48 pts to the STG and 47 pts to the IG. Between the STG and IG we found a difference per patient in costs of hospitalization of €2076 and €682 (p = 0.03), respectively, but not in the costs for pain medication per patient €78 and €46, respectively, (p = 0.382). The total costs of hospitalization in combination with prophylactic antibiotics, pain medication and anti-emetics were €2462 and €1037 (p = 0.046) in the STG and IG respectively, leading to a difference in total costs per patient of €1425 in favor of the IG. There were no significant differences in QoL between the groups. Conclusions: Prophylactic antibiotics during CRT for LAHNC did not reduce the rate of pneumonias, but reduced the number of hospitalizations in the IG, which led to a significant reduction in costs. Given the lack of adverse clinical effects, the same QoL, the cost savings and the impact of costs of hospitalization on health care globally, we recommend the use of prophylactic antibiotics in LAHNC pts receiving CRT. Clinical trial information: NCT01598402.
Fraction of diffuse gastric cancer attributable to dietary risk factors.
Authors: Marina Candido Visontai Cormedi, Rodrigo Santa Cruz Guindalini, Priscila Abduch Branas, Behrooz Alizadeh, Maria A. A. Koike Folgueira, Gertruida H, de Bock
Journal: Journal of Clinical Oncology (2018)

e16042 Background: Gastric cancer is a major health problem worldwide, especially in Brazil, where incidence rate is moderate-high. Although intestinal type of gastric cancer is clearly associated with environmental risk factors, the contribution of these modifiable risk factors to diffuse type is still under investigation. Methods: From 2013 to 2015, we interviewed 80 diffuse gastric cancer patients and 243 gender- and age-matched controls on lifestyle and dietary risk factors through structured questionnaires. Association between risk factors and gastric cancer was estimated for patient and controls, and for patient and Brazilian population databases from published government sources. Logistic regression models were used to estimate odds ratio (OR) and 95% confidence interval (95% CI). The proportional reduction of cancer cases if exposure to risk factors was ideal was estimated using Levine’s formula for population attributable fraction (PAF). Results: Patients were more likely to be born in rural areas (44.4% vs. 19.4%; p < 0.01) and to be less educated than controls (p < 0.01). Compared to hospital controls, factors associated with increased risk of diffuse gastric cancer were any alcohol intake (OR 7.00; p < 0.01), red meat intake ≥ 6x/week (OR 4.20; p < 0.01) and processed meat intake ≥ 6x/week (OR 8.58; p < 0.01). Alcohol was estimated to be responsible for 75% of stomach cancer cases, red meat for 43% and processed meat for 23% of cases. When compared to populational databases, cigarette smoking (OR 2.11; p < 0.01), alcohol (OR1.96; p = 0.029), red meat intake ≥ 6x/week (OR 1.8; p = 0.012) and processed meat ≥ 6x/week (OR 4.06; p < 0.01) were associated with increased diffuse gastric cancer risk and PAF was 26% for smoking, 32% for alcohol, 16% for red meat and 10% for processed meat. Conclusions: Dietary habits such as alcohol, red meat and processed meat intake have great impact on diffuse gastric cancer incidence in Brazil. Reduction in consumption of these products may decrease its incidence.
Off-label use of bevacizumab in relapsed and refractory pediatric sarcoma patients: The Memorial Sloan Kettering Cancer Center Experience.
Authors: Emily Kanaya Slotkin, Heather D. Magnan, Paul A. Meyers, Alexander J. Chou, Srikanth R. Ambati, Leonard H. Wexler
Journal: Journal of Clinical Oncology (2016)

10569 Background: Survival rates for children and young adults with relapsed and/or refractory sarcomas remain poor. Cytotoxic salvage options for these patients are limited and associated with significant toxicity, necessitating innovative approaches including the incorporation of targeted agents. Bevacizumab (Avastin, Genentech) is a recombinant humanized monoclonal antibody that inhibits vascular endothelial growth factor A (VEGF-A). Bevacizumab has been used in the pediatric population, predominantly in children with central nervous system tumors, but its use in pediatric sarcomas has been relatively limited. Methods: Here, we describe our institutional experience using off-label or non-protocol associated bevacizumab in combination with several cytotoxic salvage and maintenance regimens in pediatric patients with relapsed and/or refractory rhabdomyosarcoma (RMS), Ewing sarcoma (ES), and desmoplastic small round cell tumor (DSRCT). Results: Since 2007 we have used off-label or non-protocol bevacizumab in 18 patients with RMS, 3 patients with ES, and 4 patients with DSRCT. Six regimens including bevacizumab were used in combination with cyclophosphamide, vinorelbine, vincristine, topotecan, doxorubicin, etoposide, gemcitabine, and docetaxel. Patients received 5-15 mg/kg of bevacizumab, most often at a planned frequency of every 21 days. Between 1 and 70 doses were administered, with a median of 7 doses. In general, bevacizumab was generally well tolerated with the most frequent side effect being cytopenias, which were occasionally dose limiting. Other noted adverse effects included grade 2 epistaxis, grade 1 transaminitis, grade 2 acral dermatitis, grade 1-2 hypertension and grade 1 albuminuria. Conclusions: This observational study suggests that bevacizumab can be safely used for pediatric patients with relapsed and refractory sarcomas. Additionally, in several patients with widely metastatic disease, bevacizumab was successfully used as a component of “maintenance” therapy, and was associated with prolonged disease free intervals. Further investigation of bevacizumab in this setting is warranted.
Cancer peptide vaccine to suppress postoperative recurrence in esophageal SCC patients with induction of antigen-specific CD8+ T cell.
Authors: Takushi Yasuda, Kohei Nishiki, Koji Yoshida, Osamu Shiraishi, Mitsuru Iwama, Hiroaki Kato, Atsushi Yasuda, Masayuki Shinkai, Yasutaka Chiba, Kiyotaka Okuno, Yusuke Nakamura
Journal: Journal of Clinical Oncology (2017)

e14635 Background: This is a following report of the exploratory phase II study of adjuvant peptide vaccine for thoracic esophageal squamous cell carcinoma (TESCC) (abstract #3087 in ASCO2016), focusing on an association of immunological responses with clinical outcomes. Three HLA-A-24-restricted epitope peptides derived from cancer-testis antigens, up-regulated lung cancer 10 (URLC10), cell division cycle associated 1 (CDCA1) and KH domain-containing protein overexpressed in cancer 1 (KOC1), were used in this study. Methods: TESCC patients who underwent neoadjuvant therapy followed by curative resection (Dec./2009 to Sep./2014) and were found LN metastasis were enrolled. One mg each of three peptides mixed with Montanide was injected to patients with HLA-A*2402 20 times in a 6-months period. No other adjuvant therapy was given until recurrence occurred. Primary endpoint is relapse-free survival (RFS). Immunological responses were examined by ELISPOT assay and immunohistochemistry (IHC). Results: 33 patients were enrolled in the vaccine group (VG) and 30 with non-HLA-A*2402 were used as controls (CG). There was no significant difference in clinical backgrounds between the two groups. 5-year RFS in the VG was 44.6% while that in the CG group was 31.6% (p = 0.207); patients who showed CD8+ CTL induction to multiple peptides tend to show better RFS rate [3/2/1 peptides = 69.0(n = 20)/46.8(n = 11)/0%(n = 2), respectively]. Five-year esophageal cancer-specific survival (ECSS) were 58.4% in the VG compared with 35.4% in the CG (p = 0.156); 90.0% (n = 11) vs. 50.0% (n = 15) and 43.8% (n = 22) vs. 24.0%(n = 15) in pN1 and pN2-3 groups, respectively. Regarding the CD8+ positivity, ECSS was improved only in the negative group (56.6% in VG vs. 26.7% in CG). Classification by T cell positivity and PD-L1 expression [type I(+/+), II(-/-), III(-/+) and IV(+/-)] showed 5-year ECSS to be 100%(n = 3), 66.4%(n = 19), 20.0%(n = 5) and 44.4%(n = 6). Conclusions: Our cancer peptide vaccines induced the antigen-specific CD8+ T cell highly and efficiently, and suppressed recurrence with the strong immune responses. Clinical trial information: UMIN000003557.