tbuckley/cabot-search huggingface dataset:
Bispecific anti-PD-1/PD-L1 antibody CTX-8371 to promote cellular clustering and PD-1 shedding, antitumor activity and tolerability.
Authors: Diana I. Albu, Yan Qin, Xianzhe Wang, Vivian Li, Taeg Kim, Bing Gong, Thomas Schuetz, Nelly Kuklin
Journal: Journal of Clinical Oncology (2021)

e15056 Background: Checkpoint blockade therapies targeting PD-1 and PD-L1 have shown great success for the treatment of various malignancies. However, a substantial fraction of patients with PD-L1-positive tumors remain unresponsive to these therapies. Novel therapy with significantly greater activity than the leading PD-1/PD-L1 inhibitors is expected to bring additional clinical benefit to patients. Here we describe the preclinical evaluation of CTX-8371, which combines anti-PD-1 and anti-PD-L1 monoclonal antibodies in one bispecific tetravalent molecule. Methods: The immune-enhancing activity of CTX-8371 was tested in vitro in T cell activation assays and tumor cell killing assay. CTX-8371 anti-tumor efficacy in vivo was assessed using mouse tumor cells expressing human PD-L1 implanted in transgenic mice humanized at the PD-1 and PD-L1 loci. CTX-8371 anti-tumor activity was also tested in xenograft tumor models. The mechanism of action of CTX-8371 was investigated in vitro using Jurkat cells expressing PD-1 or PD-L1, human PBMCs, and in vivo in tumor-bearing, chimeric PD-1/PD-L1 transgenic mice. CTX-8371 PK was determined in mice using an MSD ELISA-based assay and in cynomolgus monkeys using a qualified ELISA method. Dose range finding and toxicokinetic studies were performed in cynomolgus monkeys. Results: CTX-8371 potently enhanced T cell activation and function in vitro and showed curative efficacy as monotherapy in multiple solid tumor models, isografts or xenografts. Furthermore, CTX-8371 demonstrated superior anti-tumor efficacy compared to Keytruda or atezolizumab in checkpoint inhibitors-sensitive and resistant syngeneic mouse tumor models. Mechanistically, in addition to blocking PD-1 interaction with PD-L1, CTX-8371 bispecific antibody facilitated cell to cell bridging between cells expressing PD-1 and cells expressing PD-L1. Furthermore, we show that simultaneous binding of CTX-8371 to both PD-1 and PD-L1 resulted in long term PD-1 shedding. This suggests that CTX-8371 may prevent or overcome T cell exhaustion within the tumor microenvironment, thus providing additional advantage over existing therapies. Lastly, excellent tolerability was observed in non-human primates given 2 weekly drug infusions at up to 50 mg/kg dose. Conclusions: CTX-8371 displays multiple mechanisms of action over monoclonal PD1/PD-L1 blockade. These unique pharmacological properties of CTX-8371 could explain the enhanced T cell responses to tumor antigens and superior efficacy over current monoclonal antibody therapies. With favorable PK/PD and toxicology profiles in mice and cynomolgus monkeys, CTX-8371 warrants further advancement to clinical testing.
Measuring disparities in quality of oncology care across oncology practices.
Authors: Nancy Lynn Keating, Mary Beth Landrum, Alan Zaslavsky, Cleo A. Samuel, Anna Sinaiko, Gabriel A. Brooks, Alexi A. Wright, Barbara Bai
Journal: Journal of Clinical Oncology (2021)

6533 Background: Equity is now recognized as an essential aspect of health care quality. Racial inequities in clinical performance diminish overall system performance. We assessed the feasibility and reliability of practice-level measures of racial disparities in chemotherapy-associated emergency department (ED) visits and hospitalizations. Methods: Using fee-for-service Medicare data, we identified 1,196,970 Black or White fee-for-service Medicare beneficiaries with cancer receiving chemotherapy in 2016-2019, who were attributed to 5511 oncology practices that treated at least 1 Black and 1 White beneficiary (96.4% of all beneficiaries). We studied two CMS quality measures: chemotherapy associated ED visits and chemotherapy associated hospitalizations. For each outcome, we estimated multi-level models with separate practice-level random intercepts for Black and White patients to quantify practice-level Black-White disparities in adjusted rates of these measures and assess the associations of these rates with the proportion of Black patients in the practice. Results: Overall, 108,177 Black and 966,381 White beneficiaries with cancer were treated at 1321 practices with reliable estimates (reliability ≥70%) of Black-White differences in rates of chemotherapy-associated ED visits; 101,411 Black and 915,895 White beneficiaries were treated at 1,012 practices with reliable estimates of chemotherapy-associated hospitalizations. These practices treated 80% or more of all Black and White beneficiaries; 10% of these practices treated 75% of Black beneficiaries. The median adjusted Black-White rate difference across practices was +8.9% [interquartile interval (IQI) +5.0%, +12.8%; 5th, 95th percentile -1.8 to +19.2%] for chemotherapy associated ED visits and +4.4% [IQI +1.3%, +7.7%; 5th, 95th percentile -3.5% to +13.5%] for chemotherapy associated hospitalizations. Chemotherapy-associated ED visit rates were 3.2 percentage points higher for Black vs White patients (P &lt;.001) at the practice with the mean % of Black patients, but the difference was smaller in practices with more Black patients (0.4 percentage points less for each 10% increase in Black share, P &lt;.001). Chemotherapy-associated hospitalization rates were 0.6 percentage points lower for Black vs White patients (P =.01) but did not vary by practice racial composition. Conclusions: Using data from more than 1000 practices over 4 years, we calculated reliable estimates of practice-level racial disparities in chemotherapy-associated ED visits and hospitalizations. Practice-level performance for these quality measures was generally lower for Black versus White beneficiaries. Measuring and providing feedback on practice-level Black-White disparities in oncology performance measures may be one effective tool for advancing racial equity in care quality for cancer patients receiving chemotherapy.
Clinical trials participation is directly influenced by the information received by cancer patients (pts) and caregivers: Real-world evidence with the use of a specialized digital health platform.
Authors: Keren Greenfeld-Barsky, Lior Hasid, Daniel A. Vorobiof, Eliran Malki
Journal: Journal of Clinical Oncology (2021)

e18779 Background: Clinical trials (CT) participation is both crucial for medical advancement and an important treatment option, at times the only one, for oncological pts. However, only an estimate of ̃3% of cancer pts worldwide enrolls into such trials. Different factors have been implicated in underlying this low participation rate, with little current data on patients’ own perspective. In this study, pts &amp; caregivers’ perception, knowledge and experience with CT were assessed via a unique digital health platform. Methods: 290 American and Israeli members of Belong.life cancer application (app) anonymously &amp; voluntarily replied to a 10 questions survey detailing their demographics, diagnosis, and experience with CT as a treatment option. Results: 234 participants were pts (81%) and 56 (19%) caregivers. 73% of participants were US based. 35 participants (12%) were &lt; 50 years of age (yoa), 94 (32%) were 50-59 yoa, 117 (40%) were 60-69 and 44 (15%) were &gt; 70 yoa. There were 79 males and 211 females.The most common diagnosis was breast cancer in 74 (26%), hematologic in 36 (12%), lung in 35 (12%), colorectal in 26 (9%) and ovarian in 26 (9%). Stages were 4 in 117 (40%) and 3 in 52 (18%), early (1&amp;2) in 73 (25%). 134 (46%) have not heard about CT participation as a treatment option. Among 125 participants of the 134 who were not familiar with CT as a treatment option, 115 (92%) stated they would like to learn more about it. Among the 156 participants who were acquainted with this option, 52 (33%) heard about it from medical staff, 41(26%) from multiple online resources, and 39 (25%) only through the Belong.life app. Only 23 participants (8%) previously participated in a CT. The most common reason for not participating was not being offered this treatment option (55, 49%) followed by lack of suitable trials for their condition (26, 23%). The most common reason for considering it was to receive an innovative treatment (60, 44%). Conclusions: Almost half of the pts and caregivers were not aware of CT participation as a valid treatment option. Among them, nearly all have expressed an interest to be better informed. This significant dissonance was also evident among those aware but who were not offered to participate, while expressing a favorable perception regarding participation. While the medical staff is a key source for CT awareness, and whilst patients are exposed to multiple online sources of information, this survey confirmed that 25% of Belong.life members received information about CT availability and participation singly from the app and 8% of them actively participated in a clinical trial. In sum, emphasis should be placed on providing personally tailored CT information to all cancer patients and caregivers. Digital health platforms are an important source for patients CT awareness.
Drivers and barriers to information seeking: Qualitative research with advanced cervical cancer patients in the United States.
Authors: Elizabeth A. Szamreta, Graceanne R. Wayser, Vimalanand S. Prabhu, Emily Mulvihill, Katherine Stockstill, Ritu Salani
Journal: Journal of Clinical Oncology (2021)

e18705 Background: Patients diagnosed with persistent, recurrent, or metastatic cervical cancer (CC) may face uncertainty about treatment options, impact of treatment on health &amp; quality of life (QoL), &amp; available resources. This study provides insight into patient concerns &amp; information seeking (IS) behaviors. Methods: In January 2021, semi-structured telephone interviews were conducted in the US with CC patients (diagnosed within 2 years) recruited through panels, social media &amp; advocacy groups. The interview focused on rational &amp; emotional drivers and barriers for IS. Transcripts were coded using NVivo qualitative analysis software to identify key themes. Results: 14 women of varied education status were interviewed (mean age 51 years (range: 37-70); 8 White, 4 Black, &amp; 2 Latina). Patients emphasized trust in their oncologist to provide sufficient information. IS was driven by the desires to confirm their oncologist’s recommendation &amp; find reassurance through the experience of other patients, and encouragement from family. Barriers to IS included: 1) hesitancy to undermine their oncologist’s recommendations, 2) pessimism about ability to find individualized answers about prognosis or QoL, 3) feeling overwhelmed &amp; fearing mis-information, 4) personal urgency to decide on a treatment plan, 5) already having sufficient information, 6) potential exposure to “negative energy” from online patient communities, &amp; 7) COVID-19 hindering opportunity for personal connections. Conclusions: While patients’ oncologist, family, &amp; common patient experience provide comfort, reluctance towards IS exists. As trusted gatekeepers, oncologists should recognize patients’ desire for accessible, reliable, &amp; personalized information. Better understanding this perspective and gaps in the availability of validated &amp; relevant resources can enable clinicians/policy makers to develop strategies &amp; tools for better communication. In turn, this will help CC patients feel more empowered &amp; informed throughout their cancer care journey.[Table: see text]
Impact of the Duration of Methotrexate Administration and the Specific HLA Alleles on the Regressive Methotrexate-Induced Lymphoproliferative Disorders
Authors: Michihide Tokuhira, Shuntaro Saito, Ayumi Okuyama, Katsuya Suzuki, Morihiro Higashi, Shuju Momose, Takayuki Shimizu, Takehiko Mori, Tomoe Anan-Nemoto, Koichi Amano, Shinichiro Okamoto, Tsutomu Takeuchi, Jun-ichi Tamaru, Masahiro Kizaki
Journal: Blood (2017)
Abstract 11545: A Relative ANP Deficiency State With Increased Risk for Cardiometabolic Disease and Worse Outcomes in Male Gender: Rationale ForANP Hormonal Replacement Therapy
Authors: Tomoko Ichiki, Christopher G Scott, Valentina Cannone, Jeson Sangaralingham, Seethalakshmi R Iyer, Kent Bailey, Jens Peter Goetze, John C Burnett
Journal: Circulation (2019)

Introduction: The cardiac hormone atrial natriuretic peptide (ANP) is a potent inhibitor of aldosterone via the activation of receptor GC-A. Increased ANP by the genetic variant rs5068 is associate...
The Management of Relapsed Hodgkin´s Lymphoma after Haploidentical Stem Cell Transplantation: Donnor Lymphocyte Infusion and Brentuximab Vedotin
Authors: Alejandro Contento-Gonzalo, Irene Sánchez-Bazán, Daniel Barrios-Decoud, Maria Magdalena Alcalá-Peña, Maria Jesus Pascual-Cascon, Ana Isabel Heiniger
Journal: Blood (2017)
High-intensity focused ultrasound ablation for treatment of chemotherapy-induced thrombocytopenia and hypersplenism.
Authors: Min Yuan, Qing Xu, Zhongzheng Zhu, Wei Mao, Xianling Guo, Hui Wang, Hong Qian, Jianguo Wu
Journal: Journal of Clinical Oncology (2021)

3082 Background: Chemotherapy-induced thrombocytopenia (CIT) contributes to treatment dose delay and/or modification, often resulting in poorer survival and disease progression. Compared with partial splenic embolization (PSE) and drugs, high-intensity focused ultrasound has the advantages as following: (1) it is a noninvasive treatment modality with potentially fewer adverse effects and complications; (2) the hospital stay and recovery time after treatment are short; (3) its cost is relatively low compared to surgery. The purpose of this work was to preliminarily investigate the efficacy and safety of high intensity focused ultrasound treatment of chemotherapy-induced thrombocytopenia (CIT) and hypersplenism. Methods: 26 patients with chemotherapy-induced thrombocytopenia and hypersplenism (15 male and 11 female; median age, 56 years; range, 51-66 years) were treated with ultrasound guided high-intensity focused ultrasound. Complications were recorded. Laboratory examination and magnetic resonance imaging were used to evaluate the efficacy. The spleen volume and ablation volume rate of the spleen were calculated by MRI after treatment. They were followed closely for at least 6 months. Results: After high-intensity focused ultrasound treatment, the MRI showed that the ablation area had turned into a non-perfused volume, the mean percent spleen ablation volume was 18.76% ± 6.1% (range, 11.17%-32.34%). After 6 months of HIFU ablation, the ablated area shrank evidently; the sunken spleen formed a lobulated shape and the splenic volume decreased. The platelet count increased 3-7 days after treatment and remained for 1-2weeks higher than baseline (53.33 ± 15.80 × 10 9 /L). The white blood cell count and platelet count of the patients were substantially improved during the follow-up period. No substantial difference was observed in RBC counts between baseline and after treatment. In addition, symptoms such as epistaxis and gingival bleeding were ameliorated or even eliminated, and the quality of life was improved. Follow-up imaging showed a nonperfused volume in the spleen. Conclusions: For the first time to our knowledge, high-intensity focused ultrasound ablation was used to treat Chemotherapy-induced thrombocytopenia (CIT) and hypersplenism. High-intensity focused ultrasound ablation of the spleen may cause damage to a certain volume of the spleen parenchyma to achieve the purpose of hypersplenism treatment. High intensity focused ultrasound may be an effective and safe alternative for treatment of CIT and hypersplenism.
Molecular mechanisms of paraptosis induction: implications for a non-genetic modified tumor vaccine
Authors: Martin Jadus, Neil Hoa, Michael Myers, Thomas Douglass, Jian Zhang, Christina Delgado, Linda Callahan, Gerald Vandeusen, Jimmy Pham, Nirav Bhakta, Harold Wepsic
Journal: Cancer Research (2008)

5294  Cell shrinkage characterizes apoptosis, also called the “silent death”, whereas, osmotic lysis distinguishes necrosis. Necrotic cells generally produce stronger immune responses than apoptotic cells. Paraptosis which leads to necrosis is the least well known of the three types of programmed cell death pathways. Previously, we demonstrated in vivo that through paraptosisrodent and human monocytes/macrophages killed glioma cells bearing the membrane macrophage colony stimulating factor; however, the molecular mechanism of this killing process was never identified. We have shown that paraptosis of rat T9 glioma cells can be initiated through a Maxi-K potassium channel dependent process initiated by reactive oxygen species. Macrophage mediated cytotoxicity of the mM-CSF expressing T9-C2 cells was not prevented by the caspase inhibitor, zVAD-fmk. By a combination of confocal and electron microscopy, flow cytometry, electrophysiology, pharmacology and genetic knock-down approaches, we have demonstrated that these ion channels control cellular swelling and vacuolization of rat T9 glioma cells through a depletion of intracellular ATP. Elucidation of this pathway also explains why the mitochondria and endoplasmic reticulum are specifically targeted in paraptosis. Rats injected with T9 cells that were killed by sustained Maxi-K channel activation developed immunity against the T9 cells. The injection of x-irradiated apoptotic T9 cells failed to produce the same vaccinating effect. These results indicate that glioma cellular death induced by prolonged Maxi-K channel activation naturally improves tumor immunogenicity. Such paraptosis inducing strategies may have value in the development of clinical immunological therapy techniques against cancer.
Trifunctional Graphene Quantum Dot@LDH Integrated Nanoprobes for Visualization Therapy of Gastric Cancer
Authors: Bin Wu, Kun Li, Feiyue Sun, Jintong Niu, Rongrong Zhu, Yechang Qian, Shilong Wang
Journal: Advanced Healthcare Materials (2021)

Abstract Visualization technology has become a trend in tumor therapy in recent years. The superior optical properties of graphene quantum dots (GQDs) make them suitable candidates for tumor diagnosis, but their tumor targeting and drug‐carrying capacities are still not ideal for treatment. Sulfur‐doped graphene quantum dots (SGQDs) with stable fluorescence are prepared in a previous study. A reliable strategy by associating layered double hydroxides (LDHs) and etoposide (VP16) is designed for precise visualization therapy. Trifunctional LDH@SGQD‐VP16 integrated nanoprobes can simultaneously achieve targeted aggregation, fluorescence visualization, and chemotherapy. LDH@SGQD‐VP16 can accumulate in the tumor microenvironment, owing to pH‐sensitive properties and long‐term photostability in vivo, which can provide a basis for cancer targeting, real‐time imaging, and effect tracking. The enhanced therapeutic and attenuated side effects of VP16 are demonstrated, and the apoptosis caused by LDH@SGQD‐VP16 is ≈2.7 times higher than that of VP16 alone, in HGC‐27 cells. This work provides a theoretical and experimental basis for LDH@SGQD‐VP16 as a potential multifunctional agent for visualization therapy of gastric cancer.
SGNTGT-001: A phase 1 study of SEA-TGT, an effector-function enhanced monoclonal antibody (mAb), in advanced malignancies (trial in progress).
Authors: Elena Garralda, Rachel E. Sanborn, Anna Rachel Minchom, Diwakar Davar, Giuseppe Curigliano, Vincent Ribrag, Amitkumar Mehta, Francine M. Foss, Jasmine M. Zain, Andres Forero-Torres, Stephen M. Ansell
Journal: Journal of Clinical Oncology (2021)

TPS2657 Background: T-cell immunoreceptor with Ig and ITIM domains (TIGIT) is an inhibitory immune checkpoint receptor expressed on subsets of T cells and NK cells. SEA-TGT is an effector-function enhanced human mAb that targets TIGIT with pico-molar affinity and blocks TIGIT’s interaction with CD155 and CD112. SEA-TGT was developed to have amplified binding to and engagement of Fcγ receptors. Enhanced effector function increases TIGIT+ T-regulatory cell depletion, enhances innate immune cell activation, and augments naïve and memory CD8+ T-cell responses. Preclinically, SEA-TGT elicits superior anti-tumor immune responses compared to other TIGIT mAbs without effector-enhanced backbones, with curative anti-tumor activity as monotherapy and in combination with other immune-modulators. Methods: This phase 1, open-label, multicenter, dose-escalation/expansion study (NCT04254107) is assessing the safety, tolerability and preliminary activity of SEA-TGT monotherapy in up to 205 adults (≥18 years) with histologically or cytologically confirmed relapsed, refractory, or progressive metastatic solid tumors (non-small cell lung, gastric/GE junction carcinomas, cutaneous melanoma, head and neck squamous cell carcinoma, bladder cancer, ovarian cancer or triple-negative breast cancer) or lymphomas (classical Hodgkin lymphoma, diffuse large B-cell lymphoma, or peripheral T-cell lymphoma, not otherwise specified). SEA-TGT will be infused on Day 1 of 21-day cycles. In Part A, the safety and tolerability of SEA-TGT will be assessed in ̃25 subjects to identify the maximum tolerated dose and recommended phase II dose (RP2D). In Part B, the safety and antitumor activity of the RP2D will be assessed in ̃180 subjects in disease-specific expansion cohorts. Primary endpoints are adverse events, laboratory abnormalities, dose-limiting toxicities, and dose-level safety and activity. Secondary endpoints are objective response (OR) rates, duration of OR, complete response, progression-free survival, overall survival, PK, and antidrug antibodies. Exploratory biomarkers of SEA-TGT-mediated pharmacodynamic (PD) effects, PK-PD correlations, and correlative analyses of predictive and PD measurements with response, toxicity, and resistance will be explored. The study was opened April 2020 and is enrolling across sites in North America and Europe. Clinical trial information: NCT04254107.