tbuckley/cabot-search huggingface dataset:
Longitudinal analysis of PD-L1 expression in patients with relapsed NSCLC
Authors: Nikolaus John, Verena Schlintl, Teresa Sassmann, Jörg Lindenmann, Melanie Fediuk, Robert Wurm, Philipp Douschan, Martin Zacharias, Lipika Kalson, Florian Posch, Gudrun Absenger, Luka Brcic, Philipp J Jost, Angelika Terbuch
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background The use and approval of immune checkpoint inhibitors for the treatment of non-small cell lung cancer (NSCLC) depends on PD-L1 expression in the tumor tissue. Nevertheless, PD-L1 often fails to predict response to treatment. One possible explanation could be a change in PD-L1 expression during the course of the disease and the neglect of reassessment. The purpose of this study was a longitudinal analysis of PD-L1 expression in patients with relapsed NSCLC. Methods We retrospectively analyzed PD-L1 expression in patients with early-stage NSCLC and subsequent relapse in preoperative samples, matched surgical specimens and biopsy samples of disease recurrence. Ventana PD-L1 (SP263) immunohistochemistry assay was used for all samples. PD-L1 expression was scored based on clinically relevant groups (0%, 1%–49%, and ≥50%). The primary endpoint was the change in PD-L1 score group between preoperative samples, matched surgical specimens and relapsed tumor tissue. Results 395 consecutive patients with stages I–III NSCLC and 136 (34%) patients with a subsequent relapse were identified. For 87 patients at least two specimens for comparison of PD-L1 expression between early stage and relapsed disease were available. In 72 cases, a longitudinal analysis between preoperative biopsy, the surgically resected specimen and biopsy of disease recurrence was feasible. When comparing preoperative and matched surgical specimens, a treatment-relevant conversion of PD-L1 expression group was found in 25 patients (34.7%). Neoadjuvant treatment showed no significant effect on PD-L1 alteration (p=0.39). In 32 (36.8%) out of 87 cases, a change in PD-L1 group was observed when biopsies of disease relapse were compared with early-stage disease. Adjuvant treatment was not significantly associated with a change in PD-L1 expression (p=0.53). 39 patients (54.2%) showed at least 1 change into a different PD-L1 score group during the course of disease. 14 patients (19.4%) changed the PD-L1 score group twice, 5 (6.9%) of them being found in all different score groups. Conclusion PD-L1 expression shows dynamic changes during the course of disease. There is an urgent need for consensus guidelines to define a PD-L1 testing strategy including time points of reassessment, the number of biopsies to be obtained and judgment of surgical specimens.
Molecular assessment of intratumoral immune cell subsets and potential mechanisms of resistance to odronextamab, a CD20×CD3 bispecific antibody, in patients with relapsed/refractory B-cell non-Hodgkin lymphoma
Authors: Jurriaan Brouwer-Visser, Nathalie Fiaschi, Raquel P Deering, Kamil J Cygan, Darius Scott, Se Jeong, Lauren Boucher, Namita T Gupta, Suraj Gupta, Christina Adler, Max S Topp, Rajat Bannerji, Johannes Duell, Ranjana H Advani, Dina M Flink, Aafia Chaudhry, Gavin Thurston, Srikanth R Ambati, Vladimir Jankovic
Journal: Journal for ImmunoTherapy of Cancer (2024)

Patients with relapsed/refractory B-cell non-Hodgkin lymphoma (R/R B-NHL) have a significant need for effective treatment options. Odronextamab is an Fc-silenced, human, CD20×CD3 bispecific antibody that targets CD20-expressing cells via T-cell-mediated cytotoxicity independent of T-cell/major histocompatibility complex interaction. Phase I results in patients with R/R B-NHL demonstrated that odronextamab monotherapy could achieve deep and durable responses with a generally manageable safety profile (ELM-1; NCT02290951). As part of a biomarker analysis of the same study, we investigated potential biomarkers and mechanisms of resistance to odronextamab. Patients with R/R B-NHL enrolled in ELM-1 received one time per week doses of intravenous odronextamab for 4×21 day cycles, then doses every 2 weeks thereafter. Patient tumor biopsies were obtained at baseline, on-treatment, and at progression. Immune cell markers were analyzed by immunohistochemistry, flow cytometry, single-cell RNA sequencing, and whole genome sequencing. Baseline tumor biopsies showed that almost all patients had high proportions of B cells that expressed the CD20 target antigen, whereas expression of other B-cell surface antigens (CD19, CD22, CD79b) was more variable. Responses to odronextamab in patients with diffuse large B-cell lymphoma were not related to the relative level of baseline CD20 expression, cell of origin, or high-risk molecular subtype. A potential link was observed between greater tumor programmed cell death-ligand 1 expression and increased likelihood of response to odronextamab. Similarly, a trend was observed between clinical response and increased levels of CD8 T cells and regulatory T cells at baseline. We also identified an on-treatment pharmacodynamic shift in intratumoral immune cell subsets. Finally, loss of CD20 expression through inactivating gene mutations was identified as a potential mechanism of resistance in patients who were treated with odronextamab until progression, as highlighted in two detailed patient cases reported here. This biomarker analysis expands on clinical findings of odronextamab in patients with R/R B-NHL, providing verification of the suitability of CD20 as a therapeutic target, as well as evidence for potential mechanisms of action and resistance.
Oral PD-L1 inhibitor GS-4224 selectively engages PD-L1 high cells and elicits pharmacodynamic responses in patients with advanced solid tumors
Authors: Jared M Odegard, Ahmed A Othman, Kai-Wen Lin, Adele Y Wang, Jonathan Nazareno, Oh Kyu Yoon, John Ling, Latesh Lad, P Rod Dunbar, Dung Thai, Edmond Ang, Nicholas Waldron, Sanjeev Deva
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Checkpoint inhibitors targeting the programmed cell death 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) pathway are effective therapies in a range of immunogenic cancer types. Blocking this pathway with an oral therapy could benefit patients through greater convenience, particularly in combination regimens, and allow flexible management of immune-mediated toxicities. Methods PD-L1 binding activity was assessed in engineered dimerization and primary cell target occupancy assays. Preclinical antitumor activity was evaluated in ex vivo and in vivo human PD-L1-expressing tumor models. Human safety, tolerability, pharmacokinetics, and biomarker activity were evaluated in an open-label, multicenter, sequential dose-escalation study in patients with advanced solid tumors. Biomarkers evaluated included target occupancy, flow cytometric immunophenotyping, plasma cytokine measurements, and T-cell receptor sequencing. Results GS-4224 binding caused dimerization of PD-L1, blocking its interaction with PD-1 and leading to reversal of T-cell inhibition and increased tumor killing in vitro and in vivo. The potency of GS-4224 was dependent on the density of cell surface PD-L1, with binding being most potent on PD-L1–high cells. In a phase 1 dose-escalation study in patients with advanced solid tumors, treatment was well tolerated at doses of 400–1,500 mg once daily. Administration of GS-4224 was associated with a dose-dependent increase in plasma GS-4224 exposure and reduction in free PD-L1 on peripheral blood T cells, an increase in Ki67 among the PD-1-positive T-cell subsets, and elevated plasma cytokines and chemokines. Conclusions GS-4224 is a novel, orally bioavailable small molecule inhibitor of PD-L1. GS-4224 showed evidence of expected on-target biomarker activity, including engagement of PD-L1 and induction of immune-related pharmacodynamic responses consistent with PD-L1 blockade. Trial registration number NCT04049617 .
The clinical outcome of COVID-19 is strongly associated with microbiome dynamics in the upper respiratory tract
Authors: Linlin Xie, Gengyan Luo, Zhongzhou Yang, Wei-Chen Wu, Jintao Chen, Yuting Ren, Zhikun Zeng, Guangming Ye, Yunbao Pan, Wen-Jing Zhao, Yao-Qing Chen, Wei Hou, Yanni Sun, Deying Guo, Zifeng Yang, Jun Li, Edward C Holmes, Yirong Li, Liangjun Chen, Mang Shi
Journal: Journal of Infection (2024)

The respiratory tract is the portal of entry for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although a variety of respiratory pathogens other than SARS-CoV-2 have been associated with severe cases of COVID-19 disease, the dynamics of the upper respiratory microbiota during disease the course of disease, and how they impact disease manifestation, remain uncertain.
Treatment-free survival outcomes from the phase II study of nivolumab and salvage nivolumab/ipilimumab in advanced clear cell renal cell carcinoma (HCRN GU16-260-Cohort A)
Authors: Michael B Atkins, Opeyemi A Jegede, Naomi B Haas, David F Mcdermott, Mehmet A Bilen, Mark Stein, Jeffrey Sosman, Robert Alter, Elizabeth R Plimack, Moshe C Ornstein, Michael Hurwitz, David J Peace, David Einstein, Paul J Catalano, Hans Hammers, Meredith M Regan
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background As part of a partitioned survival analysis, treatment-free survival (TFS) can characterize the overall survival time patients spend between the cessation of immunotherapy and the start of subsequent therapy; both with and without toxicity. Significant TFS was reported for the nivolumab/ipilimumab arms of the CheckMate 067 and 214 trials for patients with advanced melanoma or renal cell carcinoma (aRCC), respectively, where immunotherapy was often halted for toxicity rather than a predefined treatment endpoint. We therefore sought to assess TFS in the HCRN GU16-260 trial, which was designed to reduce toxicity and cap immunotherapy duration. Methods Data were analyzed from 128 patients with clear-cell aRCC treated with first-line nivolumab monotherapy for up to 2 years. Salvage nivolumab/ipilimumab for up to 1 year was provided to eligible patients with disease progression at any point or stable disease at 48 weeks (29% of patients). TFS was defined as the area between Kaplan-Meier curves for a time from registration to protocol therapy cessation and for a time from registration to subsequent systemic therapy initiation or death, estimated from 36-month mean times. The time on or off protocol treatment with grade 3+treatment-related adverse events (TRAEs) was also captured. Results At 36 months from enrollment, 68.3% of patients were alive: 96.8% of International Metastatic RCC Database Consortium (IMDC) favorable-risk patients and 56.6% of those with intermediate/poor-risk, respectively. The 36-month mean time on protocol therapy was 11.5 months including 0.6 months with grade 3+TRAEs (16.0 months for favorable-risk patients and 9.6 months for intermediated/poor-risk patients). The 36-month mean TFS for the whole population was 9.4 months (12.9 months including 1.5 months with grade 3+TRAEs for favorable-risk and 8.0 months including 1.0 months with grade 3+TRAEs for intermediate/poor-risk). At 36 months, 65.6% of favorable-risk patients and 27.1% of intermediate/poor-risk patients were alive and subsequent systemic treatment-free. Conclusions Nivolumab monotherapy with salvage nivolumab/ipilimumab in non-responders is an active treatment approach in treatment-naïve patients with aRCC and, similar to nivolumab/ipilimumab in CheckMate 214, results in substantial TFS and toxicity-free TFS. TFS was greatest in patients with favorable-risk disease, supporting the use of an immunotherapy-only regimen in this population.
Efficient CAR T cell targeting of the CA125 extracellular repeat domain of MUC16
Authors: Nicholas P Casey, Katrin Kleinmanns, Christopher Forcados, Pascal F Gelebart, Sandy Joaquina, Martine Lode, Emmanuelle Benard, Fatemeh Kaveh, Benjamin Caulier, Christiane Helgestad Gjerde, Elvira García de Jalón, David J Warren, Kristina Lindemann, Erik Rokkones, Ben Davidson, Marit Renee Myhre, Gunnar Kvalheim, Line Bjørge, Emmet McCormack, Else Marit Inderberg, Sébastien Wälchli
Journal: Journal for ImmunoTherapy of Cancer (2024)

Ovarian cancer (OC) is the leading cause of death from gynecologic malignancies in the Western world. Contributing factors include a high frequency of late-stage diagnosis, the development of chemoresistance, and the evasion of host immune responses. Currently, debulking surgery and platinum-based chemotherapy are the treatment cornerstones, although recurrence is common. As the clinical efficacy of immune checkpoint blockade is low, new immunotherapeutic strategies are needed. Chimeric antigen receptor (CAR) T cell therapy empowers patients' own T cells to fight and eradicate cancer, and has been tested against various targets in OC. A promising candidate is the MUC16 ectodomain. This ectodomain remains on the cell surface after cleavage of cancer antigen 125 (CA125), the domain distal from the membrane, which is currently used as a serum biomarker for OC. CA125 itself has not been tested as a possible CAR target. In this study, we examined the suitability of the CA125 as a target for CAR T cell therapy. We tested a series of antibodies raised against the CA125 extracellular repeat domain of MUC16 and adapted them to the CAR format. Comparisons between these candidates, and against an existing CAR targeting the MUC16 ectodomain, identified K101 as having high potency and specificity. The K101CAR was subjected to further biochemical and functional tests, including examination of the effect of soluble CA125 on its activity. Finally, we used cell lines and advanced orthotopic patient-derived xenograft (PDX) models to validate, in vivo, the efficiency of our K101CAR construct. We observed a high efficacy of K101CAR T cells against cell lines and patient-derived tumors, in vitro and in vivo. We also demonstrated that K101CAR functionality was not impaired by the soluble antigen. Finally, in direct comparisons, K101CAR, which targets the CA125 extracellular repeat domains, was shown to have similar efficacy to the previously validated 4H11CAR, which targets the MUC16 ectodomain. Our in vitro and in vivo results, including PDX studies, demonstrate that the CA125 domain of MUC16 represents an excellent target for treating MUC16-positive malignancies.
Autologous human preclinical modeling of melanoma interpatient clinical responses to immunotherapeutics
Authors: Yee Peng Phoon, Jared E Lopes, Lukas W Pfannenstiel, Claudia Marcela Diaz-Montero, Ye F Tian, Marc S Ernstoff, Pauline Funchain, Jennifer S Ko, Raymond Winquist, Heather C Losey, Jan Joseph Melenhorst, Brian R Gastman
Journal: Journal for ImmunoTherapy of Cancer (2024)

Despite recent advances in immunotherapy, a substantial population of late-stage melanoma patients still fail to achieve sustained clinical benefit. Lack of translational preclinical models continues to be a major challenge in the field of immunotherapy; thus, more optimized translational models could strongly influence clinical trial development. To address this unmet need, we designed a preclinical model reflecting the heterogeneity in melanoma patients' clinical responses that can be used to evaluate novel immunotherapies and synergistic combinatorial treatment strategies. Using our all-autologous humanized melanoma mouse model, we examined the efficacy of a novel engineered interleukin 2 (IL-2)-based cytokine variant immunotherapy. To study immune responses and antitumor efficacy for human melanoma tumors, we developed an all-autologous humanized melanoma mouse model using clinically annotated, matched patient tumor cells and peripheral blood mononuclear cells (PBMCs). After inoculating immunodeficient NSG mice with patient tumors and an adoptive cell transfer of autologous PBMCs, mice were treated with anti-PD-1, a novel investigational engineered IL-2-based cytokine (nemvaleukin), or recombinant human IL-2 (rhIL-2). The pharmacodynamic effects and antitumor efficacy of these treatments were then evaluated. We used tumor cells and autologous PBMCs from patients with varying immunotherapy responses to both model the diversity of immunotherapy efficacy observed in the clinical setting and to recapitulate the heterogeneous nature of melanoma. Our model exhibited long-term survival of engrafted human PBMCs without developing graft-versus-host disease. Administration of an anti-PD-1 or nemvaleukin elicited antitumor responses in our model that were patient-specific and were found to parallel clinical responsiveness to checkpoint inhibitors. An evaluation of nemvaleukin-treated mice demonstrated increased tumor-infiltrating CD4+ and CD8+ T cells, preferential expansion of non-regulatory T cell subsets in the spleen, and significant delays in tumor growth compared with vehicle-treated controls or mice treated with rhIL-2. Our model reproduces differential effects of immunotherapy in melanoma patients, capturing the inherent heterogeneity in clinical responses. Taken together, these data demonstrate our model's translatability for novel immunotherapies in melanoma patients. The data are also supportive for the continued clinical investigation of nemvaleukin as a novel immunotherapeutic for the treatment of melanoma.
Respiratory complex I regulates dendritic cell maturation in explant model of human tumor immune microenvironment
Authors: Rita Turpin, Ruixian Liu, Pauliina M Munne, Aino Peura, Jenna H Rannikko, Gino Philips, Bram Boeckx, Natasha Salmelin, Elina Hurskainen, Ilida Suleymanova, July Aung, Elisa M Vuorinen, Laura Lehtinen, Minna Mutka, Panu E Kovanen, Laura Niinikoski, Tuomo J Meretoja, Johanna Mattson, Satu Mustjoki, Päivi Saavalainen, Andrei Goga, Diether Lambrechts, Jeroen Pouwels, Maija Hollmén, Juha Klefström
Journal: Journal for ImmunoTherapy of Cancer (2024)

Combining cytotoxic chemotherapy or novel anticancer drugs with T-cell modulators holds great promise in treating advanced cancers. However, the response varies depending on the tumor immune microenvironment (TIME). Therefore, there is a clear need for pharmacologically tractable models of the TIME to dissect its influence on mono- and combination treatment response at the individual level.
International perspectives on measuring national digital public health system maturity through a multidisciplinary Delphi study
Authors: Laura Maaß, Hajo Zeeb, Heinz Rothgang
Journal: npj Digital Medicine (2024)

Abstract Unlocking the full potential of digital public health (DiPH) systems requires a comprehensive tool to assess their maturity. While the World Health Organization and the International Telecommunication Union released a toolkit in 2012 covering various aspects of digitalizing national healthcare systems, a holistic maturity assessment tool has been lacking ever since. To bridge this gap, we conducted a pioneering Delphi study, to which 54 experts from diverse continents and academic fields actively contributed to at least one of three rounds. 54 experts participated in developing and rating multidisciplinary quality indicators to measure the maturity of national digital public health systems. Participants established consensus on these indicators with a threshold of 70% agreement on indicator importance. Eventually, 96 indicators were identified and agreed upon by experts. Notably, 48% of these indicators were found to align with existing validated tools, highlighting their relevance and reliability. However, further investigation is required to assess the suitability and applicability of all the suggestions put forward by our participants. Nevertheless, this Delphi study is an essential initial stride toward a comprehensive measurement tool for DiPH system maturity. By working towards a standardized assessment of DiPH system maturity, we aim to empower decision-makers to make informed choices, optimize resource allocation, and drive innovation in healthcare delivery. The results of this study mark a significant milestone in advancing DiPH on a global scale.
Artificial intelligence-assisted assessment for Forrest classification of peptic ulcer bleeding: hype or reality?
Authors: Wai K. Leung
Journal: Endoscopy (2024)

Forrest et al. first described the evolution of peptic ulcer bleeding (PUB) in 1974, and their description was then widely adopted as the gold standard for risk stratification of PUB [1]. Current guidelines recommend the application of endoscopic therapy for patients with Forrest Ia (active spurting), Ib (active oozing), and IIa (nonbleeding visible vessel) [2]; however, the interobserver and intraobserver variation of this classification system may limit its role in practice [3] [4]. It is sometimes difficult to differentiate IIa from IIb lesions (with adherent clot) without proper irrigation and clot removal. Moreover, it can be controversial whether something is a less prominent vessel (IIa) or just a pigmented spot (IIc), with the latter not requiring any endoscopic intervention.
Metabolic reprogramming regulated by TRAF6 contributes to the leukemia progression
Authors: Shinichiro Matsui, Chihiro Ri, Lyndsey C. Bolanos, Kwangmin Choi, Asuka Shibamiya, Arata Ishii, Koji Takaishi, Nagisa Oshima-Hasegawa, Shokichi Tsukamoto, Yusuke Takeda, Naoya Mimura, Akihide Yoshimi, Koutaro Yokote, Daniel T. Starczynowski, Emiko Sakaida, Tomoya Muto
Journal: Leukemia (2024)

TNF receptor associated factor 6 (TRAF6) is an E3 ubiquitin ligase that has been implicated in myeloid malignancies. Although altered TRAF6 expression is observed in human acute myeloid leukemia (AML), its role in the AML pathogenesis remains elusive. In this study, we showed that the loss of TRAF6 in AML cells significantly impairs leukemic function in vitro and in vivo, indicating its functional importance in AML subsets. Loss of TRAF6 induces metabolic alterations, such as changes in glycolysis, TCA cycle, and nucleic acid metabolism as well as impaired mitochondrial membrane potential and respiratory capacity. In leukemic cells, TRAF6 expression shows a positive correlation with the expression of O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT), which catalyzes the addition of O-GlcNAc to target proteins involved in metabolic regulation. The restoration of growth capacity and metabolic activity in leukemic cells with TRAF6 loss, achieved through either forced expression of OGT or pharmacological inhibition of O-GlcNAcase (OGA) that removes O-GlcNAc, indicates the significant role of O-GlcNAc modification in the TRAF6-related cellular and metabolic dynamics. Our findings highlight the oncogenic function of TRAF6 in leukemia and illuminate the novel TRAF6/OGT/O-GlcNAc axis as a potential regulator of metabolic reprogramming in leukemogenesis.