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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 37 records · Page 2
All sourcesNASA NTRSDOE OSTI
DOE OSTI2022

A Novel DNA Repair Gene Signature for Immune Checkpoint Inhibitor-Based Therapy in Gastric Cancer

Gastric cancer is a heterogeneous group of diseases with only a fraction of patients responding to immunotherapy. The relationships between tumor DNA damage response, patient immune system and immunotherapy have recently attracted attention. Accumulating evidence suggests that DNA repair landscape is a significant factor in driving response to immune checkpoint blockade (ICB) therapy. In this study, to explore new prognostic and predictive biomarkers for gastric cancer patients who are sensitive and responsive to immunotherapies, we developed a novel 15-DNA repair gene signature (DRGS) and its related scoring system and evaluated the efficiency of the DRGS in discriminating different molecular and immune characteristics and therapeutic outcomes of patients with gastric adenocarcinoma, using publicly available datasets. The results demonstrated that DRGS high score patients showed significantly better therapeutic outcomes for ICB compared to DRGS low score patients (p < 0.001). Integrated analysis of multi-omics data demonstrated that the patients with high DRGS score were characteristic of high levels of anti-tumor lymphocyte infiltration, tumor mutation burden (TMB) and PD-L1 expression, and these patients exhibited a longer overall survival, as compared to the low-score patients. Results obtained from HPA and IHC supported significant dysregulation of the genes in DRGS in gastric cancer tissues, and a positive correlation in protein expression between DRGS and PD-L1. Therefore, the DRGS scoring system may have implications in tailoring immunotherapy in gastric cancers. A preprint has previously been published (Yuan et al., 2021).

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

An unsupervised machine-learning checkpoint-restart algorithm using Gaussian mixtures for particle-in-cell simulations

We propose an unsupervised machine-learning checkpoint-restart (CR) algorithm for particle-in-cell (PIC) algorithms using Gaussian mixtures (GM). The algorithm compresses the particle population per spatial cell by constructing a velocity distribution function using GM. Particles are reconstructed at restart time by local resampling of the Gaussians. To guarantee fidelity of the CR process, we ensure the exact preservation of invariants such as charge, momentum, and energy for both compression and reconstruction stages, everywhere on the mesh. We also ensure the preservation of Gauss' law after particle reconstruction by exactly matching the density profile at restart time. As a result, the GM CR algorithm is shown to provide a clean, conservative restart capability while potentially affording orders of magnitude savings in input/output requirements. Here, we demonstrate the algorithm using a recently developed exactly energy- and charge-conserving PIC algorithm using both electrostatic and electromagnetic tests. The tests demonstrate not only a high-fidelity CR capability, but also its potential for enhancing the fidelity of the PIC solution for a given particle resolution.

97 MATHEMATICS AND COMPUTING↗
DOE OSTI2023

Epitope topography of agonist antibodies to the checkpoint inhibitory receptor BTLA

B and T lymphocyte attenuator (BTLA) is an attractive target for a new class of therapeutics that attempt to rebalance the immune system by agonizing checkpoint inhibitory receptors (CIRs). Herpesvirus entry mediator (HVEM) binds BTLA in both trans- and cis-orientations. We report here the development and structural characterization of three humanized BTLA agonist antibodies, 22B3, 25F7, and 23C8. We determined the crystal structures of the antibody-BTLA complexes, showing that these antibodies bind distinct and non-overlapping epitopes of BTLA. While all three antibodies activate BTLA, 22B3 mimics HVEM binding to BTLA and shows the strongest agonistic activity in functional cell assays and in an imiquimod-induced mouse model of psoriasis. 22B3 is also capable of modulating HVEM signaling through the BTLA-HVEM cis-interaction. The data obtained from crystal structures, biochemical assays, and functional studies provide a mechanistic model of HVEM and BTLA organization on the cell surface and informed the discovery of a highly active BTLA agonist.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Pan‐Cancer Survival Impact of Immune Checkpoint Inhibitors in a National Healthcare System

ABSTRACT Background The cumulative, health system‐wide survival benefit of immune checkpoint inhibitors (ICIs) is unclear, particularly among real‐world patients with limited life expectancies and among subgroups poorly represented on clinical trials. We sought to determine the health system‐wide survival impact of ICIs. Methods We identified all patients receiving PD‐1/PD‐L1 or CTLA‐4 inhibitors from 2010 to 2023 in the national Veterans Health Administration (VHA) system (ICI cohort) and all patients who received non‐ICI systemic therapy in the years before ICI approval (historical control). ICI and historical control cohorts were matched on multiple cancer‐related prognostic factors, comorbidities, and demographics. The effect of ICI on overall survival was quantified with Cox regression incorporating matching weights. Cumulative life‐years gained system‐wide were calculated from the difference in adjusted 5‐year restricted mean survival times. Results There were 27,322 patients in the ICI cohort and 69,801 patients in the historical control cohort. Among ICI patients, the most common cancer types were NSCLC (46%) and melanoma (10%). ICI demonstrated a large OS benefit in most cancer types with heterogeneity across cancer types (NSCLC: adjusted HR [aHR] 0.56, 95% confidence interval [CI] 0.54–0.58,p < 0.001; urothelial: aHR 0.91, 95% CI 0.83–1.01,p = 0.066). The relative benefit of ICI was stable across patient age, comorbidity, and self‐reported race subgroups. Across VHA, 15,859 life‐years gained were attributable to ICI within 5‐years of treatment, with NSCLC contributing the most life‐years gained. Conclusion We demonstrated substantial increase in survival due to ICIs across a national health system, including in patient subgroups poorly represented on clinical trials.

Oncology↗
DOE OSTI2021

Prospective Clinical Investigation of the Efficacy of Combination Radiation Therapy With Immune Checkpoint Inhibition

Immune checkpoint inhibitors (ICIs) lead to durable responses in a subset of patients with cancer, but most patients do not respond to ICI, prompting interest in combining immunotherapy with other therapeutic regimens. Preclinical evidence supports the potential for therapeutic synergy between immunotherapy and radiation therapy through modulation of the tumor microenvironment and antitumor immune responses. Local therapy also has the potential to overcome localized sites of relative immune suppression and resistance. Prospective clinical trials have been initiated to test these hypotheses in the clinic as well as to investigate the toxicities and adverse events associated with combination immunotherapy and radiation therapy. In this review, we discuss the emerging results from prospective clinical trials of combination immunotherapy and radiation therapy, the safety and efficacy of their combination, concordance with preclinical and retrospective data, and some of the remaining open questions to be addressed by future clinical trials.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2022

Inhibiting ACK1-mediated phosphorylation of C-terminal Src kinase counteracts prostate cancer immune checkpoint blockade resistance

Solid tumours are highly refractory to immune checkpoint blockade (ICB) therapies due to the functional impairment of effector T cells and their inefficient trafficking to tumours. T-cell activation is negatively regulated by C-terminal Src kinase (CSK); however, the exact mechanism remains unknown. Here we show that the conserved oncogenic tyrosine kinase Activated CDC42 kinase 1 (ACK1) is able to phosphorylate CSK at Tyrosine 18 (pY18), which enhances CSK function, constraining T-cell activation. Mice deficient in the Tnk2 gene encoding Ack1, are characterized by diminished CSK Y18-phosphorylation and spontaneous activation of CD 8+ and CD 4+ T cells, resulting in inhibited growth of transplanted ICB-resistant tumours. Furthermore, ICB treatment of castration-resistant prostate cancer (CRPC) patients results in re-activation of ACK1/pY18-CSK signalling, confirming the involvement of this pathway in ICB insensitivity. An ACK1 small-molecule inhibitor, (R)-9b, recapitulates inhibition of ICB-resistant tumours, which provides evidence for ACK1 enzymatic activity playing a pivotal role in generating ICB resistance. Overall, our study identifies an important mechanism of ICB resistance and holds potential for expanding the scope of ICB therapy to tumours that are currently unresponsive.

60 APPLIED LIFE SCIENCES↗