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"Donington, Jessica"
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CDKN2A loss-of-function predicts immunotherapy resistance in non-small cell lung cancer
Immune checkpoint blockade (ICB) improves outcomes in non-small cell lung cancer (NSCLC) though most patients progress. There are limited data regarding molecular predictors of progression. In particular, there is controversy regarding the role of CDKN2A loss-of-function (LOF) in ICB resistance. We analyzed 139 consecutive patients with advanced NSCLC who underwent NGS prior to ICB initiation to explore the association of CDKN2A LOF with clinical outcomes. 73% were PD-L1 positive (≥ 1%). 48% exhibited high TMB (≥ 10 mutations/megabase). CDKN2A LOF was present in 26% of patients and was associated with inferior PFS (multivariate hazard ratio [MVA-HR] 1.66, 95% CI 1.02–2.63,
p
= 0.041) and OS (MVA-HR 2.08, 95% CI 1.21–3.49,
p
= 0.0087) when compared to wild-type (WT) patients. These findings held in patients with high TMB (median OS, LOF vs. WT 10.5 vs. 22.3 months;
p
= 0.069) and PD-L1 ≥ 50% (median OS, LOF vs. WT 11.1 vs. 24.2 months;
p
= 0.020), as well as in an independent dataset. CDKN2A LOF vs. WT tumors were twice as likely to experience disease progression following ICB (46% vs. 21%;
p
= 0.021). CDKN2A LOF negatively impacts clinical outcomes in advanced NSCLC treated with ICB, even in high PD-L1 and high TMB tumors. This novel finding should be prospectively validated and presents a potential therapeutic target.
Journal Article
Fibulin-3 as a Blood and Effusion Biomarker for Pleural Mesothelioma
Plasma levels of fibulin-3 reliably distinguish patients with pleural mesothelioma from patients with other types of pleural effusions and asbestos-exposed persons.
Despite advances in chemotherapy, radiation therapy, and surgical management for malignant pleural mesothelioma, the median survival remains 12 months.
1
Early detection is limited by the long latency period, an inability of imaging to detect the disease at an early stage even when it is used as a screening strategy, and the lack of sensitive and specific blood-based markers.
2
Moreover, in patients with undiagnosed pleural effusion, the ability to diagnose mesothelioma is delayed by failure to include the disease in the differential diagnosis and by the lack of noninvasive mesothelioma-specific blood-based markers. Soluble mesothelin-related protein, the most extensively studied blood-based mesothelioma . . .
Journal Article
SARS-CoV-2 Infection Severity Is Linked to Superior Humoral Immunity against the Spike
With the ongoing pandemic, it is critical to understand how natural immunity against SARS-CoV-2 and COVID-19 develops. We have identified that subjects with more severe COVID-19 disease mount a more robust and neutralizing antibody response against SARS-CoV-2 spike protein. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently causing a global pandemic. The antigen specificity of the antibody response mounted against this novel virus is not understood in detail. Here, we report that subjects with a more severe SARS-CoV-2 infection exhibit a larger antibody response against the spike and nucleocapsid protein and epitope spreading to subdominant viral antigens, such as open reading frame 8 and nonstructural proteins. Subjects with a greater antibody response mounted a larger memory B cell response against the spike, but not the nucleocapsid protein. Additionally, we revealed that antibodies against the spike are still capable of binding the D614G spike mutant and cross-react with the SARS-CoV-1 receptor binding domain. Together, this study reveals that subjects with a more severe SARS-CoV-2 infection exhibit a greater overall antibody response to the spike and nucleocapsid protein and a larger memory B cell response against the spike. IMPORTANCE With the ongoing pandemic, it is critical to understand how natural immunity against SARS-CoV-2 and COVID-19 develops. We have identified that subjects with more severe COVID-19 disease mount a more robust and neutralizing antibody response against SARS-CoV-2 spike protein. Subjects who mounted a larger response against the spike also mounted antibody responses against other viral antigens, including the nucleocapsid protein and ORF8. Additionally, this study reveals that subjects with more severe disease mount a larger memory B cell response against the spike. These data suggest that subjects with more severe COVID-19 disease are likely better protected from reinfection with SARS-CoV-2.
Journal Article
Intraoperative arteriovenous patient sampling to assess in situ non–small cell lung cancer metabolism
Here authors report intraoperative sampling of blood entering and leaving the lung allowing direct assessment of nutrient use by lung cancer.
Journal Article
What is the ideal endpoint in early-stage immunotherapy neoadjuvant trials in lung cancer?
Numerous clinical trials investigating neoadjuvant immune checkpoint inhibitors (ICI) have been performed over the last 5 years. As the number of neoadjuvant trials increases, attention must be paid to identifying informative trial endpoints. Complete pathologic response has been shown to be an appropriate surrogate endpoint for clinical outcomes, such as event-free survival or overall survival, in breast cancer and bladder cancer, but it is less established for non-small-cell lung cancer (NSCLC). The simultaneous advances reported with adjuvant ICI make the optimal strategy for early-stage disease debatable. Considering the long time required to conduct trials, it is important to identify optimal endpoints and discover surrogate endpoints for survival that can help guide ongoing clinical research. Endpoints can be grouped into two categories: medical and surgical. Medical endpoints are measures of survival and drug activity; surgical endpoints describe the feasibility of neoadjuvant approaches at a surgical level as well as perioperative attrition and complications. There are also several exploratory endpoints, including circulating tumor DNA clearance and radiomics. In this review, we outline the advantages and disadvantages of commonly reported endpoints for clinical trials of neoadjuvant regimens in NSCLC.
Journal Article
The Effect of Normothermic Machine Perfusion on the Immune Profile of Donor Liver
BackgroundNormothermic machine perfusion (NMP) allows viability assessment and potential resuscitation of donor livers prior to transplantation. The immunological effect of NMP on liver allografts is undetermined, with potential implications on allograft function, rejection outcomes and overall survival. In this study we define the changes in immune profile of human livers during NMP.MethodsSix human livers were placed on a NMP device. Tissue and perfusate samples were obtained during cold storage prior to perfusion and at 1, 3, and 6 hours of perfusion. Flow cytometry, immunohistochemistry, and bead-based immunoassays were used to measure leukocyte composition and cytokines in the perfusate and within the liver tissue. Mean values between baseline and time points were compared by Student’s t-test.ResultsWithin circulating perfusate, significantly increased frequencies of CD4 T cells, B cells and eosinophils were detectable by 1 hour of NMP and continued to increase at 6 hours of perfusion. On the other hand, NK cell frequency significantly decreased by 1 hour of NMP and remained decreased for the duration of perfusion. Within the liver tissue there was significantly increased B cell frequency but decreased neutrophils detectable at 6 hours of NMP. A transient decrease in intermediate monocyte frequency was detectable in liver tissue during the middle of the perfusion run. Overall, no significant differences were detectable in tissue resident T regulatory cells during NMP. Significantly increased levels of pro-inflammatory and anti-inflammatory cytokines were seen following initiation of NMP that continued to rise throughout duration of perfusion.ConclusionsTime-dependent dynamic changes are seen in individual leukocyte cell-types within both perfusate and tissue compartments of donor livers during NMP. This suggests a potential role of NMP in altering the immunogenicity of donor livers prior to transplant. These data also provide insights for future work to recondition the intrinsic immune profile of donor livers during NMP prior to transplantation.
Journal Article
Fair and equitable subject selection in concurrent COVID-19 clinical trials
Clinical trials emerged in rapid succession as the COVID-19 pandemic created an unprecedented need for life-saving therapies. Fair and equitable subject selection in clinical trials offering investigational therapies ought to be an urgent moral concern. Subject selection determines the distribution of risks and benefits, and impacts the applicability of the study results for the larger population. While Research Ethics Committees monitor fair subject selection within each trial, no standard oversight exists for subject selection across multiple trials for the same disease. Drawing on the experience of multiple clinical trials at a single academic medical centre in the USA, we posit that concurrent COVID-19 trials are liable to unfair and inequitable subject selection on account of scientific uncertainty, lack of transparency, scarcity and, lastly, structural barriers to equity compounded by implicit bias. To address the critical gap in the current literature and international regulation, we propose new ethical guidelines for research design and conduct that bolsters fair and equitable subject selection. Although the proposed guidelines are tailored to the research design and protocol of concurrent trials in the COVID-19 pandemic, they may have broader relevance to single COVID-19 trials.
Journal Article