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  • 1
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    Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19
    Springer Science and Business Media LLC ; 2023
    In:  Genome Medicine Vol. 15, No. 1 ( 2023-04-05)
    Details
    In: Genome Medicine, Springer Science and Business Media LLC, Vol. 15, No. 1 ( 2023-04-05)
    Abstract: We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15–20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases. Methods We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. Results No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7 , with an OR of 27.68 (95%CI 1.5–528.7, P  = 1.1 × 10 −4 ) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3–8.2], P  = 2.1 × 10 −4 ). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1–2635.4], P  = 3.4 × 10 −3 ), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3–8.4], P  = 7.7 × 10 −8 ). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients (56.0 [17.3] years; P  = 1.68 × 10 −5 ). Conclusions Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old.
    Type of Medium: Online Resource
    ISSN: 1756-994X
    URL: Article
    DOI: 10.1186/s13073-023-01173-8
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
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  • 2
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    Autoantibodies neutralizing type I IFNs are present in ~4% of uninfected individuals over 70 years old and account for ~20% of COVID-19 deaths
    American Association for the Advancement of Science (AAAS) ; 2021
    In:  Science Immunology Vol. 6, No. 62 ( 2021-08-10)
    Details
    In: Science Immunology, American Association for the Advancement of Science (AAAS), Vol. 6, No. 62 ( 2021-08-10)
    Abstract: Circulating autoantibodies (auto-Abs) neutralizing high concentrations (10 ng/ml; in plasma diluted 1:10) of IFN-α and/or IFN-ω are found in about 10% of patients with critical COVID-19 (coronavirus disease 2019) pneumonia but not in individuals with asymptomatic infections. We detect auto-Abs neutralizing 100-fold lower, more physiological, concentrations of IFN-α and/or IFN-ω (100 pg/ml; in 1:10 dilutions of plasma) in 13.6% of 3595 patients with critical COVID-19, including 21% of 374 patients 〉 80 years, and 6.5% of 522 patients with severe COVID-19. These antibodies are also detected in 18% of the 1124 deceased patients (aged 20 days to 99 years; mean: 70 years). Moreover, another 1.3% of patients with critical COVID-19 and 0.9% of the deceased patients have auto-Abs neutralizing high concentrations of IFN-β. We also show, in a sample of 34,159 uninfected individuals from the general population, that auto-Abs neutralizing high concentrations of IFN-α and/or IFN-ω are present in 0.18% of individuals between 18 and 69 years, 1.1% between 70 and 79 years, and 3.4% 〉 80 years. Moreover, the proportion of individuals carrying auto-Abs neutralizing lower concentrations is greater in a subsample of 10,778 uninfected individuals: 1% of individuals 〈 70 years, 2.3% between 70 and 80 years, and 6.3% 〉 80 years. By contrast, auto-Abs neutralizing IFN-β do not become more frequent with age. Auto-Abs neutralizing type I IFNs predate SARS-CoV-2 infection and sharply increase in prevalence after the age of 70 years. They account for about 20% of both critical COVID-19 cases in the over 80s and total fatal COVID-19 cases.
    Type of Medium: Online Resource
    ISSN: 2470-9468
    URL: Article
    DOI: 10.1126/sciimmunol.abl4340
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2021
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  • 3
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    The risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodies
    Proceedings of the National Academy of Sciences ; 2022
    In:  Proceedings of the National Academy of Sciences Vol. 119, No. 21 ( 2022-05-24)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 119, No. 21 ( 2022-05-24)
    Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection fatality rate (IFR) doubles with every 5 y of age from childhood onward. Circulating autoantibodies neutralizing IFN-α, IFN-ω, and/or IFN-β are found in ∼20% of deceased patients across age groups, and in ∼1% of individuals aged 〈 70 y and in 〉 4% of those 〉 70 y old in the general population. With a sample of 1,261 unvaccinated deceased patients and 34,159 individuals of the general population sampled before the pandemic, we estimated both IFR and relative risk of death (RRD) across age groups for individuals carrying autoantibodies neutralizing type I IFNs, relative to noncarriers. The RRD associated with any combination of autoantibodies was higher in subjects under 70 y old. For autoantibodies neutralizing IFN-α2 or IFN-ω, the RRDs were 17.0 (95% CI: 11.7 to 24.7) and 5.8 (4.5 to 7.4) for individuals 〈 70 y and ≥70 y old, respectively, whereas, for autoantibodies neutralizing both molecules, the RRDs were 188.3 (44.8 to 774.4) and 7.2 (5.0 to 10.3), respectively. In contrast, IFRs increased with age, ranging from 0.17% (0.12 to 0.31) for individuals 〈 40 y old to 26.7% (20.3 to 35.2) for those ≥80 y old for autoantibodies neutralizing IFN-α2 or IFN-ω, and from 0.84% (0.31 to 8.28) to 40.5% (27.82 to 61.20) for autoantibodies neutralizing both. Autoantibodies against type I IFNs increase IFRs, and are associated with high RRDs, especially when neutralizing both IFN-α2 and IFN-ω. Remarkably, IFRs increase with age, whereas RRDs decrease with age. Autoimmunity to type I IFNs is a strong and common predictor of COVID-19 death.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2200413119
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2022
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  • 4
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    Escherichia coli –Specific CXCL13-Producing TFH Are Associated with Clinical Efficacy of Neoadjuvant PD-1 Blockade against Muscle-Invasive Bladder Cancer
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Discovery Vol. 12, No. 10 ( 2022-10-05), p. 2280-2307
    Details
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 12, No. 10 ( 2022-10-05), p. 2280-2307
    Abstract: Biomarkers guiding the neoadjuvant use of immune-checkpoint blockers (ICB) are needed for patients with localized muscle-invasive bladder cancers (MIBC). Profiling tumor and blood samples, we found that follicular helper CD4+ T cells (TFH) are among the best therapeutic targets of pembrolizumab correlating with progression-free survival. TFH were associated with tumoral CD8 and PD-L1 expression at baseline and the induction of tertiary lymphoid structures after pembrolizumab. Blood central memory TFH accumulated in tumors where they produce CXCL13, a chemokine found in the plasma of responders only. IgG4+CD38+ TFH residing in bladder tissues correlated with clinical benefit. Finally, TFH and IgG directed against urothelium-invasive Escherichia coli dictated clinical responses to pembrolizumab in three independent cohorts. The links between tumor infection and success of ICB immunomodulation should be prospectively assessed at a larger scale. Significance: In patients with bladder cancer treated with neoadjuvant pembrolizumab, E. coli–specific CXCL13 producing TFH and IgG constitute biomarkers that predict clinical benefit. Beyond its role as a biomarker, such immune responses against E. coli might be harnessed for future therapeutic strategies. This article is highlighted in the In This Issue feature, p. 2221
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-22-0201
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
    detail.hit.zdb_id: 2607892-2
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  • 5
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    277 Safety and efficacy of intratumoral ipilimumab with IV nivolumab in metastatic melanoma. The NIVIPIT trial
    BMJ ; 2021
    In:  Journal for ImmunoTherapy of Cancer Vol. 9, No. Suppl 2 ( 2021-11), p. A300-A300
    Details
    In: Journal for ImmunoTherapy of Cancer, BMJ, Vol. 9, No. Suppl 2 ( 2021-11), p. A300-A300
    Abstract: Intratumoral (IT) administration of Ipilimumab (Ipi), could maximize its dose/efficacy ratio while preventing its on-target/off-tumor systemic adverse events. We report the results of a randomized multicenter Phase 1b study comparing IT vs IV Ipi with intravenous nivolumab (nivo) in patients with metastatic melanoma. Methods Previously untreated metastatic melanoma patients were randomly assigned 1:2, to receive IV Nivo (1mg/kg) in combination with either IV Ipi (3mg/kg) or 10x lower dose IT Ipi (0.3mg/kg) Q3W for 4 doses, followed by Nivo 3mg/kg Q2W for up to 2 years. The primary objective was to compare ≥grade 3 irAE rates at 6 months. Secondary objectives were to assess anti-tumor efficacy and related predictive immune biomarkers.Fresh tumor biopsies pre & on-treatment on both injected and non-injected tumors were analyzed by flow-cytometry, and soluble factors from their supernatant were titrated with Meso-Scale-Discovery® multiplex. Fresh sequential whole blood samples were collected for flow-cytometry phenotyping of immune cells, and for measuring systemic exposure to Ipi using ELISA Results 40 patients were treated in the IT-arm and 21 in the IV-arm. The study met its primary endpoint with lower toxicity rate at 6 months in the IT-arm, with 30% [18.1;45.4] vs 57.1% [36.5;75.5] of patients presenting ≥grade 3 treatment related AEs, and no procedure-related ≥grade 3 AEs in the IT-arm out of 162 IT injections performed (including deep seated lesions).ORR per RECIST 1.1 were observed in 50% [32.9;67.1] in the IT-arm vs 65.0% [0.41;0.85] in the IV-arm. In the IT-arm, 65.7% of the injected tumors showed a CR or PR.Serum Ipi concentrations were much lower in the IT arm (:10). At C2, patients in both arms had significant decreased circulating naïve Tregs independently from tumor responses. Presence of intratumoral CD25hi CD39hi activated Tregs that decreased significantly upon IT (but not IV) injection only in responders, was predictive of the overall tumor response in the IT-arm. Moreover, granzyme B concentrations in tumor secretome at baseline were higher in responders than non-responders in both arms. Conclusions 0.3mg/kg IT Ipi in combination with IV Nivo is not only safe but could reduce ≥grade 3 toxicity of the ICB combination. The high response rate in injected lesions was associated with the reduction of local Treg -not observed with systemic Ipi- and prompts a use in the oligometastatic and neoadjuvant setting. Direct assessment of cytolytic and regulatory pathways on fresh biopsies represents a novel, simple and rapid strategy to predict treatment efficacy. Acknowledgements Authors would like to thank the patients taking part to the Nivipit trial, and all the medical and paramedical staff that contributed to this trial. Trial Registration NCT02857569EudraCT 2015-005429-37 Ethics Approval This study was approved by the national ethics committee (CPP, ANSM). Written informed consent was obtained from all patients. Consent N/A
    Type of Medium: Online Resource
    ISSN: 2051-1426
    URL: Article
    DOI: 10.1136/jitc-2021-SITC2021.277
    Language: English
    Publisher: BMJ
    Publication Date: 2021
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  • 6
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    Endocardite à Trophyrema whipplei associée à la présence de cANCA
    Elsevier BV ; 2010
    In:  La Revue de Médecine Interne Vol. 31 ( 2010-6), p. S130-S131
    Details
    In: La Revue de Médecine Interne, Elsevier BV, Vol. 31 ( 2010-6), p. S130-S131
    Type of Medium: Online Resource
    ISSN: 0248-8663
    URL: Article
    DOI: 10.1016/j.revmed.2010.03.196
    Language: French
    Publisher: Elsevier BV
    Publication Date: 2010
    detail.hit.zdb_id: 2031063-8
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  • 7
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    The association between macrovascular complications and intensive care admission, invasive mechanical ventilation, and mortality in people with diabetes hospitalized for coronavirus disease-2019 (COVID-19)
    Springer Science and Business Media LLC ; 2022
    In:  Cardiovascular Diabetology Vol. 21, No. 1 ( 2022-10-19)
    Details
    In: Cardiovascular Diabetology, Springer Science and Business Media LLC, Vol. 21, No. 1 ( 2022-10-19)
    Abstract: It is not clear whether pre-existing macrovascular complications (ischemic heart disease, stroke or peripheral artery disease) are associated with health outcomes in people with diabetes mellitus hospitalized for COVID-19. Methods We conducted cohort studies of adults with pre-existing diabetes hospitalized for COVID-19 infection in the UK, France, and Spain during the early phase of the pandemic (between March 2020—October 2020). Logistic regression models adjusted for demographic factors and other comorbidities were used to determine associations between previous macrovascular disease and relevant clinical outcomes: mortality, intensive care unit (ICU) admission and use of invasive mechanical ventilation (IMV) during the hospitalization. Output from individual logistic regression models for each cohort was combined in a meta-analysis. Results Complete data were available for 4,106 (60.4%) individuals. Of these, 1,652 (40.2%) had any prior macrovascular disease of whom 28.5% of patients died. Mortality was higher for people with compared to those without previous macrovascular disease (37.7% vs 22.4%). The combined crude odds ratio (OR) for previous macrovascular disease and mortality for all four cohorts was 2.12 (95% CI 1.83–2.45 with an I 2 of 60%, reduced after adjustments for age, sex, type of diabetes, hypertension, microvascular disease, ethnicity, and BMI to adjusted OR 1.53 [95% CI 1.29–1.81]) for the three cohorts. Further analysis revealed that ischemic heart disease and cerebrovascular disease were the main contributors of adverse outcomes. However, proportions of people admitted to ICU (adjOR 0.48 [95% CI 0.31–0.75] , I 2 60%) and the use of IMV during hospitalization (adjOR 0.52 [95% CI 0.40–0.68], I 2 37%) were significantly lower for people with previous macrovascular disease. Conclusions This large multinational study of people with diabetes mellitus hospitalized for COVID-19 demonstrates that previous macrovascular disease is associated with higher mortality and lower proportions admitted to ICU and treated with IMV during hospitalization suggesting selective admission criteria. Our findings highlight the importance correctly assess the prognosis and intensive monitoring in this high-risk group of patients and emphasize the need to design specific public health programs aimed to prevent SARS-CoV-2 infection in this subgroup.
    Type of Medium: Online Resource
    ISSN: 1475-2840
    URL: Article
    DOI: 10.1186/s12933-022-01657-8
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
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  • 8
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    Interventional Radiology for Local Immunotherapy in Oncology
    American Association for Cancer Research (AACR) ; 2021
    In:  Clinical Cancer Research Vol. 27, No. 10 ( 2021-05-15), p. 2698-2705
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 27, No. 10 ( 2021-05-15), p. 2698-2705
    Abstract: Human intratumoral immunotherapy (HIT-IT) is under rapid development, with promising preliminary results and high expectations for current phase III trials. While outcomes remain paramount for patients and the referring oncologists, the technical aspects of drug injection are critical to the interventional radiologist to ensure optimal and reproducible outcomes. The technical considerations for HIT-IT affect the safety, efficacy, and further development of this treatment option. Image-guided access to the tumor allows the therapeutic index of a treatment to be enhanced by increasing the intratumoral drug concentration while minimizing its systemic exposure and associated on-target off-tumor adverse events. Direct access to the tumor also enables the acquisition of cancer tissue for sequential sampling to better understand the pharmacodynamics of the injected immunotherapy and its efficacy through correlation of immune responses, pathologic responses, and imaging tumor response. The aim of this article is to share the technical insights of HIT-IT, with particular consideration for patient selection, lesion assessment, image guidance, and technical injection options. In addition, the organization of a standard patient workflow is discussed, so as to optimize HIT-IT outcome and the patient experience.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-19-4073
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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    detail.hit.zdb_id: 2036787-9
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  • 9
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    Type 1 Diabetes in People Hospitalized for COVID-19: New Insights From the CORONADO Study
    American Diabetes Association ; 2020
    In:  Diabetes Care Vol. 43, No. 11 ( 2020-11-01), p. e174-e177
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 43, No. 11 ( 2020-11-01), p. e174-e177
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc20-1217
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2020
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  • 10
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    Intratumoral Immunotherapy: From Trial Design to Clinical Practice
    American Association for Cancer Research (AACR) ; 2021
    In:  Clinical Cancer Research Vol. 27, No. 3 ( 2021-02-01), p. 665-679
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 27, No. 3 ( 2021-02-01), p. 665-679
    Abstract: Systemic immunotherapies such as immune checkpoint blockade targeted at PD(L)1 and CTLA4 have demonstrated their ability to provide durable tumor responses and long-term overall survival benefits for some patients in several solid tumor types. However, a majority of patients remain resistant to these treatments and a significant proportion of them develop severe autoimmune and inflammatory adverse events. Preclinical studies have demonstrated that intratumoral injections of immunostimulatory products (oncolytics, pattern recognition receptor agonists,…) that are able to trigger type I IFN release and enhance tumor antigen presentation on immune cells could generate a strong antitumor immunity and overcome the resistance to systemic immune checkpoint blockade therapies. The intratumoral immunotherapy strategies that are currently in clinical development offer a unique therapeutic and exploratory setting to better understand the immune contexture across tumor lesions of patients with metastatic cancer. Also these local therapeutic products could turn cold tumors into hot and improve the response rates to cancer immunotherapies while diminishing their systemic exposure and toxicities. Intratumoral immunotherapies could prime or boost the immunity against tumors and therefore radically change the combinatorial therapeutic strategies currently pursued for metastatic and local cancers to improve their long-term survival. We aimed to review and discuss the scientific rationale for intratumoral immunotherapy, the challenges raised by this strategy in terms of drug development within clinical trials and the current state-of-the-art regarding the clinical practice of this innovative approach.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-20-0473
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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