Publications by authors named "Olivier Lambotte"

261 Publications

Elite and viremic HIV-1 controllers in West Africa.

AIDS 2021 Sep 14. Epub 2021 Sep 14.

Inserm 1219, University of Bordeaux, IRD, Bordeaux, France PACCI/ANRS Research Center Département de Dermatologie et Maladies Infectieuses, Université Felix Houphouët Boigny, Abidjan, Côte d'Ivoire AP-HP, CHU Necker Enfants Malades, Université Paris Descartes, Paris, France CeDReS, CHU de Treichville, Abidjan, Côte d'Ivoire Faculté de Médecine, Université Paris Descartes, Paris AP-HP Paris Saclay, Hôpital Bicêtre, Clinical Immunology Department Université Paris-Saclay, Inserm, CEA, Center for Immunology of Viral, Auto-immune, Hematological and Bacterial diseases (IDMIT/IMVA-HB), Le Kremlin Bicêtre, France.

Background: Data on HIV-1 controllers in Africa are scarce. We report the proportion of HIV-1 controllers in a group of adults prospectively monitored with frequent viral load measurements as part of a clinical trial in West Africa.

Methods: For the Temprano trial, antiretroviral therapy (ART)-naïve HIV-1 infected adults with no criteria for starting ART were randomized to start ART immediately or defer ART until the WHO starting criteria were met. Plasma viral load was measured every 6 months. The trial follow-up was 30 months. We considered all Temprano participants randomized to defer ART. Patients with all semestrial viral <2000 copies/ml and still off ART at month 30 were defined as HIV-1 controllers. Controllers with all viral loads <50 copies/ml were defined as elite controllers, the rest as viremic controllers.

Results: Of the 1023 HIV-1-infected adults randomized in the Temprano deferred-ART group, 18 (1.8%) met the criteria for classification as HIV controllers, of whom 7 (0.7%) were elite controllers and 11 (1.1%) viremic controllers. The HIV-1 controllers had low peripheral blood mononuclear cell HIV-1 DNA and low inflammatory marker levels. They maintained high CD4+ cell count and percentages and had a low morbidity rate.

Discussion: HIV controllers exist in Africa at a proportion close to that reported elsewhere. They represent a small fraction of all HIV-1-infected patients but raise important questions. Further studies should assess whether starting ART might represent more risk than benefit for some controllers, and where it does, how to identify these patients before they start ART.
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http://dx.doi.org/10.1097/QAD.0000000000003072DOI Listing
September 2021

Lymphoma complicating rheumatoid arthritis: results from a French case-control study.

RMD Open 2021 Sep;7(3)

Department of Rheumatology, FHU CARE, AP-HP, Hôpital Bicêtre, Le Kremlin-Bicetre, Île-de-France, France

Objectives: To study the characteristics of B-cell non-Hodgkin's lymphoma (NHL) or Hodgkin lymphoma complicating rheumatoid arthritis (RA) and to identify RA-related factors associated with their occurrence.

Methods: A multicentre case-control study was performed in France. Cases were patients with RA fulfilling ACR-EULAR 2010 criteria in whom B-cell NHL or Hodgkin lymphoma developed after the diagnosis of RA. For each case, 2 controls were assigned at random from the ESPOIR cohort and were matched on age at lymphoma diagnosis (cases)/age at the 10-year follow-up visit in the cohort (controls). Case and control characteristics were compared to identify parameters associated with the occurrence of lymphoma.

Results: 54 cases were included and matched to 108 controls. Lymphomas were mostly diffuse large B-cell lymphoma (DLBCL, n=27, 50.0%). On immunochemistry, 4 of 27 (14.8%) lymphoma cases were positive for Epstein-Barr virus. On univariate analysis, factors associated with the occurrence of lymphoma were male sex (OR 3.3, 95% CI 1.7 to 6.7), positivity for ACPA (OR 5.1, 95% CI 2.0 to 15.7) and rheumatoid factor (OR 3.9, 95% CI 1.6 to 12.2), and erosions on radiographs (OR 3.8, 95% CI 1.7 to 8.3) and DAS28 (OR 2.0, 95% CI 1.5 to 2.7), both at the time of matching. Methotrexate, TNF blockers and a number of previous biologics were not associated with the occurrence of lymphoma. On multivariable analysis, erosions and DAS28 remained significantly associated with increased risk of lymphoma.

Conclusion: Lymphomas complicating RA are mostly DLBCL. Risk of lymphoma in patients with RA was increased with markers of disease activity and severity, which supports the paradigm of a continuum between autoimmunity and lymphomagenesis in RA.
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http://dx.doi.org/10.1136/rmdopen-2021-001698DOI Listing
September 2021

Immune checkpoint inhibitor-associated sarcoidosis: A usually benign disease that does not require immunotherapy discontinuation.

Eur J Cancer 2021 Aug 25. Epub 2021 Aug 25.

AP-HP.Université Paris-Saclay, Hôpital Bicêtre, Department of Internal Medicine and Clinical Immunology, Le Kremlin Bicêtre, France; Université Paris-Saclay; INSERM; CEA, Centre Immunology of Viral Infections and Autoimmune Diseases, IDMIT Department, IBFJ, Le Kremlin-Bicêtre, France. Electronic address:

Objective: To analyse the clinical patterns of sarcoidosis triggered by immune checkpoint inhibitors (ICIs) in patients with cancer.

Patients And Methods: The ImmunoCancer International Registry is a big data-sharing multidisciplinary network from 18 countries dedicated to evaluating the clinical research of immune-related adverse events related to cancer immunotherapies.

Results: We identified 32 patients with biopsy-proven sarcoidosis. Underlying cancer included mainly melanoma (n = 24). Cancer immunotherapy consisted of monotherapy in 19 cases (anti-PD-1 in 18 and ipilimumab in 1) or combined ipilimumab + nivolumab in 13. The time median interval between initiation of ICI and sarcoidosis diagnosis was 3 months (range, 2-29 months). The use of combined ICI was associated with a shorter delay in developing sarcoidosis symptoms. The disease was symptomatic in 19 (59%) cases with mostly cutaneous, respiratory and general symptoms. The organs involved included mainly the mediastinal lymph nodes (n = 32), the lungs (n = 11), the skin (n = 10) and the eyes (n = 5). Pulmonary computed tomography studies showed bilateral hilar lymphadenopathy in all cases. There was no severe manifestation. Specific systemic therapy was required in only 12 patients (37%): oral glucocorticoids in 9, and hydroxychloroquine in 3. ICIs were held in 25 patients (78%) and definitively discontinued in 18 (56%) patients. Seven patients continued ICI treatment with a second flare in one case. In six additional patients, an ICI was reintroduced with no harm, and sarcoidosis relapsed in one of them.

Conclusion: Our study shows that ICI-related sarcoidosis seems to have a specific profile, possibly more benign than that of idiopathic sarcoidosis, and does not necessarily imply ICI discontinuation.
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http://dx.doi.org/10.1016/j.ejca.2021.05.041DOI Listing
August 2021

Outcomes of patients with cancer and sarcoid-like granulomatosis associated with immune checkpoint inhibitors: A case-control study.

Eur J Cancer 2021 Aug 20;156:46-59. Epub 2021 Aug 20.

Département d'Innovation Thérapeutique et d'Essais Précoces, Institute Gustave Roussy, Université Paris-Saclay, Villejuif, F-94805, France. Electronic address:

Purpose: Sarcoid-like granulomatosis (SLG) reaction caused by immunotherapy remains poorly understood. This study aims to investigate the outcome of patients with cancer and SLG associated with immunotherapy.

Patients And Methods: Between April 2016 and June 2020, 434 patients with immunological adverse events were screened from the ImmunoTOX assessment board of Gustave Roussy, an academic cancer centre in France. Among them, 28 patients had SLG associated with immunotherapy (SLG cohort) and 406 patients had other immunological adverse events (control cohort). Clinical characteristics and outcome of patients were compared from SLG and control cohort.

Results: The SLG cohort consisted of 28 patients, 14 women and 14 men, with the median (range) age of 56.5 (28.7-75.3) years. Patients in the SLG cohort with sarcoidosis were asymptomatic (only radiographical finding) in 13 (46.4%) cases; otherwise, the most frequent symptoms were dyspnoea in 8 (28.6%) patients and cough in 5 (17.8%) patients. The computerised tomography scan found sarcoidosis localisations in mediastinal or peri-hilar thoracic lymph nodes in 26 (92.9%) patients, and lung parenchymal involvement was found in 14 (50.0%) patients. The radiographic Scadding stages for sarcoidosis classification were distributed in stages 0, I, II, III and IV in 2 patients (7.1%), 13 patients (46.4%), 11 patients (39.3%), 1 patient (3.6%) and 1 patient (3.6%), respectively. Compared with patients with other immunological toxicities (cohort control), patients with sarcoidosis presented most frequently with melanoma (75.0% versus 21.9% of patients; p < 0.001) and more often received combined therapies of anti-programmed cell death 1 plus anti-cytotoxic T-lymphocyte antigen 4 protein (46.4% versus 12.6% of patients; p = 0.002). Patients with sarcoidosis had an improved overall survival (OS); the median OS was not reached in the SLG cohort and 40.4 months in the control cohort, hazard ratio = 0.232 (95% confidence interval: 0.086-0.630) (p = 0.002).

Conclusion: Sarcoidosis-like reactions in patients receiving immunotherapy were reported as non-severe immunological reactions in most cases and were correlated with improved OS. SLG should not be misdiagnosed as tumour progression in patients receiving immunotherapy treatment for cancer.
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http://dx.doi.org/10.1016/j.ejca.2021.07.015DOI Listing
August 2021

Contribution of Adipose Tissue to the Chronic Immune Activation and Inflammation Associated With HIV Infection and Its Treatment.

Front Immunol 2021 18;12:670566. Epub 2021 Jun 18.

Sorbonne Université, INSERM UMR_S 938, Centre de Recherche Saint-Antoine, Institut Hospitalo-Universitaire de Cardio-métabolisme et Nutrition (ICAN), FRM EQU201903007868, Paris, France.

White adipose tissue (AT) contributes significantly to inflammation - especially in the context of obesity. Several of AT's intrinsic features favor its key role in local and systemic inflammation: (i) large distribution throughout the body, (ii) major endocrine activity, and (iii) presence of metabolic and immune cells in close proximity. In obesity, the concomitant pro-inflammatory signals produced by immune cells, adipocytes and adipose stem cells help to drive local inflammation in a vicious circle. Although the secretion of adipokines by AT is a prime contributor to systemic inflammation, the lipotoxicity associated with AT dysfunction might also be involved and could affect distant organs. In HIV-infected patients, the AT is targeted by both HIV infection and antiretroviral therapy (ART). During the primary phase of infection, the virus targets AT directly (by infecting AT CD4 T cells) and indirectly (via viral protein release, inflammatory signals, and gut disruption). The initiation of ART drastically changes the picture: ART reduces viral load, restores (at least partially) the CD4 T cell count, and dampens inflammatory processes on the whole-body level but also within the AT. However, ART induces AT dysfunction and metabolic side effects, which are highly dependent on the individual molecules and the combination used. First generation thymidine reverse transcriptase inhibitors predominantly target mitochondrial DNA and induce oxidative stress and adipocyte death. Protease inhibitors predominantly affect metabolic pathways (affecting adipogenesis and adipocyte homeostasis) resulting in insulin resistance. Recently marketed integrase strand transfer inhibitors induce both adipocyte adipogenesis, hypertrophy and fibrosis. It is challenging to distinguish between the respective effects of viral persistence, persistent immune defects and ART toxicity on the inflammatory profile present in ART-controlled HIV-infected patients. The host metabolic status, the size of the pre-established viral reservoir, the quality of the immune restoration, and the natural ageing with associated comorbidities may mitigate and/or reinforce the contribution of antiretrovirals (ARVs) toxicity to the development of low-grade inflammation in HIV-infected patients. Protecting AT functions appears highly relevant in ART-controlled HIV-infected patients. It requires lifestyle habits improvement in the absence of effective anti-inflammatory treatment. Besides, reducing ART toxicities remains a crucial therapeutic goal.
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http://dx.doi.org/10.3389/fimmu.2021.670566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8250865PMC
June 2021

Antiretroviral therapy for HIV controllers: Reasons for initiation and outcomes in the French ANRS-CO21 CODEX cohort.

EClinicalMedicine 2021 Jul 18;37:100963. Epub 2021 Jun 18.

AP-HP, GHU Paris-Saclay, Hôpital Bicêtre, Service de Médecine Interne et Immunologie Clinique, Le Kremlin Bicêtre, 78, rue du Général Leclerc, 94275 CEDEX, France.

Background: Less than 1% of Human Immunodeficiency Virus (HIV)-infected individuals are able to achieve spontaneous viral control without requiring antiretroviral therapy (ART). Whether these HIV controllers (HIC) are at risk of HIV-associated comorbidities and could benefit from ART is debated, but recent studies reported decreased -cell activation upon ART initiation. We report the frequency of ART initiation, reasons to treat, treatment outcome on immunovirological parameters, and rate of side-effects and treatment discontinuation in the French cohort of HIC.

Methods: Participants included in the French multicenter Agence Nationale de Recherche sur le SIDA et les Hépatites (ANRS) Cohorte des extremes (CODEX) cohort of HIC between July 6, 2007 and January 3, 2018 were prospectively followed. ART initiation, indication, discontinuation, non-Acquired ImmunoDeficiency Syndrome (AIDS)-defining events, side-effects, and immunovirological parameters were recorded. Undetectable HIC (-HIC) were defined as participants with strictly undetectable viral loads based on routinely used assays throughout the follow-up and blipper HIC (b-HIC) as participants with possible detectable viral loads above the detection threshold during follow-up.

Findings: Among 302 HIC followed for a median of 14.8 years [10.3-20.2], 90 (30%) received ART (7 u-HIC and 83 b-HIC). The main reasons for ART initiation were decreased CD4 T-cell counts ( = 36, 40%), loss of virological control ( = 13, 14%), and non-AIDS-defining events ( = 12, 13%). Sixteen (18%) participants experienced 17 grade 1-2 adverse events. In b-HIC, ART slightly increased the CD4/CD8 ratio (median +0.19,  < 0.0001) and decreased the frequency of circulating CD38 HLA-DR. CD4 and CD8 lymphocytes (median -0.75%,  = 0.003, and -2%,  < 0.0001, respectively), but these changes were not observed for treated u-HIC. Thirteen (14%) participants discontinued ART (5 (38%) because of side-effects, and 10 remained HIC after treatment cessation (median follow-up: 305 days [235-728]).

Interpretation: Only 30% of participants in this large cohort of HIC required ART during a median follow-up of 14.8 years. These results show that HIC status is very stable and vouch for a patient-centered treatment decision based on the individual benefit/risk balance.
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http://dx.doi.org/10.1016/j.eclinm.2021.100963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8225698PMC
July 2021

[Specific management of the most common toxicities of anti-PD1].

Rev Prat 2021 04;71(4):408-410

"Assistance publique-Hôpitaux de Paris, hôpital Bicêtre, service de médecine interne et immunologie clinique, Le Kremlin-Bicêtre, France" - "Université Paris-Sud, Le Kremlin-Bicêtre, France".

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April 2021

[Management of adverse events associated with cancer immunotherapy].

Rev Prat 2021 Apr;71(4):400-407

"Assistance publique-Hôpitaux de Paris, hôpital Bicêtre, service de médecine interne et immunologie clinique, Le Kremlin-Bicêtre, France" - "Université Paris-Sud, Le Kremlin-Bicêtre, France".

"Management of adverse events associated with cancer immunotherapy.The role of anti-CTLA4 and anti-PD1/PD-L1 immunotherapies in the treatment of cancers is constantly evolving. Given the latest data on their use in combination with «conventional» treatments, their use should increase in the coming years, exposing a significant number of patients to immunomediated toxicities. By lifting the brakes of the immune system, these immune checkpoints blockers can induce prolonged anti-tumor responses and increase patient survival. These new immunotherapies also have a different toxicity profile compared to conventional anti-cancer treatments, known as immune-related adverse events (irAEs). They result from the activation of the immune system against normal tissues and can trigger autoimmune diseases. This singular profile of toxicity prompts us to modify our clinical practice: this is the topic of this review that will describe the different adverse events and their management."
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April 2021

Delivering adapted physical activity by videoconference to patients with fatigue under immune checkpoint inhibitors: Lessons learned from the PACTIMe-FEAS feasibility study.

J Telemed Telecare 2021 Jun 17:1357633X211021743. Epub 2021 Jun 17.

46657Gustave Roussy, Université Paris-Saclay, France.

Introduction: Fatigue is one of the most frequent symptoms in anti-cancer immune therapy. Physical activity has been proven effective in reducing fatigue, but unmet needs remain regarding the provision and access to adapted programmes, which efficiently addresses the main barriers to PA.

Methods: The PACTIMe-FEAS study primarily aimed at primarily to evaluate the feasibility and the acceptability of a videoconference-based 6-month programme promoting physical activity, and secondarily to assess its potential post-immediate and short-term effectiveness in reducing fatigue in cancer patients under immune therapy. Numeric self-reported questionnaires (Visual Analogue Scale-fatigue, Multidimensional Fatigue Inventory, International Physical Activity Questionnaire, Échelle de Motivation envers l'Activité Physique en contexte de Santé, Medical Outcomes Study 36-Item Short Form Health Survey, Hospital Anxiety and Depression Scale and Insomnia Severity Index) were completed by participants through an online secure platform at three time points: just before (T1), and after (T2) the programme, and 3 months later (T3).

Results: Sixteen participants (50% male, 50% female, mean age 54 years, 69% melanoma, 31% overweight), with moderate-to-severe fatigue, entered the internet-delivered intervention; 14 completed it, with an average completion rate of physical activity supervised sessions of 75%. Satisfaction was high, confirming a demand for group format, personalised approach, professional guidance and home-based device, to support the practice of regular physical activity. A decrease in fatigue was observed at the end of the programme.

Discussion: The recruitment process did prove to be challenging, with a relatively small eligible population, and will need to be reconsidered to envision a larger scale trial. But here and now, this feasibility study provides the first promising foundations to develop further research on the effectiveness of an original remote programme.
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http://dx.doi.org/10.1177/1357633X211021743DOI Listing
June 2021

CXCR3 and CXCR5 are highly expressed in HIV-1-specific CD8 central memory T cells from infected patients.

Eur J Immunol 2021 Aug 7;51(8):2040-2050. Epub 2021 Jun 7.

CEA-Université Paris-Saclay-INSERM U1184, Immunology of Viral Infections, Autoimmune, Hematological and Bacterial diseases, (IMVA-HB/IDMIT), Fontenay-aux-Roses & Le Kremlin-Bicêtre, Paris, France.

New ways of characterizing CD8 memory T cell responses in chronic infections are based on the measurement of chemokine receptor expression (CXCR3, CXCR5, and CX3CR1). We applied these novel phenotyping strategies to chronic HIV infection by comparing healthy donors (HDs), HIV-infected patients receiving antiretroviral therapy (ART), and spontaneous HIV controllers (HICs). In all groups, the memory cells exhibited high proportion of CXCR3 cells. Proportions of CXCR5 and CX3CR1 cells were preferentially observed among central memory cells (Tcm) and effector memory cells (Tem) respectively. Chronic controlled HIV infection impacted the chemokine receptor profile of both HIV-specific and nonspecific CD8 T cells. In total CD8 T cells, the proportions of CXCR3 CXCR5 CX3CR1 Tcm and Tem were lower in HIV-infected patients than in HDs with subtle differences between ART and HICs. Such phenotyping strategy also revealed differences in exhaustion and senescence phenotypes, the CXCR3 CXCR5 CX3CR1 being more exhausted and senescent than the CXCR3 CXCR5 CX3CR1 Tcm fraction. Among HIV-specific CD8 T cells, the vast majority of Tcm cells were CXCR3 and CXCR5 cells in contrast with their nonspecific counterparts. In conclusion, the addition of migration markers contributes to better characterize Tcm/Tem compartment.
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http://dx.doi.org/10.1002/eji.202048943DOI Listing
August 2021

Diagnostic Splenectomy: Characteristics, Pre-Operative Investigations, and Identified Pathologies for 20 Patients.

J Clin Med 2021 Apr 6;10(7). Epub 2021 Apr 6.

Service de Médecine Interne et Immunologie Clinique, APHP, Hôpitaux Universitaires Paris Saclay, Hôpital Bicêtre, 94720 Le Kremlin-Bicêtre, France.

Splenectomy is indicated in cases of trauma to the spleen or hematological and immunological diseases (hereditary spherocytosis, autoimmune cytopenia). Less frequently, splenectomy is performed for diagnostic purposes to complement unsuccessful prior etiological investigations. The splenectomy remains a surgery at risk of complications and should be considered as a last-resort procedure to make the diagnosis and to be able to treat patients. We studied the medical files of 142 patients who underwent a splenectomy for any reason over a 10-year period and identified 20 diagnostic splenectomies. Diagnostic splenectomies were mainly performed to explore unexplained splenomegaly for 13 patients and fever of unknown origin for 10. The other patients had surgery for other causes (cytopenia, abdominal symptoms, suspicion of relapsing malignant hemopathies). Splenectomy contributed to the final diagnosis in 19 of 20 cases, corresponding mostly to lymphoid hemopathies (14/20). The most frequent disease was diffuse large B-cell lymphoma (8/20). Splenectomy did not reveal any infectious disease. The most relevant pre-operative procedures to aid the diagnosis were F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) and immuno-hematological examinations. Diagnostic splenectomy is useful and necessary in certain difficult diagnostic situations. Highlights: Diagnostic splenectomy is still useful in 2020 to diagnose unexplained splenomegaly or fever of unknown origin. Lymphoma was the most common final diagnosis. FDG PET/CT was the most useful tool to aid in the diagnosis.
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http://dx.doi.org/10.3390/jcm10071519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038722PMC
April 2021

Long-term impact of immunotherapy on quality of life of surviving patients: A multi-dimensional descriptive clinical study.

Eur J Cancer 2021 May 19;148:211-214. Epub 2021 Mar 19.

Assistance Publique - Hôpitaux de Paris, Hôpital Bicêtre, Service de Médecine Interne et Immunologie Clinique, Le Kremlin-Bicêtre, France; INSERM, Institut National de La Santé et de La Recherche Médicale, Université Paris Saclay (COMUE), U1184, Immunologie des Maladies Virales et Auto-immunes, Le Kremlin-Bicêtre, France; Université Paris Saclay, Le Kremlin-Bicêtre, France; CEA, DSV/iMETI, IDMIT, Fontenay-aux-Roses, France. Electronic address:

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http://dx.doi.org/10.1016/j.ejca.2021.02.018DOI Listing
May 2021

Use of immune checkpoint inhibitors in cancer patients with pre-existing sarcoidosis.

Immunotherapy 2021 Apr 1;13(6):465-475. Epub 2021 Mar 1.

Department of General Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

To evaluate adverse events in cancer patients with pre-existing sarcoidosis receiving immune checkpoint inhibitors (ICIs). We retrospectively reviewed cancer patients with sarcoidosis who underwent treatment with ICI to determine frequency of sarcoidosis flares. 32 patients with sarcoidosis received ICIs The median time to ICI initiation was 7 years (range: 1 month to 51 years). One patient (3%) with a 20-year remote history of sarcoidosis developed a clinically symptomatic exacerbation after three doses of atezolizumab, with hilar lymphadenopathy, subcutaneous nodules, arthritis and uveitis. Atezolizumab was discontinued and prednisone initiated. She had a fluctuating course with two additional flares. Frequency of flares in patients with a remote history of sarcoidosis who receive ICIs is low.
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http://dx.doi.org/10.2217/imt-2020-0272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983044PMC
April 2021

Clinical spectrum, outcome and management of immune thrombocytopenia associated with myelodysplastic syndromes and chronic myelomonocytic leukemia.

Haematologica 2021 05 1;106(5):1414-1422. Epub 2021 May 1.

Sorbonne Université, AP-HP, Hôpital Saint-Antoine, Service de Médecine Interne and Inflammation-Immunopathology-Biotherapy Department (DMU 3iD), F-75012, Paris.

Myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) are associated with systemic inflammatory or autoimmune diseases in 10-20 % of cases. Among them, immune thrombocytopenia (ITP) has been reported but large studies assessing this association are missing. Whether such patients have a particular phenotype and require particular management is unclear. This study analyzes the clinical spectrum, outcome and therapeutic management of patients with ITP associated with MDS or CMML, in comparison (i) to patients with primary ITP without MDS/CMML and (ii) to patients with MDS/CMML without ITP. Forty-one MDS/CMML-associated ITP patients were included, with chronic ITP in 26 (63%) patients, low-risk myelodysplasia in 30 (73%) patients and CMML in 24 (59%) patients. An associated autoimmune disease was noted in 10 (24%) patients. In comparison to primary ITP patients, MDS/CMML-associated ITP patients had a higher occurrence of severe bleeding despite similar platelet counts at diagnosis. First-line treatment consisted of glucocorticoids (98%) and intravenous immunoglobulin (IVIg) (56%). Response achievement with IVIg was more frequent in primary ITP than in MDS/CMML-associated ITP patients. Response rates to second-line therapies were not statistically different between primary ITP and MDS/CMMLassociated ITP patients. Ten percent (n=4) of patients with MDS/CMML-associated ITP had multirefractory ITP versus none in primary ITP controls. After a median follow-up of 60 months, there was no difference in overall survival between MDS/CMML-associated ITP and primary ITP patients. Leukemia-free-survival was significantly better in MDS/CMMLassociated ITP patients than in MDS/CMML without ITP MDS/CMML-associated ITP have a particular outcome with more severe bleeding and multirefractory profile than primary ITP, similar response profile to primary ITP therapy except for IVIg, and less progression toward acute myeloid leukemia than MDS/CMML without ITP.
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http://dx.doi.org/10.3324/haematol.2020.272559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094121PMC
May 2021

Severe IgA-mediated autoimmune hemolytic anemia triggered by SARS-CoV-2 infection.

Leuk Lymphoma 2021 08 22;62(8):2037-2039. Epub 2021 Feb 22.

Clinical Immunology Department, AP-HP.Université Paris-Saclay, Hôpital Bicêtre, Le Kremlin Bicêtre, France.

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http://dx.doi.org/10.1080/10428194.2021.1888378DOI Listing
August 2021

Severe anti-PD1-related meningoencephalomyelitis successfully treated with anti-integrin alpha4 therapy.

Eur J Cancer 2021 03 28;145:230-233. Epub 2021 Jan 28.

Department of Neurology, University Hospital Bicêtre, Le Kremlin Bicêtre, France.

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http://dx.doi.org/10.1016/j.ejca.2020.12.014DOI Listing
March 2021

How to manage patients with corticosteroids in oncology in the era of immunotherapy?

Eur J Cancer 2020 12 16;141:239-251. Epub 2020 Nov 16.

Early Drug Development Department, Gustave Roussy, Villejuif, France. Electronic address:

Corticosteroids are among the most prescribed drugs in oncology. The indications range from cancer-related indications for refractory symptoms, anti-cancer effects mainly in hematology, supportive measures for cancer-specific treatments and more recently immune-related adverse events induced by modern immunotherapies. In oncological emergencies, corticosteroids are common first-line treatments because of their rapid effect and wide variety of actions. In the last 5 years, with the advance of immune checkpoint inhibitors, corticosteroids are becoming routinely used to manage immune-related adverse effects. Preclinical studies suggested that corticosteroid-induced immunosuppression might dampen the activity of immunotherapies. Prospective clinical studies show that corticosteroid use is a prognostic marker for the cancer outcome in metastatic setting but does not significantly alter the patient's response to immunotherapies per se. Here, we review the state of the art on corticosteroid use in oncology, with a focus on the drugs' potential impact on immunotherapy activity. The comprehensive pharmacological characteristics of corticosteroid drugs, clinical indications, modality of administration and associated precautions for use are discussed in this article.
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http://dx.doi.org/10.1016/j.ejca.2020.09.032DOI Listing
December 2020

Severe ulcerative gastrointestinal toxicity following ibrutinib therapy: two case studies.

Leuk Lymphoma 2021 04 12;62(4):984-987. Epub 2020 Nov 12.

Assistance Publique - Hôpitaux de Paris, Department of Internal Medicine and Clinical Immunology, Bicetre Hospital, Le Kremlin Bicêtre, France.

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http://dx.doi.org/10.1080/10428194.2020.1845333DOI Listing
April 2021

Infectious complications in patients treated with immune checkpoint inhibitors.

Eur J Cancer 2020 12 30;141:137-142. Epub 2020 Oct 30.

Assistance Publique - Hôpitaux de Paris, Hôpital Bicêtre, Service de Médecine Interne et Immunologie Clinique, Le Kremlin-Bicêtre, France; INSERM, U1184, Immunology of Viral Infections and Autoimmune Diseases, Le Kremlin-Bicêtre, France; Université Paris Sud, UMR 1184, Le Kremlin-Bicêtre, France; CEA, DSV/iMETI, IDMIT, Fontenay-aux-Roses, France. Electronic address:

Objective: Immune checkpoint inhibitor (ICI) antibodies constitute a new generation of cancer treatments, associated with immune-related adverse events (irAEs). A previous retrospective study of patients with metastatic melanoma (treated mostly with anti-CTLA4 antibodies) reported a serious infection rate of 7.3%. The main risk factors were corticoids and infliximab use. We sought to describe infections and risk factors among patients receiving anti-PD-1/PD-L1 ICIs.

Patients And Methods: We reviewed 200 medical records sampled randomly from a French prospective registry, which collates patients treated with anti-PD-1/PD-L1 ICIs. We recorded demographic data, the occurrence of irAEs, immunosuppressant use, and the outcome.

Results: Thirty-six patients (18%) experienced an infection by a median (interquartile range) of 47 (19.2-132) days after initiation of the ICI. Twenty-one patients (58.3%) had a lung infection, seven (19.4%) had a skin infection, seven (19.4%) had a urinary tract infection, and all of them received antibiotics. The infection was generally mild, and the patients were treated as outpatient. There were no infection-related deaths and no opportunistic infection. Sixty percent of the patients were being treated for metastatic melanoma and 35.5% for non-small cell lung cancer, and 106 irAEs (mostly grade II) were reported. Forty-seven patients received steroids for cancer symptoms or irAEs, and five received immunosuppressants during the immunotherapy. We did not observe any association between corticosteroid or immunosuppressant use and the occurrence of an infection.

Conclusion: The infection rate in patients treated with an anti-PD-1/PD-L1 ICI was 18%, without any severe or opportunistic infection. The occurrence of an infection was not associated with corticosteroid or immunosuppressant use.
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http://dx.doi.org/10.1016/j.ejca.2020.09.025DOI Listing
December 2020

Immune-related adverse events: a retrospective look into the future of oncology in the intensive care unit.

Ann Intensive Care 2020 Oct 16;10(1):143. Epub 2020 Oct 16.

Service de Réanimation Médicale, Hôpital Saint-Louis, Assistance Publique Hôpitaux de Paris, Paris, France.

Background: Immune checkpoint inhibitors have reshaped the standard of care in oncology. However, they have been associated with potentially life-threatening immune-related adverse events. With the growing indications of immune checkpoint inhibitors and their position as a pillar of cancer treatment, intensive care physicians will be increasingly confronted with their side effects. The outcome of patients with severe immune-related adverse events in the intensive care unit remains unknown. This retrospective multicentric study aims to describe the characteristics of patients admitted to the intensive care units of 4 academic hospitals in Paris area while receiving immune checkpoint inhibitor treatment between January 2013 and October 2019.

Results: Over the study period, 112 cancer patients who received immune checkpoint inhibitors were admitted to the intensive care unit within 60 days after the last dose. ICU admission was related to immune-related adverse events (n = 29, 26%), other intercurrent events (n = 39, 35%), or complications related to tumor progression (n = 44, 39%). Immune-related adverse events were pneumonitis (n = 8), colitis (n = 4), myocarditis (n = 3), metabolic disorders related to diabetes (n = 3), hypophysitis (n = 2), nephritis (n = 2), meningitis or encephalitis (n = 2), hepatitis (n = 2), anaphylaxis (n = 2) and pericarditis (n = 1). Primary tumors were mostly melanomas (n = 14, 48%), non-small-cell lung cancers (n = 7, 24%), and urothelial carcinomas (n = 5, 17%). Diagnosis of melanoma and a neutrophil/lymphocyte ratio < 10 were associated with immune-related diagnosis versus other reasons for ICU admission. During their ICU stay, immune-related adverse events patients needed vasopressors (n = 7), mechanical ventilation (n = 6), and extra-corporeal membrane oxygenation (n = 2). One-year survival was significantly higher for patients admitted for irAE compared to patients admitted for other reasons (p = 0.004).

Conclusions: Admission to the intensive care unit related to immune-related adverse event was associated with better outcome in cancer patients treated with immune checkpoint inhibitors. Our results support the admission for an intensive care unit trial for patients with suspected immune-related adverse events.
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http://dx.doi.org/10.1186/s13613-020-00761-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567777PMC
October 2020

Modulation of Cell Surface Receptor Expression by Modified Vaccinia Virus Ankara in Leukocytes of Healthy and HIV-Infected Individuals.

Front Immunol 2020 8;11:2096. Epub 2020 Sep 8.

INSERM U1184, Immunology of Viral Infections and Autoimmune Diseases, IDMIT Infrastructure, CEA-Université Paris Sud 11, Fontenay-aux-Roses, France.

Viral vectors are increasingly used as delivery means to induce a specific immunity in humans and animals. However, they also impact the immune system, and it depends on the given context whether this is beneficial or not. The attenuated vaccinia virus strain modified vaccinia virus Ankara (MVA) has been used as a viral vector in clinical studies intended to treat and prevent cancer and infectious diseases. The adjuvant property of MVA is thought to be due to its capability to stimulate innate immunity. Here, we confirmed that MVA induces interleukin-8 (IL-8), and this chemokine was upregulated significantly more in monocytes and HLA-DR dendritic cells (DCs) of HIV-infected patients on combined antiretroviral therapy (ART) than in cells of healthy persons. The effect of MVA on cell surface receptors is mostly unknown. Using mass cytometry profiling, we investigated the expression of 17 cell surface receptors in leukocytes after infection of human whole-blood samples with MVA. We found that MVA downregulates most of the characteristic cell surface markers in particular types of leukocytes. In contrast, C-X-C motif chemokine receptor 4 (CXCR4) was significantly upregulated in each leukocyte type of healthy persons. Additionally, we detected a relative higher cell surface expression of the HIV-1 co-receptors C-C motif chemokine receptor 5 (CCR5) and CXCR4 in leukocytes of HIV-ART patients than in healthy persons. Importantly, we showed that MVA infection significantly downregulated CCR5 in CD4+ T cells, CD8+ T cells, B cells, and three different DC populations. CD86, a costimulatory molecule for T cells, was significantly upregulated in HLA-DR DCs after MVA infection of whole blood from HIV-ART patients. However, MVA was unable to downregulate cell surface expression of CD11b and CD32 in monocytes and neutrophils of HIV-ART patients to the same extent as in monocytes and neutrophils of healthy persons. In summary, MVA modulates the expression of many different kinds of cell surface receptors in leukocytes, which can vary in cells originating from persons previously infected with other pathogens.
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http://dx.doi.org/10.3389/fimmu.2020.02096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7506042PMC
April 2021

Optimal Maturation of the SIV-Specific CD8 T Cell Response after Primary Infection Is Associated with Natural Control of SIV: ANRS SIC Study.

Cell Rep 2020 09;32(12):108174

Institut Pasteur, HIV Inflammation and Persistence, Paris, France. Electronic address:

Highly efficient CD8 T cells are associated with natural HIV control, but it has remained unclear how these cells are generated and maintained. We have used a macaque model of spontaneous SIVmac251 control to monitor the development of efficient CD8 T cell responses. Our results show that SIV-specific CD8 T cells emerge during primary infection in all animals. The ability of CD8 T cells to suppress SIV is suboptimal in the acute phase but increases progressively in controller macaques before the establishment of sustained low-level viremia. Controller macaques develop optimal memory-like SIV-specific CD8 T cells early after infection. In contrast, a persistently skewed differentiation phenotype characterizes memory SIV-specific CD8 T cells in non-controller macaques. Accordingly, the phenotype of SIV-specific CD8 T cells defined early after infection appears to favor the development of protective immunity in controllers, whereas SIV-specific CD8 T cells in non-controllers fail to gain antiviral potency, feasibly as a consequence of early defects imprinted in the memory pool.
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http://dx.doi.org/10.1016/j.celrep.2020.108174DOI Listing
September 2020

Characteristics of Dolutegravir and Bictegravir Plasma Protein Binding: a First Approach for the Study of Pharmacologic Sanctuaries.

Antimicrob Agents Chemother 2020 10 20;64(11). Epub 2020 Oct 20.

AP-HP, Université Paris-Saclay, Hôpital Bicêtre, Service de Pharmacie Clinique, Le Kremlin-Bicêtre, France

This study aimed to characterize dolutegravir (DTG) and bictegravir (BIC) binding. They had a preferential binding to human serum albumin (HSA) with two classes of albumin sites. Human alpha-1-acid glycoprotein (HAAG) binding of DTG and BIC showed an atypical nonlinear binding. The low-affinity site on HSA, the main plasma binding protein, suggests that the high protein binding rate should not impair passive diffusion.
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http://dx.doi.org/10.1128/AAC.00895-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577134PMC
October 2020

A FcɣRIIa polymorphism has a HLA-B57 and HLA-B27 independent effect on HIV disease outcome.

Genes Immun 2020 08 5;21(4):263-268. Epub 2020 Aug 5.

Université de Strasbourg, Laboratoire d'ImmunoRhumatologie Moléculaire, INSERM UMR_S 1109, Faculté de Médecine, plateforme GENOMAX, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), LabEx TRANSPLANTEX, Université de Strasbourg, 4 rue Kirschleger, 67085, Strasbourg, France.

Fcɣ receptors (FcɣRs) are key immune regulatory receptors that connect antibody-mediated immune responses to cellular effector functions. They are involved in the control of various immune functions including responses to infections. Genetic polymorphisms of FcɣRs coding genes (FCGR) have been associated with the regulation of HIV infection and progression. In this study, we analyzed the potential impact of five candidate FcɣR SNPs on viral control by genotyping 251 HIV controllers and 250 progressors. The rs10800309 AA genotype of the FcɣRIIa coding gene FCGR2A was found to be significantly associated with HIV control and this association was independent of HLA-B57 and HLA-B27 (OR, 2.84; 95% CI, 1.20-6.89; P = 0.033). We further confirmed the functional role of this polymorphism by showing an association of this same AA genotype with an increased in vitro FcɣRII expression on myeloid cells including dendritic cells (P = 0.0032). Together, these results suggest that the AA genotype of rs10800309 confers an improved immune response through FcɣRII upregulation and that this polymorphism may serve as an additional predictive marker of HIV control.
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http://dx.doi.org/10.1038/s41435-020-0106-8DOI Listing
August 2020

Metabolic plasticity of HIV-specific CD8 T cells is associated with enhanced antiviral potential and natural control of HIV-1 infection.

Nat Metab 2019 07 12;1(7):704-716. Epub 2019 Jul 12.

Institut Pasteur, Unité HIV Inflammation et Persistance, Paris, France.

Spontaneous control of human immunodeficiency virus (HIV) is generally associated with an enhanced capacity of CD8 T cells to eliminate infected CD4 T cells, but the molecular characteristics of these highly functional CD8 T cells are largely unknown. In the present study, using single-cell analysis, it was shown that HIV-specific, central memory CD8 T cells from spontaneous HIV controllers (HICs) and antiretrovirally treated non-controllers have opposing transcriptomic profiles. Genes linked to effector functions and survival are upregulated in cells from HICs. In contrast, genes associated with activation, exhaustion and glycolysis are upregulated in cells from non-controllers. It was shown that HIV-specific CD8 T cells from non-controllers are largely glucose dependent, whereas those from HICs have more diverse metabolic resources that enhance both their survival potential and their capacity to develop anti-HIV effector functions. The functional efficiency of the HIV-specific CD8 T cell response in HICs is thus engraved in their memory population and related to their metabolic programme. Metabolic reprogramming in vitro through interleukin-15 treatment abrogated the glucose dependency and enhanced the antiviral potency of HIV-specific CD8 T cells from non-controllers.
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http://dx.doi.org/10.1038/s42255-019-0081-4DOI Listing
July 2019

Characterization of Physicians That Might Be Reluctant to Propose HIV Cure-Related Clinical Trials with Treatment Interruption to Their Patients? The ANRS-APSEC Study.

Vaccines (Basel) 2020 Jun 23;8(2). Epub 2020 Jun 23.

Aix Marseille University, INSERM, IRD, SESSTIM, Sciences Economiques & Sociales de la Santé & Traitement de l'Information Médicale, 13005 Marseille, France.

HIV cure-related clinical trials (HCRCT) with analytical antiretroviral treatment interruptions (ATIs) have become unavoidable. However, the limited benefits for participants and the risk of HIV transmission during ATI might negatively impact physicians' motivations to propose HCRCT to patients. Between October 2016 and March 2017, 164 French HIV physicians were asked about their level of agreement with four viewpoints regarding HCRCT. A reluctance score was derived from their answers and factors associated with reluctance identified. Results showed the highest reluctance to propose HCRCT was among physicians with a less research-orientated professional activity, those not informing themselves about cure trials through scientific literature, and those who participated in trials because their department head asked them. Physicians' perceptions of the impact of HIV on their patients' lives were also associated with their motivation to propose HCRCT: those who considered that living with HIV means living with a secret were more motivated, while those worrying about the negative impact on person living with HIV's professional lives were more reluctant. Our study highlighted the need to design a HCRCT that minimizes constraints for participants and for continuous training programs to help physicians keep up-to-date with recent advances in HIV cure research.
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http://dx.doi.org/10.3390/vaccines8020334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350235PMC
June 2020

Immune checkpoint inhibitor-induced myositis, the earliest and most lethal complication among rheumatic and musculoskeletal toxicities.

Autoimmun Rev 2020 Aug 11;19(8):102586. Epub 2020 Jun 11.

Cardio-Oncology Program, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Regional Pharmacovigilance Centre, Department of Pharmacology, Sorbonne Université, INSERM CIC Paris-Est, Assistance Publique Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Paris, France. Electronic address:

Background: In addition to restoring anti-tumor immune responses, immune checkpoint inhibitors (ICI) may also induce immune-related adverse events (irAE) that can affect any organ. We aim to determine the spectrum, timing, clinical features, and fatalities of rheumatic and musculoskeletal immune-related adverse events (RMS-irAE) associated with ICI.

Patients Methods: We performed an observational, retrospective, pharmacovigilance study using the World Health Organization international pharmacovigilance database, VigiBase, from inception to January 2019. RMS-irAE reporting rate on ICI versus full database was performed using disproportionality analysis with computation of reporting-odds-ratios (ROR) and a Bayesian disproportional estimate (information component, IC). IC (lower end of the IC 95% credibility interval) >0 is deemed significant.

Results: We identified 1288 RMS-irAE significantly associated with ICI: polymyalgia rheumatica (n = 76, ROR = 14.6 [11.6-18.4], IC = 3.34), sarcoidosis (n = 94; ROR = 9.6 [7.9-11.9]; IC = 2.85), Sjogren's syndrome (n = 49; ROR = 6.9 [5.2-9.2]; IC = 2.24), myositis (n = 465; ROR = 4.9 [4.5-5.4]; IC = 2.12), arthritis (n = 606; ROR = 1.4 [1.3-1.5]; IC = 0.34) and scleroderma (n = 17; ROR = 2.0 [1.2-3.2]; IC = 0.17). Arthritis, myositis, and Sjogren's syndrome were over-reported in patients treated with ICI combination versus those treated with ICI monotherapy (ROR = 1.6-2.9, p < .05) and more frequently reported on anti-PD1/PDL1 monotherapy vs. anti-CTLA4 monotherapy (2.1-4.4, p < .05). Median time to onset occurred early for myositis (31 days [19.2-57.8]) and was the most delayed for scleroderma (395 days [323.8-457.2], p < .0001). The fatality rate for RMS-irAE ranged from 24% for myositis (n = 106/441) (up to 56.7% with concurrent myocarditis) to [0-6.7%] for other RMS-irAE (p < .0001).

Conclusions: Clinicians should be aware of the spectrum of RMS-irAE. Myositis can be particularly life-threatening, particularly when associated with myocarditis.
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http://dx.doi.org/10.1016/j.autrev.2020.102586DOI Listing
August 2020

Letter responds to the comment in 'immune thrombocytopenia of haematological immune-related adverse events in cancer immunotherapy: Most and mighty'.

Eur J Cancer 2020 07 26;134:60-61. Epub 2020 May 26.

Hôpitaux de Paris, Hôpital Bicêtre, Médecine Interne et Immunologie Clinique, F-94275, Le Kremlin-Bicêtre, France; INSERM U1184, Immunology of Viral Infections and Autoimmune Diseases, F-94276, Le Kremlin-Bicêtre, France; Université Paris Sud, UMR 1184, F-94276, Le Kremlin-Bicêtre, France; CEA, DSV/iMETI, IDMIT, F-92265, Fontenay-aux-Roses, France.

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http://dx.doi.org/10.1016/j.ejca.2020.03.012DOI Listing
July 2020
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