Gut microbiota signatures are associated with toxicity to combined CTLA-4 and PD-1 blockade
Jennifer A. WargoMiles C. AndrewsConnie P.M. DuongVancheswaran GopalakrishnanValerio IebbaWei-Shen ChenLisa DerosaBertrand RoutyGladys FerrereAurélie FluckigerMaría Paula RobertiPaule OpolonWhijae RohChristine N. SpencerIrina Fernandez CurbeloLuis M. VenceAlexandre ReubenZachary A. CooperPeter A. PrietoM.A. Wadud KhanAlexander J. LazarMichael T. TetzlaffCourtney W. HudgensPierre-Olivier GaudreauLuigi NeziDidier RaoultLauren E. HayduHussein A. TawbiPatrick HwuWen-Jen HwuRodabe N. AmariaElizabeth M. BurtonScott E. WoodmanAdi DiabSapna P. PatelIsabella C. GlitzaJianhua ZhangNadim AjamiJoseph F. PetrosinoRobert R. JenqMichael A. DaviesJeffrey E. GershenwaldPadmanee SharmaJames P. AllisonP. Andrew FutrealLaurence ZitvogelMaryam Tidjani AlouSatoru YonekuraAlexandria P. CogdillReetakshi AroraLatasha LittleCurtis GumbsKhalida WaniMargaret K. CallahanMathew AdamowMichael A. PostowCharlotte E. AriyanJulie Meeks GardnerJennifer L. McQuadeMichael K. WongLi Zhao
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Abstract Treatment with combined immune checkpoint blockade (CICB) targeting CTLA-4 and PD-1 is associated with clinical benefit across tumor types, but a high rate of immune-related adverse events (irAE). Insights into biomarkers and mechanisms of response and toxicity to CICB are needed. To address this, we profiled the blood, tumor and gut microbiome of 77 advanced melanoma patients treated with CICB, with a high rate of any ≥Grade 3 irAEs (49%) with parallel studies in pre-clinical models. Tumor-associated immune and genomic biomarkers of response to CICB were similar to those identified for ICB monotherapy, and toxicity from CICB was associated with a more diverse peripheral T cell repertoire. Profiling of gut microbiota demonstrated a significantly higher abundance of Bacteroides intestinalis in patients with toxicity, with upregulation of mucosal IL-1b in patient samples of colitis and in pre-clinical models. Together, these data offer potential new therapeutic angles for targeting toxicity to CICB.Keywords:
Immune checkpoint
CTLA-4
Bacteroides fragilis
The preparation, pharmacokinetics, clinical uses, dosage and administration, and adverse effects of intravenous immune globulin (IVIG) are reviewed. IVIG, which consists primarily of immunoglobulin G (IgG), is initially prepared from pooled human plasma by using the Cohn-Oncley fractionation procedure. Secondary treatments render the preparation suitable for i.v. use. The specific antibody content of IVIG depends on the geographic location of the plasma donors, the product, and the product lot. The metabolism of IgG appears to follow a multicompartmental, first-order process. The half-life of IgG is dependent on the half-lives of the IgG subclasses; three of the four subclasses have half-lives in the range of 23-25 days. IVIG is indicated in the treatment of idiopathic thrombocytopenic purpura (ITP) and as replacement therapy in primary humoral immunodeficiencies (PHI). IVIG has also been used for antimicrobial prophylaxis in bone marrow transplant and burn patients and in patients with malignancies. Patients with HIV infection, cystic fibrosis, neonatal sepsis, and respiratory syncytial virus infection may also benefit from prophylaxis or treatment with IVIG. The recommended dosage of IVIG in ITP is 400 mg/kg/day for two to five days. For the treatment of PHI, the usual dosage is 100-400 mg/kg every three or four weeks. Adverse reactions are often mild and are usually related to the infusion rate. Intravenous immune globulin is a valuable therapeutic tool in several immunodeficiency and autoimmune states, but IVIG products are expensive, and conclusive data on their efficacy in the treatment of many disorders remain to be obtained.
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Early bacterial stimulation of gut associated immune cells is essential for the development and maturation of the infant's immune response. This "microbial experience" has been affected due to a decrease in vaginal births (which are the first source of bacterial exposure for an infant), the substitution of breast feeding, in favor of almost sterile formulas, an increase use of antibiotics, and an increasingly "cleaner" environment. Increased hygienic measures and pasteurization perpetuate this decreased microbe-host interaction. These changes in environmental and gut microbiota are associated with an altered and inadequate development of immune response, with related health implications. The inadequate host response to infectious diseases, as well as the epidemic of immune related chronic conditions (such as allergy) can be explained in great measure by these changes. The consumption of certain probiotics (specific dietary bacteria that provide a benefit to the host) has positive effects on gut barrier function and immune response. Thus, probiotics are a means of improving host-microbe interactions for health maintenance, and for the management of a number of illnesses. This paper summarizes important aspects of these interactions as well as the role that probiotic bacteria can play in pediatric health.
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HIV-specific antibodies and CD8 + T cell antiviral responses were evaluated in three human immunodeficiency virus 1 (HIV-1) gp120 vaccine recipients who later became infected with HIV-1. Titers of neutralizing antibody to the HIV-1SF 2 vaccine isolate were boosted, but titers of antibody to the autologous infecting viruses were never high and required at least 6 months after HIV infection to develop. Similarly, a marginal noncytotoxic CD8 + T cell antiviral response was observed only in one of the three vaccinees 3 months after HIV-1 infection. The infecting virus isolates had several amino acid substitutions in the HIV-1 envelope V3 region but were similar to other regional HIV-1 clade B isolates. Viral loads were similar to those of other HIV-1-infected individuals who had not been vaccinated and transient CD4 + T cell declines were observed in each person, suggesting that the vaccine was not effective at controlling these prognostic markers early in infection.
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