Giant cell arteritis in the elderly / Maladie de Horton du sujet âgé

Introduction: Giant cell arteritis (GCA) or Horton's disease is a segmental and focal inflammation of large and medium-sized arteries mostly seen in patients of 50 years and older. There is also a peak frequency in individuals between the ages of 70 and 80. However, clinical data is scarce in this age group and especially in patients over 80. Methods: A retrospective study comprised of patients diagnosed with Horton's arteritis between 2012 and 2017, according to the American Society of Rheumatology, was conducted at Reims University Hospital. Patients were assigned to two groups according to age (≤ 75 and < 75) in order to evaluate and compare the impact of age on diagnosis, treatment and prognosis. Results: A total of 67 patients were studied. The mean age upon diagnosis was 75,85 ±8.5 years; 36 patients (53.7%) 75 years or younger and 31 patients older than 75. There was a female predominance (43 patients), 22 patients aged 75 years or younger and 21 older than 75. The mean follow up duration was 43.02 months in patients aged 75 years or younger and 30.99 in patients older than 75. This represents a difference of more than one year in terms of follow up, but is not statistically significant (p = 0.620). Eleven patients (16.4%) died during follow up: 5 patients (13.9%) aged 75 years or younger and 6 patients (19.4%) older than 75 (p = 0.547). Aortitis was significantly less seen in patients older than 75 (p = 0.0410). Conclusion: Our study showed no significant difference in either age group. However, aortitis was less seen in patients older than 75 years. Patients aged 75 or younger seemed more prone to relapses, but their follow up periods were shorter.

Introduction: L'artérite à cellules géantes (ACG) ou maladie de Horton est une artérite inflammatoire segmentaire et focale des artères de gros et moyen calibre du sujet de plus de 50 ans, avec un pic de fréquence chez le sujet très âgé entre 70 et 80 ans. Dans cette classe d'âge et au-delà de 80 ans, les données cliniques concernant l'AGC sont peu nombreuses. Notre objectif est de documenter ces dernières à travers une étude monocentrique menée sur une population avec une AGC avérée. Patients et méthode: Nous avons mené une étude rétrospective, monocentrique sur les dossiers médicaux de patients diagnostiqués artérite de Horton selon les critères de l'ASR entre 2012 et 2017 au CHU de Reims. Pour évaluer l'influence de l'âge sur le plan diagnostic, thérapeutique, du suivi et du pronostic, nous avons comparé des patients de 75 ans et moins (≤ 75 ans) à ceux de plus de 75 ans (> 75 ans) sur ces différents points. Résultats: Soixante-sept patients ont été inclus. L'âge moyen au diagnostic de ces patients était de 75,85 ± 8,5 ans ; 36 patients (53,7 %) étaient âgés de 75 ans ou moins (dont 22 femmes) et 31 patients (46,3 %) étaient âgés de plus de 75 ans (dont 21 femmes). La médiane de suivi était de 43,02 mois chez les patients ≤ 75 ans et de 30,99 mois chez les > 75 ans, soit près d'un an de différence, mais non significative (p = 0,620). Onze patients (16,4 %) étaient décédés au cours du suivi, 5 (13,9 %) chez les patients ≤ 75 ans et 6 (19,4 %) chez les patients de > 75 ans (p = 0,547). Les patients > 75 ans avaient significativement moins d'aortite (p = 0,0410). Il y avait une tendance à moins de rechute chez les patients de > 75 ans (p = 0,067). Pour les autres symptômes ou anomalies biologiques, les résultats de la biopsie d'artère temporale, la prise en charge thérapeutique, les complications iatrogènes et les décès, aucune différence significative n'était mise en évidence entre les deux groupes (p = ns). Conclusion: Notre étude montre peu de différence en ce qui concerne l'AGC entre les patients > 75 ans et ceux ≤ 75 ans. Toutefois, les patients > 75 ans ont moins d'aortite que les sujets plus jeunes. Il semble également y avoir une tendance à davantage de rechute chez les sujets les plus jeunes, sous réserve d'une durée de suivi plus courte d'un an, cliniquement pertinente, chez les sujets les plus âgés.

PD-1-cis IL-2R agonism yields better effectors from stem-like CD8+ T cells.

Expansion and differentiation of antigen-experienced PD-1+TCF-1+ stem-like CD8+ T cells into effector cells is critical for the success of immunotherapies based on PD-1 blockade1-4. Hashimoto et al. have shown that, in chronic infections, administration of the cytokine interleukin (IL)-2 triggers an alternative differentiation path of stem-like T cells towards a distinct population of 'better effector' CD8+ T cells similar to those generated in an acute infection5. IL-2 binding to the IL-2 receptor α-chain (CD25) was essential in triggering this alternative differentiation path and expanding better effectors with distinct transcriptional and epigenetic profiles. However, constitutive expression of CD25 on regulatory T cells and some endothelial cells also contributes to unwanted systemic effects from IL-2 therapy. Therefore, engineered IL-2 receptor ß- and γ-chain (IL-2Rßγ)-biased agonists are currently being developed6-10. Here we show that IL-2Rßγ-biased agonists are unable to preferentially expand better effector T cells in cancer models and describe PD1-IL2v, a new immunocytokine that overcomes the need for CD25 binding by docking in cis to PD-1. Cis binding of PD1-IL2v to PD-1 and IL-2Rßγ on the same cell recovers the ability to differentiate stem-like CD8+ T cells into better effectors in the absence of CD25 binding in both chronic infection and cancer models and provides superior efficacy. By contrast, PD-1- or PD-L1-blocking antibodies alone, or their combination with clinically relevant doses of non-PD-1-targeted IL2v, cannot expand this unique subset of better effector T cells and instead lead to the accumulation of terminally differentiated, exhausted T cells. These findings provide the basis for the development of a new generation of PD-1 cis-targeted IL-2R agonists with enhanced therapeutic potential for the treatment of cancer and chronic infections.

A Novel EGFRvIII T-Cell Bispecific Antibody for the Treatment of Glioblastoma.

T-cell bispecific antibodies (TCB) are engineered molecules that bind both the T-cell receptor and tumor-specific antigens. Epidermal growth factor receptor variant III (EGFRvIII) mutation is a common event in glioblastoma (GBM) and is characterized by the deletion of exons 2-7, resulting in a constitutively active receptor that promotes cell proliferation, angiogenesis, and invasion. EGFRvIII is expressed on the surface of tumor cells and is not expressed in normal tissues, making EGFRvIII an ideal neoantigen target for TCBs. We designed and developed a novel 2+1 EGFRvIII-TCB with optimal pharmacologic characteristics and potent antitumor activity. EGFRvIII-TCB showed specificity for EGFRvIII and promoted tumor cell killing as well as T-cell activation and cytokine secretion only in patient-derived models expressing EGFRvIII. Moreover, EGFRvIII-TCB promoted T-cell recruitment into intracranial tumors. EGFRvIII-TCB induced tumor regression in GBM animal models, including humanized orthotopic GBM patient-derived xenograft models. Our results warrant the clinical testing of EGFRvIII-TCB for the treatment of EGFRvIII-expressing GBMs.

[68Ga]Ga-DOTA-Siglec-9 Detects Pharmacodynamic Changes of FAP-Targeted IL2 Variant Immunotherapy in B16-FAP Melanoma Mice.

Vascular adhesion protein-1 (VAP-1) is an inflammation-inducible adhesion molecule, which supports contact between leukocytes and inflamed endothelium. There is evidence that VAP-1 is involved in the recruitment of leukocytes to melanoma tumors. Interleukin-2 (IL-2)-based immunotherapy is an efficient therapy that promotes immune system activity against cancers but is associated with toxicity. In the present study, we evaluated the feasibility of PET/CT imaging using the radiotracer [68Ga]Ga-DOTA-Siglec-9, which is targeted to VAP-1, to monitor pharmacodynamic effects of a novel FAP-IL2v immunocytokine (a genetically engineered variant of IL-2 fused with fibroblast activation protein) in the B16-FAP melanoma model. At 9 days after the inoculation of B16-FAP melanoma cells, mice were studied with [68Ga]Ga-DOTA-Siglec-9 PET/CT as a baseline measurement. Immediately after baseline imaging, mice were treated with FAP-IL2v or vehicle, and treatment was repeated 3 days later. Subsequent PET/CT imaging was performed 3, 5, and 7 days after baseline imaging. In addition to in vivo PET imaging, ex vivo autoradiography, histology, and immunofluorescence staining were performed on excised tumors. B16-FAP tumors were clearly detected with [68Ga]Ga-DOTA-Siglec-9 PET/CT during the follow-up period, without differences in tumor volume between FAP-IL2v-treated and vehicle-treated groups. Tumor-to-muscle uptake of [68Ga]Ga-DOTA-Siglec-9 was significantly higher in the FAP-IL2v-treated group than in the vehicle-treated group 7 days after baseline imaging, and this was confirmed by tumor autoradiography analysis. FAP-IL2v treatment did not affect VAP-1 expression on the tumor vasculature. However, FAP-IL2v treatment increased the number of CD8+ T cells and natural killer cells in tumors. The present study showed that [68Ga]Ga-DOTA-Siglec-9 can detect B16-FAP tumors and allows monitoring of FAP-IL2v treatment.

Cross-linking of T cell to B cell lymphoma by the T cell bispecific antibody CD20-TCB induces IFNγ/CXCL10-dependent peripheral T cell recruitment in humanized murine model.

Diffuse large B cell lymphomas (DLBCL) are a highly heterogeneous subtype of Non Hodgkin Lymphoma (NHL), accounting for about 25% of NHL. Despite an increased progression-free survival upon therapy, 40-50% of patients develop relapse/refractory disease, therefore there remains an important medical need. T cell recruiting therapies, such as the CD20xCD3 T cell bi-specific antibody CD20-TCB (RG6026 or glofitamab), represent a novel approach to target all stages of DLBCL, especially those that fail to respond to multiple lines of treatment. We aimed for a better understanding of the molecular features related to the mode of action (MoA) of CD20-TCB in inducing Target/T cell synapse formation and human T cell recruitment to the tumor. To directly evaluate the correlation between synapse, cytokine production and anti-tumor efficacy using CD20-TCB, we developed an innovative preclinical human DLBCL in vivo model that allowed tracking in vivo human T cell dynamics by multiphoton intravital microscopy (MP-IVM). By ex vivo and in vivo approaches, we revealed that CD20-TCB is inducing strong and stable synapses between human T cell and tumor cells, which are dependent on the dose of CD20-TCB and on LFA-1 activity but not on FAS-L. Moreover, despite CD20-TCB being a large molecule (194.342 kDa), we observed that intra-tumor CD20-TCB-mediated human T cell-tumor cell synapses occur within 1 hour upon CD20-TCB administration. These tight interactions, observed for at least 72 hours post TCB administration, result in tumor cell cytotoxicity, resident T cell proliferation and peripheral blood T cell recruitment into tumor. By blocking the IFNγ-CXCL10 axis, the recruitment of peripheral T cells was abrogated, partially affecting the efficacy of CD20-TCB treatment which rely only on resident T cell proliferation. Altogether these data reveal that CD20-TCB's anti-tumor activity relies on a triple effect: i) fast formation of stable T cell-tumor cell synapses which induce tumor cytotoxicity and cytokine production, ii) resident T cell proliferation and iii) recruitment of fresh peripheral T cells to the tumor core to allow a positive enhancement of the anti-tumor effect.

The PET-Tracer 89Zr-Df-IAB22M2C Enables Monitoring of Intratumoral CD8 T-cell Infiltrates in Tumor-Bearing Humanized Mice after T-cell Bispecific Antibody Treatment.

CD8-expressing T cells are the main effector cells in cancer immunotherapy. Treatment-induced changes in intratumoral CD8+ T cells may represent a biomarker to identify patients responding to cancer immunotherapy. Here, we have used a 89Zr-radiolabeled human CD8-specific minibody (89Zr-Df-IAB22M2C) to monitor CD8+ T-cell tumor infiltrates by PET. The ability of this tracer to quantify CD8+ T-cell tumor infiltrates was evaluated in preclinical studies following single-agent treatment with FOLR1-T-cell bispecific (TCB) antibody and combination therapy of CEA-TCB (RG7802) and CEA-targeted 4-1BB agonist CEA-4-1BBL. In vitro cytotoxicity assays with peripheral blood mononuclear cells and CEA-expressing MKN-45 gastric or FOLR1-expressing HeLa cervical cancer cells confirmed noninterference of the anti-CD8-PET-tracer with the mode of action of CEA-TCB/CEA-4-1BBL and FOLR1-TCB at relevant doses. In vivo, the extent of tumor regression induced by combination treatment with CEA-TCB/CEA-4-1BBL in MKN-45 tumor-bearing humanized mice correlated with intratumoral CD8+ T-cell infiltration. This was detectable by 89Zr-IAB22M2C-PET and γ-counting. Similarly, single-agent treatment with FOLR1-TCB induced strong CD8+ T-cell infiltration in HeLa tumors, where 89Zr-Df-IAB22M2C again was able to detect CD8 tumor infiltrates. CD8-IHC confirmed the PET imaging results. Taken together, the anti-CD8-minibody 89Zr-Df-IAB22M2C revealed a high sensitivity for the detection of intratumoral CD8+ T-cell infiltrates upon either single or combination treatment with TCB antibody-based fusion proteins. These results provide further evidence that the anti-CD8 tracer, which is currently in clinical phase II, is a promising monitoring tool for intratumoral CD8+ T cells in patients treated with cancer immunotherapy. SIGNIFICANCE: Monitoring the pharmacodynamic activity of cancer immunotherapy with novel molecular imaging tools such as 89Zr-Df-IAB22M2C for PET imaging is of prime importance to identify patients responding early to cancer immunotherapy.

Inflammasome inhibition blocks cardiac glycoside cell toxicity.

Chronic heart failure and cardiac arrhythmias have high morbidity and mortality, and drugs for the prevention and management of these diseases are a large part of the pharmaceutical market. Among these drugs are plant-derived cardiac glycosides, which have been used by various cultures over millennia as both medicines and poisons. We report that digoxin and related compounds activate the NLRP3 inflammasome in macrophages and cardiomyocytes at concentrations achievable during clinical use. Inflammasome activation initiates the maturation and release of the inflammatory cytokine IL-1ß and the programmed cell death pathway pyroptosis in a caspase-1-dependent manner. Notably, the same fluxes of potassium and calcium cations that affect heart contraction also induce inflammasome activation in human but not murine cells. Pharmaceuticals that antagonize these fluxes, including glyburide and verapamil, also inhibit inflammasome activation by cardiac glycosides. Cardiac glycoside-induced cellular cytotoxicity and IL-1ß signaling are likewise antagonized by inhibitors of the NLRP3 inflammasome or the IL-1 receptor-targeting biological agent anakinra. Our results inform on the molecular mechanism by which the inflammasome integrates the diverse signals that activate it through secondary signals like cation flux. Furthermore, this mechanism suggests a contribution of the inflammasome to the toxicity and adverse events associated with cardiac glycosides use in humans and that targeted anti-inflammatories could provide an additional adjunct therapeutic countermeasure.

CD20-TCB with Obinutuzumab Pretreatment as Next-Generation Treatment of Hematologic Malignancies.

Purpose: Despite promising clinical activity, T-cell-engaging therapies including T-cell bispecific antibodies (TCB) are associated with severe side effects requiring the use of step-up-dosing (SUD) regimens to mitigate safety. Here, we present a next-generation CD20-targeting TCB (CD20-TCB) with significantly higher potency and a novel approach enabling safer administration of such potent drug.Experimental Design: We developed CD20-TCB based on the 2:1 TCB molecular format and characterized its activity preclinically. We also applied a single administration of obinutuzumab (Gazyva pretreatment, Gpt; Genentech/Roche) prior to the first infusion of CD20-TCB as a way to safely administer such a potent drug.Results: CD20-TCB is associated with a long half-life and high potency enabled by high-avidity bivalent binding to CD20 and head-to-tail orientation of B- and T-cell-binding domains in a 2:1 molecular format. CD20-TCB displays considerably higher potency than other CD20-TCB antibodies in clinical development and is efficacious on tumor cells expressing low levels of CD20. CD20-TCB also displays potent activity in primary tumor samples with low effector:target ratios. In vivo, CD20-TCB regresses established tumors of aggressive lymphoma models. Gpt enables profound B-cell depletion in peripheral blood and secondary lymphoid organs and reduces T-cell activation and cytokine release in the peripheral blood, thus increasing the safety of CD20-TCB administration. Gpt is more efficacious and safer than SUD.Conclusions: CD20-TCB and Gpt represent a potent and safer approach for treatment of lymphoma patients and are currently being evaluated in phase I, multicenter study in patients with relapsed/refractory non-Hodgkin lymphoma (NCT03075696). Clin Cancer Res; 24(19); 4785-97. ©2018 AACR See related commentary by Prakash and Diefenbach, p. 4631.