HIV-Related Immune Activation and Inflammation: Current Understanding and Strategies

Although antiretroviral therapy effectively controls human immunodeficiency virus (HIV) replication, a residual chronic immune activation/inflammation persists throughout the disease. This aberrant immune activation and inflammation are considered an accelerator of non-AIDS-related events and one of the driving forces of CD4+ T cell depletion. Unfortunately, HIV-associated immune activation is driven by various factors, while the mechanism of excessive inflammation has not been formally clarified. To date, several clinical interventions or treatment candidates undergoing clinical trials have been proposed to combat this systemic immune activation/inflammation. However, these strategies revealed limited results, or their nonspecific anti-inflammatory properties are similar to previous interventions. Here, we reviewed recent learnings of immune activation and persisting inflammation associated with HIV infection, as well as the current directions to overcome it. Of note, a more profound understanding of the specific mechanisms for aberrant inflammation is still imperative for identifying an effective clinical intervention strategy.

A Wolf in Sheep's Clothing: Systemic Immune Activation Post Immunotherapy

ABSTRACT Introduction Immune checkpoint inhibitors (ICIs) are increasingly a standard of care for many cancers; these agents can result in immune-related adverse events (irAEs) including fever, which is common but can rarely be associated with systemic immune activation (SIA or acquired HLH). Methods All consecutive patients receiving ICIs in the Drug Development Unit of the Royal Marsden Hospital between May 2014 and November 2019 were retrospectively reviewed. Patients with fever ≥ 38°C or chills/rigors (without fever) ≤ 6 weeks of commencing ICIs were identified for clinical data collection. Results Three patients met diagnostic criteria for SIA/HLH with median time to onset of symptoms of 10 days. We describe the clinical evolution, treatment used, and outcomes for these patients. High-dose steroids are used first-line with other treatments, such as tocilizumab, immunoglobulin and therapeutic plasmapheresis can be considered for steroid-refractory SIA/HLH. Conclusion SIA/HLH post ICI is a rare but a potentially fatal irAE that presents with fever and a constellation of nonspecific symptoms. Early recognition and timely treatment are key to improving outcomes.

BDB001, an intravenously administered toll-like receptor 7 and 8 (TLR7/8) agonist, in combination with pembrolizumab in advanced solid tumors: Phase 1 safety and efficacy results.

2512 Background: BDB001 is an intravenously administered TLR 7/8 dual agonist immune modulator capable of reprogramming dendritic cells to produce antitumor activities. BDB001 monotherapy has demonstrated favorable tolerability and robust systemic immune activation leading to durable clinical responses in a phase I dose escalation trial. Here, we report on the safety and efficacy of BDB001 in combination with pembrolizumab in a phase I dose escalation trial in advanced solid tumors (NCT03486301). Methods: BDB001-101 is a phase 1, open label, dose escalation/expansion trial of BDB001 (IV, Q1W) in combination with pembrolizumab (IV, Q3W) in patients with advanced solid tumors. The primary endpoint was safety and tolerability. Secondary endpoints included efficacy, pharmacokinetics and pharmacodynamic profiling of immune activation. Results: Twenty-three subjects with 13 different tumor types were enrolled across 4 dose levels. Sixty one percent were female, median age was 63 years (range, 33-86), median number of prior therapies was 3 (range, 1-8), and 48% of tumors had progressed on prior anti-PD-(L)1 therapy. Overall, BDB001 in combination with pembrolizumab was well tolerated and dose-limiting toxicities were not observed. The most common treatment related adverse events (TRAEs) were fever (39.1%), fatigue (39.1%), chills/rigor (34.8%), pruritus/rash (21.7%), and nausea (13.0%). Most of these TRAEs were grade 1 or 2 and transient. Only 3 (13.0%) subjects experienced grade 3 TRAEs of fatigue, rash, stomatitis, and alkaline phosphatase elevation. There were no grade 4 or 5 TRAEs. Pharmacodynamic evaluation of plasma cytokine levels showed robust increases in interferon gamma and interferon inducible protein-10 (IP-10) at BDB001 Dose Level 3 and 4. Preliminary efficacy evaluation of the 14 subjects treated at Dose Level 3 and 4 showed durable and deep clinical responses in 4 (29%) subjects with anti-PD-(L)1 mAb refractory melanoma, hepatocellular carcinoma, cholangiocarcinoma, and platinum-resistant ovarian carcinoma. The responses were observed by the initial efficacy assessment at 9-weeks, with some seen as early as 4-weeks. In addition, 4 (29%) subjects had stable disease for a disease control rate of 57%. To date, median time on treatment is 14.4 weeks (range, 6.0 – 42.1+) with 3 subjects still active on treatment. Conclusions: Intravenously administered BDB001 in combination with pembrolizumab is well tolerated. Rapid and deep clinical responses were observed, supported by robust systemic immune activation. BDB001 in combination with pembrolizumab is a promising novel therapeutic option for patients with advanced solid tumors and is being evaluated in an ongoing dose expansion trial. Clinical trial information: NCT03486301.

Menopausal Symptoms and Cardiovascular Disease Risk Indices Among Women With HIV

Background: Women with HIV (WWH) (vs. women without HIV) have an increased risk of cardiovascular disease (CVD) in relation to heightened systemic immune activation/inflammation. Moreover, WWH show evidence of advanced reproductive aging and unique patterns of hot flash symptomatology. General population studies have revealed that hot flashes may relate to surrogate markers of CVD risk. The relationship between hot flashes and immune activation as well as subclinical cardiac pathology among WWH has not been previously investigated. Methods: In a prospective, cross-sectional study, 23 WWH on anti-retroviral therapy and 19 women without HIV (ages 40–75), group-matched on age and BMI, were enrolled and completed reproductive health assessments, immune phenotyping and cardiovascular MRI. Women without prior CVD or diabetes were eligible. Results: Women were similar in age and BMI (WWH vs. women without HIV: 51 ± 5 vs. 52 ± 6 years, P=0.79 and 32 ± 8 vs. 31 ± 7 kg/m2, P=0.71). There was no significant between-group difference in the percentage of women without menses in the past year (p=0.52) or in the percentage of women with undetectable levels of anti-mullerian hormone (p=0.71). No women in either group were on estrogen and/or progesterone for treatment of menopausal symptoms. Hot flash frequency (days per week with hot flashes) was higher among WWH versus women without HIV (median [IQR], 7.0 [1.3, 7.0] vs. 0.8 [0.0, 2.1], p=0.01). In sensitivity analyses excluding either women with menses in the past year or with detectable AMH, WWH still reported a significantly higher number of days per week with hot flashes (7.0 [6.3, 7.0] vs. 0.4 [0.0, 2.3], p=0.007, and 7.0 [2.4, 7.0] vs. 0.8 [0.0, 2.1], p=0.01, respectively). Among WWH experiencing (vs. not experiencing) hot flashes in the past year, longer duration of ART use was noted (21.2 [16.0, 22.7] vs. 9.3 [3.3, 16.0] years, p=0.03). Among the entire cohort and among WWH, women with more than one hot flash per day had higher levels of soluble CD14, a marker of monocyte activation, compared to women with one or fewer hot flash per day (p=0.004 and p=0.02, respectively). Among WWH and a history of hot flashes, years since onset of hot flashes related to cardiovascular MRI-derived measures of subclinical pathology. Specifically, years since onset of hot flashes related directly to myocardial steatosis (intramyocardial triglyceride content; ρ=0.80, p=0.02) and inversely to diastolic function (left atrial passive ejection fraction; ρ=─0.70, p=0.03). Conclusions: WWH experienced a higher frequency of hot flashes compared to women without HIV. Among WWH, hot flash symptomatology related to systemic immune activation and to cardiovascular MRI-derived measures of CVD risk. Additional research is required to improve understanding of mechanisms underlying these relationships and determine if hot flashes are a sex-specific risk factor for CVD in WWH.

Soluble CD163 Identifies Those at Risk for Increased Hepatic Inflammation & Fibrosis

Background Liver disease remains a significant cause of morbidity and mortality in HIV-infected persons. Soluble CD163 is a marker of Kupffer cell activation that is highly associated with development of hepatic fibrosis. The relative contributions of HIV-associated systemic immune activation versus other etiologies of injury are poorly characterized. Methods We utilized subjects in the Miami Adult Studies on HIV (MASH) cohort to evaluate 464 participants including 361 PLWH and 103 HCV/HIV uninfected controls. Subjects underwent testing for hepatic fibrosis using both MRE and ELF. Steatosis was evaluated by MRI-PDFF. Immune activation markers and cytokines were quantitated using Luminex methodologies. Results Participants with HIV with or without HCV coinfection had higher levels of sCD163 than uninfected controls (p<0.05). Soluble sCD163 was highly associated with elevated ALT, a key marker of inflammation/injury and with hepatic fibrosis. Hepatic steatosis was also associated with a cytokine pattern suggestive of Kupffer cell activation, but was not associated with an increase in sCD14 or sCD27. Conclusions Injury and resultant hepatic fibrosis occur by distinct though overlapping mechanistic pathways. In PLWH, sCD163 is highly associated with both injury and fibrosis suggesting that persistent systemic immune activation is a major contributor to long term outcomes, adding to damage caused by alcohol, steatosis and other hepatotoxic drug effects.

Acute cerebral atrophy in autoimmune encephalitis complicated by haemophagocytic lymphohistiocytosis

Autoimmune encephalitis is a disease characterised by neural-specific antibodies. This case report presents a 20-year-old young man with a recent history of suspected viral encephalitis who presented with recurrent fevers and episodes of confusion. He was found to have anti-N-methyl-D-aspartate receptor (NMDAR) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid 1 receptor (AMPAR1) positive autoantibodies and was diagnosed with autoimmune encephalitis. He subsequently developed global cerebral atrophy and was found to meet diagnostic criteria for haemophagocytic lymphohistiocytosis (HLH). This patient’s presentation was consistent with existing literature showing that autoimmune encephalitis may develop after an initial viral meningoencephalitis. However, concurrent anti-NMDAR and anti-AMPAR1 positive autoimmune encephalitis has not been reported in literature to date, and this case report represents one instance of its presentation. We speculate that multiple antibodies against neural surface antigens may increase the risk for systemic immune activation leading to HLH and acute cerebral atrophy.

Generating tumor-selective conditionally active biologic anti-CTLA4 antibodies via protein-associated chemical switches

Anticytotoxic T lymphocyte-associated protein 4 (CTLA4) antibodies have shown potent antitumor activity, but systemic immune activation leads to severe immune-related adverse events, limiting clinical usage. We developed novel, conditionally active biologic (CAB) anti-CTLA4 antibodies that are active only in the acidic tumor microenvironment. In healthy tissue, this binding is reversibly inhibited by a novel mechanism using physiological chemicals as protein-associated chemical switches (PaCS). No enzymes or potentially immunogenic covalent modifications to the antibody are required for activation in the tumor. The novel anti-CTLA4 antibodies show similar efficacy in animal models compared to an analog of a marketed anti-CTLA4 biologic, but have markedly reduced toxicity in nonhuman primates (in combination with an anti-PD1 checkpoint inhibitor), indicating a widened therapeutic index (TI). The PaCS encompass mechanisms that are applicable to a wide array of antibody formats (e.g., ADC, bispecifics) and antigens. Examples shown here include antibodies to EpCAM, Her2, Nectin4, CD73, and CD3. Existing antibodies can be engineered readily to be made sensitive to PaCS, and the inhibitory activity can be optimized for each antigen’s varying expression level and tissue distribution. PaCS can modulate diverse physiological molecular interactions and are applicable to various pathologic conditions, enabling differential CAB antibody activities in normal versus disease microenvironments.