Immune Activation In Patients Research Articles

Monocyte Anisocytosis Changes in Patients after Major Burn Injuries.

The recovery of patients after severe burns is a long and complex process. Recently, genomic analysis of white blood cells from burn and trauma patients revealed excessive and prolonged innate immune activation in patients with complicated outcomes. However, translating this knowledge into practical biomarkers has not been possible yet. Although several biomarkers for monitoring burn patients have been proposed, their ability to accurately distinguish between inflammation stemming from initial tissue destruction, infections, and organ failure complications is limited. Here, we focused on monocytes, critical innate immune cells in the response to burn injured tissues. We measured the monocyte anisocytosis (quantified as monocyte distribution width, MDW, a recently emerged marker of sepsis) throughout the recovery of patients from the time of burn injury until the end of the hospital stay. We observed that MDW increases in patients during the first week after major burns. Among the patients with major burns who survive, MDW starts decreasing in the second week and normalizes by the end of the hospital stay. The duration of hospital stay appears to be proportional to how fast MDW decreases during the second week after the injury. We also found that MDW decreases significantly in most patients after excision and debridement surgeries but not after allo- and auto-graft surgeries. Moreover, high MDW values correlated with a higher rate of positive microbiology blood culture samples and respiratory infections. These findings underscore the importance of monitoring MDW as a potential biomarker for the risk of complications during burn patient recovery.

Dynamics of Matricellular Protein Levels in Blood Predict Recovery in Patients with Human Immunodeficiency Virus-Tuberculosis Coinfection.

Chronic immune activation in tuberculosis (TB) associated with human immunodeficiency virus (HIV) infection (HIV/TB) modifies their clinical course. We prospectively measured osteopontin (OPN), full-length galectin-9 (FL-Gal9), and total-Gal9 (T-Gal9) levels in 32 patients with HIV/TB coinfection treated with anti-tuberculosis and antiretroviral therapies over 6-18 months to determine the amelioration of inflammatory conditions in response to the therapies. We observed a significant time-dependent decrease in FL-Gal9 in both pulmonary TB (PTB, n = 20) and extrapulmonary TB (EPTB, n = 12) patients. The levels of T-Gal9, OPN, and CRP decreased significantly after treatment in only PTB patients. We calculated the inflammatory score (INS) indicating immunologic recovery based on the decline in OPN, FL-Gal9, T-Gal9, and CRP levels. Baseline levels of T-Gal9 and OPN positively correlated with INS in all TB and only PTB patients, respectively, indicating that their levels predict better recovery. In contrast, FL-Gal9 levels at the second visit negatively correlated with INS in EPTB patients. The decrease rate in OPN levels at the second visit also correlated positively with INS in PTB patients. Women showed a higher INS and lower levels of FL-Gal9 than men. The patients with moderate grade severity on chest X-ray had higher CD4 cell numbers than those with limited grade severity. Monitoring these markers will help to predict and assess the response to therapy as well as to devise strategies to reduce the complications caused by chronic immune activation in patients with HIV/TB coinfection.

Changes in pain during a depressive episode and relationship to cytokine levels in major depressive disorder

Background Depressed patients have an increased incidence of pain. A pathophysiological connection between depression and pain is still not revealed. Immunological activation has been found in both depression and pain. There are few studies of pain and immune activation in patients with depression, without inflammatory and autoimmune disorders. Methods This is a naturalistic follow-up study of 50 patients with a major depressive disorder (MDD) depressive episode, without any inflammatory or autoimmune conditions. We have previously reported on the relationship between depression and cytokine levels. In this study, we obtained data of depression, pain and cytokine levels before and after 12 weeks of depression treatment. All patients were medication-free at inclusion. Results At inclusion three out of four patients experienced pain, and the pain scores correlated with the depression scores. After treatment, as depression was relieved, the pain scores dropped significantly and were no longer correlated to the depression scores. There were no correlations between pain scores and cytokine levels. Pain level at inclusion did not correlate with depression treatment outcome. Conclusion Our findings indicate that pain is a feature of depression. Pain levels and cytokine values didn’t correlate. Pain at inclusion did not predict depression treatment outcome.

Accelerated kynurenine pathway downregulates immune activation in patients with axial spondyloarthritis

Various studies reported that the kynurenine (Kyn) pathway plays a pivotal role in regulating the balance between activation and inhibition of the immune system. Proinflammatory cytokines can accelerate the Kyn pathway by altering indoleamine (2, 3)- dioxygenase (IDO) allosteric enzyme activity. Excessive cytokine release and immune system activation have essential roles in the pathogenesis of axial spondyloarthritis (axSpA). We aimed to investigate the relationship of the Kyn pathway with proinflammatory cytokines and with the severity of the disease in patients with axSpA.The study included 104 patients with axSpA and 54 healthy volunteers. The severity of the disease was determined by Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). The Kyn pathway was evaluated by IDO activity calculated with Kyn/Tryptophan (Trp) ratio. Plasma Trp and Kyn concentrations were measured with tandem mass spectrometry. Serum IL 17/23 and IFN-γ concentrations were measured with ELISA. These groups were compared in terms of IDO, IL-17, IL-23, IFN-γ, and BASDAI.Plasma IDO activity was significantly increased, however, serum IL-17, IL-23, and IFN-γ levels were significantly decreased in patients compared to healthy volunteers. While IFN-γ was positively correlated with the severity of the disease (p = 0.02), it also had a significant inverse correlation with IDO activity (p < 0.001). However, these correlations are weak.As a result of this study, the Kyn pathway is accelerated and proinflammatory cytokine levels are decreased in patients with axSpA. All of these results with an indirect weak negative association between high IDO and low disease activity suggest that an accelerated Kyn pathway may limit the immune system activation in axSpA disease.

Abstract 2740: Safe and effective delivery of antibody fragments to the solid tumor microenvironment

Abstract Promising immunotherapeutics, particularly agonists, have shown limited clinical benefit, in part because of dose-limiting toxicities, caused by potent immune activation in systemic compartments, with limited evidence of activity in the tumor microenvironment (TME). The Tumor Specific Immunogene (T-SIGn) platform is designed to generate vectors that can express combinations of transgenes producing immunotherapeutics selectively within the tumor microenvironment. T-SIGn is clinically validated for intravenous delivery, enabling the vectors to reach primary and metastatic sites to replicate and produce their therapeutic transgene payloads specifically in malignant epithelial cells. Transgene (TG) cassettes of T-SIGn vectors can be up to approximately 3.5Kb, allowing the expression of multiple distinct TGs. NG-350A is a clinical stage T-SIGn vector, with an established safety/tolerability profile, that expresses a full-length agonist CD40 antibody, and shows evidence of target engagement and adaptive immune activation in patients with different epithelial solid tumors via prolonged, dose-dependent increases in IL-12p70, IFNγ and IL-17A detected in the circulation of patients about 2 weeks after the initiation of the day 1, 3, 5 dosing regimen. NG-350A is currently being evaluated in phase I clinical studies in combination with Pembrolizumab or Ipilimumab. We have been characterizing numerous smaller fragment antibody formats that enable us to combine their expression with other antibody fragments or immunomodulatory molecules as a T-SIGn vector. An ScFv anti-CD40 fragment antibody design was identified as a potent immunotherapeutic to induce the secretion of IL-12p70 cytokine following stimulation of human monocyte-derived dendritic cells, as well as an enhanced antigen-specific T-cell activation and macrophage conversion to a more pro-inflammatory phenotype. When encoded together with CXCL9 and other immunostimulatory cytokines, the anti-CD40 ScFv has been selected as a potential follow-up to NG-350A that synergistically drives enhanced in vitro T-cell priming, activation and migration. Other checkpoint inhibitor and coactivator antibodies, as both ScFv and camelid VHH formats, have also been encoded individually, in combination with the anti-CD40 antibody fragment or other fragment antibodies to create a set of viral vectors that are being evaluated preclinically as future T-SIGn vector candidates. Data from these studies with initial vectors encoding combinations of functionally active antibody fragments will be presented. Collectively, these clinical and preclinical datasets demonstrate the broad utility of the T-SIGn platform for expressing rationally-designed combinations of antibodies and other natural and synthetic agents within tumors and thus enabling the development of new and potent immunotherapies for patients with solid epithelial cancers. Citation Format: Rachel Bergin, Amandine Pelletier, Manuela Zonca, Alice Muntzer, Meg Snowden, Samuel Hardy, Carla Cerqueira, Tae Hyun-Jang, Rochelle Lear, Masumi Fujinobu, Maria Stella Sasso, Samantha Bucktrout, Brian R. Champion. Safe and effective delivery of antibody fragments to the solid tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2740.

Efficacy and safety of gluten peptide-based antigen-specific immunotherapy (Nexvax2) in adults with coeliac disease after bolus exposure to gluten (RESET CeD): an interim analysis of a terminated randomised, double-blind, placebo-controlled phase 2 study

A gluten-free diet is insufficient to treat coeliac disease because intestinal injury persists and acute reactions with cytokine release follow gluten exposure. Nexvax2 is a specific immunotherapy using immunodominant peptides recognised by gluten-specific CD4+ T cells that might modify gluten-induced disease in coeliac disease. We aimed to assess the effects of Nexvax2 on gluten-induced symptoms and immune activation in patients with coeliac disease. This was a randomised, double-blind, placebo-controlled phase 2 trial done at 41 sites (29 community, one secondary, and 11 tertiary centres) in the USA, Australia, and New Zealand. Patients with coeliac disease aged 18-70 years who had excluded gluten for at least 1 year, were HLA-DQ2.5 positive, and had a worsening of symptoms after an unmasked 10 g vital gluten challenge were eligible for inclusion. Patients were stratified by HLA-DQ2.5 status (HLA-DQ2.5 non-homozygous vs homozygous). Patients who were non-homozygous were centrally (ICON; Dublin, Ireland) randomly assigned (1:1) to receive subcutaneous Nexvax2 (non-homozygous Nexvax2 group) or saline (0·9% sodium chloride; non-homozygous placebo group) twice a week escalating from 1 μg to 750 μg during the first 5 weeks followed by 11 weeks of maintenance therapy at 900 μg per dose. The exploratory homozygous group was centrally randomly assigned (2:1) to receive Nexvax2 (homozygous Nexvax2 group) or placebo (homozygous placebo group); patients who were homozygous received the same doseage as those who were non-homozygous. The primary endpoint was change in coeliac disease patient reported outcomes (total gastrointestinal domain) from pretreatment baseline to the day of masked bolus 10 g vital gluten challenge given in week 14 analysed in the non-homozygous intention-to-treat population. The trial is registered with ClinicalTrials.gov, NCT03644069. Between Sept 21, 2018, and April 24, 2019, 383 volunteers were screened for inclusion, of whom 179 (47%; 133 [74%] women, 46 [26%] men; median age 41 years [IQR 33-55]) were randomly assigned. One (1%) of 179 patients was excluded from analysis due to misassignment of genotype. The non-homozygous Nexvax2 group included 76 patients, the non-homozygous placebo group included 78 patients, the homozygous Nexvax2 group included 16 patients, and the homozygous placebo group included eight patients. The study was discontinued after planned interim analysis of 66 patients who were non-homozygous. We report an unmasked post-hoc analysis of all available data for the primary endpoint and secondary symptom-based endpoints combining data from 67 (66 were assessed in the planned interim analysis for the primary endpoint). Mean change from baseline to day of first masked gluten challenge in total gastrointestinal score for the non-homozygous Nexvax2 group was 2·86 (SD 2·28) compared with 2·63 (2·07) for the non-homozygous placebo group (p=0·43). Adverse events were similar between all patients who received Nexvax2 and those who received placebo. Serious adverse events were reported in five (3%) of 178 patients (two [2%] of 92 who received Nexvax2 and three [4%] of 82 who received placebo). One patient in the non-homozygous Nexvax2 group had a serious adverse event that occurred during gluten challenge (left-sided mid-back muscle strain with imaging suggestive of partial left kidney infarction). Serious adverse events were reported for three (4%) of 78 patients in the non-homozygous placebo group (one each with exacerbation of asthma and appendicitis, and one who had forehead abscess, conjunctivitis, and folliculitis) and one (1%) patient in the non-homozygous Nexvax2 group developed a pulmonary embolism. The most frequent adverse events in all 92 patients who received Nexvax2 compared with all 86 patients who received placebo were nausea (44 [48%] of 92 patients who received Nexvax2 vs 29 (34%) of 86 patients who received placebo), diarrhoea (32 [35%] vs 25 [29%]), abdominal pain (31 [34%] vs 27 [31%]), headache 32 [35%] vs 20 [23%]), and fatigue (24 [26%] vs 31 [36%]). Nexvax2 did not reduce acute gluten-induced symptoms. Masked bolus vital gluten challenge provides an alternative to extended gluten challenge in efficacy studies for coeliac disease. ImmusanT.

Updated results of a phase 1 study of SEA-CD40, gemcitabine, nab-paclitaxel, and pembrolizumab in patients with metastatic pancreatic ductal adenocarcinoma (PDAC; SGNS40-001).

708 Background: PDAC has a 5-year survival rate of &lt;5% in patients with metastatic disease. Despite established frontline therapy with gemcitabine + nab-paclitaxel (GnP), outcomes remain poor and additional therapies are urgently needed. SEA-CD40 is a receptor-agonistic, nonfucosylated IgG1 antibody directed to CD40. SEA-CD40 binding to FcγRIIIa results in enhanced effector function and CD40 agonism, allowing amplification of immune stimulation and antitumor activity. In preliminary results of a phase 1 study, SEA-CD40 + GnP + pembrolizumab (pembro) showed a tolerable safety profile and evidence of immune activation in patients (pts) with PDAC. Here, we present updated clinical results for this cohort. Methods: Pts were ≥18 years old with untreated metastatic PDAC and ECOG Performance Status of 0 or 1. Gemcitabine (1000 mg/m2) and nab-paclitaxel (125 mg/m2) were given on days 1, 8, and 15 and SEA-CD40 (10 or 30 µg/kg) was given on day 3 of each 28-day cycle. Pembro (400 mg) was given every 6 weeks starting on day 8 for up to 2 years. Results: As of August 16, 2022, 61 pts were treated with 10 µg/kg (N=40) or 30 µg/kg (N=21) SEA-CD40. Median duration of exposure was 25.1 weeks. Confirmed objective responses were observed in 19 pts (48% [95% CI 31.5, 63.9]) at 10 µg/kg and 8 pts (38% [95% CI 18.1, 61.6]) at 30 µg/kg. Median duration of response (months) was 5.7 (95% CI 3.9, 7.4) and 5.7 (95% CI 2.3, 9.2) for the 10 and 30 µg/kg dose groups, respectively. Additional efficacy results are summarized. The most common treatment-emergent adverse events (TEAEs) across dose groups were fatigue (84%), nausea (74%), and neutropenia (67%). The most common grade ≥3 TEAEs across the groups were neutropenia (61%), anemia (33%), and thrombocytopenia (20%). TEAEs leading to treatment discontinuation were reported in 10% of pts, including immune-mediated lung disease (n=3) and septic shock (n=1) in the 10 µg/kg dose group, and colitis (n=1) and portal vein thrombosis (n=1) in the 30 µg/kg dose group. Conclusions: The combination of SEA-CD40 + GnP + pembro has an acceptable safety profile and shows evidence of antitumor activity in pts with PDAC. This regimen may warrant further evaluation. Clinical trial information: NCT02376699 . [Table: see text]

Exploration of Tumor Biopsy Gene Signatures to Understand the Role of the Tumor Microenvironment in Outcomes to Lisocabtagene Maraleucel.

In the TRANSCEND NHL 001 study, 53% of patients with relapsed/refractory large B-cell lymphoma (LBCL) treated with lisocabtagene maraleucel (liso-cel) achieved a complete response (CR). To determine characteristics of patients who did and did not achieve a CR, we examined the tumor biology and microenvironment from lymph node tumor biopsies. LBCL biopsies from liso-cel-treated patients were taken pretreatment and ∼11 days posttreatment for RNA sequencing (RNA-seq) and multiplex immunofluorescence (mIF). We analyzed gene expression data from pretreatment biopsies (N = 78) to identify gene sets enriched in patients who achieved a CR to those with progressive disease. Pretreatment biopsies from month-3 CR patients displayed higher expression levels of T-cell and stroma-associated genes, and lower expression of cell-cycle genes. To interpret whether LBCL samples were "follicular lymphoma (FL)-like," we constructed an independent gene expression signature and found that patients with a higher "FL-like" gene expression score had longer progression-free survival (PFS). Cell of origin was not associated with response or PFS, but double-hit gene expression was associated with shorter PFS. The day 11 posttreatment samples (RNA-seq, N = 73; mIF, N = 53) had higher levels of chimeric antigen receptor (CAR) T-cell densities and CAR gene expression, general immune infiltration, and immune activation in patients with CR. Further, the majority of T cells in the day 11 samples were endogenous. Gene expression signatures in liso-cel-treated patients with LBCL can inform the development of combination therapies and next-generation CAR T-cell therapies.

Attenuation of immune activation in patients with multiple sclerosis on a wheat-reduced diet: a pilot crossover trial.

Western lifestyle has been associated with an increase in relapsing-remitting multiple sclerosis (RRMS). In mice, dietary wheat amylase-trypsin inhibitors (ATIs) activate intestinal myeloid cells and augment T cell-mediated systemic inflammation. The aim of this study was to assess whether a wheat- and thus ATI-reduced diet might exert beneficial effects in RRMS patients with modest disease activity. In this 6-month, crossover, open-label, bicentric proof-of-concept trial, 16 RRMS patients with stable disease course were randomized to either 3 months of a standard wheat-containing diet with consecutive switch to a > 90% wheat-reduced diet, or vice versa. The primary endpoint was negative, as the frequency of circulating pro-inflammatory T cells did not decrease during the ATI-reduced diet. We did, however, observe decreased frequencies of CD14+ CD16++ monocytes and a concomitant increase in CD14++ CD16- monocytes during the wheat-reduced diet interval. This was accompanied by an improvement in pain-related quality of life in health-related quality of life assessed (SF-36). Our results suggest that the wheat- and thus ATI-reduced diet was associated with changes in monocyte subsets and improved pain-related quality of life in RRMS patients. Thus, a wheat (ATI)-reduced diet might be a complementary approach accompanying immunotherapy for some patients. German Clinical Trial Register (No. DRKS00027967).

The Changes That Occur in the Immune System During Immune Activation in Patients With Prediabetes From All Ethnicities, Aged 25-45 Years: Protocol for a Systematic Review and Meta-analysis.

Prediabetes is an asymptomatic, intermediate state between normoglycemia and the onset of type 2 diabetes mellitus. Recent reports indicate that during prediabetes, there are subclinical changes to immune cells and inflammatory markers. Therefore, this systematic review will provide a synthesis of the available data on the changes in the concentration of immune cells and selective inflammatory markers. It will also give evidence of a demographic impact on changes or complications in the prediabetes state. The objectives of this study are to create a protocol that will be used to analyze the collected data of previously published research based on immune cells such as neutrophils, lymphocytes, monocytes, eosinophils, and basophils, as well as inflammatory markers such as C-reactive protein, tumor necrosis factor-alpha, interleukin-6, P-selectin, cluster of differentiation 40 ligand, and fibrinogen. Additionally, an impact of demographics will be determined using the previously published data collected. This protocol was prepared through adhering to the PRISMA (Preferred Reporting Items for Systemic Reviews and Meta-Analysis) 2015 guidelines for reporting protocols. Published clinical studies that involve observational (cross-sectional, comparative cross-sectional, case-control, or cohort) study designs that include normal or nondiabetic and prediabetes reports will be used in this systematic review and meta-analysis. This will be accomplished by using clinical Medical Subject Headings to search on MEDLINE, Cochrane library, and African Journal Online. Reviewers (NCM, AMS, and AK) will screen all the results and select the studies that meet the eligibility criteria. Downs and Black Checklist will be used to check the risk of bias, and then a Review Manager v5.4 forest plot will be used for meta-analysis. Additionally, the forest plot will also be used for sensitivity analysis. The strength of evidence will then be assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. Since July 5, 2020, there are no participants recruited. Publicly available data will be used in the review and will be collected after this protocol publication. No ethics approval is required as no subjects will be used, and analysis will be based on reported data. Authors will be contacted if there was a misunderstanding related to reading their reported data. The findings will clarify changes that might be observed in a study of interest based in the eThekwini district in South Africa. International Prospective Registry of Systematic Reviews (PROSPERO) CRD42020184828; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=184828. PRR1-10.2196/31619.

Anti-TNFα Drugs and Interleukin Inhibitors: Epidemiological and Pharmacovigilance Investigation in COVID-19 Positive Patients

All patients with RA, Psoriasis and IBD were included in this observational analysis and treated with anti-TNFα, IL-inhibitors, Methotrexate (MTX) and Sulfasalazine drugs during the year 2020-2021. The population consisted of 932 patients and demographic, clinical and pharmacological data were analyzed. Although no significant differences were observed between patients treated with biological and synthetic drugs in terms of hospitalization and death, the multivariate logistic model showed that the type of drug influences the possibility of COVID-19 positivity. The results of this analysis support the use of biological drugs and justify further research investigating the association of these biological therapies with COVID-19 outcomes.

Neuroimmune Crosstalk in Rheumatoid Arthritis.

Recent studies have demonstrated that immunological disease progression is closely related to abnormal function of the central nervous system (CNS). Rheumatoid arthritis (RA) is a chronic, inflammatory synovitis-based systemic immune disease of unknown etiology. In addition to joint pathological damage, RA has been linked to neuropsychiatric comorbidities, including depression, schizophrenia, and anxiety, increasing the risk of neurodegenerative diseases in life. Immune cells and their secreted immune factors will stimulate the peripheral and central neuronal systems that regulate innate and adaptive immunity. The understanding of autoimmune diseases has largely advanced insights into the molecular mechanisms of neuroimmune interaction. Here, we review our current understanding of CNS comorbidities and potential physiological mechanisms in patients with RA, with a focus on the complex and diverse regulation of mood and distinct patterns of peripheral immune activation in patients with rheumatoid arthritis. And in our review, we also discussed the role that has been played by peripheral neurons and CNS in terms of neuron mechanisms in RA immune challenges, and the related neuron-immune crosstalk.

Abstract 123: Genetic Deficiency Of The Ectoenzyme CD73 Increases Neutrophil Extracellular Trap Formation In Patients With ACDC

Background/Purpose: CD73 is a ecto-5′-nucleotidase located on the plasma membrane that generates adenosine from AMP in the extracellular space, and functions as a checkpoint against immune and vascular activation. CD73 inhibitors that eliminate this immune checkpoint blockade are being studied in phase 2/3 cancer clinical trials. We recently identified that lack of CD73 promotes vascular thromboinflammation and neutrophil extracellular trap (NET) formation in mice. The role of CD73 in human NETosis, however, remains to be studied. Arterial calcification due to deficiency of CD73 (ACDC) is a rare, autosomal recessive condition (~20 patients globally) that results in occlusive peripheral vascular disease. We hypothesized that the congenital absence of CD73 and its function as an immune checkpoint would heighten innate immune activation in patients with ACDC. Methods: To test this hypothesis, six patients with molecularly confirmed ACDC were recruited to the NIH for mechanistic studies. Using purified neutrophils from ACDC patients and healthy controls, spontaneous and LPS-induced NET formation was quantified by both Sytox extracellular DNA (eDNA) labeling and NET-associated MPO activity. Results: Absence of surface CD73 was confirmed by flow cytometry. Relative to healthy controls, four of six (4/6) patients with ACDC demonstrated increased ex vivo spontaneous NET formation, but not LPS-triggered NETosis. The four ACDC patients with increased spontaneous NETosis had a mean 1.7-fold increase in Sytox-stained eDNA and 2-fold increase in MPO activity compared with contemporary healthy controls. Conclusion: These data reveal marked, spontaneous NETosis in patients deficient in the ectoenzyme CD73. Comparison with LPS-stimulated neutrophils demonstrates near maximal NETosis at baseline in patients with ACDC, consistent with a model where CD73 tonically suppresses neutrophil activation to maintain vascular and immune homeostasis. Ongoing studies are exploring the mechanism of spontaneous NETosis, thrombin formation, and fibrinolysis in patients with ACDC. Taken together, these data will have relevance to patients with ACDC, and inform the thromboinflammatory risk of cancer patients receiving CD73 inhibitors.

Combining Radiotherapy and Immunotherapy in Metastatic Breast Cancer: Current Status and Future Directions

The role of radiotherapy and immunotherapy with immune checkpoint inhibitors (ICI) is of emerging interest in many solid tumours, including breast cancer. There is increasing evidence that the host’s immune system plays an important role in influencing the response to treatment and prognosis in breast cancer. Several pre-clinical studies and clinical trials have reported on the ‘abscopal effect—regression of distant untreated tumour sites, mediated by an immunological response following ionizing radiation to a targeted tumour site. Stereotactic Ablative Body Radiotherapy (SABR) is a non-invasive technique used to augment various immune responses with an ablative tumoricidal dose when compared to conventional radiotherapy. SABR is characterized by typically 1–5 precision radiotherapy treatments that simultaneously deliver a high dose, whilst sparing normal tissues. Following SABR, there is evidence of systemic immune activation in patients with increased PD1 expression on CD8+ and CD4+ T cells. Studies continue to focus on metastatic triple-negative disease, a highly immunogenic subtype of breast cancer with poor prognosis. In this review, we discuss the immunological effect of SABR, alone and in combination with immunotherapy, and the importance of dose and fractionation. We also propose future strategies for treating oligometastatic disease, where this approach may be most useful for producing durable responses.

A phase 1b study of intraperitoneal oncolytic viral immunotherapy in platinum-resistant or refractory ovarian cancer

ObjectiveOur objective was to assess safety and adverse events associated with intraperitoneal Olvi-Vec virotherapy in patients with platinum-resistant or refractory ovarian cancer (PRROC). Secondary objectives included objective response rate (ORR) per RECIST 1.1 and progression-free survival (PFS). MethodsOlvi-Vec is a modified vaccinia virus that causes oncolysis and immune activation. An open-label phase 1b trial using a 3 + 3 dose escalation was conducted. Intraperitoneal Olvi-Vec was given as monotherapy in two consecutive daily doses. Translational analyses included anti-virus antibody levels, viral shedding, circulating tumor cells (CTCs) and T cells. ResultsTwelve patients (median age: 69 years, range: 45–77) with median 5 prior therapies (range: 2–10) and 2 prior platinum lines (range: 1–5) were enrolled. There were three dose level cohorts: 3 × 109 (n = 6), 1 × 1010 (n = 5), and 2.5 × 1010 (n = 1) plaque forming units (PFU)/day on two consecutive days. Treatment-related adverse events (TRAEs) included G1/G2 nausea (n = 6), fever (n = 6), abdominal distention (n = 5), and abdominal pain (n = 4). There were no Grade 4 TRAEs, no dose relationship to TRAEs, and no deaths attributed to Olvi-Vec. The ORR was 9% (1/11). Stable disease (SD) was 64% (7/11), and SD ≥15 weeks was 46% (5/11). Median PFS was 15.7 weeks (95%CI: 5.7–34.5), including extended PFS in four patients (23.2, 34.5, 59.4+ and 70.8 weeks). Three patients had extended overall survival (deceased 33.6 months, and alive with disease at 54 and 59 months). CTCs diminished in 6/8 (75%) baseline-positive patients. Immune activation was demonstrated from virus-enhanced tumor infiltration of CD8+ T-cells and activation of tumor-specific T-cells in peripheral blood. ConclusionsOncolytic viral therapy with intraperitoneal Olvi-Vec showed promising safety, clinical activities, and immune activation in patients with PRROC, warranting further clinical investigation.

Immunophenotypic Analysis Reveals Differences in Circulating Immune Cells in the Peripheral Blood of Patients with Segmental and Nonsegmental Vitiligo

Accumulating studies have indicated immune-based destruction of melanocytes in both segmental vitiligo (SV) and non-SV (NSV). Whereas SV often occurs unilaterally during childhood and stabilizes after an initial period of activity, the disease course of NSV is usually slowly progressive, with new lesions occurring bilaterally during life. This suggests an involvement of distinct pathophysiology pathways, specifically increased systemic immune activation in patients with NSV but not in patients with SV. This research aimed to identify the differences in immune cells in the blood of patients with SV and NSV through immunophenotyping of circulating cells. Regulatory T cells were unaffected in patients with SV compared with that in healthy controls but decreased in patients with NSV. In patients with NSV, the reduction in regulatory T cells was associated with the presence of other systemic autoimmune comorbidities, which were less present in SV. Similarly, the absence of a melanocyte-specific antibody response in patients with SV suggests less involvement of B-cell immunity in SV. These data show that in contrast to patients with NSV, no increased systemic immunity is found in patients with SV, indicating that SV pathogenesis is associated with a localized cytotoxic reaction targeting epidermal melanocytes.

Altered gut microbiota correlate with different immune responses to HAART in HIV-infected individuals

BackgroundAlthough gut microbiota dysbiosis has been reported in HIV infected individuals recently, the relationship between the gut microbiota and immune activation in patients with different immune responses to highly active antiretroviral therapy (HAART) is still not well understood. Gut microbiota and immune activation were studied in 36 non-HIV-infected subjects (healthy controls) and 58 HIV-infected individuals, including 28 immunological responders (IR) and 30 immunological non-responders (INR) (≥500 and < 200 CD4+ T-cell counts/μl after 2 years of HIV-1 viral suppression respectively) without comorbidities.ResultsMetagenome sequencing revealed that HIV-infected immunological responders and immunological non-responders could not recover completely from the gut microbiota dysbiosis. At a 97% similarity level, the relative abundances of Fusobacterium, Ruminococcus gnavus and Megamonas were greater, whereas Faecalibacterium, Alistipes, Bifidobacterium, Eubacterium rectale and Roseburia were more depleted in the IR and INR groups than those in the healthy controls. Ruminococcaceae and Alistipes were positively correlated with nadir and current CD4+ T-cell counts, but negatively correlated with CD8 + CD57+ T-cell counts. Inflammation markers and translocation biomarkers (LPS) levels were positively correlated with the abundances of genera Ruminococcus and Fusobacterium but were negatively correlated with the genus Faecalibacterium. The relative abundances of Escherichia-Shigella and Blautia were significantly higher in the IR than those in the INR group. Escherichia-Shigella were negatively correlated with the CD4/CD8 ratio but positively correlated with the amount of CD8 + CD57+ T-cells. Roseburia and Blautia were negatively associated with nadir CD4+ T-cell and positively associated with CD8 + CD57+ T-cell counts.ConclusionsGut microbiota dysbiosis may be one of the factors contributing to different immune responses and treatment outcomes to HAART.

Immune Activation in Patients with Locally Advanced Cervical Cancer Treated with Ipilimumab Following Definitive Chemoradiation (GOG-9929).

A phase I clinical trial (GOG-9929) examined the safety and efficacy of adjuvant immune-modulation therapy with the checkpoint inhibitor ipilimumab [anti-CTL antigen-4 (anti-CTLA-4)] following chemoradiation therapy (CRT) for newly diagnosed node-positive human papillomavirus (HPV)-related cervical cancer. To better understand the mechanism of action and to identify predictive biomarkers, immunologic and viral correlates were assessed before, during, and after treatment. Twenty-one patients who received CRT and ≥2 doses of ipilimumab and 5 patients who received CRT only were evaluable for translational endpoints. Circulating T-cell subsets were evaluated by multiparameter flow cytometry. Cytokines were evaluated by multiplex ELISA. HPV-specific T cells were evaluated in a subset of patients by IFNγ ELISpot. Expression of the activation markers ICOS and PD-1 significantly increased on T-cell subsets following CRT and were sustained or increased following ipilimumab treatment. Combined CRT/ipilimumab treatment resulted in a significant expansion of both central and effector memory T-cell populations. Genotype-specific E6/E7-specific T-cell responses increased post-CRT in 1 of 8 HPV16+ patients and in 2 of 3 HPV18+ patients. Elevation in levels of tumor-promoting circulating cytokines (TNFα, IL6, IL8) post-CRT was significantly associated with worse progression-free survival. Our data indicate that CRT alone and combined with ipilimumab immunotherapy show immune-modulating activity in women with locally advanced cervical cancer and may be a promising therapeutic option for the enhancement of antitumor immune cell function after primary CRT for this population at high risk for recurrence and metastasis. Several key immune biomarkers were identified that were associated with clinical response.

FGF23 and Immune Activation are Correlated in Chronic Heart Failure and Additive Predictors of Poor Prognosis

Aims: Immune activation and disturbances of vitamin D metabolism are frequently encountered in patients with heart failure. Elevated fibroblast growth factor 23 (FGF23) levels as well as immune activation have been associated with a worse outcome in patients with heart failure. We evaluated the relationship of vitamin D metabolism and FGF23 levels with immune activation and its association with cardiac function and outcome in patients with heart failure. Methods and Results: In 149 patients with heart failure caused by nonischaemic cardiomyopathy, parameters of vitamin D metabolism (vitamin D, parathormone, phosphate, C-terminal FGF23, calcium), inflammation (hsCRP, neopterin) and cardiac function were investigated. Patients with elevated inflammatory parameters had significantly higher Ct-FGF23 levels (37.33 RU/mL vs. 17.60 RU/mL, p &lt; 0.001). The highest Ct-FGF23 and phosphate levels were found in patients with elevated neopterin and hsCRP levels as well as in in patients with progressive heart failure. Patients with high Ct-FGF23 and neopterin levels (Ct-FGF23 &gt; 22.60 RU/mL, neopterin &gt; 6.90 nmol/L) had a significantly higher risk for adverse events compared to patients with low Ct-FGF23 and neopterin levels (HR 7.386, [95%CI 2.543 – 21.447], p &lt; 0.001). Conclusions: Our study indicates a strong relationship of vitamin D metabolism, especially FGF23, with Th1 immune activation in patients with heart failure. Elevated Ct-FGF23 and neopterin levels are additive predictors for adverse cardiovascular events in patients with heart failure.

Oral and Gut Microbial Diversity and Immune Regulation in Patients with HIV on Antiretroviral Therapy.

Despite evidence of a chronic inflammatory phenotype in people living with HIV (PLWH) on antiretroviral therapy (ART), the role of oral microbiota in chronic immune activation has not been fully explored. We aimed to determine the relationship between oral and gut microbiome diversity and chronic systemic inflammation in ART-treated PLWH with prevalent severe periodontitis, an inflammatory condition commonly associated with HIV infection. We assessed bacterial and fungal communities at oral and gastrointestinal sites in a cohort (n = 52) of primarily postmenopausal women on ART using 16S rRNA and internal transcribed spacer (ITS) sequencing and measured cellular and soluble markers of inflammation and immune dysfunction. Linear mixed-effect regression and differential abundance analyses were used to associate clinical characteristics and immunological markers with bacterial and fungal diversity and community composition. Bacterial α-diversity in plaque, saliva, and gut was associated with different immunological markers, while mycobial diversity was not associated with soluble or cellular biomarkers of immune stimulation or T cell dysfunction. Furthermore, lipopolysaccharide-positive (LPS+) bacteria previously linked to inflammatory outcomes were enriched at oral sites in patients with severe periodontitis. Fungal α-diversity was reduced in plaque from teeth with higher clinical attachment loss, a marker of periodontitis, and in saliva and plaque from patients with a history of AIDS. Our results show that both bacterial and fungal oral microbiome communities likely play a role in chronic systemic immune activation in PLWH. Thus, interventions targeting both inflammation and the microbiome, particularly in the oral cavity, may be necessary to reduce chronic immune dysregulation in patients with HIV.IMPORTANCE A feedback loop between dysbiotic gut microbiota, increased translocation of microbial products such as lipopolysaccharide, and inflammation has been hypothesized to cause immune system dysfunction in early HIV infection. However, despite evidence of a chronic inflammatory phenotype in patients on antiretroviral therapy (ART), the role of oral microbiota in systemic immune activation and the relationship between oral and gut bacterial and fungal diversity have not been explored. Our study suggests a crucial role for oral bacterial and fungal communities in long-term systemic immune activation in patients on ART, expanding the current paradigm focused on gut bacteria. Our results indicate that interventions targeting both inflammation and microbial diversity are needed to mitigate oral inflammation-related comorbidities, particularly in HIV-positive patients. More broadly, these findings can bolster general models of microbiome-mediated chronic systemic immune activation and aid the development of precise microbiota-targeted interventions to reverse chronic inflammation.