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microenvironments. We also found that it also exerted an enhanced anticancer effect with immune checkpoint inhibitors. These results suggest that rSmeg-hMIF-hIL-7 is a potential adjuvant for cancer immunotherapy. This is the first report to prove anticancer potential of immunotherapeutic vaccine targeting immune response against MIF.

In conclusion, our data showed that rSmeg-hMIF-hIL-7 exerts a strong antitumor immune response in mice, possibly by inhibiting the MIF-dependent promotion of tumorigenesis by the anti-MIF immune response and via enhanced cytotoxic T cell recruitment into tumor microenvironments. We also found that it also exerted an enhanced anticancer effect with immune checkpoint inhibitors. These results suggest that rSmeg-hMIF-hIL-7 is a potential adjuvant for cancer immunotherapy. This is the first report to prove anticancer potential of immunotherapeutic vaccine targeting immune response against MIF.

GWN323 is an IgG1 monoclonal antibody (mAb) against the glucocorticoid-induced tumor necrosis factor receptor-related protein. This first-in-human, open-label phase I/Ib study aimed to investigate the safety and tolerability and to identify the recommended doses of GWN323 with/without spartalizumab, an anti-programmed cell death receptor-1 agent, for future studies. Pharmacokinetics, preliminary efficacy and efficacy biomarkers were also assessed.

Patients (aged ≥18 years) with advanced/metastatic solid tumors with Eastern Cooperative Oncology Group performance status of ≤2 were included. GWN323 (10-1500 mg) or GWN323+spartalizumab (GWN323 10-750 mg+spartalizumab 100-300 mg) were administered intravenously at various dose levels and schedules during the dose-escalation phase. Dose-limiting toxicities (DLTs) were assessed during the first 21 days in a single-agent arm and 42 days in a combination arm. Adverse events (AEs) were graded per National Cancer Institute-Common Toxicity Criteria for Adverse EventsN323 exhibited a pharmacokinetic profile typical of mAbs with a dose-dependent increase in the pharmacokinetic exposure. Inconsistent decreases in regulatory T cells and increases in CD8+ T cells were observed in the combination arm. Gene expression analyses showed no significant effect of GWN323 on interferon-γ or natural killer-cell signatures.

GWN323, as a single agent and in combination, was well tolerated in patients with relapsed/refractory solid tumors. The MAD was 1500 mg q3w for single-agent and GWN323 750 mg+spartalizumab 300 mg q3w for combination treatments. Minimal single-agent activity and modest clinical benefit were observed with the spartalizumab combination.

NCT02740270.

NCT02740270.Breast cancer has historically been a disease for which immunotherapy was largely unavailable. Recently, the use of immune checkpoint inhibitors (ICIs) in combination with chemotherapy for the treatment of advanced/metastatic triple-negative breast cancer (TNBC) has demonstrated efficacy, including longer progression-free survival and increased overall survival in subsets of patients. Based on clinical benefit in randomized trials, ICIs in combination with chemotherapy for the treatment of some patients with advanced/metastatic TNBC have been approved by the United States (US) Food and Drug Administration (FDA), expanding options for patients. Ongoing questions remain, however, about the optimal chemotherapy backbone for immunotherapy, appropriate biomarker-based selection of patients for treatment, the optimal strategy for immunotherapy treatment in earlier stage disease, and potential use in histological subtypes other than TNBC. To provide guidance to the oncology community on these and other important concerns, the Society for Immunotherapy of Cancer (SITC) convened a multidisciplinary panel of experts to develop a clinical practice guideline (CPG). The expert panel drew upon the published literature as well as their clinical experience to develop recommendations for healthcare professionals on these important aspects of immunotherapeutic treatment for breast cancer, including diagnostic testing, treatment planning, immune-related adverse events (irAEs), and patient quality of life (QOL) considerations. The evidence-based and consensus-based recommendations in this CPG are intended to give guidance to cancer care providers treating patients with breast cancer.

The adoptive transfer of chimeric antigen receptor (CAR)-T cells has emerged as a potent immunotherapy against some hematological malignancies but not yet for epithelial-derived solid tumors. One critical issue is the paucity of broadly expressed solid tumor antigens (TAs), and another is the presence of suppressive mechanisms in the tumor microenvironment (TME) that can impair CAR-T cell homing, extravasation and effector functions. TAs expressed by endothelial cells of the tumor vasculature are of clinical interest for CAR therapy because of their genomic stability and accessibility to circulating T cells, as well as their expression across multiple tumor types. In this study, we sought to explore limitations to the efficacy of second-generation (2G) murine CAR-T cells redirected against the vascular endothelial growth factor receptor-2 (VEGFR-2) with the well-characterized single-chain variable fragment DC101.

Primary murine T cells were retrovirally transduced to express a 2G anti-VEGFR-2-CAR, and theith reduced frequencies of PD-1

Ki67

and LAG-3

Ki67

CAR-T cells in the TME.

This study represents the first example of impaired function of a vasculature-targeted CAR by an angiogenic ligand and rationalizes the use of combinatorial therapies that target the tumor vasculature and augment CAR-T cell effector function.

This study represents the first example of impaired function of a vasculature-targeted CAR by an angiogenic ligand and rationalizes the use of combinatorial therapies that target the tumor vasculature and augment CAR-T cell effector function.Single-cell RNA and TCR sequencing of peripheral blood and esophageal cells of human eosinophilic esophagitis uncovers antigen-restricted TH2 cells.Eosinophilic esophagitis (EoE) is an allergic disorder characterized by the recruitment of eosinophils to the esophagus, resulting in chronic inflammation. We sought to understand the cellular populations present in tissue biopsies of patients with EoE and to determine how these populations are altered between active disease and remission. To this end, we analyzed cells obtained from esophageal biopsies, duodenal biopsies, and peripheral blood of patients with EoE diagnosed with active disease or remission with single-cell RNA and T cell receptor (TCR) sequencing. Pathogenic effector TH2 (peTH2) cells present in the esophageal biopsies of patients with active disease expressed distinct gene signatures associated with the synthesis of eicosanoids. The esophageal tissue-resident peTH2 population also exhibited clonal expansion, suggesting antigen-specific activation. Peripheral CRTH2+CD161- and CRTH2+CD161+ memory CD4+ T cells were enriched for either a conventional TH2 phenotype or a peTH2 phenotype, respectively. These cells also exhibited substantial clonal expansion and convergence of TCR sequences, suggesting that they are expanded in response to a defined set of antigens. The esophagus-homing receptor GPR15 was up-regulated by peripheral peTH2 clonotypes that were also detected in the esophagus. Finally, GPR15+ peTH2 cells were enriched among milk-reactive CD4+ T cells in patients with milk-triggered disease, suggesting that these cells are an expanded, food antigen-specific population with enhanced esophagus homing potential.Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by a chronic inflammatory process often associated with comorbid asthma. In this study, we analyzed the transcriptomes of single T helper (TH) cells from nasal polyps of patients with CRSwNP and validated these findings using multiparameter flow cytometry. Polyp tissue contained suppressive T regulatory (Treg) cells, TH2 cells, type 2 innate lymphoid cells, and three transcriptionally distinct subsets of cytotoxic CD4+ T cells (CD4+ CTL). GATA3 expression was a feature of polyp Treg cells, whereas TH2 cells highly expressed TCN1, CD200R, and HPGDS and were enriched for genes involved in lipid metabolism. Only a portion of polyp TH2 cells expressed the prostaglandin D2 receptor CRTH2, whereas a subpopulation of CD109+CRTH2- TH2 cells expressed mRNA for common inhibitor receptors including LAG3 and TIM3 and produced IL-10. Together, we resolved the complexity of TH cells in patients with CRSwNP, identifying several distinct clusters of CD4+ CTL and a population of CD109+CRTH2- TH2 cells with putative regulatory potential.Type 1 diabetes is an autoimmune disease in which insulin-secreting β-cells are destroyed, leading to a life-long dependency on exogenous insulin. There are no approved disease-modifying therapies available, and future immunotherapies would need to avoid generalized immune suppression. We developed a novel plasmid expressing preproinsulin2 and a combination of immune-modulatory cytokines (transforming growth factor-beta-1, interleukin [IL] 10 and IL-2) capable of near-complete prevention of autoimmune diabetes in non-obese diabetic mice. Efficacy depended on preproinsulin2, suggesting antigen-specific tolerization, and on the cytokine combination encoded. Diabetes suppression was achieved following either intramuscular or subcutaneous injections. SNDX-275 Intramuscular plasmid treatment promoted increased peripheral levels of endogenous IL-10 and modulated myeloid cell types without inducing global immunosuppression. To prepare for first-in-human studies, the plasmid was modified to allow for selection without the use of antibiotic resistance; this modification had no impact on efficacy. This pre-clinical study demonstrates that this multi-component, plasmid-based antigen-specific immunotherapy holds potential for inducing self-tolerance in persons at risk of developing type 1 diabetes. Importantly, the study also informs on relevant cytokine and immune cell biomarkers that may facilitate clinical trials. This therapy is currently being tested for safety and tolerability in a phase 1 trial (ClinicalTrials.gov Identifier NCT04279613).Predictive biomarkers for immune therapy must address a complex interface between the immune system and triple-negative breast cancer and still be technically reliable for diagnostic use. Two recent papers describe the assessment of spatial heterogeneity using digital methods that promise to improve the quantification of immune infiltrate or molecular targets.Circulating tumor DNA (ctDNA) has emerged as a non-invasive diagnostic and prognostic tool for colorectal cancer (CRC). Here, we discuss studies that evaluate the ability of plasma-only ctDNA assays to detect minimal residual disease (MRD) and the potential benefit of integration of methylation into ctDNA assays.

Fatigue is a frequent symptom in rheumatoid arthritis (RA) and has high impact on quality of life. We explored associations between disease activity and fatigue in patients with early RA during the initial 24 months of modern treat-to-target therapy and predictors of fatigue after 24 months of follow-up.

Data were obtained from the treat-to-target, tight control Aiming for Remission in Rheumatoid Arthritis a Randomised Trial Examining the Benefit of Ultrasound in a Clinical Tight Control Regime (ARCTIC) trial. Fatigue was measured on a visual analogue scale (VAS) from 0 to 100 mm and defined as clinically relevant if VAS was ≥20 mm. Baseline predictors of fatigue at 24 months were analysed by multivariable logistic regression.

205 patients with fatigue data at baseline and 24 months were included. Median (25th, 75th percentiles) symptom duration was 5.4 months (2.8, 10.4), fatigue VAS 37.0 mm (13.0, 62.0) and mean Disease Activity Score (DAS) 3.4 (SD 1.1) at baseline. Prevalence of fatigue declined from 69% at baseline to 38% at 24 months.