Efficacy and Safety of a New 20% Immunoglobulin Preparation for Subcutaneous Administration, IgPro20, in Patients With Primary Immunodeficiency

Subcutaneous human IgG (SCIG) therapy in primary immunodeficiency (PID) offers sustained IgG levels throughout the dosing cycle and fewer adverse events (AEs) compared to intravenous immunoglobulin (IVIG). A phase I study showed good local tolerability of IgPro20, a new 20% liquid SCIG stabilized with L-proline. A prospective, open-label, multicenter, single-arm, phase III study evaluated the efficacy and safety of IgPro20 in patients with PID over 15 months. Forty-nine patients (5–72 years) previously treated with IVIG received weekly subcutaneous infusions of IgPro20. The mean serum IgG level was 12.5 g/L. No serious bacterial infections were reported. There were 96 nonserious infections (rate 2.76/patient per year). The rate of days missed from work/school was 2.06/patient per year, and the rate of hospitalization was 0.2/patient per year. Ninety-nine percent of AEs were mild or moderate. No serious, IgPro20-related AEs were reported. IgPro20 effectively protected patients with PID against infections and maintained serum IgG levels without causing unexpected AEs

A new obesity-prone, glucose-intolerant rat strain (F.DIO)

Previous breeding for the diet-induced obese (DIO) trait from outbred Sprague-Dawley rats produced a substrain with selection characteristics suggesting a polygenic mode of inheritance. To assess this issue further, selectively bred DIO male rats were crossed with obesity-resistant inbred Fischer F344 dams. Male offspring were crossed twice more against female F344 dams. The resultant N3 (F.DIO) rats were then inbred three more times. On low-fat chow, 10-wk-old male and female DIO rats weighed 86 and 59% more than respective F344 rats. By the N3 (F.DIO) generation, they were only 12 and 10% heavier, respectively. After three additional inbreeding cycles, chow-fed F.DIO males had an exaggerated insulin response to oral glucose compared with F344 rats. After 3 wk on a 31% fat (high-energy) diet, male N3 F.DIO rats gained 16-20% more carcass and adipose weight with 98% higher plasma leptin levels, whereas F.DIO females gained 36-54% more carcass and adipose weight with 130% higher leptin levels than comparable F344 rats. After three inbreeding cycles, F.DIO males still gained more weight on high-energy diet and developed a threefold greater insulin response to oral glucose than F344 males. Preservation of the DIO and glucose intolerance traits through successive backcrosses and inbreeding cycles to produce the F.DIO strain lends further support to the idea that they inherited in a polygenic fashion. </jats:p

Splenectomized Patients Have Reduced CD27+ Memory B Cells but Protective Antibody Responses to Pneumococcal Vaccination.

Abstract Introduction : Splenectomized patients are thought to have poor antibody responses to polyvalent non-conjugate pneumococcal vaccination. Recent studies found that these patients have decreased circulating CD27+ (memory) B cells, suggesting the possibility of a specific defect in splenectomized patients’ humoral immunity. In this study we sought to verify this reduction and ascertain whether it correlates with inadequate antibody production. Thus, we enumerated peripheral blood CD27+ B cells in splenectomized patients and non-splenectomized controls, administered a polyvalent non-conjugate pneumococcal vaccine, and compared their IgG antibody titers to all 23 serotypes before and 4 to 6 weeks after immunization. Participants : 31 participants were enrolled: 21 splenectomized patients (6 male, 15 female; age: 10–80 years, mean: 47.3) and 10 non-splenectomized controls (2 male, 8 female; age: 26–64 years, mean: 37.5). Indications for splenectomy included ITP (17), spherocytosis (2), hemolytic anemia (1), and thrombocytopenia-absent radii syndrome (1). No patients received pneumococcal vaccination within 2 years, or IVIG, Rituxan or immunosuppressive therapy within 6 months of enrollment. Time since splenectomy ranged from 6 months to 50 years (mean: 12.5). 17 patients received at least one prior pneumococcal immunization, from 3 to 22 years previously (mean: 8.0). No controls formerly received a pneumococcal vaccination. Results : B Cell Enumeration: Compared to the 10 controls, the 21 splenectomized patients had a greater percentage of circulating B cells (patients: 12.05% ± 7.61; controls: 7.99% ± 2.92; ρ = 0.042), but a significantly reduced CD27+ B cell component (patients: 12.38% ± 8.48; controls: 40.46% ± 18.68; ρ = 0.001). This reduction was not specific to either of the CD27+ B cell populations (IgM+IgD+CD27+: patients: 31.64% ± 19.72; controls: 44.58% ± 16.01; ρ = 0.081. IgM−IgD−CD27+: patients: 52.05 ± 23.71; controls: 48.08% ± 13.89; ρ = 0.628.) Antibody Analysis: Antibody responses to pneumococcal vaccination did not differ significantly between splenectomized patients and non-splenectomized controls. 9 of 13 splenectomized patients and 9 of 10 controls achieved protection to immunization (χ2 = 1.433; ρ = 0.339), defined as a post-vaccination IgG titer ≥ 1.3 μg/ml or a post:pre-vaccination titer ratio ≥ 4, in at least 70% of the serotypes tested (~16 of 23 serotypes). When comparing the mean number of serotypes to which each cohort achieved protection, splenectomized patients and controls mounted statistically similar responses, at 17 and 20 serotypes, respectively (ρ = 0.134). Furthermore, the geometric means of each cohort’s post-vaccination IgG titers did not differ significantly in 22 of the 23 serotypes. Conclusion : Splenectomized patients had a significant reduction in their circulating CD27+ B cells. This decrease did not correlate with an impaired antibody response to (re-)immunization with a polyvalent non-conjugate pneumococcal vaccine however, as splenectomized patients and non-splenectomized controls achieved comparable protection and produced similar IgG responses to vaccination. For ITP patients and others who have undergone splenectomy, our data indicates that a pneumococcal vaccine can be effectively administered after splenectomy, if needed.</jats:p

OP0328 A UNIQUE PD1+CD38+ CD8+ T CELL POPULATION CHARACTERIZES CHECKPOINT INHIBITOR-ASSOCIATED INFLAMMATORY ARTHRITIS

Background:Immune checkpoint inhibitors (CI) are monoclonal antibodies that block CTLA-4, PD-1 or PD-L1, resulting in cytotoxic T cell activation in the tumor microenvironment. They have revolutionized the management of metastatic cancer but unleash “immune related adverse events” in &gt; 80% of treated patients, including inflammatory arthritis in ~4%1. CI-associated arthritis (CI-A) often presents as a symmetrical polyarthritis, phenotypically indistinguishable from rheumatoid arthritis (RA), but whether it shares cellular and molecular features of RA has not been determined.Objectives:To compare synovial fluid (SF) T cell populations from CI-A patients to those in patients with RA, phenotypically and functionally.Methods:We immunophenotyped SF mononuclear cells from patients with CI-A caused by anti-PD-(L)1 therapy (n=9), seropositive RA (n=5), and psoriatic arthritis (PsA) (n=5) using a 39-marker mass cytometry (CyTOF) panel. FlowSOM was used to cluster CD4 and CD8 T cells into 15 ‘metaclusters’ based on multidimensional phenotypes. We used Kruskal-Wallis or Mann-Whitney tests to identify significantly altered populations (p&lt;0.05), which we confirmed by biaxial gating. Flow cytometry was used to confirm SF findings in an independent cohort, and to identify cells of interest in peripheral blood. Cytokine staining was performed on sorted T cells populations after CDCD3/CD28 stimulation for 72 hours, followed by 4 hour PMA/ION+BRA/MON restimulation.Results:In CI-A patients, T cells represented 50% of SF mononuclear cells (53% CD4, 40% CD8), followed by monocytes (24%) and NK cells (8%), comparable to RA and PsA. However, FlowSOM analysis revealed expansion of a distinct population of PD-1+CD38hiCD127-CD8 T cells (CD8 metacluster2) (Fig. 1). These cells comprised 30% of CD8+ SF T cells in CI-A, a 3.4-fold increase over RA/PsA, p=0.0002 (Fig. 2). Over 40% of these cells expressed Ki67 in CI-A, suggesting active proliferation. Flow cytometry on SF cells from an independent cohort of CI-A patients (n= 5) and RA/PsA comparators (n= 9) confirmed our findings. PD-1+CD38hiCD127-CD8 T cells were also expanded in the blood of CI-A patients, where they represented 4.6% of CD8 Tcells, a 2.8-fold increase over RA, p = 0.0057. In addition to expressing high levels of PD-1, CD38hiCD127-, these CD8 T cells express other immune checkpoint receptors including ICOS and TIGIT. After in vitro stimulation, CD38hiCD127-CD8 T cells produced granzyme B along with TNF and IFN-γ at comparable levels to other CD8 populations, suggesting that they are not functionally exhausted.Figure 1.Mass cytometry CD8+T cells (tSNE plots) with FlowSOM metaclusters.Figure 2.Synovial fluid PD-1+CD38hiCD127-CD8+T cellsFlowSOM analysis of SF CD4 T cells in CI-A patients revealed the expansion of a subpopulation of CD4 cells with a similar surface phenotype of PD-1+CD38hiCD127-(metacluster2, 10% of CD4s in CI-A, a 2.4-fold increase over RA/PsA, p=0.0047). In contrast, RA patients had a significantly expanded population of PD-1hiICOS+ CD4 T peripheral helper (Tph) cells (metacluster5, 30% of CD4s in RA, p=0.006), but these cells were not expanded in CI-A (Fig 3).Figure 3.Synovial fluid CD4+T peripheral helper cellsConclusion:CyTOF analysis of SF revealed a uniquely expanded PD-1+CD38hiCD127-CD8 T cell population in CI-A not present in RA or PsA, and a similar PD-1+CD38hiCD127-CD4 T cell population. These cells may contribute to the amplified immune response seen in CI-A patients. Further functional and transcriptional analysis of these cells will help to elucidate their function may reveal key mechanisms driving CI-associated immune related adverse events.References:[1]Kostine M. Ann Rheum Dis 2018;77(3):393-398Disclosure of Interests:Runci Wang: None declared, Karmela Kim Chan: None declared, Amy Cunningham-Bussel: None declared, Laura Donlin Consultant of: Consultant – Genentech/Roche, Gregory Vitone: None declared, Aidan Tirpack: None declared, Caroline Benson: None declared, Gregory Keras: None declared, A. Helena Jonsson: None declared, Michael Brenner: None declared, Anne Bass: None declared, Deepak Rao Grant/research support from: Has received research grant support from Celgene and Merck., Consultant of: Has received consulting fees or honoraria from Merck, Pfizer, GlaxoSmithKine, Bristol-Myers Squibb, Janssen, and Scipher Medicine</jats:sec

Bridging the divide: Student grand rounds at the interface of basic science and clinical medicine

Problem: As biomedical research and clinical medicine become increasingly complex, physician-scientists and clinically oriented biomedical researchers play important roles in bridging the gap between disciplines. A lack of educational programming that addresses the unique needs of students preparing for careers at the interface of basic science and clinical medicine may contribute to trainee attrition. Approach: The MD-PhD/LHB Grand Rounds was introduced in 2008 as a trainee-driven collaborative effort of the Harvard/ Massachusetts Institute of Technology MD-PhD program at Harvard Medical School (HMS MD-PhD program), Harvard\u27s Leder Human Biology and Translational Medicine (LHB) program, and the Brigham and Women\u27s Hospital (BWH) Internal Medicine Department. Each of the program\u27s approximately 4 sessions per year begins with dinner, followed by a clinical case presentation led by a BWH MD-PhD resident with a master clinician faculty discussant, then a research presentation by an LHB PhD student or an MD-PhD student on a basic science topic related to the clinical case, and time for socialization. Outcomes: In a July 2017 survey of participating students and residents, respondents reported being highly satisfied with the program. Mean satisfaction ratings were 4.3 (SD 0.5) for 12 MD-PhD students, 4.2 (SD 0.7) for 31 LHB students, and 4.4 (SD 0.9) for 5 residents on a 5-point scale (5 = very satisfied). Free-text responses suggested MD-PhD students valued opportunities for active engagement with the resident presenter and faculty discussant. LHB students appreciated the absence of medical jargon in the clinical presentations. Residents\u27 reported reasons for participating included enjoyment of teaching and interaction with students. Next Steps: The Harvard MD-PhD/LHB Grand Rounds can serve as a template for developing similar programs at other institutions. Research is needed to determine whether such grand rounds programs can help fix the leaky pipeline in the training of future physician-scientists and clinically oriented biomedical researchers