The temporal development of autoantibodies was studied in 1,353 offspring of parents with type 1 diabetes. Islet cell antibodies (ICAs) and autoantibodies to insulin (IAAs), glutamic acid decarboxylase, and IA-2 were measured at birth, 9 months, 2 years, and 5 years of age. At birth, no offspring had islet autoimmunity other than maternally acquired antibodies, which were shown to influence antibody prevalence up to age 6 months. Antibodies detected thereafter were likely to represent a true de novo production, since prevalences were the same for offspring from mothers and fathers with diabetes, antibodies detected at 9 months were almost always confirmed in the 2-year sample and were associated with an increased likelihood of having or developing other antibodies. By 2 years of age, autoantibodies appeared in 11% of offspring, 3.5% having more than one autoantibody. IAAs were detected most frequently, and few had autoantibodies in the absence of IAAs. In 23 offspring with multiple islet autoantibodies, IAAs preceded other antibodies in 10 cases and were first detected concurrently with other antibodies in 12 and after detection of other antibodies in 1. Development of additional antibodies and changes in levels, including decline of IAAs at older age, was frequent. Nine children, all with IAAs and ICAs, developed diabetes. Overall cumulative risk for disease by 5 years of age was 1.8% (95% CI 0.2-3.4) and was 50% (95% CI 19-81) for offspring with more than one autoantibody in their 2-year sample. Autoimmunity associated with childhood diabetes is an early event and a dynamic process. Presence of IAAs is a consistent feature of this autoimmunity, and IAA detection can identify children at risk.

OBJECTIVE: Environmental factors have been suggested to play an important role in the pathogenesis of type 1 diabetes. The aim of this study was to assess the influence of breast-feeding, vaccinations, and childhood viral diseases on the initiation of islet autoimmunity in early childhood. RESEARCH DESIGN AND METHODS: Data were prospectively collected from questionnaires obtained at birth, at 9 months of age, and at 2 years of age in 823 offspring from parents with type 1 diabetes. By 2 years of age, 31 offspring had islet antibodies, and 10 developed overt diabetes by the time of follow-up. RESULTS: In offspring from mothers with type 1 diabetes, duration of exclusive and total breast-feeding did not differ between islet antibody-positive and -negative children, regardless of HLA genotype, and breast-feeding of 3 months or longer was not associated with protection from antibody development or diabetes onset. In offspring from diabetic fathers, non-statistically significant reductions in exclusive and total breast-feeding times were observed in the antibody-positive cohort. Neither type nor quantity of vaccinations (including Bacille Calmette-Guerin vaccine; haemophilus influenzae vaccine; diphtheria, tetanus, and pertussis vaccine; tick-born encephalitis vaccine; or measles, mumps, and rubella vaccine) were associated with the development of islet antibodies and diabetes. Measles, mumps, and rubella were not reported in children with islet antibodies or diabetes. CONCLUSIONS: This study showed no evidence that proposed environmental factors affect islet antibody development in the first 2 years of life in offspring from parents with type 1 diabetes.

No abstract

A new radiobinding assay for the simultaneous detection of antibodies to GAD and the tyrosine phosphatase IA2 has been recently described in patients with newly diagnosed type 1 diabetes. Here we assessed sensitivity and predictive value of this GADIA2-combi test in first-degree relatives of type 1 diabetic patients compared with islet cell antibody (ICA) and insulin autoantibody (IAA) screening. Of 1,606 relatives, 77 (4.8%) had elevated GADIA2-combi titers above the 99th percentile of 105 nondiabetic control subjects, and results were confirmed by testing these samples for GAD antibody (GADA) and tyrosine phosphatase IA2 antibody (IA2A) in the single antibody test (29 GADA+/IA2A+, 44 GADA+/IA2A-, and 4 IA2A+/GADA-). A further 9 of 1,606 relatives had detectable ICA (1) or IAA (8), but they were negative in the GADIA2-combi assay as well as in the single test for GADA or IA2A. Twenty-four relatives progressed to IDDM within a median follow-up time of 5.6 years (range 0.5-8.2). The sensitivity of antibody determination in relatives with progression to IDDM was 92% for the GADIA2-combi assay, 96% for the combined testing of IAA and GADIA2-combi antibodies, and 83, 67, 67, and 79%, respectively, for GADA, IA2A, IAA, or ICA testing alone. The cumulative life-table risk of antibody-positive relatives was related to GADIA2-combi titers (5-year risk: >50 U, 51% [95% CI 30-73]; >10 to 50 U, 12% [1-24]; <10 U, 0.17% [0-0.5]; P=0.0001) and on the presence of IA2A in addition to GADA (5-year risk: GADA+/IA2A+, 47% [25-68]; GADA+/IA2A-, 15% [2-28]; P=0.006). In those with detectable antibodies, risk was not associated with age (<15 vs. >15 years) or relation to proband (offspring, sibling, parent). Relatives with GADIA2-combi antibodies >10 U and the additional presence of IAA had a slightly higher diabetes risk than relatives without IAA (5-year: IAA+, 46% [23-68]; IAA-, 19% [6-32]; P=0.07). Furthermore, low first-phase insulin release after intravenous glucose tolerance test was associated with risk in relatives with GADIA2-combi antibodies (P=0.01). These results indicate that the GADIA2-combi test is a valuable marker for first-line screening and risk assessment of type 1 diabetes in relatives. It can be used for venous as well as capillary blood samples.

No abstract

Abstract:

No abstract

BACKGROUND: Combining anti-PD-1/L1 antibodies and agents that restore cancer cell susceptibility to apoptosis may enhance antitumor activity. We report results from a phase 1b dose-expansion cohort of xevinapant, a first-in-class, oral, small-molecule IAP (inhibitor of apoptosis protein) inhibitor that restores cancer cell sensitivity to apoptosis, and avelumab (anti-PD-L1) in pts with advanced NSCLC. METHODS: The recommended phase 2 dose (RP2D; 28-day cycles of xevinapant 200 mg/day [days 1-10 and 15-24] + avelumab 10 mg/kg [days 1 and 15]) was previously established during the dose-escalation part of this phase 1, open-label study. In this dose-expansion cohort, pts with advanced NSCLC who progressed on first-line (1L) platinum-based chemotherapy (CTx) or anti-PD-1/L1 ± platinum-based CTx received xevinapant (at RP2D) + avelumab for 13 cycles. The primary endpoint was objective response rate (ORR) per RECIST 1.1. Secondary endpoints included duration of response (DoR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), safety, and pharmacokinetics (PK). RESULTS: 38 pts were treated: most had squamous cell carcinoma (45%) or adenocarcinoma (42%) of the lung, 11% had prior anti-PD-L1 therapy, 71% were men, and median age was 62 years (range, 35-75). 1 pt completed 13 cycles, and 37 permanently discontinued treatment; most common reasons were progressive disease (PD; 70%) and adverse events (AEs; 27%). ORR was 10.5% (95% CI 2.9-24.8). Best overall response (BOR): 4 pts had a confirmed partial response (PR), 19 had stable disease, and 15 had PD. Median DoR in responders was 15.9 months (95% CI 3.5-29.7); DCR was 60.5% (95% CI 43.4-76.0). Median PFS was 3.5 months (95% CI 1.9-5.1); median OS was 9.4 months (95% CI 6.7-16.2). Most pts (n=37; 97.4%) had treatment-emergent AEs (TEAEs); 21 (55.3%) had grade ≥3. Most common TEAEs were decreased appetite (n=13; 34.2%) and ALT increase (n=11; 28.9%). Nine pts died due to TEAEs; none were considered treatment-related. Xevinapant and avelumab PK were comparable to monotherapy at the same doses. In exploratory biomarker analyses, plasma IL-10 levels increased during the study treatment period. In blood, activated CD4 T cells and Tregs increased during cycle 1, and activated CD8 T cells increased during the treatment period; however, these did not correlate with antitumor activity. In tumor samples, low Ki67 expression was associated with BOR of PR (n=4), and increases in macrophages, Tregs, Th1 cells, and dendritic cells were associated with disease control. CONCLUSION: Xevinapant + avelumab had tolerable safety in pts with advanced NSCLC who progressed on 1L platinum-based CTx or anti-PD-1/L1 ± platinum-based CTx; however, the study did not meet its primary endpoint as antitumor activity was comparable to historic data for avelumab second-line monotherapy. Citation Format: Quincy Chu, Tudor Ciuleanu, Rodryg Ramlau, Daniel Renouf, Rosalyn Juergens, Ewa Kalinka, Piotr Sawrycki, Jonathan Bramson, Brad Nelson, Rafael Crabbé, Daniela A. Sahlender, Philippa Crompton, Elisabeth Rouits, Dany Spaggiari, Franck Brichory, Luke Piggott, Mike Schenker, Glenwood Goss. Xevinapant plus avelumab in patients (pts) with advanced or metastatic non-small cell lung cancer (NSCLC): Phase 1b dose-expansion results and exploratory biomarker analyses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT202.