Short term air pollution exposure during pregnancy and associations with maternal immune markers.

BACKGROUND: Air pollution exposure during pregnancy has been associated with numerous adverse pregnancy, birth, and child health outcomes. One proposed mechanism underlying these associations is maternal immune activation and dysregulation. We examined associations between PM2.5 and NO2 exposure during pregnancy and immune markers within immune function groups (TH1, TH2, TH17, Innate/Early Activation, Regulatory, Homeostatic, and Proinflammatory), and examined whether those associations changed across pregnancy. METHODS: In a pregnancy cohort study (n = 290) in Rochester, New York, we measured immune markers (using Luminex) in maternal plasma up to 3 times during pregnancy. We estimated ambient PM2.5 and NO2 concentrations at participants' home addresses using a spatial-temporal model. Using mixed effects models, we estimated changes in immune marker concentrations associated with interquartile range increases in PM2.5 (2.88 µg/m3) and NO2 (7.82 ppb) 0-6 days before blood collection, and assessed whether associations were different in early, mid, and late pregnancy. RESULTS: Increased NO2 concentrations were associated with higher maternal immune markers, with associations observed across TH1, TH2, TH17, Regulatory, and Homeostatic groups of immune markers. Furthermore, the largest increases in immune markers associated with each 7.82 ppb increase in NO2 concentration were in late pregnancy (e.g., IL-23 = 0.26 pg/ml, 95% CI = 0.07, 0.46) compared to early pregnancy (e.g., IL-23 = 0.08 pg/ml, 95% CI = -0.11, 0.26). CONCLUSIONS: Results were suggestive of NO2-related immune activation. Increases in effect sizes from early to mid to late pregnancy may be due to changes in immune function over the course of pregnancy. These findings provide a basis for immune activation as a mechanism for previously observed associations between air pollution exposure during pregnancy and reduced birthweight, fetal growth restriction, and pregnancy complications.

IL-15 Superagonist NAI in BCG-Unresponsive Non-Muscle-Invasive Bladder Cancer.

BACKGROUND: Patients with Bacillus Calmette­Guérin (BCG)­unresponsive non­muscle-invasive bladder cancer (NMIBC) have limited treatment options. The immune cell­activating interleukin-15 (IL-15) superagonist Nogapendekin alfa inbakicept (NAI), also known as N-803, may act synergistically with BCG to elicit durable complete responses (CRs) in this patient population. METHODS: In this open-label, multicenter study, patients with BCG-unresponsive bladder carcinoma in situ (CIS) with or without Ta/T1 papillary disease were treated with intravesical NAI plus BCG (cohort A) or NAI alone (cohort C). Patients with BCG-unresponsive high-grade Ta/T1 papillary NMIBC also received NAI plus BCG (cohort B). The primary end point was the incidence of CR at the 3- or 6-month assessment visit for cohorts A and C, and the disease-free survival (DFS) rate at 12 months for cohort B. Durability, cystectomy avoidance, progression-free survival, disease-specific survival (DSS), and overall survival were secondary end points for cohort A. RESULTS: In cohort A, CR was achieved in 58 (71%) of 82 patients (95% confidence interval [CI]=59.6 to 80.3; median follow-up, 23.9 months), with a median duration of 26.6 months (95% CI=9.9 months to [upper bound not reached]). At 24 months in patients with CR, the Kaplan­Meier estimated probability of avoiding cystectomy and of DSS was 89.2% and 100%, respectively. In cohort B (n=72), the Kaplan­Meier estimated DFS rate was 55.4% (95% CI=42.0% to 66.8%) at 12 months, with median DFS of 19.3 months (95% CI=7.4 months to [upper bound not reached]). Most treatment-emergent adverse events for patients receiving BCG plus NAI were grade 1 to 2 (86%); three grade 3 immune-related treatment-emergent adverse events occurred. CONCLUSIONS: In patients with BCG-unresponsive bladder carcinoma in situ and papillary NMIBC treated with BCG and the novel agent NAI, CRs were achieved with a persistence of effect, cystectomy avoidance, and 100% bladder cancer­specific survival at 24 months. The study is ongoing, with an estimated target enrollment of 200 participants (Funded by ImmunityBio.)