Purpose This multinational study evaluated the antitumor activity of nivolumab in nasopharyngeal carcinoma (NPC). Tumor and plasma-based biomarkers were investigated in an exploratory analysis. Patients and Methods Patients with multiply pretreated recurrent or metastatic NPC were treated with nivolumab until disease progression. The primary end point was objective response rate (ORR) and secondary end points included survival and toxicity. The expression of programmed death-ligand 1 (PD-L1) and human leukocyte antigens A and B in archived tumors and plasma clearance of Epstein-Barr virus DNA were correlated with ORR and survival. Results A total of 44 patients were evaluated and the overall ORR was 20.5% (complete response, n = 1; partial response, n = 8). Nine patients received nivolumab for > 12 months (20%). The 1-year overall survival rate was 59% (95% CI, 44.3% to 78.5%) and 1-year progression-free survival (PFS) rate was 19.3% (95% CI, 10.1% to 37.2%). There was no statistical correlation between ORR and the biomarkers; however, a descriptive analysis showed that the proportion of patients who responded was higher among those with PD-L1 positive tumors (> 1% expression) than those with PD-L1-negative tumors. The loss of expression of one or both human leukocyte antigen class 1 proteins was associated with better PFS than when both proteins were expressed (1-year PFS, 30.9% v 5.6%; log-rank P = .01). There was no association between survival and PD-L1 expression or plasma Epstein-Barr virus DNA clearance. There was no unexpected toxicity to nivolumab. Conclusion Nivolumab has promising activity in NPC and the 1-year overall survival rate compares favorably with historic data in similar populations. Additional evaluation in a randomized setting is warranted. The biomarker results were hypothesis generating and validation in larger cohorts is needed.

Key Points Lenalidomide consolidation repairs T-cell immune synapses in CLL patients. Lenalidomide consolidation improved the quality of response in CLL patients treated with chemoimmunotherapy.

Ofatumumab (OFA), a human CD20 targeting mAb, kills B-lymphocytes utilizing the innate immune system including complement dependent cytotoxicity (CDC). The efficacy of OFA in patients with chronic lymphocytic leukemia (CLL) is limited by drug resistance, which is not well characterized. To better understand mechanisms of resistance, we prospectively studied CLL cells isolated from blood samples collected before and after in vivo exposure to the initial dose of OFA therapy in 25 patients undergoing their first treatment for progressive CLL. As previously reported, OFA therapy rapidly decreased the absolute lymphocyte count, CD20 expression by CLL cells, and serum complement levels. We now show that after administration of the first dose of OFA, there was a modest rebound in the absolute lymphocyte count and serum complement levels, but substantial ongoing loss of CD20 expression by CLL cells. These post-OFA treatment CLL cells were highly resistant to OFA-mediated CDC but retained sensitivity to alemtuzumab-mediated CDC in vitro. Post-therapy serum OFA levels correlated inversely with both the amount of pre-treatment circulating cell bound CD20 and with the decrease in this value following treatment. In vitro OFA-mediated CDC did not predict clinical responses and the patients with “first dose” reactions to OFA did not have markers of increased complement activation in vivo. We propose that optimal efficacy of CD20 targeted therapy for CLL requires determining a mAb dose size and frequency that optimizes CLL killing without exceeding the capacity of the cytotoxic mechanisms and thus minimizes loss of CD20 expression in the surviving CLL cells.

Summary 1.Immunity may trade-off against other important life history traits, with recent work suggesting that reproduction and parental care in particular impinge on immune defence. However, whereas the effect of parental care on immunocompetence has been intensively studied in birds and mammals, virtually nothing is known about how it affects insect immunity. 2. Burying beetles provide extensive biparental care that includes the burial, preparation and defence of a carcass, as well as the subsequent feeding of the larvae. In addition, they cover the carcass with anal exudates that have been shown to serve an antimicrobial function (social immunity sensu Behavioral Ecology, 21, 663-668). We examined the effect of sex, mating and parental care on measurements of individual and social immunity in the burying beetle Nicrophorus orbicollis. 3. Both males and females showed a rapid upregulation of the encapsulation response upon discovery of a carcass. The high encapsulation rate was maintained during the entire period of parental care. Lytic activity in anal exudates, a measure of social immunity, likewise increased. Mating had no effect on individual or social immunity, but females generally exhibited higher individual immunity than male N. orbicollis. 4. Our results suggest that the unusual breeding environment of burying beetles -a microbe-rich carcass -has selected for an atypical pattern of immune defence, with a significant upregulation of individual and social immunity during the physically demanding period of reproduction and parental care. The simultaneous investment in two life history traits that normally compete for resources may be an adaptive response in species that breed in environments with high densities of micro-organisms.

Trade‐offs between life‐history variables can be manifested at either the phenotypic or genetic level, with vastly different evolutionary consequences. Here, we examined whether male decorated crickets (Gryllodes sigillatus) from eight inbred lines and the outbred founder population from which they were derived, trade‐off immune effort [lytic activity, phenoloxidase (PO) activity or encapsulation] to produce spermatophylaxes: costly nuptial food gifts essential for successful sperm transfer. Canonical correlation analysis of the outbred population revealed a trade‐off between spermatophylax mass and lytic activity. Analysis of our inbred lines, however, revealed that although PO activity, encapsulation, body mass, spermatophylax mass and ampulla (sperm capsule) mass were all highly heritable, lytic activity was not, and there was, therefore, no negative genetic correlation between lytic activity and spermatophylax mass. Thus, males showed a phenotypic but not a genetic trade‐off between spermatophylax mass and lytic activity, suggesting that this trade‐off is mediated largely by environmental factors.