The ORR according to RECISTv1.1 was 21.1% with confirmed ORR of 13.2%. The DCR was 63.2% with median duration of clinical benefit of 5.7 months. In the intention-to-treat population, median PFS was 3.8 months and median OS was 6.6 months. The triple combination was safe and well tolerated, with toxicity comparable with the NAPOLI-1 regimen. Notably, the incidence of grade 3 or higher neutropenia and infection was 7%, lower than expected for this chemotherapy regimen.

Triple combination of motixafortide, pembrolizumab, and chemotherapy was safe and well tolerated, and showed signs of efficacy in a population with poor prognosis and aggressive disease.

Triple combination of motixafortide, pembrolizumab, and chemotherapy was safe and well tolerated, and showed signs of efficacy in a population with poor prognosis and aggressive disease.

Although Bruton tyrosine kinase (BTK) inhibitors have demonstrated promising efficacy in patients with Waldenström macroglobulinemia (WM), data in Asian populations are scarce. This trial is the first to investigate the effect of a BTK inhibitor in Chinese patients with relapsed/refractory (R/R) WM.

R/R WM patients with at least one prior regimen were enrolled into this single-arm, multicenter, phase II study (NCT03332173) and received zanubrutinib 160 mg twice daily until disease progression or unacceptable toxicity. The primary endpoint was major response rate (MRR), as assessed by an independent review committee. Secondary endpoints included progression-free survival (PFS), overall response rate (ORR), duration of major response, and safety.

Forty-four patients were enrolled. After a median follow-up of 33.0 (range, 3.2-36.5) months, MRR in all patients was 69.8%, with very good partial response or better in 32.6% of patients. All mutation groups benefited from zanubrutinib treatment (MRR in patients with

mutation, 73%; MRR in patients with

wild type mutation, 50%). A higher response rate was seen in the

/

population, compared to the other populations. Median PFS and median duration of major response were not reached. The most frequently reported grade greater than or equal to3 treatment-emergent adverse events were neutrophil count decreased (31.8%), and platelet count decreased and pneumonia (20.5% each). No case of atrial fibrillation/flutter occurred.

Zanubrutinib achieved a high rate of response that was durable and deep in R/R WM patients across all subgroups, and potentially confers a positive benefit-risk profile for WM.

Zanubrutinib achieved a high rate of response that was durable and deep in R/R WM patients across all subgroups, and potentially confers a positive benefit-risk profile for WM.The linear ubiquitin chain assembly complex (LUBAC) plays pivotal roles in regulating lymphocyte activation, inflammation, and cell death. This is highlighted by the fact that patients with mutations in LUBAC catalytic subunit HOIP suffer from autoinflammation combined with immunodeficiency. Although defective development of T and B cells resulting from HOIP deficiency in adaptive immunity can explain immunodeficiency, the pathogenesis of autoinflammation is not clear. In this study, we found that dendritic cell (DC)-specific deletion of HOIP resulted in spontaneous inflammation, indicating the essential role of HOIP in maintaining DC homeostasis. Although HOIP deficiency in DCs did not affect TNF-α-induced NF-κB activation, it enhanced TNF-α-induced apoptosis and necroptosis. However, crossing HoipDC KO mice with TNFR1-knockout mice surprisingly could not rescue the systematic inflammation, suggesting that the autoinflammation is not due to the effect of HOIP on TNF-α signaling. In contrast, treatment of HoipDC KO mice with antibiotics reduced the inflammation, implying that TLR signaling may contribute to the inflammatory phenotype found in HoipDC KO mice. Consistently, we found that LPS induced more cell death and significantly higher levels of IL-1α and IL-1β in HoipDC KO cells. Importantly, MyD88 deficiency rescued the inflammatory phenotype in HoipDC KO mice. Together, these findings reveal the indispensable function of HOIP in maintaining DC homeostasis, and MyD88-dependent proinflammatory signal plays a substantial role in the pathogenesis of human autoinflammation associated with HOIP mutations.SIGIRR has been described as a negative regulator of several IL-1R/TLR family members and has been implicated in several inflammatory disease conditions. However, it is unknown whether it can suppress IL-36 family cytokines, which are members of the broader IL-1 superfamily that have emerged as critical orchestrators of psoriatic inflammation in both humans and mice. In this study, we demonstrate that SIGIRR is downregulated in psoriatic lesions in humans and mice, and this correlates with increased expression of IL-36 family cytokines. Using Sigirr -/- mice, we identify, for the first time (to our knowledge), SIGIRR as a negative regulator of IL-36 responses in the skin. Mechanistically, we identify dendritic cells and keratinocytes as the primary cell subsets in which IL-36 proinflammatory responses are regulated by SIGIRR. Both cell types displayed elevated IL-36 responsiveness in absence of SIGIRR activity, characterized by enhanced expression of neutrophil chemoattractants, leading to increased neutrophil infiltration to the inflamed skin. Blockade of IL-36R signaling ameliorated exacerbated psoriasiform inflammation in Sigirr-/- mice and inhibited neutrophil infiltration. These data identify SIGIRR activity as an important regulatory node in suppressing IL-36-dependent psoriatic inflammation in humans and mice.

In this study, we determined whether

(

) infection dampens the efficacy of cancer immunotherapies.

Using mouse models, we evaluated whether immune checkpoint inhibitors or vaccine-based immunotherapies are effective in reducing tumour volumes of

-infected mice. In humans, we evaluated the correlation between

seropositivity and the efficacy of the programmed cell death protein 1 (PD-1) blockade therapy in patients with non-small-cell lung cancer (NSCLC).

In mice engrafted with MC38 colon adenocarcinoma or B16-OVA melanoma cells, the tumour volumes of non-infected mice undergoing anticytotoxic T-lymphocyte-associated protein 4 and/or programmed death ligand 1 or anti-cancer vaccine treatments were significantly smaller than those of infected mice. We observed a decreased number and activation status of tumour-specific CD8

T cells in the tumours of infected mice treated with cancer immunotherapies independent of the gut microbiome composition. mTOR signaling pathway Additionally, by performing an in vitro co-culture assay, we observed that dendritic cells of infected mice promote lower tumour-specific CD8

T cell proliferation.