The pro-inflammatory cytokine interleukin-17A (IL-17A) is a key driver of multiple inflammatory and immune disorders. Therapeutic antibodies targeting IL-17A have been proven effective in treating patients with these diseases; however, large variations in clinical outcomes have been observed with different antibodies. In this study, we developed HB0017, a novel monoclonal antibody that targets human IL-17A. HB0017 specifically and strongly bound to human, cynomolgus monkey, and mouse IL-17A at the physiological interface with the IL-17A receptor. In human and monkey cells, HB0017 potently antagonized the functions of IL-17A through competitive binding. HB0017 functioned equivalently to that of clinically approved antibodies in terms of therapeutic efficacy for inflammatory disorders and psoriasis in a mouse model. The results indicate that HB0017 may be an alternative biological therapy for treating patients with inflammation and autoimmune diseases.

Oncolytic viruses offer an in situ vaccination approach to activate tumor-specific T cell responses. However, the upregulation of PD-L1 expression on tumor cells and immune cells leads to tumor resistance to oncolytic immunotherapy. In this study, we generate an engineered oncolytic virus that coexpresses a PD-L1 inhibitor and GM-CSF. We find that the oncolytic virus is able to secrete the PD-L1 inhibitor that systemically binds and inhibits PD-L1 on tumor cells and immune cells. Importantly, the intratumoral injection with the oncolytic virus overcomes PD-L1-mediated immunosuppression during both the priming and effector phases, provokes systemic T cell responses against dominant and subdominant neoantigen epitopes derived from mutations, and leads to an effective rejection of both virus-injected and distant tumors. In summary, this engineered oncolytic virus is able to activate tumor neoantigen-specific T cell responses, providing a potent, individual tumor-specific oncolytic immunotherapy for cancer patients, especially those resistant to PD-1/PD-L1 blockade therapy.

Eriodictyol is a flavonoid that belongs to a subclass of flavanones and is widespread in citrus fruits, vegetables, and medicinally important plants. Eriodictyol has been anticipated to explain the method of its activity via multiple cellular signaling cascades. Eriodictyol is an effective natural drug source to maintain higher health standards due to its excellent therapeutic roles in neuroprotection, cardioprotective activity, hepatoprotective activity, antidiabetes and obesity, and skin protection and having highly analgesic, antioxidant, and anti-inflammatory effects, antipyretic and antinociceptive actions, antitumor activity, and much more. This review aims to highlight the modes of action of eriodictyol against various diseases via multiple cellular signaling pathways.

Anti-CD19 chimeric antigen receptor (CAR) T cell therapies can cause severe cytokine-release syndrome (CRS) and neurotoxicity, impeding their therapeutic application. Here we generated a new anti-CD19 CAR molecule (CD19-BBz(86)) derived from the CD19-BBz prototype bearing co-stimulatory 4-1BB and CD3ζ domains. We found that CD19-BBz(86) CAR T cells produced lower levels of cytokines, expressed higher levels of antiapoptotic molecules and proliferated more slowly than the prototype CD19-BBz CAR T cells, although they retained potent cytolytic activity. We performed a phase 1 trial of CD19-BBz(86) CAR T cell therapy in patients with B cell lymphoma (ClinicalTrials.gov identifier NCT02842138 ). Complete remission occurred in 6 of 11 patients (54.5%) who each received a dose of 2 × 108–4 × 108 CD19-BBz(86) CAR T cells. Notably, no neurological toxicity or CRS (greater than grade 1) occurred in any of the 25 patients treated. No significant elevation in serum cytokine levels after CAR T cell infusion was detected in the patients treated, including in those who achieved complete remission. CD19-BBz(86) CAR T cells persistently proliferated and differentiated into memory cells in vivo. Thus, therapy with the new CD19-BBz(86) CAR T cells produces a potent and durable antilymphoma response without causing neurotoxicity or severe CRS, representing a safe and potent anti-CD19 CAR T cell therapy. A new anti-CD19 CAR T cell therapy induces potent antitumor responses without causing severe cytokine-release syndrome or neurotoxicity in patients with lymphoma.

Background Patients with relapsed or refractory B-cell non-Hodgkin lymphoma have poor outcomes with the available strategies. Based on the promising results seen in patients treated with anti-CD19 CAR T-cell therapy in relapsed or refractory B-cell non-Hodgkin lymphoma, we initiated a phase 1 study to evaluate the safety and efficacy in patients. Autologous T cells were genetically modified to express a chimeric antigen receptor consisting of an anti-CD19-scFv domain with CD3ζ and 4–1BB signalling domains. Methods We did this phase 1 study in patients with relapsed or refractory B-cell non-Hodgkin lymphoma in Peking University Cancer Hospital, Beijing, China. Patients received a CAR T-cell infusion after a conditioning regimen of cyclophosphamide (250 mg/m2) and fludarabine (25 mg/m2) daily for 3 days. Three CAR T cell doses were tested: 5 × 104 CAR T cells/kg, 1 × 105 CAR T cells/kg, and 1 × 106 CAR T cells/kg. Primary endpoints included safety and pharmacokinetics of CAR T cells. Secondary endpoints include complete response, overall response, and duration of response per International Working Group Criteria. This trial is registered at ClinicalTrials, number NCT02842138. Findings As of March 2017, 14 patients were enrolled and ten patients, with a median age of 37 years (range 24–68) underwent response evaluation. Of the ten evaluable patients, four were women, six were men, three had follicular lymphoma, and seven had diffuse large B-cell lymphoma. The median number of previous therapies was 2·5 (range 2–7). The first group of three patients (two with follicular lymphoma and one with diffuse large B-cell lymphoma) received 5 × 104 CAR T cells/kg. Two patients with follicular lymphoma achieved partial remission on day 28, and one of these patients achieved complete remission 3 months later. The second group of three patients (one with follicular lymphoma and two with diffuse large B-cell lymphoma) received 1 × 105 CAR T cells/kg. The patient with follicular lymphoma achieved partial remission on day 28. The last group of four patients (all were diagnosed with diffuse large B-cell lymphoma) received 1 × 106 CAR T cells/kg. Three patients (75%) achieved partial remission on day 28. One patient attained progressive disease on day 28, and died 10 days later due to disease progression. A significant CAR T-cell expansion was detected in this case. On day 26, 26·8% of the patient's peripheral blood mononuclear cells were CAR T cells. PD1 expression was significant in her expanded CAR T cells. 78·3% of CD8-positive CAR T cells and 71·4% of CD4-positive CAR T cells expressed PD1 on day 26, as compared with 22% and 42% on day 13, respectively in the same patient. Increased PD1-expressing CAR T cells were also found in other patients' peripheral blood. No serious adverse event was observed in any patient. Two patients had mild fever (grade 1–2). In-vivo expansion of CAR T cells was detected in all patients between day 14–28. All responding patients were still in remission at the last follow-up (range 2·5–9·0 months). Interpretation This study demonstrated early promising activity of anti-CD19 CAR T cells in patients with relapsed or refractory B-cell non-Hodgkin lymphoma. The toxicities of cytokine release syndrome were mild and manageable. Our study also provided the first clinical evidence that expanded CAR T cells could express PD1. Blocking PD1 pathway might enhance the effector function of CAR T cells and improve the clinical outcomes of CAR T-cell therapy. Funding Marino Biotechnology Co, Ltd.

Hepatitis C virus (HCV) infection often causes long-term persistent hepatitis, which eventually leads to liver cirrhosis and hepatocellular carcinoma. HCV-encoded NS3/4A protease plays an important role in HCV immune evasion by cleaving key adapter proteins VISA and TRIF of the RIG-I-like receptors and Toll-like receptors mediated interferon (IFN) induction pathways. To further understand the roles of NS3/4A in HCV life cycle, we identified DDB1 as a cellular substrate of NS3/4A protease by biochemical purification and mass spectrometry analysis. NS3/4A interacted with DDB1 and cleaved DDB1 in HCV-infected cells. Mutagenesis indicated that NS3/4A cleaved DDB1 at the residue of C378. Overexpression of DDB1 potentiated HCV replication, whereas knockdown of DDB1 dramatically inhibited HCV replication. Furthermore, our data indicated that the cleavage of DDB1 by NS3/4A protease was required for HCV replication. Our findings suggest that DDB1 is a cellular substrate of NS3/4A required for HCV replication and provide new insight into the interaction between HCV and host cells.

SummaryNKG2D ligands are cell surface proteins that activate NKG2D, a receptor used by natural killer (NK) cells to detect virus‐infected and transformed cells. When tumour cells express high levels of NKG2D ligands, they are rejected by the immune system. Hence, reagents that increase NKG2D ligand expression on tumour cells can be important for tumour immunotherapy. To identify genes that regulate the NKG2D ligand H60a, we performed a microarray analysis of 3′‐methylcholanthrene‐induced sarcoma cell lines expressing high versus low H60a levels. A20, an inhibitor of nuclear factor‐κB (NF‐κB) activation, was differentially expressed in H60a‐hi sarcoma cells. Correspondingly, treatment of tumour cells with inhibitors of NF‐κB activation, such as sulfasalazine (slz), BAY‐11‐7085, or a non‐phosphorylatable IκB, led to increased levels of H60a protein, whereas transduction of cells with an active form of IκB kinase‐β (IKKβ) led to decreased levels of H60a. The regulation probably occurred at the transcriptional level, because NF‐κB pathway inhibition led to increased H60a transcripts and promoter activity. Moreover, treatment of tumour cells with slz enhanced their killing by NK cells in vitro, suggesting that NF‐κB inhibition can lead to tumour cell rejection. Indeed, when we blocked the NF‐κB pathway specifically in tumour cells, there was decreased tumour growth in wild‐type but not immune‐deficient mice. Our results suggest that reagents that can block NF‐κB activity specifically in the tumour and not the host immune cells would be efficacious for tumour therapy.