ImmunoTargets and Therapy最新文献

Purpose: Prostate cancer is the most common malignancy among older man and often a challenge owing to its rapid spread and age-related comorbidities. SL-28 (Leukocyte-Tells) is a novel cell therapy that uses allogeneic leukocytes whose anticancer activity is altered ex vivo using the recently discovered Universal Receptive System.

Patients and methods: A 79-year-old man with Т2сNOMx1, Gleason 7 (3+4) adenocarcinoma of the prostate, with a total PSA level of 10.6 ng/mL and free PSA:total PSA ratio of 11.4% received hormone therapy. Due to an insufficient clinical response and poor tolerance to the therapy, the patient underwent novel allogeneic SL-28 cell therapy.

Results: SL-28 therapy was well-tolerated, with no serious adverse effects. The levels of laboratory markers of prostate cancer, such as prostate-specific antigen, gradually improved from the second week of SL-28 therapy. Complete responses, including the resolution of bone metastasis within 4 months of therapy, were confirmed by computed tomography and histology.

Conclusion:  SL-28 was efficient and safe approach in a patient with stage IV prostate cancer, supporting its potential in an allogeneic cell therapy for advanced malignancies.

Purpose: To evaluate the efficacy and safety of sorafenib combined with tislelizumab (a programmed death-1 inhibitor) and transarterial chemoembolization (TACE) in patients with advanced-stage hepatocellular carcinoma (HCC).

Patients and methods: This was a single-center, single-arm phase II trial. Patients with HCC at Barcelona Clinic Liver Cancer stage C were recruited. Treatment with sorafenib (400 mg orally twice daily) and tislelizumab (200 mg intravenously every 3 weeks) was initiated 3-7 days after the first TACE procedure. Repeated TACE was performed on-demand. The primary endpoint of this study was overall survival (OS).

Results: Thirty patients were enrolled. The median OS for the patients was 18.3 (95% CI = 14.6-22.0) months, with 12-, 18-, and 24-month OS rates of 90.0%, 54.0%, and 28.3%, respectively. The objective response rate was 53.3% per modified Response Evaluation Criteria in Solid Tumors (mRECIST) and 20.0% per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). The disease control rate was 86.7% per mRECIST/RECIST 1.1. The median progression-free survival was 6.8 (95% CI = 4.5-9.0) months per mRECIST/RECIST 1.1. The median duration of response was 7.1 (95% CI = 6.1-8.1) months per mRECIST (n = 16) and 4.4 (95% CI = 0.9-7.9) months per RECIST 1.1 (n = 6). Treatment-related adverse events (TRAEs) occurred in 28 patients (93.3%), and grade 3 TRAEs were observed in 11 patients (36.7%). There were no grade 4/5 TRAEs.

Conclusion: Sorafenib combined with tislelizumab and TACE showed promising antitumor activities with a manageable safety profile in patients with advanced-stage HCC. These preliminary findings warrant further evaluation in Phase III randomized trials.

Tuberculosis (TB) is a chronic infectious disease caused by Mycobacterium tuberculosis (Mtb). Despite significant advancements in anti-tuberculosis treatment strategies in recent years, TB remains a major infectious disease threat worldwide. Chronic Mtb infection drives T cell exhaustion-characterized by upregulated co-inhibitory receptors-which correlates with TB chronicity, treatment failure, and relapse. Immune checkpoint inhibitors (ICIs) targeting co-inhibitory receptors have achieved groundbreaking progress in the treatment of various malignancies. However, their application in the field of tuberculosis remains controversial. This study provides a comprehensive analysis of TB disease assessment and treatment from the perspective of T cell exhaustion. We investigate the correlation between co-inhibitory receptor expression levels and both disease activity and progression. Furthermore, we analyze the dual impact of targeting these receptors on anti-TB immunity: While blockade of co-inhibitory receptors in T cell exhaustion states restores anti-tuberculosis immunity, excessive inhibition-particularly in hyperimmune conditions-induces detrimental hyperinflammation, exacerbating tissue damage and disrupting immune homeostasis, ultimately worsening clinical outcomes. To address this duality, we emphasize the necessity of personalized immunotherapy strategies based on individual immune profiling, alongside developing novel co-inhibitory receptor blockers and immune modulatory vaccines. This review presents a novel perspective on the application of targeting co-inhibitory receptors in tuberculosis treatment, which will advance the development and application of immunotherapy.

Background: Inflammatory resolution is an active and coordinated process. Histone acetylation represents the primary epigenetic alteration associated with inflammatory diseases. However, the precise role of histone acetylation in the resolution of inflammation remains poorly understood.

Methods: Lipopolysaccharide (1 µg/mL, 10 ng/mL) and Escherichia coli (10⁵ c.f.u. 10⁶ c.f.u.) were employed to establish inflammatory models both in vitro and in vivo. UPLC-MS/MS was utilized to quantify acetyl CoA and lipid mediators. qPCR was conducted to assess the expression of specific genes. Flow cytometry analysis was performed to enumerate polymorphonuclear neutrophils and monocytes/macrophages. Histone acetylation was evaluated using Western blotting.

Results: Our analysis reveals that histone acetylation and acetyl CoA are temporally regulated during the inflammatory response. A low-dose challenge results in heightened histone acetylation and reduced acetyl CoA. Metabolic repatterning during the inflammatory response promotes the generation of acetyl CoA and histone acetylation. Furthermore, the overexpression of histone acetylation enhances the production of anti-inflammatory lipid mediators, particularly the specialized pro-resolving lipid mediators (SPMs).

Conclusion: These findings illustrate that histone acetylation is not only temporally and differentially regulated during inflammatory responses but also interacts with metabolic reprogramming to promote the production of SPMs, thereby facilitating inflammation resolution.

Background: Chronic refractory primary immune thrombocytopenia is defined as thrombocytopenia refractory to multiple therapies using second-line agents with or without splenectomy. Patients face the threat of severe bleeding, and it is challenging to achieve effective treatment. Although thrombopoietin receptor agonists (TPO-RAs) and immunomodulators have been established as second-line options, their efficacy as monotherapy remains suboptimal.

Methods: Here, we report the early and durable response to a novel triple regimen combining romiplostim, danazol, and either hetrombopag or eltrombopag in two patients with chronic refractory primary immune thrombocytopenia at our center, with a follow-up exceeding 4 months.

Results: The bleeding score decreased from grade 3/4 to grade 0 during the follow-up. No significant treatment-related adverse events were observed during the follow-up.

Conclusion: Romiplostim in combination with danazol and hetrombopag or eltrombopag may be a safe and efficacious therapy for chronic refractory primary immune thrombocytopenia; however, this needs to be further explored.

Purpose: This study aimed to evaluate the efficacy and safety of tacrolimus as an add-on therapy in patients with chronic inflammatory demyelinating polyneuropathy (CIDP).

Patients and methods: This retrospective cohort analysis was conducted using data from CIDP patients in the database of Xuanwu Hospital, Capital Medical University between April 2019 and June 2023. This study compared the efficacy of tacrolimus plus prednisone (T&P) versus prednisone monotherapy (PM) as maintenance immunosuppressive therapy. The primary endpoint was the response rate, defined as ≥1-point improvement in INCAT score, assessed at 3, 6, and 12 months. Secondary endpoints included: (1) I-RODS score changes from baseline to 3, 6, and 12 months; (2) the monthly median daily prednisone dose; (3) relapse rate (INCAT score worsening ≥1 point) in the 12-month follow-up; and (4) adverse event profiles over the 12-month follow-up period.

Results: Among 74 screened CIDP patients, 34 (45.9%) were included, with 16 receiving T&P and 18 receiving PM. All patients completed follow-up (median: 1.4 years; range: 1.0-6.5 years). The T&P group demonstrated significantly higher response rates at 3 and 6 months compared to PM, though this difference attenuated by 12 months. I-RODS improvements were significantly greater in the T&P group at all time points. The relapse rate was lower in the T&P group (12.5% vs 33.3%). The T&P group maintained significantly lower prednisone doses from month 2 onward, with higher prednisone discontinuation rates at 12 months (43.8% vs 11.1%; p=0.01). Both groups showed comparable safety profiles, with no serious adverse reactions reported.

Conclusion: Tacrolimus plus prednisone therapy demonstrated superior clinical outcomes compared to prednisone monotherapy in CIDP maintenance treatment, including accelerated symptomatic improvement, reduced relapse risk, and facilitated corticosteroid tapering. The combination regimen maintained an acceptable safety profile without serious adverse events, supporting its corticosteroid-sparing role in CIDP management.

2B4 (CD244), the fourth member of the signaling lymphocyte activation molecule (SLAM) family, is expressed by virtually all human and murine hematopoietic lineages and functions as a context-dependent activating or inhibitory receptor. This review provides a comprehensive update on the gene organization, molecular architecture, glycosylation patterns, and alternatively spliced isoforms of 2B4, highlighting how these structural variables dictate ligand (CD48) affinity and downstream signaling outcome. The roles of 2B4 in natural killer (NK) cells, CD8⁺ T cells, dendritic cells, myeloid-derived suppressor cells, B cells, eosinophils, and basophils were then systematically demonstrated, emphasizing their dual capacity to either potentiate cytotoxicity and cytokine production or enforce immune tolerance and exhaustion. Mechanistically, the balance between SLAM-associated protein (SAP)-mediated activation and SHP-1/2/SHIP-driven inhibition emerges as a central rheostat that is dynamically tuned by SAP availability, and the microenvironment. Clinically, exaggerated 2B4 signaling is associated with viral persistence in MCMV, HCV, HIV, and SARS-CoV-2 infections, promotes tumor immune escape in melanoma, multiple myeloma, and head-and-neck cancer, and compromises maternal-fetal tolerance, whereas insufficient signaling weakens antimicrobial immunity. Parallel pre-clinical studies validate 2B4 blockade as a rational combinatorial strategy to reinvigorate exhausted CD8⁺ T and NK cells, while soluble CD48 emerges as a dynamic biomarker of disease activity. Collectively, these insights redefine 2B4 as a systems-level integrator of immune homeostasis and a tractable precision-immunotherapy node whose therapeutic manipulation can rebalance immunity across infection, cancer, and pregnancy.

Aim: This study aimed to evaluate and compare the therapeutic efficacy and adverse effects of two sequential treatment strategies in patients with unresectable advanced pancreatic cancer (aPC), albumin-bound-paclitaxel plus gemcitabine administered follow by mFOLFIRINOX or SOXIRI (AG-F(S)FX_m) versus the reverse sequence regimen F(S)FX_m-AG.

Methods: In this retrospective analysis, patients with unresectable advanced pancreatic cancer (aPC) who received either AG-F(S)FX_m or F(S)FX_m-AG were included. Key endpoints were overall survival (OS), progression-free survival (PFS), and treatment-related toxicity. Survival outcomes were assessed using Kaplan-Meier curves, and differences between groups were examined through hazard ratios (HR) and corresponding p-values.

Results: A total of 107 patients were analyzed, including 49 who underwent AG-F(S)FX_m and 58 who received F(S)FX_m-AG. The median OS was 14.60 months for F(S)FX_m-AG and 12.20 months for AG-F(S)FX_m (HR: 1.04, 95% CI: 0.69-1.57, p= 0.86). Median PFS1, median PFS2 and median total PFS (tPFS) were 5.20 months versus 4.83 months (HR: 0.81, 95% CI: 0.54-1.21, p= 0.3), 4.53 months versus 5.77 months (HR: 1.15, 95% CI: 0.71-1.88, p= 0.60) and 13.80 months versus 12.80 months (HR: 0.90, 95% CI: 0.55-1.48, p= 0.67) for F(S)FX_m-AG versus AG-F(S)FX_m. Given their comparable efficacy, we further compared the safety profiles of both regimens. The toxicity profiles differed between the two sequential treatments. Leukopenia was more common with first-line AG, while gastrointestinal toxicity, fatigue, and sensory neuropathy were more frequent with first-line F(S)FX_m. Additionally, elevated aspartate aminotransferase was more often reported with second-line AG.

Conclusion: Both AG-F(S)FX_m and F(S)FX_m-AG demonstrated comparable efficacy in treating aPC, with F(S)FX_m-AG showing a trend toward improved outcomes. The choice of sequential treatment should be guided by toxicity profiles and patient-specific factors. Further prospective studies are warranted to optimize treatment sequencing and personalize therapy for improved patient outcomes.

Purpose: This study aimed to investigate the risk of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAVs) among patients with psoriasis in a large population.

Patients and methods: In this population-based study using the collaborative electronic health record research network, the risk of developing AAVs (ie, eosinophilic granulomatosis with polyangiitis (EGPA), granulomatosis with polyangiitis (GPA), and microscopic polyangiitis (MPA)) was analyzed in a cohort of patients diagnosed with psoriasis between 2006 and 2024. Non-psoriasis controls were selected in a 1:1 ratio using propensity score matching. Patients who were diagnosed with AAVs before the index date were excluded. Univariate Cox proportional hazard model and subgroup analyses were used to estimate the hazard ratio (HR) with a 95% confidence interval (CI) for developing AAVs. The Kaplan-Meier method was used to plot the cumulative incidence curves. The risk of AAVs in psoriatic patients treated with biological agents was explored.

Results: After matching, 436,201 patients were included in each cohort. There were 281 incident cases of AAV during follow-up in the psoriasis cohort and 122 incident cases of AAV in the non-psoriasis cohort. The risk of developing AAVs in the psoriasis cohort was significantly higher than in the non-psoriasis cohort (HRs (95% CI) for AAVs, EGPA, and GPA were 2.01 (1.63 to 2.49), 1.84 (1.11 to 3.06), and 2.11 (1.65 to 2.71), respectively. Compared with psoriasis patients who did not receive biologics, those treated with biologics showed no statistically significant increase in AAVs risk (HR 1.31, 95% CI 0.65 to 2.66).

Conclusion: Patients with psoriasis have a higher risk of AAVs development. Treatment with biologic agents is not associated with an elevated risk of AAVs.

Background: Achieving a complete radiofrequency ablation (RFA) for a solid malignant tumor of large size or at high-risk locations is challenging. A slow release of doxorubicin by liposomal doxorubicin (L-Dox) in solid tumors can selectively suppress the immune suppressive cells. In this study, the feasibility of using anti-CD24 antibody plus L-Dox was explored to inhibit residual cancers after incomplete RFA (iRFA) of hepatocellular carcinoma (HCC), with an attempt to reduce the tumor recurrences post-RFA.

Methods: The expressions of CD24 protein and sialic-acid-binding lg-like lectin 10 (Siglec-10) in residual cancers after iRFA of human HCC were evaluated. The mice orthotopic HCC models were treated by (1) pseudo iRFA: the ablation electrode was only put in the live tumor but without ablation treatment; (2) iRFA: the tumors only received iRFA treatment; (3) iRFA+anti-CD24 antibody; (4) iRFA+L-Dox; (5) iRFA+anti-CD24 antibody+L-Dox. The treatment effects and the immune microenvironment of treated tumors in each group were assessed and compared.

Results: The CD24 protein and Siglec-10 were highly expressed in the residual cancers (p<0.001). The iRFA+anti-CD24 antibody+L-Dox group had the smallest tumor size and the longest survival time (p<0.001). The anti-CD24 antibody in combination with L-Dox significantly decreased the expressions of CD24 and Siglec-10, significantly promoted the polarization of M2-like tumor-associated macrophages (TAMs) towards M1-like TAMs, significantly reduced the regulatory T cells and myeloid-derived suppressor cells, and significantly increased the infiltrations of natural killer cells and functional CD8⁺T cells into residual cancers.

Conclusion: The combined therapy of anti-CD24 antibody with L-Dox could significantly improve the suppressive tumor immune microenvironment and result in a strong tumor-killing immunity in residual cancers, which significantly inhibited the residual cancers after iRFA of HCC. These findings may lead to a new strategy of enhancing the curative efficacy of RFA for large-sized HCC or HCC at high-risk locations.