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Background B-cell non-Hodgkin lymphoma (B-NHL) constitutes the majority of NHL cases. Patients with B-NHL often experience multiple recurrences, necessitating several lines of antitumor therapy, and develop drug resistance. The recent success of therapeutic strategies targeting CD19 and CD20 highlights the therapeutic potential of identifying unique molecular markers in B-NHL for precision medicine, although challenges like immunogenicity and limited tumor penetration persist. Methods In this study, whole-cell phage display was employed to identify the specific binding peptide TG-1 towards B-NHL cells which was confirmed in vitro and in vivo, and its corresponding target CD30 ligand (CD30L) was identified by mass spectrometry and validated by functional assays, molecular docking, bioinformational analyses, knockdown, and rescue experiments. Additionally, the effects of TG-1 and functional roles of CD30L in B-NHL cells were investigated by exploring the molecular mechanisms of CD30/CD30L interactions. Furthermore, TG-1 peptide and doxorubicin co-functionalized gold nanoparticles (AuNPs) were characterized, and their effects on B-NHL cell proliferation were studied both in vitro and in vivo. Results Here, we identified and validated the CD30L as a novel target on B-NHL cells, along with its highly specific binding peptide TG-1, using whole-cell phage display. TG-1 binds CD30L, impairing lymphoma cell viability by disrupting the CD30-CD30L signaling axis, which is crucial for B-NHL cell survival. It demonstrates strong inhibitory effects on lymphoma cell proliferation both in vitro and in vivo. Additionally, the peptide and doxorubicin co-functionalized AuNPs demonstrated significant inhibitory effects on B-NHL cell proliferation, highlighting their potential as a promising therapeutic strategy. Conclusions In summary, our findings underscore the potential of CD30L as a novel target for B-NHL treatment and demonstrate the promise of CD30L-targeted peptides in advancing precision medicine for B-NHL, paving the way for future clinical developments.

Introduction Although CD30-directed chimeric antigen receptor (CAR)-T cell therapy has demonstrated antitumor activity in CD30 + lymphomas, its therapeutic efficacy remains suboptimal. We therefore conducted a prospective, phase II, single-arm, multicenter clinical trial (ChiCTR-2100046763) to evaluate the efficacy and safety of CD30 CAR-T cell therapy in combination with camrelizumab, an immune checkpoint inhibitor, in patients with relapsed/refractory (r/r) CD30 + lymphomas. Methods All participants received a lymphodepleting regimen followed by infusion of CD30 CAR-T cells at a dose of 1 × 10 7 cells/kg. Camrelizumab was subsequently administered on a scheduled basis starting 15 days after CAR-T infusion and continued until unacceptable toxicity or disease progression. Results A total of 18 patients were enrolled, of whom 12 (66.7%) completed the CD30 CAR-T infusion, including eight with classical Hodgkin lymphoma (cHL) and four with T-cell lymphomas. Among 11 efficacy-evaluable patients, the best objective response rate (ORR) was 63.6%, including four complete responses (CR, 36.3%). After a median follow-up of 30.8 months, the median overall survival (OS) was not reached, and the median progression-free survival (PFS) was 11.1 months (95% CI, 0–26.2). In the subset of seven cHL patients, the ORR and CR rates were 100.0% and 57.1%, with 2-year PFS and OS of 57.1% and 100.0%, respectively. Remarkably, five cHL patients who had previously failed PD-1 blockade still achieved an ORR of 100.0% and a CR rate of 40.0%; median OS was not reached, and median PFS was 15.0 months. In contrast, none of the four T-cell lymphoma patients achieved an objective response. Cytokine release syndrome occurred in eight patients (66.7%), all grade 1–2. The most frequent grade 3–4 toxicities were lymphopenia (58.3%) and neutropenia (41.7%). Conclusions The combination of CD30 CAR T-cell therapy with camrelizumab demonstrated a favorable safety profile and elicited durable, clinically meaningful responses in patients with r/r cHL, including those who had failed prior PD-1 blockade. In contrast, although this regimen remained therapeutically well tolerated, its antitumor activity was limited in T-cell lymphomas, underscoring the need for alternative approaches or more effective combinatorial strategies in this disease context.

Anti-CD30 CAR-T is a potent candidate therapy for relapsed/refractory (r/r) CD30+ lymphomas with therapy limitations, and the efficacy needed to be further improved. Herein a multi-center phase II clinical trial (NCT03196830) of anti-CD30 CAR-T treatment combined with PD-1 inhibitor in r/r CD30+ lymphoma was conducted. After a lymphocyte-depleting chemotherapy with fludarabine and cyclophosphamide, 4 patients in cohort 1 and 3 patients in cohort 2 received 10 6 /kg and 10 7 /kg CAR-T cells, respectively, and 5 patients in cohort 3 received 10 7 /kg CAR-T cells combined with anti-PD-1 antibody. The safety and the efficacy of CAR-T cell therapy were analyzed. Cytokine release syndrome (CRS) was observed in 4 of 12 patients, and only 1 patient (patient 9) experienced grade 3 CRS and was treated with glucocorticoid and tocilizumab. No CAR-T-related encephalopathy syndrome was observed. Only two patients in cohorts 2 and 3 experienced obviously high plasma levels of IL-6 and ferritin after CD30 CAR-T cell infusion. The overall response rate (ORR) was 91.7% (11/12), with 6 patients achieving complete remission (CR) (50%). In cohorts 1 and 2, 6 patients got a response (85.7%), with 2 patients achieving CR (28.6%). In cohort 3, 100% ORR and 80% CR were obtained in 5 patients without ≥3 grade CRS. With a median follow-up of 21.5 months (range: 3 - 50 months), the progression-free survival and the overall survival rates were 45 and 70%, respectively. Of the 11 patients who got a response after CAR-T therapy, 7 patients (63.6%) maintained their response until the end of follow-up. Three patients died last because of disease progression. Taken together, the combination of anti-PD-1 antibody showed an enhancement effect on CD30 CAR-T therapy in r/r CD30+ lymphoma patients with minimal toxicities.

Tertiary lymphoid tissues (TLTs) facilitate local T and B cell interactions in chronically inflamed organs. However, the cells and molecular pathways that govern TLT formation are poorly defined. Here, we identified TNF superfamily CD153/CD30 signaling between 2 unique age-dependent lymphocyte subpopulations, CD153+PD-1+CD4+ senescence-associated T (SAT) cells and CD30+T-bet+ age-associated B cells (ABCs), as a driver for TLT expansion. SAT cells, which produced ABC-inducing factors IL-21 and IFN-γ, and ABCs progressively accumulated within TLTs in aged kidneys after injury. Notably, in kidney injury models, CD153 or CD30 deficiency impaired functional SAT cell induction, which resulted in reduced ABC numbers and attenuated TLT formation with improved inflammation, fibrosis, and renal function. Attenuated TLT formation after transplantation of CD153-deficient bone marrow further supported the importance of CD153 in immune cells. Clonal analysis revealed that SAT cells and ABCs in the kidneys arose from both local differentiation and recruitment from the spleen. In the synovium of aged rheumatoid arthritis patients, T peripheral helper/T follicular helper cells and ABCs also expressed CD153 and CD30, respectively. Together, our data reveal a previously unappreciated function of CD153/CD30 signaling in TLT formation and propose targeting the CD153/CD30 signaling pathway as a therapeutic target for slowing kidney disease progression.

Normal CD30 B cells represent a distinct B-cell differentiation stage with features of strong activation. We lack an in depth understanding of these cells, because they are not present in peripheral blood and are typically very rare in reactive lymphoid organs. CD30 B cells have been discussed as a potential precursor population for the malignant CD30 Hodgkin and Reed-Sternberg cells in classical Hodgkin lymphoma. As CD30 B cells can be more numerous in some cases of reactive lymphadenitis, we aimed to characterize these CD30 B cells in terms of their differentiation stage and clonal composition, also as a means to clarify whether such CD30 B-cell populations may represent potential precursor lesions of Hodgkin lymphoma. We microdissected single CD30 B cells from tissue sections of eight reactive lymph nodes with substantial numbers of such cells and sequenced their rearranged immunoglobulin (Ig) heavy chain V region (IGHV) genes. The CD30 B cells were polyclonal B cells in all instances, and they not only encompass post-germinal center (GC) B cells with mutated IGHV genes, but also include a substantial fraction of pre-germinal center B cells with unmutated IGHV genes. In five of the lymph nodes, mostly small clonal expansions were detected among the CD30 B cells. Most of the expanded clones carried somatically mutated IGHV genes and about half of the mutated clones showed intraclonal diversity. We conclude that in human reactive lymph nodes with relatively many CD30 B cells, these cells are a heterogenous population of polyclonal B cells encompassing activated pre-GC B cells as well as GC and post-GC B cells, with some clonal expansions. Because of their polyclonality and frequent pre-GC differentiation stage, there is no indication that such cell-rich CD30 B-cell populations represent precursor lesions of Hodgkin lymphoma.

Cutaneous T-cell lymphomas are rare, generally incurable, and associated with reduced quality of life. Present systemic therapies rarely provide reliable and durable responses. We aimed to assess efficacy and safety of brentuximab vedotin versus conventional therapy for previously treated patients with CD30-positive cutaneous T-cell lymphomas. In this international, open-label, randomised, phase 3, multicentre trial, we enrolled adult patients with CD30-positive mycosis fungoides or primary cutaneous anaplastic large-cell lymphoma who had been previously treated. Patients were enrolled across 52 centres in 13 countries. Patients were randomly assigned (1:1) centrally by an interactive voice and web response system to receive intravenous brentuximab vedotin 1·8 mg/kg once every 3 weeks, for up to 16 3-week cycles, or physician's choice (oral methotrexate 5–50 mg once per week or oral bexarotene 300 mg/m2 once per day) for up to 48 weeks. The primary endpoint was the proportion of patients in the intention-to-treat population achieving an objective global response lasting at least 4 months per independent review facility. Safety analyses were done in all patients who received at least one dose of study drug. This trial was registered with ClinicalTrials.gov, number NCT01578499. Between Aug 13, 2012, and July 31, 2015, 131 patients were enrolled and randomly assigned to a group (66 to brentuximab vedotin and 65 to physician's choice), with 128 analysed in the intention-to-treat population (64 in each group). At a median follow-up of 22·9 months (95% CI 18·4–26·1), the proportion of patients achieving an objective global response lasting at least 4 months was 56·3% (36 of 64 patients) with brentuximab vedotin versus 12·5% (eight of 64) with physician's choice, resulting in a between-group difference of 43·8% (95% CI 29·1–58·4; p<0·0001). Grade 3–4 adverse events were reported in 27 (41%) of 66 patients in the brentuximab vedotin group and 29 (47%) of 62 patients in the physician's choice group. Peripheral neuropathy was seen in 44 (67%) of 66 patients in the brentuximab vedotin group (n=21 grade 2, n=6 grade 3) and four (6%) of 62 patients in the physician's choice group. One of the four on-treatment deaths was deemed by the investigator to be treatment-related in the brentuximab vedotin group; no on-treatment deaths were reported in the physician's choice group. Significant improvement in objective response lasting at least 4 months was seen with brentuximab vedotin versus physician's choice of methotrexate or bexarotene. Millennium Pharmaceuticals Inc (a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd), Seattle Genetics Inc.

Recent data from mice and non-human primate models of tuberculosis suggested that CD153, a TNF super family member, plays an important role in Mycobacterium tuberculosis (Mtb) control. However, this molecule has not been comprehensively evaluated in humans. Here, we show that the proportion of Mtb-specific CD4 T cells expressing CD153 was significantly reduced in active TB patients compared to latently infected persons. Importantly, the CD153+ Mtb-specific CD4 response inversely correlated with lung bacterial load, inferred by Xpert cycle threshold, irrespective of HIV status. Antitubercular treatment partially restored CD153 expression on Mtb-specific CD4 T cells. This is the first report of a subset of Mtb-specific CD4 T cells showing strong negative correlation with bacterial burden. Building on substantial evidence from animal models implicating CD153 as a mediator of host protection, our findings suggest it may play a similar role in humans and its measurement may be useful to evaluate TB vaccine efficacy.

Objectives: Several studies suggested that CD30 expression is a favorable prognostic marker in transformed mycosis fungoides (tMF). However, evidence in this field is still unclear. This systematic review and meta-analysis aimed to evaluate the prognostic significance of CD30 in tMF. Methods: Electronic databases were searched from their inception to June 2020 for all studies assessing the prognostic value of CD30 in tMF. Pooled hazard ratio (HR) for death was calculated; a P value less than.05 was considered significant. Inconsistency index (I2) was used to assess statistical heterogeneity among studies. Results: Seven studies with 323 patients were included. CD30 expression in tMF was significantly associated with a decreased hazard of death both on univariate (HR, 0.459; 95% confidence interval [CI], 0.319- 0.660; P <.001) and multivariate analysis (HR, 0.503; 95% CI, 0.345-0.734; P <.001), and the statistical heterogeneity among studies was null in all analyses ([I.sup.2] = 0%). Conclusions: tMF cases with CD30 expression in large cells have a hazard of death two times lower than CD30-negative cases. Key Words: CD30; Cutaneous lymphoma; Mycosis fungoides; Prognosis; Transformation

EWSR1/FUS::TFCP2 -rearranged rhabdomyosarcoma (RMS) is a rare tumor with an aggressive clinical course, a predilection for craniofacial bones, spindled and/or epithelioid histomorphology, and positive immunohistochemistry (IHC) for epithelial and myogenic markers, along with variable ALK expression. Herein, we present four additional cases of primary cutaneous TFCP2 -rearranged RMS. Notably, one tumor (case 1) displayed a varied pathological spectrum, initially presenting as a low-grade spindle cell neoplasm, but progressed into a high-grade spindle/epithelioid tumor. Another case (case 2) exhibited a predominant high-grade epithelioid/rhabdoid morphology. The third case (case 3) demonstrated a biphasic appearance of spindle and epithelioid cell proliferation, presenting with a low-grade morphology, and the last case (case 4) showed a predominant epithelioid morphology. All cases showed myogenic differentiation associated with keratins and ALK immunoreactivity. Interestingly, the two cases with high-grade and epithelioid morphology demonstrated CD30 immunoexpression. RNAseq or FISH revealed EWSR1 or FUS::TFCP2 gene fusion, and two cases with aggressive evolution showed ALK cluster-amplification as well, a finding that has not been previously reported. Two cases displayed aggressive behavior, with case 1 experiencing local recurrences and undergoing transformation into a high-grade epithelioid tumor, whereas case 2 initially presented as an epithelioid high-grade neoplasm, subsequently developing lymph node metastases and shortly thereafter distant metastases. In contrast, patients 3 and 4 are alive with no evidence of disease. The distinctive morphology and immunoprofile of this neoplasm may pose challenges in the differential diagnosis with cutaneous neoplasms showing keratins, ALK, and CD30 immunoreactivity. Nonetheless, ALK and CD30 overexpression may offer avenues for targeted therapy.

Background Relapsed/refractory classic Hodgkin lymphoma (R/R cHL) remains challenging to treat, and anti-CD30 chimeric antigen receptor T (CAR-T) cell therapy may be effective. This meta-analysis investigates the efficacy and safety of anti-CD30 CAR-T cell therapy for treating R/R cHL. Methods A systematic literature search of PubMed, Cochrane, Embase, ClinicalTrials.gov, and Web of Science databases was conducted until February 2024. The odds ratio (OR) with a 95% confidence interval (CI) was analysed using Review Manager 5.4. Outcomes including overall response rate (ORR), complete response (CR), partial response (PR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were extracted for meta-analysis. We used the Methodological Index for Non-Randomized Studies (MINORS) to evaluate the quality of the included literature. Results A total of 151 participants from 8 records were included. Meta-analysis showed the ORR of CD30 CAR-T cell therapy for R/R cHL was 57% (95%CI 0.36–0.76, P  = 0.50), with a CR of 34% (95%CI 0.13–0.64, P  = 0.29) and a PR of 32% (95%CI 0.15–0.55, P  = 0.12). With the median follow-up range from 9.5 to 71.5 months, the 1-year PFS was 39% (95% CI 0.30–0.49, P  = 0.04), and the 1-year OS was 89% (95% CI 0.65–0.97, P  = 0.005). The most common hematologic AE was leukopenia (72%, 95% CI: 0.50–0.87), and the most common non-hematological AE was cytokine release syndrome (CRS) (43%, 95% CI: 0.14–0.76). The grade ≥ 3 AEs was 66% (95%CI 0.06–0.98, I2 = 93%, P  = 0.70), 34% (95%CI 0.07–0.78, I2 = 85%, P  = 0.51) in neutropenia and thrombocytopenia, respectively. All AEs were tolerable and resolved with treatment. Conclusion Current evidence suggests that anti-CD30 CAR-T cell therapy is effective and safe in treating R/R cHL and is worth considering as a viable therapeutic option.