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Chimeric antigen receptor T-cell therapies have markedly improved the survival rates of patients with B-cell malignancies. However, their efficacy in other hematological cancers, such as acute myeloid leukemia, and in solid tumors has been limited. Key obstacles include the downregulation or loss of antigen expression on cancer cells, restricted accessibility to target cells, and the poor persistence of these "living drugs" because of the highly immunosuppressive tumor microenvironment. Additionally, manufacturing these immunotherapies presents significant challenges, and patients frequently experience side effects such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. This review emphasizes the potential of small-molecule inhibitors, many of which are already approved for clinical use, to facilitate chimeric antigen receptor T-cell manufacturing, enhance their anti-tumor efficacy, and mitigate their side effects. Although substantial work remains, the robust pre-clinical data and the growing clinical interest suggest significant promise for using cancer signaling pathway inhibitors to enhance and refine chimeric antigen receptor T-cell therapy for both hematological and solid tumors. Exploring these combination strategies could lead to more effective therapies, offering new hope for patients with resistant forms of cancer.

Hidradenitis suppurativa (HS) is a chronic, debilitating, inflammatory dermatosis that significantly impacts patients' quality of life, primarily manifesting as inflammatory nodules, abscesses, and tunnels. The pathogenesis of HS is not fully understood and appears to be multifactorial, involving genetic, immunological, and endocrinological factors, as well as dysbiosis of skin microbiota. Increasing evidence highlights the role of the interleukin (IL)-17 pathway in the inflammatory process and pathogenesis of HS. Consequently, IL-17 inhibitors have emerged as a promising alternative to current therapies. Recently, secukinumab received approval from both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), while bimekizumab received approval from the EMA, for the treatment of moderate-to-severe HS in adults, with ongoing clinical trials aiming to further clarify the efficacy and safety of other drugs within this class. IL-17 inhibitors have shown effectiveness in treating moderate-to-severe HS, with safety profiles of drugs such as secukinumab and bimekizumab being comparable to their use in other dermatological conditions. On the other hand, innovative drugs such as sonelokimab and izokibep show promising results and are currently in phase III clinical trials. This review provides a comprehensive overview of current knowledge and scientific advances in HS, focusing on the IL-17 pathway's role and its inhibition as a treatment strategy, alongside examining the most recent and significant clinical studies on various IL-17 inhibitors in the treatment of HS.

After decades of gradual progress from conceptualization to early clinical trials (1960-2000), the therapeutic potential of bispecific antibodies (bisp Abs) is now being fully realized. Insights gained from both successful and unsuccessful trials are helping to identify which mechanisms of action, antibody formats, and targets prove most effective, and which may benefit from further refinement. While T-cell engagers remain the most commonly used class of bisp Abs, current efforts aim to increase their effectiveness by co-engaging costimulatory molecules, reducing escape mechanisms, and countering immunosuppression. Strategies to minimize cytokine release syndrome (CRS) are also actively under development. In addition, novel antibody formats that are selectively activated within tumors are an exciting area of research, as is the precise targeting of specific T-cell subsets. Beyond T cells, the recruitment of macrophages and dendritic cells is attracting increasing interest, with researchers exploring various macrophage receptors to promote phagocytosis or to carry out specialized functions, such as the immunologically silent clearance of amyloid-beta plaques in the brain. While bisp Abs targeting B cells are relatively limited, they are primarily aimed at inhibiting B-cell activity in autoimmune diseases. Another evolving application involves the forced interaction between proteins. Beyond the successful development of Hemlibra for hemophilia, bispecific antibodies that mimic cytokine activity are being explored. Additionally, the recruitment of cell surface ubiquitin ligases and other enzymes represents a novel and promising therapeutic strategy. In regard to antibody formats, some applications such as the combination of T-cell engagers with costimulatory molecules are driving the development of trispecific antibodies, at least in preclinical settings. However, the increasing structural complexity of multispecific antibodies often leads to more challenging development paths, and the number of multispecific antibodies in clinical trials remains low. The clinical success of certain applications and well-established production methods position this therapeutic class to expand its benefits into other therapeutic areas.

Chimeric antigen receptor (CAR) T-cell therapy, initially successful in treating hematological malignancies, is emerging as a potential treatment for autoimmune diseases, including rheumatic conditions. CAR T cells, engineered to target and eliminate autoreactive B cells, offer a novel approach to managing diseases like systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and inflammatory myopathies, where B cells play a pivotal role in disease pathology. Early case reports have demonstrated promising results, with patients achieving significant disease remission, normalization of serological markers, and the ability to discontinue traditional immunosuppressive therapies, which supported the initiation of several clinical trials. However, the application of CAR T-cell therapy in chronic inflammatory rheumatic disorders poses unique challenges, including patient heterogeneity, the risk of adverse effects such as cytokine release syndrome, and the high costs associated with the therapy. Despite these challenges, the potential for CAR T cells to provide long-term remission or even a cure in refractory autoimmune diseases is significant. Ongoing research aims to optimize CAR T-cell constructs and improve safety profiles, paving the way for broader application in rheumatic diseases. If these challenges can be addressed, CAR T-cell therapy could revolutionize the treatment landscape for chronic inflammatory rheumatic disorders, offering new hope for patients with severe, treatment-resistant conditions.

B-cell depleting therapy (BCDT) has revolutionised the treatment of B-cell malignancies and autoimmune diseases by targeting specific B-cell surface antigens, receptors, ligands, and signalling pathways. This narrative review explores the mechanisms, applications, and complications of BCDT, focusing on the therapeutic advancements since the introduction of rituximab in 1997. Various monoclonal antibodies and kinase inhibitors are examined for their roles in depleting B cells through antibody-dependent and independent mechanisms. The off-target effects, such as hypogammaglobulinemia, infections, and cytokine release syndrome, are discussed, emphasising the need for immunologists to identify and help manage these complications. The increasing prevalence of BCDT has necessitated the involvement of clinical immunologists in addressing treatment-associated immunological abnormalities, including persistent hypogammaglobulinemia and neutropenia. We highlight the importance of considering underlying inborn errors of immunity (IEI) in patients presenting with these complications. Furthermore, we discuss the impact of BCDT on other immune cell populations and the challenges in predicting and managing long-term immunological sequelae. The potential for novel BCDT agents targeting the BAFF/APRIL-TACI/BCMA axis and B-cell receptor signalling pathways to treat autoimmune disorders is also explored, underscoring the rapidly evolving landscape of B-cell targeted therapies.

Background: Pegunigalsidase alfa is a newly approved drug for the treatment of Fabry disease, designed to increase the plasma half-life and reduce immunogenicity of infused α-galactosidase A (AGAL). We provide the first comprehensive pharmacokinetic and immunogenic data apart from industry-initiated studies.

Methods: Pharmacokinetics of pegunigalsidase alfa, amino acid, and polyethylene glycol (PEG)-specific antibodies and immune complexes were measured in treated patients (11 switched, two naïve). Measurements were performed in serum samples drawn directly before and after infusions over three to ten consecutive infusions. Only three patients started directly with 1.0 mg/kg body weight.

Results: No infusion-associated reactions were reported under pegunigalsidase alfa during the observation. Patients without pre-existing neutralizing anti-AGAL antibodies showed high enzymatic AGAL peak activities and sustained AGAL serum concentrations until the next infusion, which was not observed in those with neutralizing anti-AGAL antibodies. Nine (69.2%) patients presented with pre-existing anti-PEG antibodies (IgG or IgM), which seemed to have no impact on pharmacokinetics during the observation. No new anti-PEG or anti-AGAL antibody formation was observed after treatment initiation. Three (75.0%) patients with pre-existing neutralizing anti-AGAL antibodies showed a titer increase and one (25.0%) patient a decrease. In patients with anti-AGAL antibodies (n = 4) immune-complex formation was detected.

Conclusion: The pharmacokinetics of pegunigalsidase alfa show different profiles depending on the presence of pre-existing neutralizing antibodies, with reduced plasma half-life and peak enzyme activity after infusion in patients with antibodies. The clinical significance of a reduced pegunigalsidase alfa half-life and the formation of immune complexes in antibody-positive patients needs to be analyzed in future studies.

Functional cure of chronic hepatitis B (CHB)-defined as sustained seroclearance of hepatitis B surface antigen (HBsAg) with unquantifiable hepatitis B virus (HBV) DNA at 24 weeks off treatment, is an optimal treatment endpoint. Nonetheless, it cannot be consistently attained by current treatment modalities. RNA interference (RNAi) is a novel treatment strategy using small-interfering RNA (siRNA) or antisense oligonucleotide (ASO) to target HBV post-transcriptional RNA, in turn suppressing viral protein production and replication. Hence, RNAi has indirect effects in promoting host immune reconstitution against HBV. Multiple RNAi therapeutics have entered phase II/III clinical trials, demonstrating potent, dose-dependent, and sustainable effects in suppressing HBsAg. Incidences of HBsAg seroclearance, particularly with the use of ASO, have also been documented. The combination of RNAi with other antivirals/immunomodulators (e.g. pegylated interferon), have shown promising results in potentiating RNAi effects and enhancing treatment durability. Further research will be required to establish predictors of response, optimal treatment protocols, and long-term outcomes in patients on RNAi. RNAi therapeutics have shown promising results and will likely be the keystone of future HBV treatment.