Search Results (1,233)

Over the past decade, chronic lymphocytic leukaemia (CLL) treatment has shifted from chemoimmunotherapy to targeted oral agents, predominantly Bruton’s tyrosine kinase inhibitors (BTKis) and the BCL-2 inhibitor venetoclax. These therapies have significantly improved outcomes and are now established as first-line treatment options. However, CLL remains incurable, and resistance or intolerance to both drug classes (double-refractory disease) is an emerging challenge. This has driven the development of novel therapeutic strategies, including non-covalent BTKis such as pirtobrutinib and nemtabrutinib, which retain activity in BTK C481-mutated disease. Next-generation BCL-2 inhibitors (sonrotoclax, lisaftoclax) and BTK degraders are promising in early clinical trials. Immunotherapeutic approaches, such as bispecific T-cell engagers, CD20/CD3 antibodies, and CAR-T cell therapies, provide additional options for high-risk patients. Although PI3K inhibitors remain under investigation, their role is yet to be defined due to safety concerns. Minimal residual disease (MRD)-guided, fixed-duration regimens represent a significant paradigm shift toward personalised treatment and potentially deeper remissions. Ongoing clinical studies are expected to introduce new effective therapies that may further transform the management of CLL in the coming years. Full article

Multiple myeloma (MM) is a clonal malignancy of plasma cells that remains largely incurable despite major advances in proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies. Chimeric antigen receptor (CAR)-engineered immune cells have transformed the therapeutic landscape, but CAR-T cell therapy faces challenges such as severe cytokine release syndrome (CRS), neurotoxicity, limited persistence, and logistical complexity. In recent years, natural killer (NK) cells have emerged as a promising platform for next-generation cellular immunotherapy, offering innate antitumor activity, a reduced risk of graft-versus-host disease (GvHD), and the feasibility of “off-the-shelf” allogeneic production. This review summarizes current advances in CAR-NK cell therapy for MM, focusing on two major aspects: the diversity of cell sources—including NK-92, peripheral (PB) and cord blood (CB), and induced pluripotent stem cell (iPSC)-derived NK cells—and the expanding repertoire of target antigens such as BCMA (B-cell maturation antigen), NKG2D, CD38, CD70, SLAMF7, CD138, and GPRC5D. We highlight preclinical and early clinical studies demonstrating potent cytotoxicity, favorable safety profiles, and innovative multi-targeting strategies designed to overcome antigen escape and enhance persistence. Emerging clinical data suggest that CAR-NK cell therapy may combine the specificity of CAR recognition with the inherent safety and versatility of NK biology, offering a potential paradigm shift in the treatment of relapsed or refractory MM. Further clinical validation will determine whether CAR-NK cell therapy can achieve durable remission and complement or surpass current CAR-T modalities. Full article

Oncolytic viruses (OVs) are gaining traction as advanced tools in cancer therapy. They are distinguished by their ability to destroy malignant cells while sparing normal tissue specifically. In addition to their direct tumor-lysing properties, an essential benefit of oncolytic virus therapy is its capacity to activate both the innate and adaptive immune systems. To enhance these therapeutic actions, many OVs have been genetically engineered to encode immune-modulating factors that reestablish or strengthen antitumor immune responses. Recent studies show that combining OVs with other forms of immunotherapy—such as immune checkpoint inhibitors, CAR-T cells, specific T-cell receptor therapies, or autologous tumor-infiltrating lymphocytes—offers significant advances in cancer treatment. This article reviews how OVs work, discusses strategies to enhance their immunogenicity further, and presents the latest rational combinations of oncolytic viruses with other immunotherapies based on current preclinical and clinical research. Full article

Despite recent progress in lymphoma immunotherapy, outcomes for patients with peripheral T cell lymphomas (PTCLs) remain poor. The challenge of PTCLs reflects the profound biological heterogeneity and relative rarity of this disease group and its resistance to conventional chemotherapy, as well as the formidable challenge of generating definitive clinical evidence. However, deepening insight into the immunogenomic and microenvironmental basis of PTCL has revealed diverse mechanisms of immune escape, spanning defects in antigen presentation, apoptotic signaling, adhesion, and extensive tumor microenvironmental remodeling. These vulnerabilities provide a sound rationale for novel immunotherapeutic strategies—checkpoint inhibitors, CAR-T and NK cell platforms, bispecific antibodies, oncolytic viruses, and immunomodulatory agents. Early studies show encouraging but inconsistent activity, and the variability in response highlights the urgent need for biomarker-driven stratification to deliver personalized approaches and clinically meaningful efficacy. This review synthesizes the current literature on the immune dysregulation of PTCLs, as well as advances in PTCL immunotherapy, outlining the biological rationale underpinning these approaches. We discuss approaches to molecular, transcriptomic, and microenvironmental profiling with circulating biomarkers that could enable adaptive trial designs and personalized treatment strategies. Together, these developments chart a path away from empiricism and toward precision therapy in PTCLs. Full article

The immune system plays a pivotal role in the progression of tumors. Recent advancements in immunotherapies, notably CAR-T cell therapy and checkpoint inhibitors, have markedly improved clinical outcomes. However, a significant proportion of patients continue to experience treatment resistance, posing a persistent and formidable challenge. The gut microbiota has been established as a critical determinant of responses to immunotherapy. Enriched with bioactive components such as polysaccharides, (poly)phenols, and flavonoids, edible and medicinal plants (EMPs) exhibit significant potential to enhance host immunity by reshaping the gut microbiota, increasing the production of microbiota-derived metabolites (e.g., short-chain fatty acids), strengthening the intestinal barrier, and reducing intestinal inflammation. The bioactive components derived from EMPs not only demonstrate substantial pharmacological activities but also serve dual roles: functioning either as inherent drug carriers or as effective modifiers for existing carrier systems, which facilitates targeted drug delivery to specific sites such as the liver and intestinal, enhancing therapeutic efficacy. In summary, this review highlights that bioactive components from EMPs hold significant promise for enhancing cancer immunotherapy by modulating complex interactions with the gut microbiota. Full article

Human Immunodeficiency Virus (HIV) infection is associated with a wide spectrum of urological manifestations, reflecting both the direct effects of viral infection and the indirect consequences of immunosuppression, opportunistic infections, malignancies and long-term combined antiretroviral therapy (cART). This narrative review provides a contemporary, multifaceted overview of the clinical and pathological presentations of urological conditions in people living with HIV (PLWHIV), based on articles published between 1989 and 2025. Conditions discussed include HIV-associated nephropathy (HIVAN), opportunistic genitourinary infections, malignancies such as Kaposi sarcoma and lymphoma, as well as non-infectious complications such as HIV-associated nephropathy and erectile dysfunction (ED). The review highlights the evolving epidemiology of these conditions in the cART era, with a noted decline in opportunistic infections but a rising burden of chronic kidney disease and malignancies, largely due to improved survival and ageing of the HIV-positive population. Pathological insights are explored and discussed, including mechanisms of HIV-associated renal injury, such as direct viral infection of renal epithelial cells and genetic predispositions linked to Apolipoprotein L1 (APOL1) variants. In addition, psychosocial factors, including anxiety, stress, stigma, and alcohol use, are discussed, as they may contribute to late presentation to clinical urology services. The review also considers the challenges faced in low and middle-income countries, the impact of HIV on urological services, and the important role of palliative care in advanced disease. Ultimately, this review underscores the need for early recognition, comprehensive diagnostic and surgical evaluation, and integrated social, psychological, and palliative management strategies tailored to the unique needs of PLWHIV. A deeper understanding of the interplay between HIV, cART, psychosocial determinants, and urological health is essential for improving patient outcomes and guiding future research in this evolving field. Full article

Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by T-cell-mediated destruction of pancreatic beta cells, resulting in insulin deficiency. Both genetic predisposition and environmental factors contribute to T1D development, with growing evidence implicating the gut microbiome as a critical environmental modulator in disease pathogenesis. Gut microbial composition and derived metabolites influence immune homeostasis and autoimmunity. This review summarizes recent advances elucidating immune dysregulations in T1D and novel therapeutic strategies to preserve beta cell function. We discuss approaches such as immune cell engineering, including CAR-Treg therapy, and targeted modulation of immune signaling pathways like JAK-STAT. Furthermore, we explore the role of the gut microbiota and its metabolites in modulating host immunity and describe emerging microbiome-targeting interventions, including fecal microbiota transplantation and metabolite supplementation. These interventions show promise in modulating disease progression in preclinical and early clinical studies. An integrated understanding of immune and microbiome-related mechanisms is critical for developing next-generation therapies. Further research and clinical trials are needed to optimize these approaches and translate them into durable, personalized treatments for individuals with T1D. Full article

Background: B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor T-cell (CAR-T) therapy has demonstrated substantial efficacy in relapsed and/or refractory multiple myeloma. While toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) have been well characterized, the incidence and clinical consequences of the coagulopathy associated with CRS remain underexplored. Methods: We conducted a prospective analysis of 108 adult patients with multiple myeloma or light chain amyloidosis treated with the academic anti-BCMA CAR-T HBI0101 in a single-center trial (NCT04720313). Coagulopathy was evaluated via serial fibrinogen measurements, with hypofibrinogenemia defined as <200 mg/dL and severe coagulopathy as <100 mg/dL. Laboratory markers, tocilizumab and blood product use, and thrombotic and bleeding complications were recorded. Patients received a short (3-day) or extended course of enoxaparin thromboprophylaxis as well as fresh frozen plasma in cases of severe coagulopathy. Results: CRS grades 1–3 occurred in 100 patients (93%). Hypofibrinogenemia was observed in 79 patients (73%), including 20 (19%) with severe coagulopathy. Fibrinogen levels were significantly associated with CRS severity (p < 0.001), number of tocilizumab doses (p < 0.001), peak levels of the inflammation markers LDH (p = 0.001) and ferritin (p = 0.006), and neutropenia (p = 0.33). Five thrombotic events (4.6%) and three minor bleeding events (2.7%) occurred within 3 months post-CAR-T infusion and were not associated with degree of coagulopathy or CRS. No cases of major bleeding or fatal thrombosis occurred. Conclusions: CRS-related coagulopathy is common following BCMA-targeted CAR-T treatment and correlates closely with CRS severity. Despite the high rate of laboratory coagulopathy, thrombosis and bleeding events were infrequent, suggesting the benefit of the prophylactic strategies used. Full article

Background: Chimeric Antigen Receptor T-cell (CAR-T) cell therapy has revolutionized cancer treatment and is now being explored as a novel approach to treat refractory autoimmune diseases by targeting autoreactive immune components, especially B cells. Objective: Our aim was to provide a narrative review of the current evidence, mechanisms, efficacy, safety, and future directions of CAR-T cell therapy in autoimmune diseases. Methods: A structured literature search was conducted in MEDLINE via PubMed using keywords such as “CAR-T”, “chimeric antigen receptor T-cell”, “autoimmune diseases”, “lupus”, “rheumatoid arthritis”, “multiple sclerosis”, and “vasculitis”. Studies on CAR-T mechanisms, efficacy, safety, and clinical outcomes were included. Results: CAR-T cell therapies, especially CD19-directed constructs, demonstrated sustained drug-free remission in all patients across early SLE case series (n = 5–7), with normalization of serological markers and improved renal outcomes. Emerging preclinical and early clinical data in rheumatoid arthritis, multiple sclerosis, ANCA-associated vasculitis, juvenile autoimmune diseases, and idiopathic inflammatory myopathies also report clinical improvement and biomarker normalization. Reported adverse events in autoimmune cohorts were limited to mild cytokine release syndrome in a minority of cases, with no severe neurotoxicity or life-threatening infections, suggesting a more favorable safety profile compared to oncology settings. In parallel, next-generation innovations—including dual-target CARs, CAR-Tregs, and molecular safety switches—are advancing toward clinical translation. Conclusions: CAR-T cell therapy is emerging as a transformative strategy for autoimmune disease management, especially in refractory cases. Although initial outcomes are promising, long-term safety, cost-effectiveness, and broader accessibility remain key challenges. Future research should focus on optimizing cell targets, minimizing off-target effects, and improving affordability. Full article

Cancer therapy is rapidly evolving from a one-size-fits-all paradigm toward highly personalized approaches. Traditional chemotherapies and radiotherapies, while broadly applied, often yield suboptimal outcomes due to tumor heterogeneity and are limited by significant toxicities. In contrast, precision oncology tailors prevention, diagnosis, and treatment to the individual patient’s genetic and molecular profile. Key advancements underscore this shift: molecularly targeted drugs (e.g., trastuzumab for HER2-positive breast cancer, EGFR and ALK inhibitors for lung cancer) have improved efficacy and reduced toxicity compared to conventional therapy. Pharmacokinetic (PK) and pharmacodynamic (PD) considerations are central to personalizing treatment, explaining variability in drug exposure and response among patients and guiding dose optimization. Modern strategies like therapeutic drug monitoring and model-informed precision dosing seek to maintain drug levels in the therapeutic range, improving outcomes. Immunotherapies, including checkpoint inhibitors and CAR-T cells, have transformed oncology, though patient selection via biomarkers (such as PD-L1 expression or tumor mutational burden) is critical to identify likely responders. Innovative drug delivery systems, notably nanomedicine, address PK challenges by enhancing tumor-specific drug accumulation and enabling novel therapeutics. Furthermore, rational combination regimens (informed by PK/PD and tumor biology) are being designed to achieve synergistic efficacy and overcome resistance. Key barriers include the high cost of biomarker testing, insufficient laboratory infrastructure, and inconsistent reimbursement policies. Operational inefficiencies such as long turnaround times or lack of clinician awareness further limit the use of precision diagnostics. Regulatory processes also remain complex, particularly around the co-development of targeted drugs and companion diagnostics, and the evidentiary requirements for rare subgroups. Addressing these barriers will require harmonized policies, investment in infrastructure, and educational initiatives to ensure that the promise of personalized medicine becomes accessible to all patients. Ensuring that advances are implemented responsibly—guided by pharmacological insights, supported by real-world evidence, and evaluated within ethical and economic frameworks—will be critical to realizing the full potential of personalized cancer medicine. Full article

Cancer immunotherapy has become a powerful clinical strategy for cancer management, while its efficacy is frequently limited by primary and acquired resistance. The tumor microenvironment (TME) plays a pivotal role in mediating such resistance through multifaceted mechanisms involving cellular, metabolic, mechanical, and microbial components. This review systematically examines how the TME contributes to immunotherapy failure. We compare resistance mechanisms common to both immune checkpoint inhibitors (ICIs) and chimeric antigen receptor T-cell (CAR-T) therapies, two cornerstone modalities in clinical practice. Furthermore, we discuss emerging strategies designed to overcome these barriers, including immune microenvironment, stromal normalization, metabolic modulation, and microbiota engineering. By integrating recent preclinical and clinical insights, this review aims to provide a comprehensive framework for understanding and targeting microenvironmental resistance, ultimately facilitating the translation of novel combination therapies into improved patient outcomes. Full article

Signaling Lymphocyte Activation Molecule Family member 7 (SLAMF7) represents a potential target for CAR T-cell therapy in the treatment of multiple myeloma (MM), and it is a promising alternative to classic BCMA-CAR therapy. The receptor is expressed on immune cells, particularly natural killer cells and T cells, that can trigger both activating and inhibitory signals. It is highly expressed in MM cells at all disease stages, playing a crucial role in cell adhesion and communication between immune cells, and being involved in the development and progression of the disease. The target has a proven clinical success with Elotuzumab (anti-SLAMF7 antibody); it works by activating immune cells to kill myeloma cells, and limited expression on normal tissues, with, potentially, few side effects. SLAMF7’s combination of specificity, stability, and clinical validation makes it an excellent target for current and future MM therapies. However, ‘fratricide death’, a phenomenon where the engineered CAR-T cells attack and kill each other, is a critical issue that requires safe engineering solutions. In this work, we will provide an overview on the field with a specific focus on SLAMF7 as an emerging CAR-T cell target in MM. Full article

Treatment paradigms for B-cell lymphomas have evolved significantly in the last decades. Nevertheless, the widespread clinical use of immunotherapy has demonstrated that it invariably leads to the development of resistance. This review outlines the underlying molecular mechanisms of resistance associated with emerging immunotherapeutic strategies, including Chimeric Antigen Receptor (CAR) T cell therapy and bispecific antibodies (BsAbs). In high-grade B-cell lymphomas, nearly 50% of patients progress following CAR T treatment due to host-related factors affecting CAR T cell proliferation and persistence, as well as tumor-intrinsic factors, such as loss of CD19 epitope expression, trogocytosis, and other genomic alterations (e.g., CD19 mutations, chromothripsis, APOBEC mutational activity, and deletions of RHOA). Additional genomic and epigenetic events, including mutations, alternative splicing of CD19, and aberrant promoter methylation, further contribute to resistance. BsAbs, representing an off-the-shelf T-cell-redirecting strategy, have recently shown promising single-agent efficacy with a manageable toxicity profile, predominantly characterized by T cell overactivation syndromes. Similarly to CAR T cell therapy, BsAb resistance arises through diverse mechanisms, such as antigen loss, T cell dysfunction (exhaustion and regulatory T cell activation), tumor-intrinsic alterations (e.g., TP53 mutations and MYC amplifications), and immunosuppressive influences from the tumor microenvironment. These findings underscore the complexity of immune evasion in B-cell lymphomas and highlight the ongoing need to optimize immunotherapeutic strategies and develop combination approaches to overcome resistance. Full article

Cutaneous T-Cell Lymphomas (CTCL) are a heterogenous group of T-cell malignancies in the skin and have poor treatment outcomes in advanced stages. CD5, a surface glycoprotein expressed on most mature T cells, has emerged as a promising target for chimeric antigen receptor (CAR) T-cell therapy in systemic T-cell lymphomas. However, its expression profile in CTCL and relevance for targeted therapy remain unclear. Notably, in CTCL, the cell surface expression of receptors, such as CD7 and CD26, tends to become downregulated on the surfaces of malignant T cells In this study, we analyzed single-cell RNA sequencing (scRNA-seq) data from patients at two institutions with mycosis fungoides (MF), the most common subtype of CTCL with a predominantly CD4 phenotype. We utilized 5 patch/plaque MF skin biopsies (majority from early-stage patients), 8 MF tumor biopsies (all from advanced-stage patients), and 8 healthy control biopsies to evaluate lesion-specific CD5 gene expression on CD4 T cells. We found that CD5 was significantly increased in malignant MF CD4 T cells compared to healthy control CD4 T cells (21.1% of MF CD4 T cells expressed CD5 vs. 5.2% of healthy control CD4 T cells, respectively). In subgroup analysis, patch/plaque stage MF biopsies showed higher expression of CD5 in CD4 T cells than tumor stage MF biopsies. Notably, 94.3% of malignant CD4⁺ T cells in tumor stage MF lesions exhibited complete CD5 loss compared to only 76.6% in patch-plaque MF lesions, suggesting antigen escape in tumor stage disease. These findings demonstrate that CD5 expression in CTCL is dynamic and varies based on lesion type. Our work suggests CD5 may be a viable therapeutic target in MF with patch/plaque presentations but may not be as effective in advanced stages of MF with tumor presentations. This work informs CD5 gene expression in MF based on clinical lesion type and further information is needed to clarify clinical implications as a future therapeutic target. Full article