Search Results (452)

Prostate cancer (PCa) is the leading cause of cancer-related deaths worldwide and the second most common cancer among men. Treatment options depend on factors like age, androgen sensitivity, PSA levels, Gleason score, TNM stage, and recurrence risk. Available treatments include hormonal therapy, radiation, surgery, and chemotherapy. Early immunological treatments were limited by poor lymphocyte infiltration and an immunosuppressive environment. Today, strategies such as dendritic cell vaccines, immune checkpoint inhibitors (ICIs), and adoptive cell therapy (ACT) are used. ACT, especially CAR T-cell strategies, aims to overcome traditional treatment limitations, particularly in advanced and metastatic castration-resistant prostate cancer (mCRPC), though it remains in early development. Personalized medicine uses molecular insights from the diseased tissue to tailor treatments. Variability in patient response, due to tumor heterogeneity and prior treatments, highlights the importance of personalized and combination therapies as future strategies for effective immunotherapy. This review explores the current landscape of PCa. We analyze treatment guidelines established by NCCN and EANM-ESTRO-ESUR-ISUP-SIOG. We comprehensively examine immunotherapeutic strategies currently available or under investigation for prostate cancer, with particular emphasis on ICIs, ACT with a focus on CAR T-cell therapy, combination approaches and therapeutic synergies, and predictive biomarkers of immunotherapy response. Additionally, we discuss the challenges and future directions in the implementation of immunotherapy for the management of prostate cancer. Full article

Metastatic uveal melanoma (MUM) remains largely refractory to immune-checkpoint inhibition, so recent research has turned to bispecific T-cell engagers (BTCEs), adoptive-cell therapies (ACTs), and oncolytic viruses (OVs). To summarize the available clinical evidence, we performed a structured literature search across PubMed, Scopus, and Europe PMC for primary studies published between 1 January 2010 and 31 May 2025 that enrolled at least three adults with MUM, treated with one of these modalities, and that reported efficacy or grade-3+ safety outcomes; two reviewers independently performed screening, data extraction, and risk-of-bias assessment, and because of notable heterogeneity, we synthesized the findings narratively. Twenty-two studies met the criteria—thirteen phase I–III trials, eight observational cohorts, and one case series—covering fifteen BTCE cohorts, four ACT cohorts, and three OV cohorts. Tebentafusp, the dominant BTCE evaluated in roughly 1150 HLA-A*02:01-positive patients, extended median overall survival from 16.0 to 21.7 months (hazard ratio 0.51, with three-year follow-up HR 0.68) in its pivotal phase-III trial despite objective response rates of only 5–12%, with early skin rash and week-12 circulating-tumor-DNA clearance emerging as consistent markers of benefit. Tumor-infiltrating lymphocyte therapy, administered to about thirty patients, produced objective responses in 11–35% and occasional durable complete remissions, although median progression-free survival remained 2–6 months and severe cytopenias were universal. Three early-phase OV studies, totaling twenty-nine patients, yielded no radiographic responses but showed tumor-specific T-cell expansion and transient disease stabilization. Safety profiles reflected the mechanism of action: tebentafusp most often caused rash, pyrexia, and usually manageable cytokine-release syndrome with grade-3+ events in 40–70% yet discontinuation in roughly 2%; TIL therapy toxicity was driven by lymphodepleting chemotherapy and high-dose interleukin-2 with one treatment-related death; and OVs were generally well tolerated with no more than 20% grade-3 events. Full article

Lentiviral transduction remains the gold standard in adoptive modified cellular therapy, such as CAR-T; however, genome integration is not always desirable, such as when treating non-fatal autoimmune disease or for additional editing steps using CRISPR to produce allogeneic CAR-modified cells. Delivering in vitro-transcribed (IVT) mRNA represents an alternative solution but the labile nature of mRNA has led to efforts to improve half-life and translation efficiencies using a range of approaches including chemical and structural modifications. In this study, we explore the role of N⁶–methyladenosine (m6A) in a CD19-CAR sequence when delivered to T cells as an IVT mRNA. In silico analysis predicted the presence of four m6A consensus (DRACH) motifs in the CAR coding sequence and treating T cells with an inhibitor of the m6A methyltransferase (METTL3) resulted in a significant reduction in CAR protein expression. RNA analysis confirmed m6A bases at three of the predicted sites, indicating that the modification occurs independently of nuclear transcription. Synonymous mutation of the DRACH sites reduced the levels of CAR protein from 15 to >50% depending on the T cell donor. We also tested a panel of CAR transcripts with different UTRs, some containing m6A consensus motifs, and identified those which further improved protein expression. Furthermore, we found that the methylation of consensus m6A sites seems to be somewhat sequence-context-dependent. These findings demonstrate the importance of the m6A modification in stabilising and enhancing expression from IVT-derived mRNA and that this occurs within the cell, meaning targeted in vitro chemical modification during mRNA manufacturing may not be necessary. Full article

Systemic sclerosis (SSc) is a disease in which malfunctioning immune cells lead to the formation of autoantibodies that damage blood vessels and body tissues. Fibrosis then develops in the affected organs. Its complex pathogenesis involves multiple immune and stromal cell types, soluble mediators, and dysregulated tissue repair, resulting in heterogeneous clinical manifestations and poor prognosis. Current disease-modifying therapies provide only modest benefits, often slowing but rarely reversing disease progression, and are associated with considerable adverse effects. These limitations have spurred the development of cell-based therapeutic strategies aimed at restoring immune tolerance and promoting tissue repair. In this review, we summarize recent advances in hematopoietic stem cell transplantation, mesenchymal stem cell therapy, and adoptive regulatory T cell transfer and highlight the emerging role of chimeric antigen receptor (CAR)-T cell therapy as a transformative approach for SSc. Collectively, these evolving strategies hold the potential to improve survival, achieve durable remissions, and significantly enhance quality of life for patients with SSc. Full article

Background: Adoptive cell therapy using genetically engineered recombinant T cell receptors (rTCRs) expressed in T cells (TCR-T cell therapy) provides precision targeting of cancer cells expressing tumor-associated or tumor-specific antigens recognized by the rTCRs. Standardized analytical tools are lacking to easily quantify receptor expression. Methods: To overcome this hindrance, a universal tagging system (UniTope & TraCR) was designed consisting of a minimal peptide epitope (UniTope) inserted into the constant region of the rTCR α or β chain and a high-affinity monoclonal antibody (TraCR) specific to this tag. Detailed biophysical, biochemical, and functional assays were performed to evaluate rTCR expression, folding, pairing, and antigen recognition, as well as antibody performance, using the UniTope & TraCR System. Results: Tagged rTCRs were stably expressed in human T cells with surface densities comparable to untagged rTCRs. The TraCR antibody bound UniTope with nanomolar affinity and no detectable cross-reactivity was observed for endogenous proteins expressed by human cells of diverse origin, importantly, including T cells of the natural T cell repertoires of multiple human donors. Functional assays confirmed that UniTope-tagged rTCRs preserved their antigen-specific cytokine secretion and cytolytic activity upon antigen-specific stimulation. The UniTope & TraCR System enabled robust detection of rTCR-expressing T cells by flow cytometry, and rTCR protein expression by Western blot or immunoprecipitation, supporting the quantitative assessment of receptor copy number and structural integrity. Conclusions: The UniTope & TraCR System provides a modular, construct-agnostic platform for monitoring engineered rTCRs, integrated into TCR-T cell therapies currently in development. Full article

Dendritic cells (DCs) are a heterogeneous population known for antigen presentation and immune modulation, playing a key role in priming a T cell response against pathogens and tumor cells. Despite their putative therapeutic value, their scarcity in peripheral blood limited their direct use in therapeutic applications until recently. The discovery that DCs can be generated from circulating monocytes ex vivo, however, gave a boost of extensive research in the use of DCs in clinical applications. Still, despite the numerous clinical trials, the introduction of DCs in the everyday clinical oncology practice is delayed. In this narrative review, we provide an updated summary of the field covering the theoretical and practical aspects of the concept of the use of DCs in adoptive cellular immunotherapy and the completed or ongoing clinical trials for the use of these species in clinical oncology practice. To better understand the current developments of the field, we included those clinical trial reports that published evaluable data to date. Based on our literature survey, DC-based adoptive cellular therapy is a safe therapeutic intervention with valuable clinical potential. Its widespread implementation, however, is likely delayed due to a number of factors that make meaningful evaluation of clinical trial results complicated. These include the great variety of preclinical trial concepts, difficult and heterogenous patient cohorts, and the diversity of intervention techniques applied. Since these factors might hinder the routine implementation of DC-based applications in the more widespread forms of immunotherapy, one of the urgent short-term future directions seems to be the standardization of the DC-based methodologies. Full article

Adoptive cell therapy (ACT) with T cells modified with a chimeric antigen receptor (CAR T cells) has dramatically improved outcomes in hematologic cancers. However, its efficacy in solid tumors, such as melanoma, is hampered by several factors. These include heterogeneous expression of tumor-associated antigens (TAA) and an immunosuppressive, profibrotic tumor microenvironment (TME), which restricts cytotoxic CAR T cells trafficking into the tumor, as well as their persistence and cytolytic activity. As a result, responses to CAR T cell monotherapy in melanoma and other solid tumors are typically weak, transient or even absent. Emerging evidence suggests that combining traditional chemotherapy with CAR T cell therapy can enhance the antitumor activity of CAR T cells in solid malignancies. Partial tumor cell killing by chemotherapy improves access to TAA and disrupts the TME by affecting the global structure of the tumor tissue. Here, we developed an immunocompetent syngeneic B16 melanoma mouse model to test a combination of classical dacarbazine (DTIC) chemotherapy with ACT with murine CAR T cells. B16-F10 (next as B16) melanoma cells were modified to express a human/murine hybrid epidermal growth factor receptor (EGFR) recognized by a murine CAR bearing a single-chain variable fragment (scFv) derived from cetuximab, an anti-EGFR monoclonal antibody approved for the treatment of colorectal and certain other solid tumors. Prior to CAR T cells administration, cyclophosphamide (CPA) pre-conditioning was used. We demonstrated that DTIC therapy followed by infusion of murine CAR T cells targeting the human/murine hybrid EGFR (EGFR mCAR T cells) provided superior tumor control and prolonged survival compared to monotherapy with either DTIC or EGFR mCAR T cells alone. These findings support the potential feasibility of a combined therapeutic strategy for human melanoma involving DTIC treatment followed by EGFR CAR T cells infusion after CPA pre-conditioning. Full article

Adoptive cellular therapy with donor-derived T cells has always been an attractive strategy after allogeneic hematopoietic stem cell transplantation (allo-HSCT) to reduce the risk of relapse in acute myeloid and lymphoid leukemias. Donor lymphocyte infusion (DLI) is still the best-established option, especially in the preemptive phase when measurable residual disease (MRD) becomes positive and in the prophylactic setting—when MRD is not detectable. However, the clinical benefit of DLI is counterbalanced by the possible onset of graft-versus-host disease (GvHD), which continues to restrict its wide application. To address this challenge, several alternative cell-based strategies have been developed. One of these is represented by cytokine-induced killer (CIK) cells, generated from donor peripheral blood mononuclear cells through stimulation with anti-CD3 antibodies, interferon-γ, and interleukin-2. These cells are characterized by a hybrid phenotype, combining T-cell functions with natural killer-like properties, and exhibit antitumor activity in an MHC-unrestricted manner. CIK cells are generally well tolerated and associated with low toxicity but their efficacy is so far modest. Based on the experience of CAR-T in the treatment of B-cell lymphoid disease, CIK cells have been engineered with chimeric antigen receptors (CAR) developing the CARCIK cells. This novel cellular strategy represents a promising approach in the treatment of acute myeloid and lymphoid leukemia relapsed post-allo-HSCT. This review provides an overview of the current CAR-CIK experiences in the setting of acute leukemias and outlines future directions for their clinical translation. Full article

Pediatric kidney transplantation (KTx) offers the best outcomes for children with end-stage renal disease (ESRD), offering dramatic improvements in survival, quality of life, growth, and developmental outcomes compared to dialysis. Modern regimens centered on tacrolimus, mycophenolate mofetil, and risk-adapted induction have substantially reduced acute rejection and improved graft survival. This viewpoint summarizes the evolution of pediatric immunosuppression, current practice trends, and emerging strategies aimed at minimizing toxicity while preserving long-term graft function. Recent data show increasing use of T-cell-depleting induction, selective application of IL-2 receptor antagonists, and gradual adoption of steroid-sparing and mTOR-based protocols. Nevertheless, progress is limited by a scarcity of pediatric randomized trials, continued reliance on extrapolated adult evidence, infection risk, long-term metabolic complications, and adherence challenges during adolescence. Insights from recent trials including steroid minimization, everolimus-based regimens, and selective Belatacept use highlight opportunities for more individualized, risk-adapted therapy. Future efforts must prioritize precision approaches supported by biomarkers, multicenter collaboration, and long-term follow-up. Overall, contemporary trends support a shift toward tailored immunosuppression that balances efficacy with safety to optimize outcomes in pediatric KTx recipients. Full article

Cancer immunotherapy has transformed oncology, but lasting responses are still limited due to resistance mechanisms within the tumor microenvironment. MicroRNAs (miRNAs) have emerged as critical regulators of immune checkpoint pathways, antigen presentation, T-cell activity, and macrophage polarization. By modulating both tumor-intrinsic and immune cell–intrinsic processes, miRNAs influence the efficacy of immune checkpoint inhibitors, therapeutic vaccines, and adoptive cell therapies. Additionally, circulating and exosomal miRNAs are being investigated as minimally invasive biomarkers to predict patient response and resistance to immunotherapy. Clinical trials of miRNA-based treatments, including mimics and inhibitors, have highlighted both the promise and challenges of translating these molecules into clinical use. Advances in delivery systems, RNA chemistry, and combinatorial strategies are paving the way for their integration into precision immuno-oncology. This review offers a comprehensive overview of the mechanistic, biomarker, and therapeutic roles of miRNAs in cancer immunotherapy, highlighting ongoing clinical progress and prospects. Full article

Inflammatory bowel disease (IBD) is a chronic condition whose pathogenesis is not entirely clear. Impaired immune regulation has been hypothesized as the mechanism responsible for the abnormal response of adoptive immunity to enteric microbial antigens. Regulatory T cells (Tregs) have been regarded as the crucial element of immune regulation, since the discovery that humans lacking Tregs due to mutation of FOXP3 develop autoimmune disorders, including severe bowel inflammation. The existing publications concerning T regulatory cells in human IBD have been reviewed, and current evidence does not clearly indicate quantitative disturbances or functional defects of Tregs in human inflammatory bowel disease. The possible mechanisms explaining immunoregulatory failure in IBD have been summarized. So far, only one clinical trial with Tregs infusion has been completed, and its results do not provide sufficient data on the efficacy or safety of Tregs-based therapies in IBD. It will probably be difficult to implement them in clinical practice in the near future. Full article

Cell-mediated drug delivery systems represent a promising frontier in dermatologic therapy by offering enhanced targeting precision, prolonged drug release, and reduced systemic toxicity. These systems leverage the intrinsic properties of immune cells, stem cells, and skin-resident cells to migrate toward inflamed or diseased skin and deliver therapeutic agents in a controlled and biocompatible manner. This review explores the mechanistic foundations of cell-mediated delivery, including chemotaxis, phagocytosis, and immune modulation, and examines current applications in inflammatory skin diseases such as atopic dermatitis and psoriasis, cutaneous malignancies such as melanoma and cutaneous T-cell lymphoma, and chronic wound healing. Engineering approaches such as cell surface modification, exosome loading, and integration with gene editing technologies are also discussed. Finally, we highlight translational challenges related to immunogenicity, manufacturing scalability, and regulatory considerations, and propose future directions for clinical adoption in dermatology. This review provides a comprehensive overview of the current landscape and outlines the potential for cell-based delivery systems to transform the treatment of chronic and refractory skin diseases. Full article

Regulatory T cells (Tregs) are a distinctive subset of CD4⁺ T cells critical in self-tolerance maintenance to prevent the development of autoimmunity. The mechanisms by which these cells provide immune regulation are numerous and, consequently, deeply involved in the pathogenesis of many autoimmune disorders. Treg-based adoptive cell transfer (ACT) therapy has generated interest as a novel, promising strategy to restore self-tolerance in autoimmunity. Polyclonal Treg-based ACT therapy was first implemented in clinical trials, presenting adequate safety profiles. Subsequent preclinical studies have shown antigen-specific Tregs to be safer and more effective than polyclonal approaches, so research has recently moved in this direction. Antigen-specificity can be conferred to Tregs by viral transduction of genes coding for engineered T cell receptors (eTCRs) or chimeric antigen receptors (CARs), with encouraging outcomes in different animal models of autoimmunity. This review focuses on the biology of Tregs, as well as on current preclinical and clinical data for Treg-based ACT in the field of autoimmunity. Full article

Background/Objectives: T cell dysfunction represents a fundamental barrier to effective cancer immunotherapy. Although immune checkpoint blockades and adoptive cell transfer have achieved clinical success, therapeutic resistance remains prevalent across cancer types. Thymopentin (TP5), a synthetic immunomodulatory pentapeptide (Arg-Lys-Asp-Val-Tyr), has demonstrated immunostimulatory properties, yet its anticancer potential remains unexplored. The aim of this study was to investigate TP5’s antitumor efficacy and underlying immunological mechanisms. Methods: We evaluated TP5’s therapeutic effects in multiple murine tumor models, including B16-F10 melanoma, MC38 colorectal carcinoma, Hepa 1-6, and LM3 hepatocellular carcinoma. Immune cell populations and functional states were characterized using flow cytometry, ELISAs, and immunofluorescence analyses. The potential of TP5 as an adjuvant for T cell-based therapies was also systematically assessed. Results: The TP5 treatment markedly suppressed tumor growth across caner models through strictly T cell-dependent mechanisms. Critically, TP5 promoted thymic rejuvenation under immunocompromised conditions, restoring the thymus–tumor immunological balance and revitalizing peripheral T cell immunity. TP5 functionally reprogrammed T cell states, preserving effector function while ameliorating exhaustion. Furthermore, TP5 demonstrated synergistic efficacy when combined with adoptive T cell therapies, enhancing both proliferation and effector functions. Conclusions: TP5 represents a promising immunomodulator that addresses fundamental limitations of current T cell therapies by simultaneously enhancing T cell function and reversing thymic involution under immunocompromised conditions. Our findings provide compelling evidence for TP5’s clinical translation in cancer treatment. Full article

Background: Gorlin syndrome (GS) is a rare autosomal dominant disorder, associated with pathogenic PTCH1 or SUFU variants, predisposing to tumors such as basal cell carcinoma, medulloblastoma (MB), odontogenic keratocyst, and, rarely, cardiac fibroma (CF). MB occurs in ~5% of GS cases, typically in early childhood, while CF appears in 1–3%. Their coexistence in childhood is extremely rare. This report describes a pediatric GS case with synchronous MB and CF, focusing on the management priorities between oncologic and cardiac interventions. Methods: A 15-year follow-up is reported for a girl diagnosed at 22 months with desmoplastic/nodular MB and left ventricular CF. GS diagnosis was based on clinical features, imaging, and confirmation of a pathogenic PTCH1 variant (c.3306+1G>T). A literature narrative review on CF in GS was also conducted. Results: MB gross total resection was followed by chemotherapy, during which ventricular tachycardia episodes occurred, managed with cardioversion and antiarrhythmics. Given the favorable prognosis of early-treated MB in GS, oncologic therapy was prioritized. Cardiac status was monitored with ECG, Holter, echocardiography, and cardiac MRI. An adapted AIEOP protocol minimized cardiotoxicity. CF was managed conservatively, with no further arrhythmias and preserved ventricular function throughout 15 years. MB has not recurred. Conclusions: In GS patients with concurrent MB and CF, prioritizing MB treatment and adopting a conservative, closely monitored approach to CF can yield excellent long-term outcomes. In children with MB, especially syndromic forms, routine echocardiography is recommended to detect CF. This case underscores the value of multidisciplinary care in managing complex GS presentations. Full article