Search Results (158)

Classical Hodgkin lymphoma (cHL) is a biologically and clinically unique malignancy characterized by rare Hodgkin and Reed–Sternberg (HRS) cells surrounded by a dense and diverse inflammatory infiltrate. These malignant cells actively reshape the tumor microenvironment (TME) through metabolic reprogramming and immune evasion strategies. This review synthesizes current knowledge on how metabolic alterations contribute to tumor survival, immune dysfunction, and therapeutic resistance in cHL. We discuss novel therapeutic approaches aimed at disrupting these processes and examine the potential of combining metabolic interventions with immune-based strategies—such as immune checkpoint inhibitors (CPIs), epigenetic modulators, bispecific antibodies, and CAR-T/CAR-NK cell therapies—which may help overcome resistance and enhance anti-tumor responses. Several agents are currently under investigation for their ability to modulate immune cell metabolism and restore effective immune surveillance. Altogether, targeting metabolic vulnerabilities within both tumor and immune compartments offers a promising, multifaceted strategy to improve clinical outcomes in patients with relapsed or refractory cHL. Full article

Adoptive cell therapies have transformed the treatment landscape for hematologic malignancies. Yet, translation to solid tumors remains constrained by antigen heterogeneity, an immunosuppressive tumor microenvironment (TME), and poor persistence of conventional CAR-T cells. In response, innate immune cell platforms, particularly chimeric antigen receptor–engineered natural killer (CAR-NK) cells and chimeric antigen receptor–macrophages (CAR-MΦ), have emerged as promising alternatives. This review summarizes recent advances in the design and application of CAR-NK and CAR-MΦ therapies for solid tumors. We highlight key innovations, including the use of lineage-specific intracellular signaling domains (e.g., DAP12, 2B4, FcRγ), novel effector constructs (e.g., NKG7-overexpressing CARs, TME-responsive CARs), and scalable induced pluripotent stem cell (iPSC)-derived platforms. Preclinical data support enhanced antitumor activity through mechanisms such as major histocompatibility complex (MHC)-unrestricted cytotoxicity, phagocytosis, trogocytosis, cytokine secretion, and cross-talk with adaptive immunity. Early-phase clinical studies (e.g., CT-0508) demonstrate feasibility and TME remodeling with CAR-MΦ. However, persistent challenges remain, including transient in vivo survival, manufacturing complexity, and risks of off-target inflammation. Emerging combinatorial strategies, such as dual-effector regimens (CAR-NK⁺ CAR-MΦ), cytokine-modulated cross-support, and bispecific or logic-gated CARs, may overcome these barriers and provide more durable, tumor-selective responses. Taken together, CAR-NK and CAR-MΦ platforms are poised to expand the reach of engineered cell therapy into the solid tumor domain. Full article

Background/Objectives: Chimeric antigen receptor T-cell (CAR-T) therapy is a novel form of adoptive cellular immunotherapy that involves modifying autologous T cells to recognize and target tumor-associated antigens (TAAs) on malignant cells, independent of major histocompatibility complex (MHC) restriction. Although CAR-T therapy has shown remarkable success in treating hematologic malignancies, its efficacy in solid tumors remains limited, largely due to the lack of tumor-specific antigens and the complexity of the tumor microenvironment. This review aims to explore the rationale for continuing the development of adoptive cellular therapies in head and neck cancer (HNC), offering insights into the diagnostic and therapeutic challenges associated with this heterogeneous group of malignancies. Methods: We conducted a comprehensive literature review using the PubMed database to identify relevant studies on the application of CAR-T cell therapy in the management of HNC. Results: HNC presented numerous barriers to CAR-T cell infiltration, primarily due to the unique characteristics of its tumor microenvironment (TME). The TME in HNC is notably immunosuppressive, with a lymphocytic infiltrate predominantly composed of regulatory T cells (Tregs) and natural killer (NK) cells. These immune cells typically exhibit low expression of the CD16 receptor, which plays a crucial role in mediating antibody-dependent cellular cytotoxicity (ADCC), thereby limiting the effectiveness of CAR-T cell therapy. Conclusions: This comprehensive review suggests a potential clinical applicability of CAR-T therapy in HNC management. Full article

Cancer remains one of the leading causes of death worldwide. New treatments like immunotherapy—especially checkpoint inhibitors and CAR-T cell therapy—have improved outcomes for some patients. However, these therapies often struggle to treat solid tumours effectively. Natural killer (NK) cells are part of the immune system and can naturally detect and destroy cancer cells without previous adaption. Scientists are now enhancing these cells by adding special receptors, called CARs (chimeric antigen receptors), to help them better recognize and attack cancer, an approach originally developed for T cells. CAR-NK cell therapy has some advantages over CAR-T therapy. It tends to cause fewer severe side effects, such as strong immune reactions or off-target effects in healthy tissues. Within some limitations, the allogenic use of CAR-NK cells is possible, as these cells exert less graft-versus-host activity. Such CAR-NK cell products can be produced in larger quantities and stored, making treatment more accessible. Still, there are challenges. It can be difficult to create enough modified NK cells, and the tumour microenvironment can block their activity. This review highlights recent progress in CAR-NK therapy, including early lab and clinical research. It also explores ways to improve these treatments and how they might work alongside other cancer therapies to help more patients in the future. Full article

Chimeric antigen receptor (CAR)-engineered natural killer (NK) cells are a promising platform for off-the-shelf immunotherapy due to their safety advantages over CAR-T cells, including lower risk of graft-versus-host disease, cytokine release syndrome, and neurotoxicity. However, their persistence and efficacy are limited by immunological challenges such as host T-cell-mediated rejection, NK cell fratricide, and macrophage-mediated clearance. This review summarizes gene editing strategies to overcome these barriers, including β2-microglobulin (B2M) knockout and HLA-E overexpression to evade T and NK cell attacks, CD47 overexpression to inhibit phagocytosis, and TIGIT deletion to enhance cytotoxicity. In addition, we discuss functional enhancements such as IL-15 pathway activation, KIR modulation, and transcriptional reprogramming (e.g., FOXO1 knockout) to improve persistence and antitumor activity. We also highlight the role of induced pluripotent stem cell (iPSC)-derived NK platforms, enabling standardized, scalable, and multiplex gene-edited products. Finally, we explore artificial intelligence (AI) applications in immunogenomic profiling and predictive editing to tailor NK cell therapies to patient-specific HLA/KIR/SIRPα contexts. By integrating immune evasion, functional reinforcement, and computational design, we propose a unified roadmap for next-generation CAR-NK development, supporting durable and broadly applicable cell-based therapies. Full article

Chimeric antigen receptor (CAR)-engineered cell therapy represents a landmark advancement in cancer immunotherapy. While αβ CAR-T therapy has demonstrated remarkable success in hematological malignancies, its efficacy in solid tumors remains constrained mainly by factors such as antigen heterogeneity, immunosuppressive microenvironments, and on-target/off-tumor toxicity. To overcome these limitations, emerging CAR platforms that utilize alternative immune effectors, including natural killer (NK) cells, macrophages, and γδ T lymphocytes, are rapidly gaining traction. This review systematically analyzes the mechanistic advantages of CAR-NK, CAR-M, and CAR-γδ T cell therapies, while critically evaluating persistent challenges in clinical translation, including limited cell persistence, manufacturing scalability, and dynamic immune evasion mechanisms. We further discuss innovative strategies to enhance therapeutic efficacy through some viable strategies. By bridging fundamental immunology with translational engineering, this work provides a roadmap for developing CAR therapies capable of addressing the complexities of solid tumor eradication. Full article

The NK-92 cell line has become a very relevant tool for natural killer (NK) cell research, largely because it largely mirrors the characteristics of human blood-derived NK cells. It also has a doubling time of less than 30 h, making it possible to generate a significant number of cells in a relatively short time. Its safety as an anti-cancer cell therapy has been documented in over 200 cancer patients. Various genetically engineered variants have been generated that express a high-affinity Fc-receptor and various chimeric antigen receptors (CARs) and secrete immune-active cytokines. NK-92 cells expressing CARs for HER-2, PD-L1, and CD19 CAR are in advanced clinical trials in cancer patients. These cells also have cytotoxic activity against targets infected with bacteria, fungi, and viruses. More recently, the cellular lysate of NK-92 cells, generated by simple freeze/thaw, has shown anti-cancer potential when injected intra-tumor. Since a comprehensive review of NK-92 was recently published on the occasion of its 30-year “anniversary”, this review will focus on more recent research initiatives and results with the cell line. Full article

Background: The remarkable efficacy of B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T-cell therapy (CAR-T) has had a significant impact on treatment strategies for relapsed/refractory multiple myeloma (RRMM). However, response durability remains a concern, necessitating the optimization of CAR-T procedures. Therapies preceding CAR-T therapy are crucial for disease control and preserving T-cell fitness. Methods: This review summarizes the evidence supporting the potential of selinexor-based regimens as holding or bridging therapy with preclinical research, demonstrating selinexor’s ability to foster an anti-inflammatory tumor microenvironment. Results: Selinexor enhances CD8+ T-lymphocyte and NK cell activation, re-polarizes macrophages, and inhibits immunosuppressive cells. Bone marrow samples from patients in clinical studies show that selinexor increases CD8 and granzyme B expression in T-cells. Selinexor also disrupts NK cell inhibition, enhances anti-tumor activity, and reduces pro-inflammatory cytokines. Selinexor may upregulate BCMA expression and increase myeloma cell immunogenicity. Real-world data suggests selinexor as bridging therapy does not compromise CAR-T outcomes and may even improve them. Conclusions: Overall, the evidence indicates selinexor’s potential to optimize CAR-T outcomes, warranting further investigation as a holding or bridging therapy for CAR-T. Full article

Neuroblastoma (NB) is the most prevalent extracranial childhood tumor and the third leading cause of death from cancer in children. Despite having a high overall survival rate for low- and intermediate-risk patients, survival rates for high-risk cases remain unsatisfactory. The current standard treatment for high-risk NB involves surgery, chemotherapy, radiotherapy, autologous stem cell transplantation, immunotherapy with anti-ganglioside GD2, and differentiation therapy with isotretinoin. Besides not being enough to achieve a high survival rate in high-risk patients, these treatments are associated with significant side effects. With next-generation sequencing technologies, a better understanding of the genetic and epigenetic landscapes of NB has been achieved. This has led to the study of novel treatments to improve the overall survival rate of high-risk NB and reduce the toxicity of conventional treatments. Current research is focusing on the development of targeted drugs for genetic and epigenetic alterations, and protein degraders. Moreover, immunotherapy to enhance anticancer immune responses and by using cell-engineering techniques with chimeric antigen receptor (CAR) T and NK cells are being explored to target NB cells. Here, we review promising novel treatment strategies for NB, which target genetics, epigenetics, the tumor microenvironment, and the immune landscape, highlighting preclinical studies and ongoing clinical trials. Full article

Non-Hodgkin lymphomas (NHLs) encompass a diverse group of neoplasms arising from the clonal proliferation of B-cell progenitors, T-cell progenitors, mature B-cells, mature T-cells, and natural killer (NK) cells. These malignancies account for over 90% of lymphoid neoplasms. The link between the gut microbiome and neoplasms has been extensively studied in recent years. Growing evidence suggests that the gut microbiome may be involved not only in the development of the disease, but also in modulating the efficacy of implemented therapies. In this review, we summarize the current knowledge on the potential involvement of the gut microbiome in the development of diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, and NK/T-cell lymphoma, including cutaneous T-cell lymphoma (CTCL). Moreover, we discuss the relationship between gut microbiome changes before and after treatment and their association with treatment outcomes, focusing on chemotherapy and CAR T-cell therapy. Full article

The clinical use of T lymphocytes engineered with chimeric antigen receptors (CARs) has revolutionized the treatment of patients with refractory or relapsed hematological malignancies. CAR natural killer (CAR-NK) cells are NK cells engineered with CARs to specifically target cell antigens expressed on the membrane of tumor cells. CAR-NK cells could offer some advantages with respect to CAR-T cells, related to their specific and innate anti-tumor activity, availability as an “off the shelf” cellular therapy, reduced costs, and improved safety. Promising efficacy of CAR-Nk cell therapy was observed in clinical trials based on the treatment of some hematological malignancies. However, to date, the clinical experience of CAR-NK cell therapy has been preliminary, with the evaluation of only a limited number of patients. Furthermore, CAR-NK cell therapy has been limited by the short persistence of these cells and by the suboptimal cytotoxic activity of some CAR-NK preparations. Therefore, studies based on the enrollment of a number of patients is required to carefully assess and confirm the safety and the efficacy of CAR-NK cell therapy in hematological malignancies and to compare their efficacy with respect to allogeneic CAR-T cells. Full article

Background/Objectives: Natural killer (NK) cells play a crucial role in tumor surveillance by exerting cytotoxic activity and modulating immune responses. However, tumors employ diverse evasion strategies that limit NK cell effectiveness. This review aims to explore the molecular mechanisms of NK cell activation and inhibition in cancer, the influence of the tumor microenvironment, and the latest advancements in NK cell-based immunotherapies, including adoptive NK cell transfer and Chimeric Antigen Receptor-Natural Killer (CAR-NK) cell therapies. Methods: A comprehensive literature review was conducted, prioritizing peer-reviewed studies from the last decade on NK cell biology, tumor immune evasion, and immunotherapeutic applications. The analysis includes data from preclinical models and clinical trials evaluating NK cell expansion strategies, cytokine-based stimulation, and CAR-NK cell therapy developments. Results: NK cells eliminate tumors through cytotoxic granule release, death receptor pathways, and cytokine secretion. However, tumor cells evade NK-mediated immunity by downregulating activating ligands, secreting immunosuppressive molecules, and altering the tumor microenvironment. Novel NK cell-based therapies, such as CAR-NK cells and combination approaches with immune checkpoint inhibitors, enhance NK cell persistence and therapeutic efficacy against both hematologic and solid malignancies. Clinical trials suggest improved safety profiles compared to CAR-T therapies, with reduced cytokine release syndrome and graft-versus-host disease. Conclusions: While NK cell-based immunotherapies hold great promise, challenges remain, including limited persistence and tumor-induced immunosuppression. Addressing these hurdles will be critical for optimizing NK cell therapies and advancing next-generation, off-the-shelf immunotherapeutics for broader clinical applications. Full article

Hsp70, a 70 kDa molecular chaperone, plays a crucial role in maintaining protein homeostasis. It interacts with the DnaJ family of co-chaperones to modulate the functions of client proteins involved in various cellular processes, including transmembrane transport, extracellular vesicle trafficking, complex formation, and proteasomal degradation. Its presence in multiple cellular organelles enables it to mediate stress responses, apoptosis, and inflammation, highlighting its significance in disease progression. Initially recognized for its essential roles in protein folding, disaggregation, and degradation, later studies have demonstrated its involvement in several human diseases. Notably, Hsp70 is upregulated in multiple cancers, where it promotes tumor proliferation and serves as a tumor immunogen. Additionally, epichaperome networks stabilize protein–protein interactions in large and long-lived assemblies, contributing to both cancer progression and neurodegeneration. However, extracellular Hsp70 (eHsp70) in the tumor microenvironment can activate immune cells, such as natural killer (NK) cells, suggesting its potential in immunotherapeutic interventions, including CAR T-cell therapy. Given its multifaceted roles in cellular physiology and pathology, Hsp70 holds immense potential as both a biomarker and a therapeutic target across multiple human diseases. This review highlights the structural and functional importance of Hsp70, explores its role in disease pathogenesis, and discusses its potential in diagnostic and therapeutic applications. Full article

Background: The heterogeneity of sarcomas and resulting distinct sub-type specific characteristics, their high recurrence rates, and tendency for distant metastasis, continue to present significant challenges to providing optimal treatments. Objective: To provide a comprehensive review of current literature and clinical trials in gene and cell therapies for sarcomas. Methods: A comprehensive literature search was conducted utilizing the following databases: PubMed, Medline, Google Scholar and clinicaltrials.gov. Search terms included “gene therapy”, “cell therapy”, “NK cell therapy, “CAR-T therapy”, “virotherapy”, “sarcoma”, “gene therapy”, and “solid tumors”. Additional sources were identified through manual searching for references of relevant studies. No language restrictions were set. The NCT number, study status, condition, and phase were noted for clinical trials. Results: There are only three gene and cell therapies for sarcomas that have been approved by a federal regulatory agency. Rexin-G: the first tumor-targeted gene therapy vector designed to target all advanced solid malignancies, including chemo-refractory osteosarcomas and soft tissue sarcomas, was approved by the Philippine FDA in 2007. Gendicine was the first oncolytic virus approved for intratumoral delivery in China in 2003. Afami-cel, an innovative chimeric antigen receptor (CAR) T cell therapy, was approved for synovial sarcoma in the United States in 2024. Other promising therapies are discussed in the text. Conclusions: The future of gene and cell therapy for sarcomas holds great promise, as research moves to late-stage clinical development. The integration of gene and cell therapies into standard sarcoma treatment protocols has the potential to significantly improve the quality of life and outcomes for patients with this rare and challenging group of cancers. Full article

Mesothelin (MSLN), a glycoprotein-based tumor antigen, is elevated in several malignancies and it is related to a poor prognosis, as it enhances tumor aggression, dissemination and chemotherapy resistance. MSLN plays a crucial role in epigenetic and signal pathway regulation and it can be an important biomarker. MSLN targeting is in particular, associated with CA125/MUC16, which offers the potential to improve lung, pancreatic, colon and ovarian cancer detection as well as therapeutic strategies. MSLNtargeted therapies have shown favorable results, such as CAR NK cells, 227Th conjugate and CAR-T cells, which target mesothelin. Significant advancements can be achieved with novel techniques, such as mesothelin-targeting BiTEs and simultaneous CAR-T cells. Immunotherapies targeting mesothelin have the potential to completely transform the way cancer is therapy in patients with limited options. To fully comprehend the mechanisms of MSLN, more investigation is required to explore its role in cancer for improved patient outcomes. The complex control, cellular functions and clinical significance of MSLN in the advancement of cancer are highlighted in this review.  Full article