Tumor immunotherapy is a developing and promising therapeutic method. However, the mechanism of tumor immune microenvironment and individual differences of patients make the clinical application of immunotherapy still very limited. The resulting targeting of the tumor environment and immune system is a suitable strategy for tumor therapy. Biomimetic nanodelivery systems (BNDS) coated with nanoparticles has brought new hope for tumor immunotherapy. Due to its high targeting, maximum drug delivery efficiency and immune escape, BNDS has become one of the options for tumor immunotherapy in the future. BNDS combines the advantages of natural cell membranes and nanoparticles and has good targeting properties. This review summarizes the relationship between tumor and immune microenvironment, classification of immunotherapy, engineering modification of cell membrane, and a comprehensive overview of different types of membrane BNDS in immunotherapy. Furthermore, the prospects and challenges of biomimetic nanoparticles coated with membranes in tumor immunotherapy are further discussed.

Colorectal cancer (CRC) continues to be a major worldwide health issue, with elevated death rates linked to late stages of the illness. Immunotherapy has made significant progress in developing effective techniques to improve the immune system's capacity to identify and eradicate cancerous cells. This study examines the most recent advancements in CAR-T cell treatment and exosome-based immunotherapy for CRC. CAR-T cell therapy, although effective in treating blood cancers, encounters obstacles when used against solid tumours such as CRC. These obstacles include the presence of an immunosuppressive tumour microenvironment and a scarcity of tumour-specific antigens. Nevertheless, novel strategies like dual-receptor CAR-T cells and combination therapy involving cytokines have demonstrated promise in surmounting these obstacles. Exosome-based immunotherapy is a promising approach for targeted delivery of therapeutic drugs to tumour cells, with high specificity and minimal off-target effects. However, there are still obstacles to overcome in the field, such as resistance to treatment, adverse effects associated with the immune system, and the necessity for more individualised methods. The current research is focused on enhancing these therapies, enhancing the results for patients, and ultimately incorporating these innovative immunotherapeutic approaches into the standard treatment protocols for CRC.

A substantial proportion of patients diagnosed with rheumatologic and musculoskeletal diseases (RMDs) exhibit resistance to conventional therapies or experience recurrent symptoms. These diseases, which include autoimmune disorders such as multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus, are marked by the presence of autoreactive B cells that play a critical role in their pathogenesis. The persistence of these autoreactive B cells within lymphatic organs and inflamed tissues impairs the effectiveness of B-cell-depleting monoclonal antibodies like rituximab. A promising therapeutic approach involves using T cells genetically engineered to express chimeric antigen receptors (CARs) that target specific antigens. This strategy has demonstrated efficacy in treating B-cell malignancies by achieving long-term depletion of malignant and normal B cells. Preliminary data from patients with RMDs, particularly those with lupus erythematosus and dermatomyositis, suggest that CAR T-cells targeting CD19 can induce rapid and sustained depletion of circulating B cells, leading to complete clinical and serological responses in cases that were previously unresponsive to conventional therapies. This review will provide an overview of the current state of preclinical and clinical studies on the use of CAR T-cells and other cellular therapies for RMDs. Additionally, it will explore potential future applications of these innovative treatment modalities for managing patients with refractory and recurrent manifestations of these diseases.

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive lymphoma that is isolated in the central nervous system (CNS) or vitreoretinal space. High-dose methotrexate (HD-MTX)-based immunochemotherapy is the frontline for its treatment, with a high early response rate. However, relapsed or refractory (R/R) patients present numerous difficulties and challenges in clinical treatment. Chimeric antigen receptor (CAR)-T cells offer a promising option for the treatment of hematologic malignancies, especially in the R/R B-cell lymphoma and multiple myeloma. Despite the exclusion of most PCNSL cases from pivotal CAR-T cell trials due to their specific tumor microenvironment (TME), available preclinical and clinical studies with small cohorts suggest an overall acceptable safety profile and remarkable anti-tumor effects. In this review, we will provide the development process of CAR-T cells and summarize the research progress, limitations, and future perspectives of CAR-T cell therapy in patients with R/R PCNSL.

T cell therapy efficacy can be compromised if cytokine-induced Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling is dysregulated or insufficient to sustain functionality. Here, we demonstrate that LCK kinase activity can be recruited to noncanonical protein substrates to directly activate targeted STAT proteins in T cells. STAT activation was accomplished by engineering the herpesvirus saimiri tyrosine kinase interacting protein (TIP) to provide a platform for the enforced recruitment of LCK to STAT proteins. We determined that a minimal region of TIP that binds to LCK could be combined with STAT binding sites derived from endogenous cytokine receptors. These constructs activated targeted STAT proteins in a cytokine-independent manner. We identified a STAT5 activator that sustained CD8+ T cell survival and cytotoxic function ex vivo in the absence of interleukin-2. Tumor outgrowth was reduced in vivo because of enhanced T cell persistence and functionality. Single-cell transcriptomics revealed that the STAT5 activator prevented the expression of genes associated with an exhausted T cell fate. Our findings demonstrate that signaling pathways can be rewired in T cells to sustain their function in solid tumors.

Recent advancements in immunotherapy, particularly Chimeric antigen receptor (CAR)-T cell therapy and cancer vaccines, have significantly transformed the treatment landscape for leukemia. CAR-T cell therapy, initially promising in hematologic cancers, faces notable obstacles in solid tumors due to the complex and immunosuppressive tumor microenvironment. Challenges include the heterogeneous immune profiles of tumors, variability in antigen expression, difficulties in therapeutic delivery, T cell exhaustion, and reduced cytotoxic activity at the tumor site. Additionally, the physical barriers within tumors and the immunological camouflage used by cancer cells further complicate treatment efficacy. To overcome these hurdles, ongoing research explores the synergistic potential of combining CAR-T cell therapy with cancer vaccines and other therapeutic strategies such as checkpoint inhibitors and cytokine therapy. This review describes the various immunotherapeutic approaches targeting leukemia, emphasizing the roles and interplay of cancer vaccines and CAR-T cell therapy. In addition, by discussing how these therapies individually and collectively contribute to tumor regression, this article aims to highlight innovative treatment paradigms that could enhance clinical outcomes for leukemia patients. This integrative approach promises to pave the way for more effective and durable treatment strategies in the oncology field. These combined immunotherapeutic strategies hold great promise for achieving more complete and lasting remissions in leukemia patients. Future research should prioritize optimizing treatment sequencing, personalizing therapeutic combinations based on individual patient and tumor characteristics, and developing novel strategies to enhance T cell persistence and function within the tumor microenvironment. Ultimately, these efforts will advance the development of more effective and less toxic immunotherapeutic interventions, offering new hope for patients battling this challenging disease.

Chimeric antigen receptor (CAR) T-cell therapy targeting B cells has shown promising results, including drug-free remission, in adult-onset autoimmune diseases. Extending this therapeutic approach to the pediatric population, particularly for juvenile autoimmune diseases, presents an exciting opportunity. However, challenges specific to juvenile-onset autoimmune conditions, such as long-term adverse events, heightened disease activity, and the imperative to reduce steroid exposure, must be considered. While this strategy appears viable for these severe conditions, the limited data available for this population and the absence of evidence on cases with a high genetic component, such as monogenic lupus, represent significant challenges. Most monogenic lupus cases are associated with innate immune defects, and the involvement of B cells in these genetic anomalies remains poorly understood. In this review, we examine the potential indications, current knowledge, and limitations of CAR-T cell therapy in juvenile-onset autoimmune diseases, extending the discussion beyond early-onset lupus.

Chimeric antigen receptor (CAR)-T cell therapy has revolutionized cancer immunotherapy in the 21st century, providing innovative solutions and life-saving therapies for previously untreatable diseases. This approach has shown remarkable success in treating various hematological malignancies and is now expanding into clinical trials for solid tumors, such as prostate cancer and glioblastoma, as well as infectious and autoimmune diseases. CAR-T cell therapy involves harvesting a patient's T cells, genetically engineering them with viral vectors to express CARs targeting specific antigens and reinfusing the modified cells into the patient. These CAR-T cells function independently of major histocompatibility complex (MHC) antigen presentation, selectively identifying and eliminating target cells. This review highlights the key milestones in CAR-T cell evolution, from its invention to its clinical applications. It outlines the historical timeline leading to the invention of CAR-T cells, discusses the major achievements that have transformed them into a breakthrough therapy, and addresses remaining challenges, including high manufacturing costs, limited accessibility, and toxicity issues such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. Additionally, the review explores future directions and advances in the field, such as developing next-generation CAR-T cells aiming to maximize efficacy, minimize toxicity, and broaden therapeutic applications.

Immune checkpoint blockade is, as of today, the most successful form of cancer immunotherapy, with more than 43 % of cancer patients in the US eligible to receive it; however, only up to 12.5 % of patients respond to it. Similarly, adoptive cell therapy using bioengineered chimeric antigen receptorT (CAR-T) cells and T-cell receptor (TCR) cells has provided excellent responses against liquid tumours, but both forms of immunotherapy have encountered challenges within a tumour microenvironment that is both lacking in tumour-specific T-cells and is strongly immunosuppressive toward externally administered CAR-T and TCR cells. This review focuses on understanding approved checkpoint blockade and adoptive cell therapy at both biological and clinical levels before delving into how and why their combination holds significant promise in overcoming their individual shortcomings. The advent of next-generation checkpoint inhibitors has further strengthened the immune checkpoint field, and a special section explores how these inhibitors can address existing hurdles in combining checkpoint blockade with adoptive cell therapy and homing in on our cancer target for long-term immunity.

Despite current technological advancements in the treatment of glioma, immediate alleviation of symptoms can be catered by therapeutic modalities, including surgery, chemotherapy, and combinatorial radiotherapy that exploit aberrations of glioma. Additionally, a small number of target antigens, their heterogeneity, and immune evasion are the potential reasons for developing targeted therapies. This oncologic milestone has catalyzed interest in developing immunotherapies against Glioblastoma to improve overall survival and cure patients with high-grade glioma. The next-gen CAR-T Cell therapy is one of the effective immunotherapeutic strategies in which autologous T cells have been modified to express receptors against GBM and it modulates cytotoxicity.

In this review article, we examine preclinical and clinical outcomes, and limitations as well as present cutting-edge techniques to improve the function of CAR-T cell therapy and explore the possibility of combination therapy.

To date, several CAR T-cell therapies are being evaluated in clinical trials for GBM and other brain malignancies and multiple preclinical studies have demonstrated encouraging outcomes.

CAR-T cell therapy represents a promising therapeutic paradigm in the treatment of solid tumors but a few limitations include, the blood-brain barrier (BBB), antigen escape, tumor microenvironment (TME), tumor heterogeneity, and its plasticity that suppresses immune responses weakens the ability of this therapy. Additional investigation is required that can accurately identify the targets and reflect the similar architecture of glioblastoma, thus optimizing the efficiency of CAR-T cell therapy; allowing for the selection of patients most likely to benefit from immuno-based treatments.

Claudin18 isoform 2 (CLDN18.2), primarily expressed in gastric tissue and upregulated in pancreatic cancer (PC), is a key target for innovative treatments like chimeric antigen receptor T (CAR-T) cell therapy. However, CAR-T's effectiveness comes with a significant risk of on-target, off-tumor (OTOT) toxicity due to CLDN18.2's presence in normal gastric mucosa. To address this, we developed CLDN18.2-specific synthetic T cell receptor and antigen receptor T (STAR-T) cells. Our research shows that STAR-T and CAR-T cells have comparable in vitro cytotoxicity, but STAR-T cells cause less gastric damage in vivo despite having weaker antitumor effects than CAR-T cells. Clinical tests with gastroscopes confirmed the gastric safety of STAR-T cell therapy, which effectively controlled the disease. Additionally, incorporating the IL12β p40 subunit into STAR-T cells enhanced their function in both lab and animal studies. This evidence suggests that CLDN18.2 STAR-T cell could be a safer alternative to CAR-T cell therapy for PC, meriting further clinical trials.

Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5), a transcriptional target gene of the Wnt signalling pathway, is overexpressed in multiple cancers, including colorectal cancer (CRC), hepatocellular carcinoma (HCC) and pre-B acute lymphoblastic leukaemia (pre-B ALL) and has emerged as a promising therapeutic target. Here, we reflect on the bottom-up development of a novel α-LGR5 therapeutic antibody we have recently reported, into a palette of LGR5-targeting immunotherapeutic modalities: antibody-drug conjugates (ADCs), bispecific T cell engagers (bispecific engagers), and chimeric antigen receptor (CAR) T cells. The α-LGR5 antibody is highly specific and accurately detects LGR5 protein expression levels, enabling its use as a prognostic biomarker for identifying LGR5+ tumour types. Preclinical studies road-testing the various α-LGR5-based modalities established potent and safe elimination of LGR5-expressing cancer cells in vitro and efficacy in a mouse model of human cancer in vivo. In this review, we discuss the utility of our antibody as the building block for a novel set of immunotherapeutics and highlight the importance of matching specific α-LGR5-based therapeutic modalities to individual tumour type and patient characteristics.

Asthma is characterized by reversible airway inflammation, obstruction, and structural remodeling, which lead to the eosinophils and lymphocytes accumulation at inflammation sites and the release of inflammatory cells, like mast cells and dendritic cells, from lungs' epithelial and smooth muscle cells that trigger the activation and release of cytokines and chemokines, attracting more cells and contributing to asthma development. Available pharmacological interventions, like bronchodilators and anti-inflammatory agents, are considered generally safe and effective to treat asthma, but many affected individuals with severe asthma still struggle with symptom control. This review highlights recent innovative therapies, such as chemoattractant receptor-homologous molecule expressed on Th2 cell (CRTH2) antagonists, S-nitrosoglutathione reductase (GSNOR) and phosphodiesterase (PDE) inhibitors, and other novel biological agents, which offer potential new strategies for managing severe asthma and may alter the disease's course. Kew words. Inflammation; CRTH2; GSNOR; PDE; Interleukins; Biological agents.

The adoptive transfer of T cells expressing chimeric antigen receptors (CARs) is effective in B cell malignancies. However, the persistence of cancer cells with low levels or complete absence of the target antigen, thereby evading detection by CAR T cells, leads to relapse. These evasion mechanisms highlight the need for receptors with enhanced sensitivity and multispecificity. We introduce a synthetic chimeric T cell receptor (ChTCR) that confers superior antigen sensitivity compared with CARS and previous hybrid TCR designs and is readily adapted for bispecific targeting. ChTCRs replicate the structure of natural TCRs, form classical immune synapses and demonstrate TCR-like signaling. T cells expressing bispecific ChTCRs (Bi-ChTCRs) are more effective than bispecific CAR T cells in eradicating tumors with heterogeneous antigen expression in vivo in female mice. The Bi-ChTCR architecture is resilient and can be designed to target pairs of B cell and multiple myeloma antigens. These findings provide a widely applicable strategy to combat tumor heterogeneity and prevent relapse.

Over the past few decades, there has been significant advancement in the field of tumor immunotherapy. For many years vaccination against infectious diseases have been available. On the other hand very few cancer vaccines have been approved for human use. Ideal Cancer vaccines are biological response modifier work by stimulating both humoral and cellular immunity while overcoming the immunological suppression found in tumor. Two types of cancer vaccine: Prophylactic and therapeutic cancer vaccines are recommended for clinical use of individuals. HPV and HBV vaccines are the two widely used preventive vaccine used for treatment of cervical and hepatocellular carcinoma respectively and are approved by Food and Drug Administration (FDA). In therapeutic vaccine only three are approved: Sipuleucel T-cell vaccine for treatment refractory prostatic cancer, BCG vaccine for early bladder cancer and T-VEC for inoperable melanoma. Active ingredient in all cancer vaccines is an antigen. Antigens used for formulating cancer vaccines along with adjuvants optimizes immunogenicity in it. Heterogeneity within and between cancer types, screening and identifying suitable antigen specific to tumors and selection of vaccine delivery platforms are challenges in the development of vaccines. Adoptive cell therapy, Chimeric antigen receptor T cell therapy are recent breakthrough for cancer treatment.

The use of bismuth and its compounds in biomedicine has developed rapidly in recent years. Due to their unique properties, there are great opportunities for the development of new non-invasive strategies for the early diagnosis and effective treatment of cancers. This perspective highlights key fabrication methods to generate well-defined and clinically relevant bismuth materials of varying characteristics. On the one hand, this opens up a wide range of possibilities for unimodal and multimodal imaging. On the other hand, effective treatment strategies, which are increasingly based on combinatorial therapies, are given a great deal of attention. One of the biggest challenges remains the selective tumour targeting, whether active or passive. Here we present an overview on new developments of bismuth based materials moving forward from a simple enrichment at the tumour site via uptake by the mononuclear phagocytic system (MPS) to a more active tumour specific targeting via covalent modification with tumour-seeking molecules based on either small or antibody-derived molecules.

Chimeric Antigen Receptor (CAR) T cell therapy represents a groundbreaking advancement in immunotherapy, initially gaining FDA approval for treating hematological malignancies. This therapy has shown promising results in solid tumors, particularly in pediatric brain tumors, which are the leading cause of cancer-related death in children. CAR T cells are engineered to target specific antigens on tumor cells, thereby reducing off-target effects and increasing the cytotoxic impact on cancer cells. Over the years, CAR T cell technology has evolved through five generations, each enhancing the structure, functionality, and safety of these cells. Despite these advancements, the application of CAR T cells in solid tumors, especially within the central nervous system (CNS), faces significant challenges. These include the physical barrier posed by the blood-brain barrier (BBB), the immunosuppressive tumor microenvironment (TME), and the heterogeneity of tumor antigens. The review discusses several promising antigenic targets for CAR T cells in pediatric brain tumors, such as HER2, EphA2, IL-13Rα2, and Survivin, which have been explored in recent clinical trials. These trials have shown early promise in improving patient outcomes, though the risks of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) remain concerns. The future of CAR T cell therapy lies in overcoming these barriers through innovative approaches like "Armored CARs" or TRUCKs, designed to modulate the TME and improve CAR T cell efficacy in solid tumors. Additionally, combination therapies and safety switches in next-generation CAR T cells are being explored to enhance therapeutic potential while minimizing adverse effects.

Immune-mediated disorders are a broad range of diseases, arising as consequence of immune defects, exaggerated/misguided immune response or a mixture of both conditions. Their frequency is on a rise in the developed societies and they pose a significant challenge for diagnosis and treatment. Traditional pharmacological, monoclonal antibody-based or polyclonal antibody replacement-based therapies aiming at modulation of the immune responses give very often dissatisfactory results and/or are burdened with unacceptable adverse effects. In recent years, a new group of treatment modalities has emerged, utilizing cells as living drugs, especially with the use of the up-to-date genetic engineering. These modern cellular therapies are designed to offer a high potential for more targeted, safe, durable, and personalized treatment options. This work briefly reviews the latest advances in the treatment of immune-mediated disorders, mainly those related to exaggeration of the immune response, with such cellular therapies as hematopoietic stem cells (HSCs), mesenchymal stromal cells (MSCs), regulatory T cells (Tregs), chimeric antigen receptor (CAR) T cells and others. We highlight the main features of these therapies as new treatment options for taming the dysregulated immune system. Undoubtfully, in near future such therapies can provide lasting remissions in a range of immune-mediated disorders with reduced treatment burden and improved quality of life for the patients.

Chimeric Antigen Receptor T-cell (CAR-T) therapy has emerged as a transformative approach for cancer treatment, demonstrating remarkable success in patients with relapsed and refractory hematological malignancies. However, challenges persist in optimizing CAR-T cell production and improving therapeutic outcomes. One of the major hurdles is the efficiency of retroviral or lentiviral transduction during CAR-T cell manufacturing. Additionally, the heterogeneity of T-cell populations isolated from patients can impact CAR-T cell effectiveness and persistence in vivo. This article explores a novel strategy to address these challenges by focusing on serum-free medium and additive optimization. We propose a unique approach that incorporates the culturing of T cells in Nutri-T medium, along with 24 h of exposure to combined low concentrations of BX795 and rosuvastatin, to enhance the transduction efficacy and functionality of CAR-T cells. The results presented here provide promising insights into the potential of this strategy to produce more effective CAR-T cells for immunotherapy, ultimately advancing the field and benefiting cancer patients worldwide.

Chimeric antigen receptor (CAR) T-cell therapy has shown remarkable efficacy in treating hematological malignancies and is expanding into other indications such as autoimmune diseases, fibrosis, aging and viral infection. However, clinical challenges persist in treating solid tumors, including physical barriers, tumor heterogeneity, poor in vivo persistence, and T-cell exhaustion, all of which hinder therapeutic efficacy. This review focuses on the critical role of tonic signaling in CAR-T therapy. Tonic signaling is a low-level constitutive signaling occurring in both natural and engineered antigen receptors without antigen stimulation. It plays a pivotal role in regulating immune cell homeostasis, exhaustion, persistence, and effector functions. The "Peak Theory" suggests an optimal level of tonic signaling for CAR-T function: while weak tonic signaling may result in poor proliferation and persistence, excessively strong signaling can cause T cell exhaustion. This review also summarizes the recent progress in mechanisms underlying the tonic signaling and strategies to fine-tune the CAR tonic signaling. By understanding and precisely modulating tonic signaling, the efficacy of CAR-T therapies can be further optimized, offering new avenues for treatment across a broader spectrum of diseases. These findings have implications beyond CAR-T cells, potentially impacting other engineered immune cell therapies such as CAR-NK and CAR-M.

Despite the remarkable success of CAR-T cell therapy in hematologic malignancies, its progress in solid tumors has been slow. Overcoming challenges such as the recruitment and infiltration of CAR-T cells into the tumor site and the survival issues in the harsh tumor microenvironment are crucial for successful application in solid tumors. In this study, CAR-T cells were engineered to secrete both IL-15 and CCL19, and their efficacy was evaluated in a human glioblastoma orthotopic xenograft model. The results reveal that 15 × 19 CAR-T cells exhibit superior proliferation, chemotaxis, and phenotypic characteristics compared to conventional CAR-T cells in vitro. In vivo, 15 × 19 CAR-T cells exhibit superior control over tumors compared to conventional counterparts. Mechanistically, the improved efficacy can be attributed, in part, to IL-15 and CCL19 enhancing T-cell infiltration at the tumor site and fortifying resistance to exhaustion within the tumor microenvironment. In conclusion, the incorporation of IL-15 and CCL19 into CAR-T cells emerges as a promising strategy to elevate the anti-tumor efficacy of CAR-T cell therapy, positioning 15 × 19 CAR-T cells as a potential breakthrough for enhancing the application of CAR-T therapy in solid tumors.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic malignancy characterized by the overexpression of CD123 and CD303 surface antigens. These molecular markers play a crucial role in diagnosing diseases and developing targeted therapies. Traditional treatment options for BPDCN have demonstrated limited effectiveness, highlighting the need for new and innovative therapeutic strategies. Recent advances in immunotherapy, particularly therapeutic monoclonal antibodies, bispecific T-cell engagers, and CAR T-cell therapy, have provided promising alternatives. Tagraxofusp, the first FDA-approved CD123-targeted therapy, has significantly improved patient outcomes. Additionally, emerging CD303-targeting strategies offer the potential for further advancements. Despite these breakthroughs, challenges such as treatment resistance and toxicity remain. This review explores the latest developments in BPDCN treatment, emphasizing the potential of CD123 and CD303 as targets for precision medicine interventions. The ongoing evolution of targeted immunotherapies holds promise for improving patient survival and redefining treatment paradigms in hematologic malignancies.

Cancer treatment is continually advancing, with immunotherapy gaining prominence as a standard modality that has markedly improved the management of various malignancies. Despite these advancements, the efficacy of immunotherapy remains variable, with certain cancers exhibiting limited response and patient outcomes differing considerably. Thus, enhancing the effectiveness of immunotherapy is imperative. A promising avenue is mRNA delivery, employing carriers such as liposomes, peptide nanoparticles, inorganic nanoparticles, and exosomes to introduce mRNA cargos encoding tumor antigens, immune-stimulatory, or immune-modulatory molecules into the tumor immune microenvironment (TIME). This method aims to activate the immune system to target and eradicate tumor cells. In this review, we introduce the characteristics and limitations of these carriers and summarize the application and mechanisms of currently prevalent cargos in mRNA-based tumor treatment. Additionally, given the significant clinical application of immune checkpoint inhibitors (ICIs) and chimeric antigen receptor (CAR)-based cell therapies in solid tumors (including melanoma, non-small-cell lung cancer, head and neck squamous cell carcinoma, triple-negative breast cancer, gastric cancer) and leukemia, which have become first-line treatments, we highlight and discuss recent progress in combining mRNA delivery with ICIs, CAR-T, CAR-NK, and CAR-macrophage therapies. This combination enhances the targeting capabilities and efficacy of ICIs and CAR-cell-based therapies, while also mitigating the long-term off-target toxicities associated with conventional methods. Finally, we analyze the limitations of current mRNA delivery systems, such as nuclease-induced mRNA instability, immunogenicity risks, complex carrier production, and knowledge gaps concerning dosing and safety. Addressing these challenges is crucial for unlocking the potential of mRNA in cancer immunotherapy. Overall, exploring mRNA delivery enriches our comprehension of cancer immunotherapy and holds promise for developing personalized and effective treatment strategies, potentially enhancing the immune responses of cancer patients and extending their survival time.

CAR-T cells are genetically modified T lymphocytes that express chimeric antigen receptors (CAR) on their surfaces. These receptors enable T lymphocytes to recognize specific antigens on target cells, triggering a response that leads to targeted cytotoxicity. While CAR-T therapy has effectively treated various blood cancers, it faces significant challenges in addressing solid tumors. These challenges include identifying precise tumor antigens, overcoming antigen evasion, and enhancing the function of CAR-T cells within the tumor microenvironment. Single domain antibody, versatile tools with low immunogenicity, high stability, and strong affinity, show promise for improving the efficacy of CAR-T cells against solid tumors. By addressing these challenges, single domain antibody has the potential to overcome the limitations associated with ScFv antibody-based CAR-T therapies. This review highlights the benefits of utilizing single domain antibody in CAR-T therapy, particularly in targeting tumor antigens, and explores development strategies that could advance the field.

Chimeric antigen receptors (CARs) are synthetic receptors that reprogram the target specificity and functions of CAR-expressing effector cells. The design of CAR constructs typically includes an extracellular antigen-binding moiety, hinge (H), transmembrane (TM), and intracellular signaling domains. Conventional CAR constructs are primarily designed for T cells but have been directly adopted for other effector cells, including natural killer (NK) cells, without tailored optimization. Given the benefits of CAR-NK cells over CAR-T cells in terms of safety, off-the-shelf utility, and antigen escape, there is an increasing emphasis on tailoring them to NK cell activation mechanisms.

We first have taken a stepwise approach to modifying CAR components such as the combination and order of the H, TM, and signaling domains to achieve such tailoring in NK cells. Functionality of NK-tailored CARs were evaluated in vitro and in vivo in a model of CD19-expressing lymphoma, along with their expression and signaling properties in NK cells.

We found that NK-CAR driven by the synergistic combination of NK receptors NKG2D and 2B4 rather than DNAM-1 and 2B4 induces potent activation in NK cells. Further, more effective CAR-mediated cytotoxicity was observed following the sequential combination of DAP10, but not NKG2D TM, with 2B4 signaling domain despite the capacity of NKG2D TM to recruit endogenous DAP10 for signaling. Accordingly, an NK-CAR incorporating DAP10, 2B4, and CD3ζ signaling domains coupled to CD8α H and CD28 TM domains was identified as the most promising candidate to improve CAR-mediated cytotoxicity. This NK-tailored CAR provided more potent antitumor activity than a conventional T-CAR when delivered to NK cells both in vitro and in vivo.

Hence, NK receptor-based domains hold great promise for the future of NK-CAR design with potentially significant therapeutic benefits.

Regulatory T cells (Tregs) are key regulators in maintaining tissue homeostasis. Disrupted immune homeostasis is associated with Crohn's disease (CD) pathogenesis. Thus, Treg therapy represents a promising long-acting treatment to restore immune balance in the diseased intestine. Chimeric antigen receptor (CAR) T-cell therapy has revolutionized cancer treatment. This innovative approach also provides the opportunity to improve therapy for CD. By targeting a disease-relevant protein, interleukin-23 receptor (IL23R), we engineered Tregs expressing IL23R-CAR for treating active CD.

Intestinal IL23R expression from active CD was verified by immunohistochemical analysis. Phenotypic and functional characteristics of IL23R-CAR Tregs were assessed using in vitro assays and their migration capacity was monitored in a xenograft tumor model. Transcriptomic and proteomic analyses were performed to associate molecular profiles with IL23R-CAR Treg activation against colon biopsy-derived cells from active CD patients.

Our study showed that IL23R-CAR displayed negligible tonic signaling and a strong signal-to-noise ratio. IL23R-CAR Tregs maintained regulatory phenotype during in vitro expansion, even when chronically exposed to proinflammatory cytokines and target antigen. IL23R engagement on IL23R-CAR Tregs triggered CAR-specific activation and significantly enhanced their suppressive activity. Also, IL23R-CAR Tregs migrated to IL23R-expressing tissue in humanized mice. Finally, IL23R-CAR Tregs elicited a specific activation against colon biopsy-derived cells from active CD, suggesting an efficient CAR engagement in active CD. Molecular profiling of CD patient biopsies also revealed transcriptomic and proteomic patterns associated with IL23R-CAR activation.

Overall, our results demonstrate that IL23R-CAR Tregs represent a promising therapy for active CD.

Autoimmune diseases are a group of diseases in which the body's immune system misrecognizes its own antigens resulting in an abnormal immune response, which can lead to pathological damage to or abnormal functioning of its own tissues. Current treatments are mainly hormones and broad-spectrum immunosuppressants, but these can lead to a decline in the patient's immunity. Chimeric antigen receptor T (CAR-T) Cell therapy has emerged, and now the structure of CAR has changed from first generation to fourth generation of CAR. The significant achievement of CAR-T therapy to B-cell leukemia has also inspired the treatment of autoimmune diseases, and by investigating the mechanisms of different autoimmune diseases, different designs of CAR-T can be used to specifically treat autoimmune diseases. In this review, we will discuss the therapeutic strategies of CAR-T cells in different autoimmune diseases and the limitations of the treatment.

Cancer remains a significant public health issue worldwide, standing as a primary contributor to global mortality, accounting for approximately 10 million fatalities in 2020 [...].

Engineered T cells that express chimeric antigen receptors (CARs) have transformed the treatment of haematological cancers. CARs combine the tumour-antigen-binding function of antibodies with the signalling functions of the T cell receptor (TCR) ζ chain and co-stimulatory receptors. The resulting constructs aim to mimic the TCR-based and co-receptor-based activation of T cells. Although these have been successful for some types of cancer, new CAR formats are needed, to limit side effects and broaden their use to solid cancers. Insights into the mechanisms of TCR signalling, including the identification of signalling motifs that are not present in the TCR ζ chain and mechanistic insights in TCR activation, have enabled the development of CAR formats that outcompete the current CARs in preclinical mouse models and clinical trials. In this Perspective, we explore the mechanistic rationale behind new CAR designs.

T-cell lymphomas (TCLs) are heterogeneous malignancies with limited treatment options and poor outcomes. The efficacy of traditional T-cell therapies, including chimeric antigen receptor (CAR) T cells, is often constrained by immunosuppressive factors and the tumor microenvironment. On the other hand, although direct Granzyme B (GrB) administration can effectively induce tumor cell apoptosis, it lacks universal tumor targeting and efficient cellular entry mechanisms. To address these limitations, we developed a novel nanoparticle-based therapy for the precise targeting of TCL tumor cells and the delivery of GrB. We fused nanobody (Nb) targeting CD30 and CD5 with GrB and coupled them to human ferritin (h-HFn) using the Gv/Sd system, creating a novel therapeutic nanoparticle named BiCD30/5-GF, which specifically targets CD30 and CD5 receptors on TCL tumor cells. The Nb-GrB conjugation enhances tumor targeting, while a Gv/Sd linker coupled to h-HFn further improves cellular transport and targeting. Additionally, the multimerization of GrB enhances its effectiveness. These nanoparticles demonstrated superior binding affinity and cytotoxicity in vitro compared to conventional treatments. In vivo studies on tumor-bearing mice showed significant tumor suppression and prolonged survival following treatment with BiCD30/5-GF nanoparticles. We also extended similar nanoparticle strategies for gastric cancer therapy, targeting FGFR4-expressing tumor cells. Our findings highlight the potential of engineered nanoparticles as effective and targeted therapeutic agents across various tumor types, offering promising prospects for clinical translation in cancer treatment.

Cancer immunotherapy has reshaped the landscape of cancer treatment over the past decades. Genetic manipulation of T cells to express synthetic receptors, known as chimeric antigen receptors (CAR), has led to the creation of tremendous commercial and therapeutic success for the treatment of certain hematologic malignancies. However, since the engagement of CAR-T cells with their respective antigens is solely what triggers their cytotoxic reactions against target cells, the slightest changes to the availability and/or structure of the target antigen often result in the incapacitation of CAR-T cells to enforce tumoricidal responses. This results in the resistance of tumor cells to a particular CAR-T cell therapy that requires meticulous heeding to sustain remissions in cancer patients. In this review, we highlight the antigen-dependent resistance mechanisms by which tumor cells dodge being recognized and targeted by CAR-T cells. Moreover, since substituting the target antigen is the most potent strategy for overcoming antigen-dependent disease relapse, we tend to highlight the current status of some target antigens that might be considered suitable alternatives to the currently available antigens in various cancers. We also propose target antigens whose targeting might reduce the off-tumor adverse events of CAR-T cells in certain malignancies.

The development and wider adoption of adoptive cell therapies is constrained by complex and costly manufacturing processes and by inconsistent efficacy across patients. Here we discuss how microfluidic and other fluidic devices can be implemented at each stage of cell manufacturing for adoptive cell therapies, from the harvesting and isolation of the cells to their editing, culturing and functional selection. We suggest that precise and controllable microfluidic systems can streamline the development of these therapies by offering scalability in cell production, bolstering the efficacy and predictability of the therapies and improving their cost-effectiveness and accessibility for broader populations of patients with cancer.

Clinical trials evaluating chimeric antigen receptor (CAR) T-cell therapy in patients with malignant gliomas have shown some early promise in pediatric and adult patients. However, the long-term benefits and safety for patients remain to be established. The ultimate success of CAR T-cell therapy for malignant glioma will require the integration of an in-depth understanding of the immunology of the central nervous system (CNS) parenchyma with strategies to overcome the paucity and heterogeneous expression of glioma-specific antigens. We also need to address the cold (immunosuppressive) microenvironment, exhaustion of the CAR T-cells, as well as local and systemic immunosuppression. Here, we discuss the basics and scientific considerations for CAR T-cell therapies and highlight recent clinical trials. To help identify optimal CAR T-cell administration routes, we summarize our current understanding of CNS immunology and T-cell homing to the CNS. We also discuss challenges and opportunities related to clinical trial design and patient safety/monitoring. Finally, we provide our perspective on future prospects in CAR T-cell therapy for malignant gliomas by discussing combinations and novel engineering strategies to overcome immuno-regulatory mechanisms. We hope this review will serve as a basis for advancing the field in a multiple discipline-based and collaborative manner.

Over the years, extensive research has been dedicated to performing in-depth analysis of cancer to uncover the intricate details of its nature - including the types of cancer, causative agents, stimulators of disease progression, factors contributing to poor prognosis, and efficient therapies to restrict the metastatic aggressiveness. This chapter highlights the mechanisms through which different arms of the host immune system - namely cytokines, lymphocytes, antigen-presenting cells (APCs) -can be mobilized to eradicate cancer. Most malignant tumors are either poorly immunogenic, or are harbored in a highly immuno-suppressive microenvironment. This is why reinforcing the host's anti-tumor defenses, through infusion of pro-inflammatory cytokines, tumor antigen-loaded APCs, and anti-tumor cytotoxic cells has emerged as a viable treatment option against cancer. The chapter also highlights the ongoing preclinical and clinical studies in different malignancies and the outcome of various therapies. Although these methods are not foolproof, and antigen escape variants can still evade or develop resistance to customized therapies, they achieve disease stabilization in several cases when conventional treatments fail. In many instances, combination therapies involving cytokines, T cells, and vaccinations prove more effective than monotherapies. The limitations of the current therapies are also discussed, along with ongoing modifications aimed at improving efficacy.

The liver is one of the most frequent sites of primary malignancies in humans. Hepatocellular carcinoma (HCC) is one of the most prevalent solid tumors with poor prognosis. Current treatments showed limited efficacy in some patients, and, therefore, alternative strategies, such as immunotherapy, cancer vaccines, adoptive cell therapy (ACT), and recently chimeric antigen receptors (CAR)-T cells, are developed to offer better efficacy and safety profile in patients with HCC. Unlike other ACTs like tumor-infiltrating lymphocytes (TILs), CAR-T cells are equipped with engineered CAR receptors that effectively identify tumor antigens and eliminate cancer cells without major histocompatibility complex (MHC) restriction. This process induces intracellular signaling, leading to T lymphocyte recruitment and subsequent activation of other effector cells in the tumor microenvironment (TME). Until today, novel approaches have been used to develop more potent CAR-T cells with robust persistence, specificity, trafficking, and safety. However, the clinical application of CAR-T cells in solid tumors is still challenging. Therefore, this study aims to review the advancement, prospects, and possible avenues of CAR-T cell application in HCC following an outline of the CAR structure and function.

Alzheimer's disease is the most common form, accounting for 60-70% of 55 million dementia cases. Even though the precise pathophysiology of AD is not completely understood, clinical trials focused on antibodies targeting aggregated forms of β amyloid (Aβ) have demonstrated that reducing amyloid plaques can arrest cognitive decline in patients in the early stages of AD. In this study, we provide an overview of current research and innovations for controlled release from nano-biomaterial-assisted chimeric antigen receptor macrophage (CAR-M) therapeutic strategies targeted at AD. Nano-bio materials, such as iron-oxide nanoparticles (IONPs), can be made selectively (Hp-Hb/mannose) to bind and take up Aβ plaques like CAR-M cells. By using nano-bio materials, both the delivery and stability of CAR-M cells in brain tissue can be improved to overcome the barriers of the BBB and enhance therapeutic effects. By enhancing the targeting capabilities and stability of CAR-M cells, mRNA-loaded nano-biomaterials can significantly improve the efficacy of immunotherapy for plaque reduction in AD. This novel strategy holds promise for translating preclinical successes into clinical applications, potentially revolutionising the management of AD.

Efforts to produce adoptive cell therapies in AML have been largely unfruitful, despite the success seen in lymphoid malignancies. Identifying targetable antigens on leukemic cells that are absent on normal progenitor cells remains a major obstacle, as is the hostile tumor microenvironment created by AML blasts. In this review, we summarize the challenges in the development of adoptive cell therapies such as CAR-T, CAR-NK, and TCR-T cells in AML, discussing both autologous and allogeneic therapies. We also discuss methods to address myelotoxicity associated with these therapies, including rapidly switchable CAR platforms and CRISPR-Cas9 genetic engineering of hematopoietic stem cells. Finally, we present the current clinical landscape in these areas, along with future directions in the field.

Chimeric antigen receptor (CAR) T cell therapy has revolutionized cancer immunotherapy, particularly for hematological malignancies. This personalized approach is based on genetically engineering T cells derived from the patient to target antigens expressed-among others-on malignant cells. Nowadays they offer new hope where conventional therapies, such as chemotherapy and radiation, have often failed. Since the first FDA approval in 2017, CAR T cell therapy has rapidly expanded, proving highly effective against previously refractory diseases with otherwise a dismal outcome. Despite its promise, CAR T cell therapy continues to face significant challenges, including complex manufacturing, the management of toxicities, resistance mechanisms that impact long-term efficacy, and limited access as well as high costs, which continue to shape ongoing research and clinical applications. This review aims to provide an overview of CAR T cell therapy, including its fundamental concepts, clinical applications, current challenges, and future directions in hematological malignancies.

Chimeric Antigen Receptor (CAR)-T cell therapy has rapidly emerged as a groundbreaking approach in cancer treatment, particularly for hematologic malignancies. However, the application of CAR-T cell therapy in solid tumors remains challenging. This review summarized the development of CAR-T technologies, emphasized the challenges and solutions in CAR-T cell therapy for solid tumors. Also, key innovations were discussed including specialized CAR-T, combination therapies and the novel use of CAR-Treg, CAR-NK and CAR-M cells. Besides, CAR-based cell therapy have extended its reach beyond oncology to autoimmune disorders. We reviewed preclinical experiments and clinical trials involving CAR-T, Car-Treg and CAAR-T cell therapies in various autoimmune diseases. By highlighting these cutting-edge developments, this review underscores the transformative potential of CAR technologies in clinical practice.

This brief overview is inspired by seminal contributions by the late Dr. Martin C. Mihm, Jr. who provided a basis for recognition and better understanding of interactions between lymphocytes (tumor-infiltrating lymphocytes [TILs]) that home to and permeate cancers. In primary melanomas, this phenomenon may produce what Dr. Mihm called white depressed areas, prescient clues to what would fuel future attempts at harnessing anticancer immunity. The critical and sequential TIL attributes of antigenic stimulation, homing, and effector-target cell apoptotic injury herein are briefly reviewed in light of more recent advances in the field of immuno-oncology. The intent is to emphasize how fundamental clinical and histopathological observations, as forged by Dr. Mihm and his associates, have led to critically important prognostic paradigms as well as to translational insights that now have become transformative in the field of cancer immunotherapy.

In the past decades, Chimeric Antigen Receptor (CAR)-T cell therapy has achieved remarkable success, leading to the approval of six therapeutic products for haematological malignancies. Recently, the therapeutic potential of this therapy has also been demonstrated in non-tumoral diseases. Currently, the manufacturing process to produce clinical-grade CAR-T cells is complex, time-consuming, and highly expensive. It involves multiple steps, including the collection of T cells from patients or healthy donors, in vitro engineering and expansion, and finally reinfusion into patients. Therefore, despite the impressive clinical outcomes, ex vivo manufacturing process makes CAR-T cells out of reach for many cancer patients. Direct in vivo engineering of T cells could be a more rapid solution able to circumvent both the complexity and the costs associated with ex vivo manufactured CAR-T cells. This novel approach allows to completely eliminate ex vivo cell manipulation and expansion while producing therapeutic cell populations directly in vivo. To date, several studies have demonstrated the feasibility of in vivo T cell reprogramming, by employing injectable viral- or nanocarrier-based delivery platforms in tumour animal models. Additionally, in vivo production of CAR-T cells might reduce the incidence, or at least the severity, of systemic toxicities frequently occurring with ex vivo produced CAR-T cells, such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. In this review, we highlight the challenges associated with the current ex vivo manufacturing protocols and review the latest progresses in the emerging field of in vivo CAR-T therapy, by comparing the various platforms so far investigated. Moreover, we offer an overview of the advantages deriving from in vivo reprogramming of other immune cell types, such as Natural Killer and macrophages, with CAR constructs.