Colorectal cancer (CRC), a major global health concern, necessitates innovative treatments. Chimeric antigen receptor (CAR) T cells have shown promises, yet they grapple with challenges. The spotlight pivots to the rising heroes: CAR natural killer (NK) cells, offering advantages such as higher safety profiles, cost-effectiveness, and efficacy against solid tumors. Nevertheless, the specific mechanisms underlying CAR NK cell trafficking and their interplay within the complex tumor microenvironment require further in-depth exploration. Herein, we provide insights into the design and engineering of CAR NK cells, antigen targets in CRC, and success in overcoming resistance mechanisms with an emphasis on the potential for clinical trials.
Colorectal Neoplasms/immunology* ; Humans ; Killer Cells, Natural/metabolism* ; Receptors, Chimeric Antigen/genetics* ; Immunotherapy, Adoptive/methods* ; Tumor Microenvironment/immunology* ; Animals

The remarkable efficacy of chimeric antigen receptor (CAR) T cell therapy in hematological malignancies has provided a solid basis for the therapeutic concept, wherein specific pathogenic cell populations can be eradicated by means of targeted recognition. During the past few years, CAR-based cell therapies have been extensively investigated in preclinical and clinical research across various non-tumor diseases, with particular emphasis in the treatment of autoimmune diseases (ADs), yielding significant advancements. The recent deployment of CD19-directed CAR T cells has induced long-lasting, drug-free remission in patients with systemic lupus erythematosus (SLE) and other systemic ADs, alongside a more profound immune reconstruction of B cell repertoire compared with conventional immunosuppressive agents and B cell-targeting biologics. Despite the initial success achieved by CAR T cell therapy, it is critical to acknowledge the divergences in its application between cancer and ADs. Through examining recent clinical studies and ongoing research, we highlight the transformative potential of this therapeutic approach in the treatment of SLE, while also addressing the challenges and future directions necessary to enhance the long-term efficacy and safety of CAR-based cell therapies in clinical practice.
Humans ; Lupus Erythematosus, Systemic/immunology* ; Receptors, Chimeric Antigen/metabolism* ; Immunotherapy, Adoptive/methods* ; Cell- and Tissue-Based Therapy/methods* ; Animals ; T-Lymphocytes/immunology*

BACKGROUND: Several studies have demonstrated the occurrence of secondary tumors as a rare but significant complication of chimeric antigen receptor T (CAR-T) cell therapy, underscoring the need for a detailed investigation. Given the limited variety of secondary tumor types reported to date, a comprehensive characterization of the various secondary tumors arising after CAR-T therapy is essential to understand the associated risks and to define the role of the immune microenvironment in malignant transformation. This study aims to characterize the immune microenvironment of a newly identified secondary tumor post-CAR-T therapy, to clarify its pathogenesis and potential therapeutic targets. METHODS: In this study, the bone marrow (BM) samples were collected by aspiration from the primary and secondary tumors before and after CD19 CAR-T treatment. The CD45 + BM cells were enriched with human CD45 microbeads. The CD45 + cells were then sent for 10× genomics single-cell RNA sequencing (scRNA-seq) to identify cell populations. The Cell Ranger pipeline and CellChat were used for detailed analysis. RESULTS: In this study, a rare type of secondary chronic myelomonocytic leukemia (CMML) were reported in a patient with diffuse large B-cell lymphoma (DLBCL) who had previously received CD19 CAR-T therapy. The scRNA-seq analysis revealed increased inflammatory cytokines, chemokines, and an immunosuppressive state of monocytes/macrophages, which may impair cytotoxic activity in both T and natural killer (NK) cells in secondary CMML before treatment. In contrast, their cytotoxicity was restored in secondary CMML after treatment. CONCLUSIONS This finding delineates a previously unrecognized type of secondary tumor, CMML, after CAR-T therapy and provide a framework for defining the immune microenvironment of secondary tumor occurrence after CAR-T therapy. In addition, the results provide a rationale for targeting macrophages to improve treatment strategies for CMML treatment.
Humans ; Lymphoma, Large B-Cell, Diffuse/therapy* ; Tumor Microenvironment/genetics* ; Antigens, CD19/metabolism* ; Leukemia, Myelomonocytic, Chronic/genetics* ; Immunotherapy, Adoptive/adverse effects* ; Male ; Single-Cell Analysis/methods* ; Female ; Sequence Analysis, RNA/methods* ; Receptors, Chimeric Antigen ; Middle Aged

Chimeric antigen receptor T (CAR-T) cells have reshaped the treatment landscape of hematological malignancies, offering a potentially curative option for patients. Despite these major milestones in the field of immuno-oncology, growing experience with CAR-T cells has also highlighted several limitations of this strategy. The production process of CAR-T cells is complex, time-consuming, and costly, thus leading to poor drug accessibility. The potential carcinogenic risk of viral transfection systems remains a matter of controversy. Treatment-related side effects, such as cytokine release syndrome, can be life-threatening. And the biggest challenge is the inadequate efficacy related to poor infiltration and retention of CAR-T cells in tumor tissues and impaired T cell activation caused by the immunosuppressive tumor microenvironment (TME). Innovative strategies are urgently needed to address these problems, and nanomedicine offers good solutions to these challenges. In this review, we provide a comprehensive summary of recent advancements in the application of nanomaterials to enhance CAR-T cell therapy. We examine the role of innovative nanoparticle-based delivery systems in the production of CAR-T cells, with a particular focus on polymeric delivery systems and lipid nanoparticles (LNPs). Furthermore, we explore various strategies for delivering immune stimulators, which significantly enhance the efficacy of CAR-T cells by modulating T cell viability and functionality or by reprogramming the immunosuppressive TME. In addition, we discuss several novel therapeutic approaches aimed at mitigating the adverse effects associated with CAR-T therapies. Finally, we offer an integrated perspective on the future challenges and opportunities facing CAR-T therapies.
Humans ; Nanomedicine/methods* ; Receptors, Chimeric Antigen/metabolism* ; Immunotherapy, Adoptive/methods* ; T-Lymphocytes/immunology* ; Nanoparticles/chemistry* ; Animals

Tumor immunotherapy has revolutionized the treatment prospects for various malignant tumors. Immune checkpoint inhibitors (ICIs) and chimeric antigen receptor T-cell therapy (CAR-T) , as representative of tumor immunotherapy, have achieved tremendous success in clinical practice and have become the first-line clinical treatment options for certain tumors. This article summarizes the progress and challenges of immune checkpoint inhibitors and CAR-T therapy in tumor treatment, and discusses the future direction of tumor therapeutic vaccines development. Identifying novel therapeutic targets within the realm of tumor immunology, engineering innovative drug delivery systems, and employing combinatorial therapeutic strategies are poised to enhance therapeutic efficacy and patient outcomes in oncology, thereby extending benefits to a broader patient population.
Humans ; Neoplasms/immunology* ; Immune Checkpoint Inhibitors/therapeutic use* ; Receptors, Chimeric Antigen/genetics* ; Immunotherapy/methods* ; Immunotherapy, Adoptive/methods* ; Animals ; Cancer Vaccines/therapeutic use*

Chimeric antigen receptor T (CAR-T) lymphocytes are at the forefront of adoptive immunotherapy research, and this technology has significantly advanced the prospects of tumor immunotherapy. CAR-T therapy has demonstrated remarkable efficacy in haematological tumours of lymphoid origin and provided therapeutic possibility for solid tumours. Currently, CAR-T cell preparation predominantly involves transfection of T cells with viral vectors. However, the production of viral vectors is time-consuming, expensive, and the vectors have low loading capacity, along with insertion instability. Consequently, there is a pressing need to develop more convenient and precise non-viral gene delivery methods. This paper reviews the most promising non-viral gene delivery technologies, including CRISPR/Cas9 gene editing, transposon systems such as Sleeping Beauty (SB) and PiggyBac (PB), and mRNA, and anticipates the future development of non-viral vector-based CAR-T therapies.
Humans ; Immunotherapy, Adoptive/methods* ; Receptors, Chimeric Antigen/immunology* ; Animals ; Gene Transfer Techniques ; Genetic Vectors/genetics* ; Gene Editing ; CRISPR-Cas Systems/genetics* ; DNA Transposable Elements/genetics* ; T-Lymphocytes/immunology* ; Neoplasms/immunology*

Adoptive cell transfer (ACT) shows significant efficacy against hema-tological malignancies but is limited in solid tumors due to poor homing, immunosuppre-ssion, and potential toxicity. Biomaterials spanning from nano- to macroscales-including nanoparticles, microspheres/micropatches, and hydrogels-offer unique advantages for ex vivo cell engineering, in vivo delivery, and modulation of the tumor microenvironment. Specifically, nanoparticles enable gene delivery, artificial antigen-presenting cell engi-neering, and immune microenvironment remodeling. Microspheres/micropatches improve immune cell expansion, targeted activation, and localized retention. Hydrogels enhance ACT via in situ genetic engineering, 3D culture support, and cytokine co-delivery. This review summarizes advances in biomaterial-enhanced ACT, highlighting their potential to improve delivery efficiency, amplify antitumor responses, and reduce toxicity. These insights may accelerate the clinical translation of ACT for solid tumors.
Humans ; Neoplasms/therapy* ; Biocompatible Materials/chemistry* ; Immunotherapy, Adoptive/methods* ; Nanoparticles ; Hydrogels ; Adoptive Transfer/methods* ; Animals

OBJECTIVE: To investigate the predictive role of the modified Endothelial Activation and Stress Index (mEASIX) in the efficacy of chimeric antigen receptor T-cell (CAR-T) therapy and cytokine release syndrome (CRS). METHODS: The clinical data of 70 relapsed and refractory (R/R) B-cell tumor patients who were treated with CAR-T therapy from September 1, 2018 to February 28, 2023 in the Department of Hematology, Affiliated Hospital of Xuzhou Medical University, were retrospectively analyzed. The value of log-2 mEASIX before conditioning (-7 d) was calculated, and the patients were divided into a low-mEASIX group (42 patients) and a high-mEASIX group (28 patients) based on the cut-off value of 5.443 determined by the receiver operating characteristic (ROC) curve. Eventually, the predictive role of mEASIX before conditioning on the efficacy of CAR-T cell therapy and CRS was analyzed. RESULTS: The high-mEASIX group exhibited significantly worse median overall survival (OS) and median progression-free survival (PFS) in comparison to the low mEASIX group (OS: 3.2 months vs not reached, P < 0.01; PFS: 1.3 months vs 6.0 months, P =0.009). The incidence of grade ≥2 CRS in the high-mEASIX group was substantially higher than that in the low-mEASIX group (57.1% vs 19.0%, P =0.007). The degree of remission after CAR-T therapy (P =0.001), whether CRS occurs or not (P =0.041), the lactate dehydrogenase (LDH) level before conditioning (P =0.046), and the mEASIX score before conditioning (P =0.047) were independent influencing factors for the OS of patients receiving CAR-T cell therapy. CONCLUSION The mEASIX score before conditioning can predict OS and the incidence of grade ≥2 CRS in patients with relapsed and refractory B-cell tumors who receive CAR-T cell therapy.
Cytokine Release Syndrome/therapy* ; Immunotherapy, Adoptive/methods* ; Humans ; Lymphoma, B-Cell/therapy* ; Retrospective Studies ; Hematology ; China ; Receptors, Chimeric Antigen/blood* ; Predictive Value of Tests

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.
Humans ; Immunotherapy, Adoptive/methods* ; Receptors, Chimeric Antigen/immunology* ; Signal Transduction/immunology* ; T-Lymphocytes/immunology* ; Neoplasms/immunology* ; Animals

Cancer immunotherapy including immune checkpoint inhibitors and adoptive cell therapy has gained revolutionary success in the treatment of hematologic tumors; however, it only gains limited success in solid tumors. For example, chimeric antigen receptor T (CAR-T) cell therapy has shown significant effects and potential for curing patients with B-cell malignancies. In contrast, it remains a challenge for CAR-T cell therapy to gain similar success in solid tumors. The anti-tumor effect of endogenous or adoptively transferred tumor-specific T cells depends largely on their differentiation status. T cells at early differentiation stage show better anti-tumor therapeutic effects than fully differentiated effector T cells. In cancer patients, the persistence of tumor-specific T cells with the stem cell memory or precursor phenotype is significantly associated with improved therapeutic outcomes; therefore, adoptively transfered CAR-T cells with stem cell memory and/or central memory is expected to gain better anti-tumor effects. Herein we focused on the in vitro optimized culture and expansion system to obtain CAR-T cells with stem cell memory or central memory phenotype for the review.
Humans ; Immunotherapy, Adoptive/methods* ; Receptors, Chimeric Antigen/genetics* ; Neoplasms/immunology* ; Immunologic Memory ; T-Lymphocytes/immunology* ; Memory T Cells/immunology* ; Animals ; Stem Cells/cytology* ; Cell Differentiation