A nanobody-guided multifunctional T cell engager promotes strong anti-tumor responses via synergistic immuno-photothermal effects.

BACKGROUND: T cell-based immunotherapies are facing great challenges in the recruitment and activation of tumor-specific T cells against solid tumors. Among which, utilizing nanobody (Nb) or nanobodies (Nbs) to construct T cell engager has emerged as a more practical potential for enhancing the anti-tumor effectiveness of T cells. Here, we designed a new Nb-guided multifunctional T cell engager (Nb-MuTE) that not only recruited effector T cells into the tumor tissues, but also efficiently activated T cells anti-tumor immunity when synergies with photothermal effect. RESULTS: The Nb-MuTE, which was constructed based on an indocyanine green (ICG)-containing liposome with surface conjugation of CD105 and CD3 Nbs, and showed excellent targetability to both tumor and T cells, following enhancement of activation, proliferation and cytokine secretion of tumor-specific T cells. Notably, the immunological anti-tumor functions of Nb-MuTE-mediated T cells were further enhanced by the ICG-induced photothermal effect in vitro and in vivo. CONCLUSIONS: Such a new platform Nb-MuTE provides a practical and "all-in-one" strategy to potentiate T cell responses for the treatment of solid tumor in clinic.

Potential of gamma/delta T cells for solid tumor immunotherapy.

Gamma/delta T (γδ T)cells possess a unique mechanism for killing tumors, making them highly promising and distinguished among various cell therapies for tumor treatment. This review focuses on the major histocompatibility complex (MHC)-independent recognition of antigens and the interaction between γδ T cells and solid tumor cells. A comprehensive review is provided regarding the classification of human gamma-delta T cell subtypes, the characteristics and mechanisms underlying their functions, as well as their r545egulatory effects on tumor cells. The involvement of γδ T cells in tumorigenesis and migration was also investigated, encompassing potential therapeutic targets such as apoptosis-related molecules, the TNF receptor superfamily member 6(FAS)/FAS Ligand (FASL) pathways, butyrophilin 3A-butyrophilin 2A1 (BTN3A-BTN2A1) complexes, and interactions with CD4, CD8, and natural killer (NK) cells. Additionally, immune checkpoint inhibitors such as programmed cell death protein 1/Programmed cell death 1 ligand 1 (PD-1/PD-L1) have the potential to augment the cytotoxicity of γδ T cells. Moreover, a review on gamma-delta T cell therapy products and their corresponding clinical trials reveals that chimeric antigen receptor (CAR) gamma-delta T therapy holds promise as an approach with encouraging preclinical outcomes. However, practical issues pertaining to manufacturing and clinical aspects need resolution, and further research is required to investigate the long-term clinical side effects of CAR T cells. In conclusion, more comprehensive studies are necessary to establish standardized treatment protocols aimed at enhancing the quality of life and survival rates among tumor patients utilizing γδ T cell immunotherapy.

Clinical characteristics and surgical strategy of sporadic cerebellar hemangioblastomas.

Hemangioblastoma is a rare benign vascular tumor that occurs mostly in the cerebellum. The aim of the present study was to analyze the clinical characteristics of sporadic cerebellar hemangioblastoma and its surgical strategy. A total of 76 cases of sporadic cerebellar hemangioblastoma (42 males and 34 females; age, 46.4±13.9 years; age range, 23-72 years) admitted to the Department of Neurosurgery of the General Hospital of Northern Theater Command (Shenyang, China) from July 2012 to April 2021 were retrospectively analyzed. All patients had only one isolated tumor and underwent surgical resection. Their basic characteristics, serial radiographic examinations, surgical records and follow-up were analyzed. A total of 57 patients with cystic hemangioblastoma and eight patients with cystic solid hemangioblastoma directly underwent resection treatment. Of 11 patients with solid hemangioblastoma, 8 underwent vascular embolization prior to surgical resection. Furthermore, 3 patients with solid hemangioblastoma who were not embolized prior to surgery had intraoperative hemorrhage and poor prognosis. In addition, 3 patients underwent partial resection of the tumor and all of them suffered recurrence after the surgery. A total of 71 patients achieved good neurologic improvement. However, 5 patients had a poor prognosis after the initial surgery. In conclusion, total microsurgical resection is essential to improve the health status of patients with sporadic cerebellar cystic hemangioblastoma. In addition, preoperative embolization of arteries supplying solid hemangioblastomas can reduce intraoperative bleeding and improve prognosis.

Personalized neoantigen cancer vaccines: current progression, challenges and a bright future.

Tumor neoantigens possess specific immunogenicity and personalized therapeutic vaccines based on neoantigens which have shown promising results in some clinical trials, with broad application prospects. However, the field is developing rapidly and there are currently few relevant review articles. Summarizing and analyzing the status of global personalized neoantigen vaccine clinical trials will provide important data for all stakeholders in drug development. Based on the Trialtrove database, a retrospective analysis was conducted using trial quantity as a key indicator for neo-adjuvant and adjuvant therapy anti-PD-1/PD-L1 clinical trials initiated before the end of 2022. The time trend of newly initiated trials was investigated. The sponsor type, host country, treatment mode, combination strategy, tested drugs, and targeted cancer types of these trials were summarized. As of December 2022, a total of 199 trials were included in the analysis. Among these studies, Phase I studies were the most numerous (119, 59.8%), and Phase I studies have been the predominant study type since 2015. Peptide vaccines were the largest neoantigen vaccines type, accounting for 64.8% of all clinical trials. Based on peptide delivery platforms, the proportion of trials was highest for the DC system (32, 16.1%), followed by LNP (11, 5.5%), LPX (11, 5.5%), and viruses (7, 3.5%). Most vaccines were applied in trials as a monotherapy (133/199, 66.8%), meanwhile combining immunotherapeutic drugs was the most common form for combination therapy. In terms of indications, the largest number of trials involved three or more unspecified solid tumors (50/199, 25.1%), followed by non-small cell lung cancer (24/199, 12.1%) and pancreatic cancer (15/199, 7.5%). The clinical development of personalized neoantigen cancer vaccines is still in the early stage. A clear shift in delivery systems from peptides to DC and liposomal platforms, with the largest number of studies in Asia, collectively marks a new era in the field. The adjuvant or maintenance therapy, and the combination treatment with ICIs are becoming the important clinical development orientation. As research on tumor-immune interactions intensifies, the design, development, and application of neoantigen vaccines are bound to develop rapidly, which will bring a new revolution in the future cancer treatment.

Lysosomal transmembrane protein 5: Impact on immune cell function and implications for immune-related deficiencies.

Lysosomal transmembrane protein 5 (LAPTM5) is a lysosomal-associated protein that interacts with surface receptors on various immune cells, including B cells, T cells, macrophages and dendritic cells. Dysregulated expression of LAPTM5 is implicated in the development of multiple immune system-related diseases. In the context of tumors, elevated LAPTM5 levels in immune cells are associated with decreased cell membrane levels of T cell receptors (TCR) or B cell receptors (BCR), leading to impaired antigen presentation and immune escape, thereby promoting tumor progression. Besides, LAPTM5 is critical for inducing non-apoptotic cell death in tumor parenchymal cells since its downregulation leads to inhibition of the cell death pathway in the tumor parenchyma and subsequent enhanced tumorigenesis. LAPTM5 also affects the cell cycle as the elevated LAPTM5 expression in solid tumors causes its inability to block the G0/G1 stage. In non-solid tumors, abnormal LAPTM5 expression disrupts blood cell development and causes irregular proliferation. Furthermore, in the nervous system, aberrant LAPTM5 expression in microglia is correlated with Alzheimer's disease severity. In this context, further preclinical research is essential to validate LAPTM5 as a potential target for diagnosis, therapy, and prognosis in immune-related disorders and tumors. This review summarized the current insights into LAPTM5's role in tumors and immune-related deficits, highlighting its potential as a valuable biomarker and therapeutic target.

FNA diagnosis of secondary malignancies in the parotid gland: over 20 years of experience from a single institute.

INTRODUCTION: Metastatic solid tumors account for a significant portion of malignancies in the parotid gland. Fine-needle aspiration (FNA) is a primary tool to diagnose these tumors. MATERIALS AND METHODS: We retrospectively reviewed 134 FNA cases of metastatic solid tumors affecting the parotid gland, spanning from 2000 to 2023 at our institute. We summarized the medical histories, cytology diagnoses, correlations with surgical resections, clinical treatments, and follow-up outcomes. RESULTS: The patient cohort included 107 male and 27 female patients, with a median age of 71 years (range: 4-96 years). Eighty-five percent of metastases (113 of 134) originated from head and neck (H&N) malignancies, comprising 66% from cutaneous source and 19% from mucosal sites. The most frequent primary sites outside the H&N were lung (4%), kidney (2%), and non-H&N skin (2%). Sixty-eight percent of metastases (92 of 134) were squamous cell carcinoma (SqCC) including 61% conventional type and 7% human papillomavirus-related SqCC. Melanoma is the second most common metastatic malignancy (28 of 134, 21%). The median time from primary diagnosis to metastasis was 10 months (range: 0 to 132 months). During clinical follow-up, 59 (44%) patients died from the disease in a median follow-up of 10 months (range: 2 to 56 months). CONCLUSIONS: This study represents one of the largest series of secondary malignancies in the parotid gland collected from a single institution. Most of these tumors are metastases from H&N malignancies, with cutaneous SqCC being the most prevalent primary site and histology. Accurate diagnosis relies heavily on clinical history, morphologic evaluation, and ancillary studies.

Emissive Lipid Nanoparticles as Biophotonic Contrast Agent for Site-Selective Solid Tumor Imaging in Pre-Clinical Models.

Small organic dye-based fluorescent agents are highly potent in solid tumor imaging but face challenges such as poor photostability, nonspecific distribution, low circulation, and weak tumor binding. Nanocarriers overcome these issues with better physicochemical and biological performance, particularly in cancer imaging. Among the various nanosized carriers, lipid formulations are clinically approved but yet to be designed as bright nanocontrast agents for solid tumor diagnosis without affecting surrounding tissues. Herein, indocyanine green (ICG) encapsulated targetable lipid nanoparticles (698 ICG/LNPs) as safe contrast agents (∼200 nm) have been developed and tested for solid tumor imaging and biodistribution. Our findings reveal that nanoprecipitation produces ICG-LNPs with a unique assembly, which contributes to their high brightness with improved quantum yield (3.5%) in aqueous media. The bright, optically stable (30 days) biophotonic agents demonstrate rapid accumulation (within 1 h) and prolonged retention (for up to 168 h) at the primary tumor site, with better signal intensity following a one-time dose administration (17.7 × 109 LNP per dose). Incorporated folic acid (735 folic acid/LNPs) helps in selective tumor binding and the specific biodistribution of intravenously injected nanoparticles without affecting healthy tissues. Designed targetable ICG-LNP (634 MESF) demonstrates high-contrast fluorescence and resolution from the tumor area as compared to the targetable ICG-liposomal nanoparticles (532 MESF). Various in vitro and in vivo findings reveal that the cancer diagnostic efficacy elicited by designed bright lipid nanoparticles are comparable to reported clinically accepted imaging agents. Thus, such LNPs hold translational potential for cancer diagnosis at an early stage.

Real-world assessment of comprehensive genome profiling impact on clinical outcomes: A single-institution study in Japan.

INTRODUCTION: Comprehensive genome profiling (CGP) has revolutionized healthcare by offering personalized medicine opportunities. However, its real-world utility and impact remain incompletely understood. This study examined the extent to which CGP leads to genomically matched therapy and its effectiveness. METHODS: We analyzed data from advanced solid tumor patients who underwent CGP panel between December 2019 and May 2023 at the Osaka International Cancer Institute. Patient demographics, specimen details, and expert panel assessments were collected. Turnaround time (TAT) and genomically matched therapy outcomes were analyzed. Gene alterations and their co-occurrence patterns were also assessed. RESULTS: Among 1437 patients, 1096 results were available for analysis. The median TAT was 63 [28-182] days. There were 667 (60.9%) cases wherein recommended clinical trials were presented and there were 12 (1.1%) cases that could be enrolled in the trial and 25 (2.3%) cases that could lead to therapies under insurance reimbursement. The median progression free survival of the trial treatment was 1.58 months (95% CI: 0.66-4.37) in clinical trials and 3.66 months (95% CI: 2.14-7.13) in treatment under insurance. Pathologic germline variants were confirmed in 15 patients (1.3%). Co-alteration of CDKN2A, CDKN2B, and MTAP was significantly observed in overall population. CONCLUSION: The effectiveness of the genomically matched therapy based on the CGP panel was unsatisfactory. Expansion of clinical trials and utilization of remote clinical trials are required to ensure that the results of the CGP panel can be fully returned to patients.

Therapeutic vaccine targeting dual immune checkpoints induces potent multifunctional CD8+ T cell anti-tumor immunity.

BACKGROUND: Vaccines targeting immune checkpoints represent a promising immunotherapeutic approach for solid tumors. However, the therapeutic efficacy of dual targeting immune checkpoints is still unclear in renal carcinoma. METHODS: An adenovirus (Ad) vaccine targeting B7H1 and B7H3 was developed and evaluated for its therapeutic efficacy in subcutaneous, lung metastasis or orthotopic renal carcinoma mouse and humanized models using flow cytometry, Enzyme-linked immunosorbent spot (ELISPOT), cytotoxic T lymphocyte (CTL) killing, cell deletion, hematoxylin and eosin (HE) staining, and immunohistochemistry (IHC) assays. RESULTS: The Ad-B7H1/B7H3 immunization effectively inhibited tumor growth and increased the induction and percentages of CD8+ T cells in subcutaneous tumor models. The vaccine enhanced the induction and maturation of CD11c+ or CD8+CD11c+ cells, promoting tumor-specific CD8+ T cell immune responses. This was evidenced by increased proliferation of CD8+ T cells and enhanced CTL killing activity. Deletion of CD8+ T cells in vivo abolished the anti-tumor effect of the Ad-B7H1/B7H3 vaccine, highlighting the pivotal role of functional CD8+ T cell immune responses. Moreover, significant therapeutic efficacy of the Ad-B7H1/B7H3 vaccine was observed in lung metastasis, orthotopic, and humanized tumor models through multifunctional CD8+ T cell immune responses. CONCLUSIONS: The Ad vaccine targeting dual immune checkpoints B7H1 and B7H3 exerts a potent therapeutic effect for renal carcinoma and holds promise for solid tumor treatment.

Targeting HER2 in solid tumors: Unveiling the structure and novel epitopes.

Human epidermal growth factor receptor-2 (HER2) is overexpressed in various solid tumor types, acting as an established therapeutic target. Over the last three decades, the fast-paced development of diverse HER2-targeted agents, notably marked by the introduction of the antibody-drug conjugate (ADC), yielding substantial improvements in survival rates. However, resistance to anti-HER2 treatments continues to pose formidable challenges. The complex structure and dynamic dimerization properties of HER2 create significant hurdles in the development of novel targeted therapeutics. In this review, we synthesize the latest insights into the structural intricacies of HER2 and present an unprecedented overview of the epitope characteristics of HER2-targeted antibodies and their derivatives. Furthermore, we delve into the correlation between anti-HER2 antibody binding epitopes and their respective functions, with a particular focus on their efficacy against resistant tumors. In addition, we highlight the potential of emerging anti-HER2 agents that target specific sites or non-overlapping epitopes, poised to transform the therapeutic landscape for HER2-positive tumors in the foreseeable future.

Incidence and Risk Factors of Hypomagnesemia in Patients With Bone Metastasis From Solid Malignancies Treated With Denosumab: A Retrospective Chart Review.

BACKGROUND: Hypomagnesemia is associated with poor clinical outcomes in cancer patients. Patients with bone metastasis from solid malignancies receiving denosumab (Dmab) to prevent skeletal-related events often receive concurrent antineoplastic agents for cancer treatment. The incidence and risk factors of hypomagnesemia in patients receiving Dmab and the optimal frequency of monitoring serum magnesium (Mg) levels have not been studied in these patient populations. OBJECTIVE: The objective is to investigate the incidence and potential risk factors of hypomagnesemia and the optimal frequency of monitoring serum Mg levels. METHODS: A retrospective chart review identified patients with solid malignancies with bone metastases treated with Dmab at the Loma Linda University Cancer Center between January 2013 and February 2024. The incidence of hypomagnesemia was determined using the number of patients with hypomagnesemia and the total number of patients in the study. Univariate and multivariate logistic regression analyses identified risk factors for hypomagnesemia. RESULTS: Hypomagnesemia was observed in 19% (29/153) of patients, the majority of whom were on concurrent antineoplastic agents with ≥15% hypomagnesemia incidence (high-hypomagnesemic antineoplastics) or nonantineoplastic drugs with documented cases or incidence of hypomagnesemia (hypomagnesemic nonantineoplastics) in addition to high-hypomagnesemic antineoplastics. Multivariate analysis showed increased odds of developing hypomagnesemia with high-hypomagnesemic antineoplastics (odds ratio [OR]: 174.93, 95% confidence interval [CI]: 12.82 to 387.43, P < 0.001); hypomagnesemic nonantineoplastics plus high-hypomagnesemic antineoplastics (OR: 210.09, 95% CI: 11.80 to 3740.12, P < 0.001); and Mg level ≤ 0.85 prior to Dmab administration (OR: 16.79, 95% CI: 2.30 to 122.41, P = 0.005). CONCLUSION AND RELEVANCE: This study describes the incidence and potential risk factors for hypomagnesemia in patients with solid malignancies and metastatic bone disease treated with Dmab. This study's findings provide additional clinical insight into potential risk factors for hypomagnesemia and the need for more frequent serum Mg level monitoring of at-risk patients. Future prospective studies are needed to determine the exact frequencies most appropriate in monitoring serum Mg levels in this group of patients.

Extracellular matrix regulation of cell spheroid invasion in a 3D bioprinted solid tumor-on-a-chip.

Tumor organoids and tumors-on-chips can be built by placing patient-derived cells within an engineered extracellular matrix (ECM) for personalized medicine. The engineered ECM influences the tumor response, and understanding the ECM-tumor relationship accelerates translating tumors-on-chips into drug discovery and development. In this work, we tuned the physical and structural characteristics of ECM in a 3D bioprinted soft-tissue sarcoma microtissue. We formed cell spheroids at a controlled size and encapsulated them into our gelatin methacryloyl (GelMA)-based bioink to make perfusable hydrogel-based microfluidic chips. We then demonstrated the scalability and customization flexibility of our hydrogel-based chip via engineering tools. A multiscale physical and structural data analysis suggested a relationship between cell invasion response and bioink characteristics. Tumor cell invasive behavior and focal adhesion properties were observed in response to varying polymer network densities of the GelMA-based bioink. Immunostaining assays and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) helped assess the bioactivity of the microtissue and measure the cell invasion. The RT-qPCR data showed higher expressions of HIF-1α, CD44, and MMP2 genes in a lower polymer density, highlighting the correlation between bioink structural porosity, ECM stiffness, and tumor spheroid response. This work is the first step in modeling STS tumor invasiveness in hydrogel-based microfluidic chips. STATEMENT OF SIGNIFICANCE: We optimized an engineering protocol for making tumor spheroids at a controlled size, embedding spheroids into a gelatin-based matrix, and constructing a perfusable microfluidic device. A higher tumor invasion was observed in a low-stiffness matrix than a high-stiffness matrix. The physical characterizations revealed how the stiffness is controlled by the density of polymer chain networks and porosity. The biological assays revealed how the structural properties of the gelatin matrix and hypoxia in tumor progression impact cell invasion. This work can contribute to personalized medicine by making more effective, tailored cancer models.

A thermoresponsive chitosan-based in situ gel formulation incorporated with 5-FU loaded nanoerythrosomes for fibrosarcoma local chemotherapy.

Local administration of drugs at tumor sites over an extended period of time shows potential as a promising approach for cancer treatment. In the present study, the temperature-induced phase transition of chitosan and poloxamer 407 is used to construct an injectable hydrogel encapsulating 5-FU-loaded nanoerythrosome (5-FU-NER-gel). The 5-FU-NERs were found to be spherical, measuring approximately 115 ± 20 nm in diameter and having a surface potential of -7.06 ± 0.4. The drug loading efficiency was approximately 40 %. In situ gel formation took place within 15 s when the gel was exposed to body temperature or subcutaneous injection. A sustained release profile was observed at pH 7.4 and 6.8, with a total 5-FU release of 76.57 ± 4.4 and 98.07 ± 6.31 in 24 h, respectively. MTT, Live/dead, and migration assays confirmed the cytocompatibility of the drug carrier and its effectiveness as a chemotherapeutic formulation. After in vivo antitumor assessment in a subcutaneous autograft model, it was demonstrated that tumor growth inhibition in 14 days was 90 %. Therefore, the obtained injectable chitosan-based hydrogel containing 5-FU-loaded nanoerythrosomes illustrated promising potential as a candidate for local and enhanced delivery of chemotherapeutics at the tumor site.

[Adoptive cell therapy for solid tumors].

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment paradigm for refractory/relapsed (R/R) hematologic malignancies, with six products approved for B-cell tumors and multiple myeloma as of the end of 2023. However, adoptive cell therapy (ACT) for solid tumors is hindered by critical challenges in multiple areas, including (1) lack of appropriate tumor-specific antigens, (2) inefficient T-cell trafficking and infiltration into the tumor microenvironment, and (3) immunosuppressive signals within the tumor milieu that induce T-cell dysfunction. This review examines the existing clinical trial data on ACT for solid tumors to elucidate the current landscape of ACT development for solid tumors. It also outlines the trajectory of ACT for solid tumors and integrative approaches to overcoming the complex tumor microenvironment.

Clinical Utility of Optical Genome Mapping for Improved Cytogenomic Analysis of Gliomas.

A glioma is a solid brain tumor which originates in the brain or brain stem area. The diagnosis of gliomas based on standard-of-care (SOC) techniques includes karyotyping, fluorescence in situ hybridization (FISH), and chromosomal microarray (CMA), for detecting the pathogenic variants and chromosomal abnormalities. But these techniques do not reveal the complete picture of genetic complexity, thus requiring an alternative technology for better characterization of these tumors. The present study aimed to evaluate the clinical performance and feasibility of using optical genome mapping (OGM) for chromosomal characterization of gliomas. Herein, we evaluated 10 cases of gliomas that were previously characterized by CMA. OGM analysis showed concordance with the results of CMA in identifying the characterized Structural Variants (SVs) in these cases. More notably, it also revealed additional clinically relevant aberrations, demonstrating a higher resolution and sensitivity. These clinically relevant SVs included cryptic translocation, and SVs which are beyond the detection capabilities of CMA. Our analysis highlights the unique capability of OGM to detect all classes of SVs within a single assay, thereby unveiling clinically significant data with a shorter turnaround time. Adopting this diagnostic tool as a standard of care for solid tumors like gliomas shows potential for improving therapeutic management, potentially leading to more personalized and timely interventions for patients.

Reshaping the tumor immune microenvironment to improve CAR-T cell-based cancer immunotherapy.

In many hematologic malignancies, the adoptive transfer of chimeric antigen receptor (CAR) T cells has demonstrated notable success; nevertheless, further improvements are necessary to optimize treatment efficacy. Current CAR-T therapies are particularly discouraging for solid tumor treatment. The immunosuppressive microenvironment of tumors affects CAR-T cells, limiting the treatment's effectiveness and safety. Therefore, enhancing CAR-T cell infiltration capacity and resolving the immunosuppressive responses within the tumor microenvironment could boost the anti-tumor effect. Specific strategies include structurally altering CAR-T cells combined with targeted therapy, radiotherapy, or chemotherapy. Overall, monitoring the tumor microenvironment and the status of CAR-T cells is beneficial in further investigating the viability of such strategies and advancing CAR-T cell therapy.

Personalized Dendritic-cell-based Vaccines Targeting Cancer Neoantigens.

Cancer immunotherapy activates the host immune system against tumor cells and has the potential to lead to the development of innovative strategies for cancer treatment. Neoantigens are non-self-antigens produced by genetic mutations in tumor cells that induce a strong immune response against tumor cells without central immune tolerance. Along with advances in neoantigen analysis technology, the development of vaccines focusing on neoantigens is being accelerated. Whereas there are various platforms for neoantigen vaccines, combined immuno-therapies are being developed simultaneously with the clinical application of synthetic long peptides and mRNA and dendritic-cell (DC)-based vaccines. Personalized DC-based vaccines not only can load various antigens including neoantigens, but also have the potential to elicit a strong immune response in T cells as antigen-presenting cells. In this review, we describe the properties of neoantigens and the basic characteristics of DCs. We also discuss the clinical applications of neoantigen vaccines, focusing on personalized DC-based vaccines, as well as future research and development directions and challenges.

CAR-T Therapy can be a Useful Treatment Modality for more than Just Hematologic Malignancies.

Chimeric antigen receptor-T-cell (CAR-T) therapy for hematologic malignancies has made significant advancements over the years, and it is now incorporated as a treatment algorithm. Early phase clinical trials are underway for various solid tumors, and the effectiveness of CAR-T cell therapy has been demonstrated for specific types of glioma and several solid tumors. However, its efficacy does not match that observed in hematological malignancies. Recently, a case series reported CAR-T therapy targeting CD19 for autoimmune diseases such as systemic lupus erythematosus, leading to a dramatic improvement in the clinical symptoms and the possibility of discontinuing immunosuppressive agents. Furthermore, CAR-T cell therapy is expected to be effective against various viruses and Aspergillus spp. Finally, attempts have been made to introduce CAR constructs into regulatory T cells to target their immunosuppressive effects. This article introduces the current progress in CAR-T cell therapy beyond the treatment of only hematologic malignancies and discusses future directions, considering the current medical situation in Japan.

Efficacy and safety evaluation of cross-reactive Fibroblast activation protein scFv-based CAR-T cells.

Introduction: Fibroblast activation protein (FAP) overexpression on cancer-associated fibroblasts (CAFs) is associated with poor prognosis and worse clinical outcomes. Selective ablation of pro-tumorgenic FAP+ stromal cells with CAR-T cells may be a new therapeutic strategy. However, the clinical use of FAP-CAR T cells is suggested to proceed with caution for occasional poor efficacy and induction of on-target off-tumor toxicity (OTOT), including lethal osteotoxicity and cachexia. Hence, more investigations and preclinical trials are required to optimize the FAP-CAR T cells and to approve their safety and efficacy. Methods: In this study, we designed second-generation CAR T cells targeting FAP with 4-1BB as a co-stimulatory molecule, and tested their cytotoxicity against FAP-positive cells (hFAP-HT1080 cells and a variety of primary CAFs) in vitro and in Cell line-derived xenograft (CDX) and a patient-derived xenograft (PDX) model. Results: Results showed that our FAP-CAR T cells were powerfully potent in killing human and murine FAP-positive tumor cells and CAFs in multiple types of tumors in BALB/c and C57BL/6 mice and in patient-derived xenografts (PDX) model. And they were proved to be biologically safe and exhibit low-level OTOT. Discussion: Taken together, the human/murine cross-reactive FAP-CAR T cells were powerfully potent in killing human and murine FAP positive tumor cells and CAFs. They were biologically safe and exhibit low-level OTOT, warranting further clinical investigation into our FAP-CAR T cells.

CAR Macrophages: a promising novel immunotherapy for solid tumors and beyond.

With the advent of adoptive cellular therapy, chimeric antigen receptor (CAR)-T cell therapy has gained widespread application in cancer treatment and has demonstrated significant efficacy against certain hematologic malignancies. However, due to the limitations of CAR-T cell therapy in treating solid tumors, other immune cells are being modified with CAR to address this issue. Macrophages have emerged as a promising option, owing to their extensive immune functions, which include antigen presentation, powerful tumor phagocytosis, and particularly active trafficking to the tumor microenvironment. Leveraging their unique advantages, CAR-macrophages (CAR-M) are expected to enhance the effectiveness of solid tumor treatments as a novel form of immunotherapy, potentially overcoming major challenges associated with CAR-T/NK therapy. This review outlines the primary mechanism underlying CAR-M and recent progressions in CAR-M therapy, while also discussing their further applications.