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Clinical trials of Chimeric Antigen Receptor T-cell (CAR-T) therapy have demonstrated remarkable success in treating both solid tumors and hematological malignancies. Nanobodies (Nbs) have emerged as promising antigen-targeting domains for CARs, owing to their high specificity, robust stability, and strong affinity, leading to significant advancements in the field of Nb-CAR-T. In the realm of T-cell acute lymphoblastic leukemia (T-ALL) targets, CD5 stands out as a potentially excellent candidate for T-cell-based CAR therapy, due to its distinct expression on the surface of malignant T-ALL cells. To mitigate graft-versus-host disease associated with allogeneic CAR-T, γδT cells are selected and stimulated from peripheral blood mononuclear cells, and γδT cells are engineered via CRISPR/Cas9 to eliminate fratricide, enabling the creation of fratricide-resistant CAR-γδTCD5- cells. In vitro transcribed (IVT) mRNA is used to construct CAR-T, presenting a safer, faster, and cost-effective method compared to traditional viral vector approaches. In this study, a CD5-VHH library is constructed, and specific CD5-nanobodies are screened for subsequent use in CD5-CAR-γδTCD5- therapy. IVT-mRNA-CD5-CAR-γδTCD5- cells exhibited favorable functional characteristics and demonstrated antitumor efficacy against malignant T cell lines, underlining the potential for advancing mRNA-CD5-CAR-γδTCD5- therapy.
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Recent studies have indicated that combining oncolytic viruses with CAR-T cells in therapy has shown superior anti-tumor effects, representing a promising approach. Nonetheless, the localized delivery method of intratumoral injection poses challenges for treating metastatic tumors or distal tumors that are difficult to reach. To address this obstacle, we employed HSV-1-infected CAR-T cells, which systemically delivery HSV into solid tumors. The biological function of CAR-T cells remained intact after loading them with HSV for a period of three days. In both immunocompromised and immunocompetent GBM orthotopic mouse models, B7-H3 CAR-T cells effectively delivered HSV to tumor lesions, resulting in enhanced T-cell infiltration and significantly prolonged survival in mice. We also employed a bilateral subcutaneous tumor model and observed that the group receiving intratumoral virus injection exhibited a significant reduction in tumor volume on the injected side, while the group receiving intravenous infusion of CAR-T cells carrying HSV displayed suppressed tumor growth on both sides. Hence, CAR-THSV cells offer notable advantages in the systemic delivery of HSV to distant tumors. In conclusion, our findings emphasize the potential of CAR-T cells as carriers for HSV, presenting significant advantages for oncolytic virotherapy targeting distant tumors.
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Inmunoterapia Adoptiva , Viroterapia Oncolítica , Virus Oncolíticos , Receptores Quiméricos de Antígenos , Animales , Ratones , Viroterapia Oncolítica/métodos , Humanos , Virus Oncolíticos/inmunología , Virus Oncolíticos/genética , Inmunoterapia Adoptiva/métodos , Receptores Quiméricos de Antígenos/inmunología , Herpesvirus Humano 1/inmunología , Ensayos Antitumor por Modelo de Xenoinjerto , Línea Celular Tumoral , Linfocitos T/inmunología , Femenino , Glioblastoma/terapia , Glioblastoma/inmunologíaRESUMEN
The development of innovative therapeutic strategies for head and neck squamous cell carcinoma (HNSCC) is a critical medical requirement. Antibody-drug conjugates (ADC) targeting tumor-specific surface antigens have demonstrated clinical effectiveness in treating hematologic and solid malignancies. Our investigation revealed high expression levels of SLC3A2 in HNSCC tissue and cell lines. This study aimed to develop a novel anti-SLC3A2 ADC and assess its antitumor effects on HNSCC both in vitro and in vivo. This study developed a potent anti-SLC3A2 ADC (19G4-MMAE) and systematically investigated its drug delivery potential and antitumor efficacy in preclinical models. This study revealed that 19G4-MMAE exhibited specific binding to SLC3A2 and effectively targeted lysosomes. Moreover, 19G4-MMAE induced a significant accumulation of reactive oxygen species (ROS) and apoptosis in SLC3A2-positive HNSCC cells. The compound demonstrated potent antitumor effects derived from MMAE against SLC3A2-expressing HNSCC in preclinical models, displaying a favorable safety profile. These findings suggest that targeting SLC3A2 with an anti-SLC3A2 ADC could be a promising therapeutic approach for treating HNSCC patients.
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BACKGROUND: BCMA-directed autologous chimeric antigen receptor T (CAR-T) cells have shown excellent clinical efficacy in relapsed or refractory multiple myeloma (RRMM), however, the current preparation process for autologous CAR-T cells is complicated and costly. Moreover, the upregulation of CD47 expression has been observed in multiple myeloma, and anti-CD47 antibodies have shown remarkable results in clinical trials. Therefore, we focus on the development of BCMA/CD47-directed universal CAR-T (UCAR-T) cells to improve these limitations. METHODS: In this study, we employed phage display technology to screen nanobodies against BCMA and CD47 protein, and determined the characterization of nanobodies. Furthermore, we simultaneously disrupted the endogenous TRAC and B2M genes of T cells using CRISPR/Cas9 system to generate TCR and HLA double knock-out T cells, and developed BCMA/CD47-directed UCAR-T cells and detected the antitumor activity in vitro and in vivo. RESULTS: We obtained fourteen and one specific nanobodies against BCMA and CD47 protein from the immunized VHH library, respectively. BCMA/CD47-directed UCAR-T cells exhibited superior CAR expression (89.13-98.03%), and effectively killing primary human MM cells and MM cell lines. BCMA/CD47-directed UCAR-T cells demonstrated excellent antitumor activity against MM and prolonged the survival of tumor-engrafted NCG mice in vivo. CONCLUSIONS: This work demonstrated that BCMA/CD47-directed UCAR-T cells exhibited potent antitumor activity against MM in vitro and in vivo, which provides a potential strategy for the development of a novel "off-the-shelf" cellular immunotherapies for the treatment of multiple myeloma.
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Antígeno de Maduración de Linfocitos B , Antígeno CD47 , Inmunoterapia Adoptiva , Mieloma Múltiple , Receptores Quiméricos de Antígenos , Mieloma Múltiple/terapia , Mieloma Múltiple/inmunología , Humanos , Animales , Antígeno CD47/inmunología , Antígeno de Maduración de Linfocitos B/inmunología , Ratones , Inmunoterapia Adoptiva/métodos , Línea Celular Tumoral , Receptores Quiméricos de Antígenos/inmunología , Anticuerpos de Dominio Único/inmunología , Anticuerpos de Dominio Único/farmacología , Linfocitos T/inmunología , Sistemas CRISPR-Cas , FemeninoRESUMEN
Lithophobic Li2CO3/LiOH contaminants and high-resistance lithium-deficient phases produced from the exposure of garnet electrolyte to air leads to a decrease in electrolyte ion transfer ability. Additionally, garnet electrolyte grain boundaries (GBs) with narrow bandgap and high electron conductivity are potential channels for current leakage, which accelerate Li dendrites generation, ultimately leading to short-circuiting of all-solid-state batteries (ASSBs). Herein, a stably lithiophilic Li2ZO3 is in situ constructed at garnet electrolyte surface and GBs by interfacial modification with ZrO2 and Li2CO3 (Z+C) co-sintering to eliminate the detrimental contaminants and lithium-deficient phases. The Li2ZO3 formed on the modified electrolyte (LLZTO-(Z+C)) surface effectively improves the interfacial compatibility and air stability of the electrolyte. Li2ZO3 formed at GBs broadens the energy bandgaps of LLZTO-(Z+C) and significantly inhibits lithium dendrite generation. More Li+ transport paths found in LLZTO-Z+C by first-principles calculations increase Li+ conductivity from 1.04×10-4 to 7.45×10-4 S cm-1. Eventually, the Li|LLZTO-(Z+C)|Li symmetric cell maintains stable cycling for over 2000 h at 0.8 mA cm-2. The capacity retention of LiFePO4|LLZTO-(Z+C)|Li battery retains 70.5% after 5800 ultralong cycles at 4 C. This work provides a potential solution to simultaneously enhance the air stability and modulate chemical characteristics of the garnet electrolyte surface and GBs for ASSBs.
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One of the ways in which macrophages support tumorigenic growth is by producing adenosine, which acts to dampen antitumor immune responses and is generated by both tumor and immune cells in the tumor microenvironment (TME). Two cell surface expressed molecules, CD73 and CD39, boost catalytic adenosine triphosphate, leading to further increased adenosine synthesis, under hypoxic circumstances in the TME. There are four receptors (A1, A2A, A2B, and A3) expressed on macrophages that allow adenosine to perform its immunomodulatory effect. Researchers have shown that adenosine signaling is a key factor in tumor progression and an attractive therapeutic target for treating cancer. Several antagonistic adenosine-targeting biological therapies that decrease the suppressive action of tumor-associated macrophages have been produced and explored to transform this result from basic research into a therapeutic advantage. Here, we'll review the newest findings from studies of pharmacological compounds that target adenosine receptors, and their potential therapeutic value based on blocking the suppressive action of macrophages in tumors.
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Adenosina , Inmunoterapia , Neoplasias , Receptores Purinérgicos P1 , Transducción de Señal , Microambiente Tumoral , Humanos , Adenosina/metabolismo , Neoplasias/inmunología , Neoplasias/terapia , Neoplasias/metabolismo , Neoplasias/tratamiento farmacológico , Inmunoterapia/métodos , Microambiente Tumoral/inmunología , Animales , Receptores Purinérgicos P1/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos Asociados a Tumores/inmunología , Macrófagos Asociados a Tumores/metabolismo , Terapia Molecular Dirigida , Antagonistas de Receptores Purinérgicos P1/farmacología , Antagonistas de Receptores Purinérgicos P1/uso terapéuticoRESUMEN
Oncolytic viruses have emerged as a promising modality for cancer treatment due to their unique abilities to directly destroy tumor cells and modulate the tumor microenvironment. Bispecific T-cell engagers (BsAbs) have been developed to activate and redirect cytotoxic T lymphocytes, enhancing the antitumor response. To take advantage of the specific infection capacity and carrying ability of exogenous genes, we generated a recombinant herpes simplex virus type 1 (HSV-1), HSV-1dko-B7H3nb/CD3 or HSV-1dko-B7H3nb/mCD3, carrying a B7H3nb/CD3 or B7H3nb/mCD3 BsAb that replicates and expresses BsAb in tumor cells in vitro and in vivo. The new generation of oncolytic viruses has been genetically modified using CRISPR/Cas9 technology and the cre-loxp system to increase the efficiency of HSV genome editing. Additionally, we used two fully immunocompetent models (GL261 and MC38) to assess the antitumor effect of HSV-1dko-B7H3nb/mCD3. Compared with the HSV-1dko control virus, HSV-1dko-B7H3nb/mCD3 induced enhanced anti-tumor immune responses and T-cell infiltration in both GL261 and MC38 models, resulting in improved treatment efficacy in the latter. Furthermore, flow cytometry analysis of the tumor microenvironment confirmed an increase in NK cells and effector CD8+ T cells, and a decrease in immunosuppressive cells, including FOXP3+ regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and CD206+ macrophages (M2). Overall, our study identified a novel camel B7H3 nanobody and described the genetic modification of the HSV-1 genome using CRISPR/Cas9 technology and the cre-loxp system. Our findings indicate that expressing B7H3nb/CD3 BsAb could improve the antitumor effects of HSV-1 based oncolytic virus.
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Herpesvirus Humano 1 , Neoplasias , Viroterapia Oncolítica , Virus Oncolíticos , Humanos , Herpesvirus Humano 1/genética , Linfocitos T CD8-positivos , Virus Oncolíticos/genética , Neoplasias/genética , Viroterapia Oncolítica/métodos , Microambiente TumoralRESUMEN
In the treatment of relapsed or refractory multiple myeloma patients, BCMA-directed autologous CAR-T cells have showed excellent anti-tumor activity. However, their widespread application is limited due to the arguably cost and time-consuming. Multiple myeloma cells highly expressed CD47 molecule and interact with the SIRPα ligand on the surface of macrophages, in which evade the clearance of macrophages through the activation of "don't eat me" signal. In this study, a BCMA-directed universal CAR-T cells, BC404-UCART, secreting a CD47-SIRPα blocker was developed using CRISPR/Cas9 gene-editing system. BC404-UCART cells significantly inhibited tumor growth and prolonged the survival of mice in the xenograft model. The anti-tumor activity of BC404-UCART cells was achieved via two mechanisms, on the one hand, the UCAR-T cells directly killed tumor cells, on the other hand, the BC404-UCART cells enhanced the phagocytosis of macrophages by secreting anti-CD47 nanobody hu404-hfc fusion that blocked the "don't eat me" signal between macrophages and tumor cells, which provides a potential strategy for the development of novel "off-the-shelf" cellular immunotherapies for the treatment of multiple myeloma.
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Mieloma Múltiple , Neoplasias , Humanos , Ratones , Animales , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/genética , Antígeno de Maduración de Linfocitos B , Antígeno CD47/genética , Receptores Inmunológicos/genética , Linfocitos T , Antígenos de Diferenciación , Neoplasias/patología , FagocitosisRESUMEN
Multiple myeloma (MM) remains a challenging hematologic malignancy despite advancements in chimeric antigen receptor T-cell (CAR-T) therapy. Current targets of CAR-T cells used in MM immunotherapy have limitations, with a subset of patients experiencing antigen loss resulting in relapse. Therefore, novel targets for enhancing CAR-T cell therapy in MM remain needed. Fc receptor-like 5 (FCRL5) is a protein marker with considerably upregulated expression in MM and has emerged as a promising target for CAR-T cell therapeutic interventions, offering an alternative treatment for MM. To further explore this option, we designed FCRL5-directed CAR-T cells and assessed their cytotoxicity in vitro using a co-culture system and in vivo using MM cell-derived xenograft models, specifically focusing on MM with gain of chromosome 1q21. Given the challenges in CAR-T therapies arising from limited T cell persistence, our approach incorporates interleukin-15 (IL-15), which enhances the functionality of central memory T (TCM) cells, into the design of FCRL5-directed CAR-T cells, to improve cytotoxicity and reduce T-cell dysfunction, thereby promoting greater CAR-T cell survival and efficacy. Both in vitro and xenograft models displayed that FCRL5 CAR-T cells incorporating IL-15 exhibited potent antitumor efficacy, effectively inhibiting the proliferation of MM cells and leading to remarkable tumor suppression. Our results highlight the capacity of FCRL5-specific CAR-T cells with the integration of IL-15 to improve the therapeutic potency, suggesting a potential novel immunotherapeutic strategy for MM treatment.
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Mieloma Múltiple , Receptores Quiméricos de Antígenos , Humanos , Mieloma Múltiple/genética , Mieloma Múltiple/terapia , Receptores Quiméricos de Antígenos/genética , Interleucina-15/genética , Interleucina-15/metabolismo , Línea Celular Tumoral , Linfocitos T , Receptores Fc/metabolismoRESUMEN
Negative checkpoint regulators (NCRs) reduce the T cell immune response against self-antigens and limit autoimmune disease development. V-domain Ig suppressor of T cell activation (VISTA), a novel immune checkpoint in the B7 family, has recently been identified as one of the NCRs. VISTA maintains T cell quiescence and peripheral tolerance. VISTA targeting has shown promising results in treating immune-related diseases, including cancer and autoimmune disease. In this review, we summarize and discuss the immunomodulatory role of VISTA, its therapeutic potential in allergic, autoimmune disease, and transplant rejection, as well as the current therapeutic antibodies, to present a new method for regulating immune responses and achieving durable tolerance for the treatment of autoimmune disease and transplantation.
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Enfermedades Autoinmunes , Hipersensibilidad , Humanos , Autoantígenos , Enfermedades Autoinmunes/terapia , División Celular , Rechazo de Injerto , Proteínas de Punto de Control InmunitarioRESUMEN
BACKGROUND: To explore the extraperitoneal laparoscopic urachal mass excision technique and its safety and efficacy in treating urachal mass. METHODS: Baseline characteristics were collected from patients who underwent surgery to diagnose a urachal cyst or abscess in our hospital between January 2020 and August 2021. The full-length of the urachus and part of the top bladder wall were completely removed through the extraperitoneal approach. Patient outcomes were collected to evaluate surgical safety and efficacy, including operation time, intraoperative blood loss, drainage tube removal time, length of stay (LOS), and postoperative complications. RESULTS: All 20 surgeries were successfully performed laparoscopically, and no case was converted to open surgery. The mean body mass index of the patients was 24.6 ± 2.2. The mean patient age was 49.3 ± 8.7 years. The mean size of the cysts was 3.0 ± 0.4 cm. The mean operation time was 56.3 ± 12.0 min. The mean intraoperative blood loss was 28.0 ± 6.4 mL. The mean drainage tube removal time was 3.0 ± 0.5 days. The mean LOS was 5.2 ± 0.4 days. The mean follow-up was 13.4 ± 2.1 months. No postoperative complications were observed during the follow-up period. The short-term follow-up and small patient cohort limited our outcome evaluation. CONCLUSION: Our results indicated that the extraperitoneal laparoscopic approach was a safe and effective method to treat urachal mass. Given the limitations of the study, further multiple and larger sample-sized trials are required to confirm our findings.
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Laparoscopía , Quiste del Uraco , Uraco , Humanos , Adulto , Persona de Mediana Edad , Uraco/cirugía , Pérdida de Sangre Quirúrgica , Estudios Retrospectivos , Quiste del Uraco/cirugía , Laparoscopía/métodos , Complicaciones Posoperatorias/cirugíaRESUMEN
BACKGROUND: Chimeric antigen receptor (CAR) T cells and immune checkpoint blockades (ICBs) have made remarkable breakthroughs in cancer treatment, but the efficacy is still limited for solid tumors due to tumor antigen heterogeneity and the tumor immune microenvironment. The restrained treatment efficacy prompted us to seek new potential therapeutic methods. METHODS: In this study, we conducted a small molecule compound library screen in a human BC cell line to identify whether certain drugs contribute to CAR T cell killing. Signaling pathways of tumor cells and T cells affected by the screened drugs were predicted via RNA sequencing. Among them, the antitumor activities of JK184 in combination with CAR T cells or ICBs were evaluated in vitro and in vivo. RESULTS: We selected three small molecule drugs from a compound library, among which JK184 directly induces tumor cell apoptosis by inhibiting the Hedgehog signaling pathway, modulates B7-H3 CAR T cells to an effector memory phenotype, and promotes B7-H3 CAR T cells cytokine secretion in vitro. In addition, our data suggested that JK184 exerts antitumor activities and strongly synergizes with B7-H3 CAR T cells or ICBs in vivo. Mechanistically, JK184 enhances B7-H3 CAR T cells infiltrating in xenograft mouse models. Moreover, JK184 combined with ICB markedly reshaped the tumor immune microenvironment by increasing effector T cells infiltration and inflammation cytokine secretion, inhibiting the recruitment of MDSCs and the transition of M2-type macrophages in an immunocompetent mouse model. CONCLUSION: These data show that JK184 may be a potential adjutant in combination with CAR T cells or ICB therapy.
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Proteínas Hedgehog , Neoplasias , Humanos , Animales , Ratones , Evaluación Preclínica de Medicamentos , Detección Precoz del Cáncer , Inmunoterapia , Citocinas , Inmunoterapia Adoptiva/métodos , Línea Celular Tumoral , Ensayos Antitumor por Modelo de Xenoinjerto , Microambiente Tumoral , Neoplasias/terapiaRESUMEN
BACKGROUND: SARS-CoV-2 has a significant impact on healthcare systems all around the world. Due to its high pathogenicity, live SARS-CoV-2 must be handled under biosafety level 3 conditions. Pseudoviruses are useful virological tools because of their safety and versatility, but the low titer of these viruses remains a limitation for their more comprehensive applications. METHOD: Here, we constructed a Luc/eGFP based on a pseudotyped lentiviral HIV-1 system to transduce SARS-CoV-2 S glycoprotein to detect cell entry properties and cellular tropism. RESULTS: The furin cleavage site deletion of the S protein removed (SFko) can help SARS-CoV-2 S to be cleaved during viral packaging to improve infection efficiency. The furin cleavage site in SARS-CoV-2-S mediates membrane fusion and SFko leads to an increased level of S protein and limits S1/S2 cleavage to enhance pseudovirus infection in cells. Full-length S (SFL) pseudotyped with N, M, and E helper packaging can effectively help SFL infect cells. Finally, pseudotyped SFko particles were successfully used to detect neutralizing antibodies in RBD protein-immunized mouse serum. CONCLUSION: Overall, our study indicates a series of modifications that result in the production of relatively high-titer SARS-COV-2 pseudo-particles that may be suitable for the detection of neutralizing antibodies from COVID-19 patients.
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COVID-19 , Animales , Humanos , Ratones , SARS-CoV-2/metabolismo , Furina/genética , Furina/metabolismo , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/metabolismo , Anticuerpos NeutralizantesRESUMEN
Photoelectrochemical (PEC) water splitting is a promising approach for renewable solar light conversion. However, surface Fermi level pinning (FLP), caused by surface trap states, severely restricts the PEC activities. Theoretical calculations indicate subsurface oxygen vacancy (sub-Ov ) could release the FLP and retain the active structure. A series of metal oxide semiconductors with sub-Ov were prepared through precisely regulated spin-coating and calcination. Etching X-ray photoelectron spectroscopy (XPS), scanning transmission electron microscopy (STEM), and electron energy loss spectra (EELS) demonstrated Ov located at sub â¼2-5â nm region. Mott-Schottky and open circuit photovoltage results confirmed the surface trap states elimination and Fermi level de-pinning. Thus, superior PEC performances of 5.1, 3.4, and 2.1â mA cm-2 at 1.23â V vs. RHE were achieved on BiVO4 , Bi2 O3 , TiO2 with outstanding stability for 72â h, outperforming most reported works under the identical conditions.
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The therapeutic use of bispecific T-cell engaging (BiTE) antibodies has shown great potential for treating malignancies. BiTE can simultaneously engage CD3ε on T cells and tumor antigen on cancer cells, thus exerting an effective antitumor effect. Nevertheless, challenges in production, manufacturing, and short serum half-life of BiTE have dampened some of the promise and impeded the pace of BiTE-based therapeutics to combat diseases. Nowadays, in vitro-transcribed mRNA has achieved programmed production, which is more flexible and cost-effective than the traditional method of producing recombinant antibody. Here, the authors have developed a BiTE-based mRNA treatment by encapsulating mRNA encoding B7H3×CD3 BiTE into a novel ionizable lipid nanoparticles (LNPs). The authors have found that LNPs have high transfection efficiency, and the hepatosplenic targeting capability of produce high concentrations of BiTE. Above all, a single intravenous injection of BiTE mRNA-LNPs could achieve high levels of protein expression in vivo and significantly prolonged the half-life of the BiTE, which can elicit robust and durable antitumor efficacy against hematologic malignancies and melanoma. Therefore, their results suggested that the therapeutic strategy based on mRNA expression of B7H3×CD3 BiTE is of potential research value and has promising clinical application prospects.
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Anticuerpos Biespecíficos , Melanoma , Humanos , ARN Mensajero/metabolismo , Linfocitos T , Melanoma/metabolismoRESUMEN
OBJECTIVE: To present the extraperitoneal laparoscopic radical cystectomy (ELRC) technique, and initial outcomes of organ-preserving and orthotopic neobladder (ONB) techniques for bladder cancer in selected females. MATERIALS AND METHODS: Data including patient characteristics, operative time, blood loss, transfusion rate, length of hospital stay, and pathologic outcomes, as well as 30- and 90-day complications were collected between April 2018 and May 2021 from females who underwent ONB after ELRC. Regular follow-up focused on patients' oncological and functional outcomes, and postoperative sexual function status was assessed using the Female Sexual Function Index (FSFI). RESULTS: Eleven females with a mean age of 53 years who underwent ELRC with pelvic organ-preservation and ONB were analyzed retrospectively. All procedures were completed successfully. The mean operative time was 264.82 ± 33.81 min, and the average intraoperative blood loss was 128 ± 18.19 mL. All patients had negative pathological margins and no lymph node metastases. The average hospital stay was 10.72 days. The single J ureteral stent and catheter were usually removed 3-4 weeks after the procedure. The FIFS assessment of postoperative sexual function showed that the patients were relatively satisfied. CONCLUSION: ELRC with pelvic organ preservation and ONB technology was a safe and feasible surgical strategy for the selected female patients. Preserving organs and vascular nerve bundles seemed to be safe in oncological and produced encouraging functional results. Further rigorous prospective studies with more patients and long-term follow-up data are needed to assess the oncologic and functional results.
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Laparoscopía , Neoplasias de la Vejiga Urinaria , Derivación Urinaria , Reservorios Urinarios Continentes , Humanos , Femenino , Persona de Mediana Edad , Cistectomía/métodos , Estudios Retrospectivos , Estudios Prospectivos , Reservorios Urinarios Continentes/patología , Resultado del Tratamiento , Neoplasias de la Vejiga Urinaria/cirugía , Neoplasias de la Vejiga Urinaria/patología , Laparoscopía/métodos , Derivación Urinaria/métodosRESUMEN
OBJECTIVES: Medulloblastoma is the most common malignant brain tumor in childhood. Although metastasis constitutes one of the poorest prognostic indicators in this disease, the mechanisms that drive metastasis have received less attention. The aim of our study is to provide valid biological information for the metastasis mechanism of medulloblastoma. METHODS: Gene expression profile of GSE468 was downloaded from GEO database and was analyzed using limma R package. Function and enrichment analyses of DEGs were performed based on PANTHER database. PPI network construction, hub gene selection and module analysis were conducted in Cytoscape software. RESULTS: Nine upregulated genes and 34 downregulated genes were selected as DEGs. The upregulated genes were mainly enriched in molecular function and cell component, which mainly included protein binding and nucleus respectively. A total of 120 enriched GO terms and 40 KEGG pathways were identified. The main enriched GO terms were the biological process such as apoptosis and MAPK activity. Besides, the enriched KEGG pathways also included MAPK signaling pathway. A PPI network was obtained, and JUN was identified as a hub gene. Also, we firstly investigated the role and regulatory mechanism of JUN in the metastasis of medulloblastoma. CONCLUSIONS: Through the bioinformatics analysis of the gene microarray in GEO, we found some crucial genes and pathways associated with the metastasis of medulloblastoma.
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Neoplasias Cerebelosas , Meduloblastoma , Humanos , Transcriptoma , Perfilación de la Expresión Génica , Mapas de Interacción de Proteínas/genética , Redes Reguladoras de Genes/genética , Meduloblastoma/genética , Neoplasias Cerebelosas/genética , Biología Computacional , Regulación Neoplásica de la Expresión Génica/genéticaRESUMEN
OBJECTIVES: There is substantial concern about traditional transperitoneal laparoscopic radical cystectomy (TLRC) due to multiple postoperative complications. In contrast, extraperitoneal laparoscopic radical cystectomy (ELRC) appears to cause a lower rate of morbidity. The present study aimed to compare the efficacy of ELRC and TLRC for bladder cancer (BCa). METHODS: The clinical data of patients undergoing laparoscopic radical cystectomy for BCa from April 2018 to October 2021 were retrospectively analyzed, as ELRC and TLRC groups. The postoperative follow-up data of 275 patients were collected and the incidence of postoperative complications and other perioperative outcomes were compared between the two groups. RESULTS: Surgery was successfully completed in all patients without conversion to open surgery. There was no significant difference in the duration of cystectomy surgery (67.32 ± 23.53 vs 72.17 ± 25.72 min, p = 0.106), intraoperative blood loss (178.06 ± 110.4 vs. 174.56 ± 127.40 ml, p = 0.413), or the number of lymph node dissection (15.1 ± 5.7 vs. 14.5 ± 5.1, p = 0.380) between the two groups. The length of stay (11.6 ± 3.8 vs 14.7 ± 5.6 d, p < 0.001), time to resume food intake after surgery (2.3 ± 0.9 vs 3.0 ± 1.3 d, p < 0.001), and the incidence of ileus (p < 0.001) in the ELRC group were significantly lower than in the TLRC group. CONCLUSIONS: ELRC is a safe procedure that can reduce the incidence of postoperative complications, shorten postoperative hospital stay, reduce the duration of recovery of patients, and, therefore, should be promoted.
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Laparoscopía , Neoplasias de la Vejiga Urinaria , Derivación Urinaria , Humanos , Cistectomía/efectos adversos , Cistectomía/métodos , Derivación Urinaria/métodos , Estudios Retrospectivos , Laparoscopía/efectos adversos , Laparoscopía/métodos , Resultado del Tratamiento , Neoplasias de la Vejiga Urinaria/cirugía , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/cirugíaRESUMEN
Glioblastoma (GBM) is the most aggressive primary malignant brain cancer and urgently requires effective treatments. Chimeric antigen receptor T (CAR-T) cell therapy offers a potential treatment method, but it is often hindered by poor infiltration of CAR-T cells in tumors and highly immunosuppressive tumor microenvironment (TME). Here, we armed an oncolytic adenovirus (oAds) with a chemokine CXCL11 to increase the infiltration of CAR-T cells and reprogram the immunosuppressive TME, thus improving its therapeutic efficacy. In both immunodeficient and immunocompetent orthotopic GBM mice models, we showed that B7H3-targeted CAR-T cells alone failed to inhibit GBM growth but, when combined with the intratumoral administration of CXCL11-armed oAd, it achieved a durable antitumor response. Besides, oAd-CXCL11 had a potent antitumor effect and reprogramed the immunosuppressive TME in GL261 GBM models, in which increased infiltration of CD8+ T lymphocytes, natural killer (NK) cells, and M1-polarized macrophages, while decreased proportions of myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs) and M2-polarized macrophages were observed. Furthermore, the antitumor effect of the oAd-CXCL11 was CD8+ T cell dependent. Our findings thus revealed that CXCL11-armed oAd can improve immune-virotherapy and can be a promising adjuvant of CAR-T therapy for GBM.
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Neoplasias Encefálicas , Quimiocina CXCL11 , Glioblastoma , Inmunoterapia Adoptiva , Viroterapia Oncolítica , Receptores Quiméricos de Antígenos , Animales , Ratones , Adenoviridae/genética , Línea Celular Tumoral , Quimiocina CXCL11/genética , Glioblastoma/terapia , Receptores Quiméricos de Antígenos/genética , Microambiente Tumoral , Ensayos Antitumor por Modelo de Xenoinjerto , Neoplasias Encefálicas/terapiaRESUMEN
A craniopharyngioma (CP) is a rare epithelial tumor of the sellar and parasellar region. CPs are difficult to treat due to their anatomical proximity to critical nervous structures, which limits the ability of the surgeon to completely resect the lesion, exposing patients to a high risk of recurrence. The treatment of craniopharyngiomas is primarily surgery and radiotherapy. So far, neither a cell line nor an animal model has been established, and thus data on other treatment options, such as chemotherapy and immunotherapy, are limited. Here, the expression profile of the pan-cancer antigen B7-H3 in various cancer types including CP was examined by immunohistochemistry. An in vitro organoid model was established by using fresh tissue biospecimens of CP. Based on the organoid model, we evaluated the antitumor efficacy of B7-H3-targeted immunotherapy on CP. As a result, the highest expression of B7-H3 was observed in CP tissues across various cancer types. Although B7-H3-targeted chimeric antigen-receptor T cells show obvious tumor-killing effects in the traditional 2D cell culture model, limited antitumor effects were observed in the 3D organoid model. The B7-H3-targeted antibody-DM1 conjugate exhibited a potent tumor suppression function both in 2D and 3D models. In conclusion, for the first time, we established an organoid model for CP and our results support that B7-H3 might serve as a promising target for antibody-drug conjugate therapy against craniopharyngioma.