Treatment Of Solid Tumors Research Articles

Construction and characterization of a novel secreted MsC-CAR-T cell in solid tumors

The CD47-SIRPα signaling has been acknowledged as a significant immune checkpoint and CD47 blocking has been proved as a potential therapeutic strategy for the treatment of solid tumor. However, the potential application of CAR-T cells secreted antibody fragment simultaneously in solid tumor is rarely explored. In this study, we searched bioinformatic databases and investigated the characteristics of CD47 in solid tumors. Then we consulted bioinformatic databases to design, optimize and construct a novel MsC-CAR which could target MAGE-A1 and self-secrete CD47-scFv. The engineering T cells containing MsC-CAR were transfected, verified and characterized. The tumor-inhibitory role of MsC-CART cells was further determined in vitro and in vivo. The results showed that MsC-CARs were successfully constructed and MsC1-CARs demonstrated the preferable features of recognizing MAGE-A1 and secreting CD47-scFv. Engineering T cells transfecting with MsC1-CAR (MsC1-CART cells) exerted the prominent tumor-inhibitory effectiveness, both in different cancer cell lines and LUAD xenograft tumors. The present data highlighted that MsC1-CART cells elaborately combined the adoptive cellular immunotherapy and immune checkpoint inhibitor therapy, may represent a new direction for the treatment of MAGE-A1 positive solid tumors.

Transarterial infusion chemotherapy and embolization (TAICE) as a pre-operative therapy for patients with locally advanced gastric cancer (LAGC): A prospective, single-arm, pilot study.

436 Background: Interventional therapy is a local intensive therapy for tumor control, often utilized in palliative treatment for solid organ tumors. Yet, its application in tumors of hollow viscera still lacks evidence. Our previous retrospective study revealed transarterial infusion chemotherapy and embolization (TAICE) not only effectively managed tumor-related hemorrhage but also exhibited a notable anti-tumor efficacy in gastric cancer. This prospective study aims to further explore the feasibility and safety of TAICE as a pre-operative therapy for locally advanced gastric cancer (LAGC). Methods: Patients diagnosed with locally advanced adenocarcinoma of stomach and gastrointestinal junction (GEJ) with no distant metastasis (cT3-4N+M0) were enrolled. They were given 4 cycles of pre-operative treatments: 2 cycles of TAICE-SOX (Oxaliplatin [85mg/m 2 transarterial infusion on Day 1] and S-1 [40/50/60mg po bid on Day 1-14]) and 2 cycles of SOX (Oxaliplatin [130mg/m 2 IV on Day 1] and S-1 [same as above]), alternately. Then, they received D2 radical gastrectomy, and 4 cycles of SOX post-operatively. In brief, the TAICE procedure was summarized into 4 steps: 1) Celiac arteriography, 2) Super-selection of tumor feeding artery (TFA), 3) Infusion chemotherapy and embolization of TFA, 4) Celiac re-arteriography to ensure the success of embolization. The primary endpoint was pathological complete response (pCR) rate. Other endpoints included major pathological response (MPR) rate, overall survival (OS), progression-free survival (PFS), treatment-related adverse events (TRAEs). Results: Between December 2020 and June 2023, twenty patients were enrolled and all of them received TAICE. Among them, 18 (90.0%) patients received 2 cycles of TAICE. The pCR and MPR rate were 55.0% and 70.0%, respectively. The 1-year and 3-year OS rate were 100.0% and 82.6%. The 1-year and 3-year PFS rate were 90.0% and 67.3%. There was no difference in OS between the groups of high and low tumor residual rate with the threshold of 50%. Patients achieving low tumor residual rate had significantly longer PFS (NR vs. 12.17 months, p=0.018) than those with high rate after TAICE. Moreover, we divided TFA into two subtypes: dispersive and branching, depending on the vascular pattern presented in the angiography at the first cycle TAICE. Patients with dispersive TFA had higher risk of recurrence after TAICE (NR vs. 15.17 months, p=0.0264). All patients had TRAEs (vomiting, nausea, abdominal pain and fever) of grade 1 or 2 after the first cycle of TAICE. Only one patient experienced nausea of grade 3 after the second cycle of TAICE. The most common TRAEs were vomiting and nausea. Conclusions: TAICE is a promising pre-operative therapy for patients with LAGC for it displaying the satisfactory oncological effectiveness and safety profile. Clinical trial information: NCT05396326 .

HERIZON-BTC-302: A phase 3 study of zanidatamab with standard-of-care (SOC) therapy vs SOC alone for first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive advanced/metastatic biliary tract cancer (BTC).

TPS648 Background: Zanidatamab is a humanized, IgG1-like, HER2-targeted bispecific antibody that simultaneously binds to 2 non-overlapping domains on HER2. Zanidatamab is being investigated for the treatment of HER2-expressing solid tumors, including BTC. In the phase 2 HERIZON-BTC-01 trial, zanidatamab monotherapy demonstrated promising antitumor activity in 80 patients with previously treated HER2-positive BTC. Confirmed objective response rate (cORR) was 41.3% with rapid and durable responses and a manageable safety profile. This phase 3 trial is assessing zanidatamab + SOC therapy vs SOC alone for first-line treatment of HER2-positive advanced/metastatic BTC. Methods: This ongoing, global, phase 3, randomized, open-label trial (NCT06282575) is investigating the efficacy and safety of zanidatamab with cisplatin and gemcitabine (CisGem) vs CisGem alone ± a programmed cell death protein-1/ligand 1 (PD-1/L1) inhibitor (pembrolizumab or durvalumab at physician’s discretion if locally approved) as first-line treatment for patients with advanced HER2-positive BTC. Eligibility criteria include ≥18 years of age; locally advanced, unresectable, or metastatic HER2-positive BTC by immunohistochemistry and in situ hybridization assay (IHC 3+ or IHC 2+/ISH+); and Eastern Cooperative Oncology Group performance status ≤1. Patients may have received ≤2 cycles of a gemcitabine-based regimen ± pembrolizumab or durvalumab. Prior HER2-targeted therapy is not allowed except for patients who completed it for breast cancer >5 years prior to BTC diagnosis. Eligible patients will be randomized to receive zanidatamab (flat 2-tiered dosing: 1800 mg intravenous [IV; body weight <70 kg] or 2400 mg IV [body weight ≥70 kg] every 3 weeks) + a standard dose of CisGem ± a PD1/L1 inhibitor or CisGem alone ± a PD1/L1 inhibitor (≤8 cycles). The primary endpoint is progression-free survival (PFS) in patients with IHC 3+ tumors. Secondary/exploratory endpoints include overall survival (IHC 3+ subgroup; overall population), PFS (overall population), cORR, incidence and severity of adverse events, and patient-reported outcomes. The study is currently recruiting patients. Clinical trial information: NCT06282575 .

Alternative dosing regimens of tislelizumab proposed using modeling and simulation.

394 Background: Tislelizumab (TIS; BGB-A317) is approved for the treatment of multiple solid tumors, administered at 200 mg every 3 weeks (Q3W), and has demonstrated a flat exposure–response relationship across a wide range of doses. We evaluated alternative dosing regimens of TIS at 150 mg every 2 weeks (Q2W), 300 mg every 4 weeks (Q4W), and 400 mg every 6 weeks (Q6W) using a model-based approach with the aim of alleviating patient burden by providing longer dosing intervals and/or treatment flexibility compatible with background chemotherapy to meet the needs of patients and healthcare practitioners. Methods: A previously developed population pharmacokinetic (PK) model was used for simulating PK exposure of the alternative regimens, which were selected by exposure-matching to the reference dose of 200 mg Q3W. PK-based criteria (peak concentration [C max ] within 25% and trough concentration [C trough ] within 20% of the reference dose) were also used. Alternative dosing regimen exposures in the first least common time interval and at steady state were compared with the reference. Deviations from PK-based criteria were bridged using appropriate safety and efficacy references and exposure–response analyses using data from four phase 1, 2, and 3 clinical trials of TIS in patients with solid tumors, including gastric cancer and esophageal squamous cell carcinoma. Results: Simulations at steady state shown here demonstrate that the TIS alternative dosing regimens of 150 mg Q2W, 300 mg Q4W, and 400 mg Q6W produce comparable exposures to the 200 mg Q3W reference regimen. Although the simulated C max at 300 mg Q4W and 400 mg Q6W were higher than with the 200 mg Q3W reference dose, these were below the C max of the 5 mg/kg Q3W safety reference (Table). And while the C trough for the 400 mg Q6W dosing regimen was lower than with the 200 mg Q3W reference dose, it was 10.7% higher compared with the 2 mg/kg efficacy reference dose; therefore, it was within the concentration range where a flat exposure–efficacy relationship of TIS has previously been established. Conclusions: TIS alternative dosing regimens of 150 mg Q2W, 300 mg Q4W, and 400 mg Q6W are expected to result in similar safety and efficacy profiles as the 200 mg Q3W reference dosing regimen and may be used interchangeably for indications where 200 mg Q3W is approved. Clinical trial information: NCT04716634 , NCT05014828 , NCT04379635 , NCT02407990 , NCT04068519 , NCT03430843 and NCT03358875 . Steady-state PK exposure metrics for alternative TIS doses vs reference doses. Parameter 150 mg Q2W vs 200 mg Q3W 300 mg Q4Wvs 200 mg Q3W 300 mg Q4Wvs 5 mg/kg Q3W a 400 mg Q6Wvs 200 mg Q3W 400 mg Q6Wvs 5 mg/kg Q3W a 400 mg Q6Wvs 2 mg/kg Q3W b C max −5.8 (Yes) 31.4 (No) −18.7 (Yes) 52.2 (No) −5.8 (Yes) – C average 12.3 (Yes) 12.6 (Yes) – 0.4 (Yes) – – C trough 27.2 (Yes) 0.1 (Yes) – −28.4 (No) – 10.7 (Yes) Data are presented as difference (% = [GM test − GM reference /GM reference ] × 100) vs the 200 mg Q3W reference, a safety reference, or b efficacy reference (meets regulatory criteria, Yes/No). C average , average concentration; GM, geometric mean.

Cystine-Modified Lignin-Copper Coordination Nanocarriers Improve the Therapeutic Efficacy of Tyrosine Kinase Inhibition via Cuproptosis.

The clinical application of tyrosine kinase inhibitors (TKIs) is rapidly growing and has emerged as a cornerstone in the treatment of both solid tumors and hematologic malignancies. However, resistance to TKI targets and disease progression remain inevitable. Nanocarrier-mediated delivery has emerged as a promising strategy to overcome the limitations of the TKI application. We utilized the facile modification of lignin polyhydroxyl groups to synthesize cystine-grafted lignin-copper coordinated nanoparticles for TKI delivery via the Mannich reaction. The materials exhibited a stable, uniform morphology and effectively encapsulated and delivered a variety of TKI inhibitors. Moreover, we optimized the fabrication process and found that the material could release the encapsulated drug in response to both pH and GSH. These nanoparticles significantly enhanced the therapeutic activity of TKIs both in vitro and in vivo through cuproptosis while demonstrating good biosafety. We propose a novel strategy for the targeted delivery of TKI inhibitors by combining cuproptosis with modified lignin. This approach not only offers new strategies for the clinical application of TKIs but also provides novel insights and inspiration for the modified use of lignin.

Precision oncology: The role of minimally-invasive ablation therapy in the management of solid organ tumors.

Solid organ tumors present a significant healthcare challenge, both economically and logistically, due to their high incidence and treatment complexity. In 2023, out of the 1.9 million new cancer cases in the United States, over 73% were solid organ tumors. Ablative therapies offer minimally invasive solutions for malignant tissue destruction in situ, often with reduced cost and morbidity compared to surgical resection. This review examines the current Food and Drug Administration-approved locoregional ablative therapies (radiofrequency, microwave, cryogenic, high-intensity focused ultrasound, histotripsy) and their evolving role in cancer care. Data were collected through a comprehensive survey of the PubMed-indexed literature on tumor ablation techniques, their clinical indications, and outcomes. Over time, emerging clinical data will help establish these therapies as the standard of care in solid organ tumor treatment, supported by improved long-term outcomes and progression-free survival.

Inavolisib: First Approval.

Inavolisib (Itovebi™) is an orally administered, phosphatidylinositol-3-kinase alpha (PI3Kα) inhibitor being developed by Genentech, a member of the Roche group, for the treatment of solid tumours. On 10 October 2024, inavolisib received its first approval in the USA in combination with palbociclib and fulvestrant for the treatment of adults with endocrine-resistant, PIK3CA-mutated, hormone receptor (HR)-positive, human epidermal growth factor 2 (HER2)-negative, locally advanced or metastatic breast cancer, as detected by an FDA-approved test, following recurrence on or after completing adjuvant endocrine therapy. In the EU and other countries worldwide, regulatory review of inavolisib is currently underway. This article summarises the milestones in the development of inavolisib leading to this first approval for endocrine-resistant, PIK3CA-mutated, HR-positive, HER2-negative, locally advanced or metastatic breast cancer.

Lignin-Based Nanocarrier for Simultaneous Delivery of 131I and SN-38 in the Combined Treatment of Solid Tumors by a Nanobrachytherapy Approach

Lignin-Based Nanocarrier for Simultaneous Delivery of 131I and SN-38 in the Combined Treatment of Solid Tumors by a Nanobrachytherapy Approach

Bispecific T-Cell Engagers for the Recruitment of T cells in Solid Tumors: A Literature Review

Abstract In the past decade, T-cell based immunotherapies have grown to become some of the most promising treatments for cancer. Following the success of immune checkpoint inhibitors, other T-cell based therapies emerged including CAR-T cells and bispecific T-cell engagers (BiTEs). BiTEs have the unique ability to crosslink T cells and tumor cells independently of MHC restriction. They do not rely on TCR specificity or the CD4+/CD8+ costimulatory molecules, overcoming tumor MHC downregulation and low-affinity TCR binding. However, like many other immunotherapies, BiTEs have shown limited success beyond the treatment of hematological malignancies. BiTEs for the treatment of solid tumors still face challenges. Studies in gastrointestinal tumors have revealed Fc toxicity, short half-lives, and immunotoxicity, leading to Fc-silenced half-life extended BiTEs with humanized single-chain variable fragments. Studies in prostate tumors, lung tumors, and malignant gliomas have identified promising targets in PSMA, DLL3, and EGFRvIII, respectively, but also highlighted the problems of on-target off-tumor and BiTE-specific toxicities and inaccessible and immunosuppressive tumor microenvironments. Ongoing research to overcome these limitations remains an interesting field to follow, as BiTEs have the potential to be a powerful tool, especially when used in combination with other immunotherapies.

Microenvironment actuated CAR T cells improve solid tumor efficacy without toxicity.

A major limiting factor in the success of chimeric antigen receptor (CAR) T cell therapy for the treatment of solid tumors is targeting tumor antigens also found on normal tissues. CAR T cells against GD2 induced rapid, fatal neurotoxicity because of CAR recognition of GD2+ normal mouse brain tissue. To improve the selectivity of the CAR T cell, we engineered a synthetic Notch receptor that selectively expresses the CAR upon binding to P-selectin, a cell adhesion protein overexpressed in tumor neovasculature. These tumor microenvironment actuated T (MEAT) cells ameliorated T cell infiltration in the brain, preventing fatal neurotoxicity while maintaining antitumor efficacy. We found that conditional CAR expression improved the persistence of tumor-infiltrating lymphocytes because of enhanced metabolic fitness of MEAT cells and the infusion of a less differentiated product. This approach increases the repertoire of targetable solid tumor antigens by restricting CAR expression and subsequent killing to cancer cells only and provides a proof-of-concept model for other targets.

A new weapon: the application of tumor vaccines based on extracellular exosomal heat shock proteins in immunotherapy

Despite the significant advancements in cancer research, innovative approaches are still needed to reduce tumor incidence, progression, and dissemination, as well as for prolonging patient survival. Currently, the development of cancer vaccines is gaining attention as a novel preventative and therapeutic strategy. Although the concept of cancer vaccination is not new, a limited number of vaccines have received approval for tumor therapy. Heat shock protein (HSP)-based vaccination represents a promising strategy that harnesses specific tumor antigens to activate immune responses. Exosomes (Exs) are highly heterogeneous bilayer vesicles capable of transporting various types of molecules through extracellular space. Compared with conventional anticancer drugs, exosomes exhibit low toxicity and good biocompatibility, and they can stimulate the immune system either directly or indirectly. Ex-based vaccines may elicit an antitumor immune response that generates memory cells capable of recognizing cancer antigens, thereby inhibiting disease progression. This paper reviews the potential applications of HSPs and exosomes in the prevention and treatment of solid tumors. Finally, we discuss the advantages of the extracellular exosomal heat shock protein (HSP-Ex1) vaccine and future research directions aimed at optimizing heat shock protein-based cancer immunotherapy strategies.

Trop2-Expression in Correlation to the Molecular Subtype in Vulvar Squamous Cell Carcinomas (VSCC).

Targeted therapy with antibody-drug conjugates (ADCs) has shown promising results in the treatment of various solid tumours. Sacituzumab-govitecan (SG), a humanised anti-Trop2 monoclonal antibody in combination with the cytotoxic topoisomerase I inhibitor SN38, has been approved for the treatment of metastatic triple-negative breast cancer. The treatment approach with SG requires the expression of Trop2 in the tumour cells. Trop2 is overexpressed in many other cancers, suggesting a broader therapeutic application of these ADCs beyond breast cancer. We are investigating the expression of Trop2 in vulvar squamous cell carcinoma (VSCC) and how this relates to molecular classification. Immunohistochemical Trop2 expression was assessed in diagnostic biopsies of VSCC using an immunoreactive score. The staining results were compared with the molecular subtype of VSCC. 57 cases were included in the study. 63.2% of VSCC were 16-ve/p53abn (HPV-independent (p53abn)) molecular subtype, 29.8% p16+ve/p53wt (HPV-associated) and 1.4% p16-ve/p53wt-(HPV-independent (p53wt)) tumors. All diagnostic biopsies (N=57) showed at least weak Trop2-expression. Expression was significantly higher, as assessed by an immunreactive score, in the HPV-associated VSCC, compared to HPV-independent. VSCC have high expression of Trop2 and represents a promising therapeutic target. Clinical trials exploring Trop2 directed ADCs such as Sacituzumab-Govitecan are warranted in this rare cancer type, including in the prognostically poor HPV-independent VSCC with a TP53-mutation (p16-ve/p53abn molecular subtype). The targetable molecule Trop2 can be easily assessed by immunohistochemistry on diagnostic biopsies from VSCC. ree version).

CD133+PD-L1+ cancer cells confer resistance to adoptively transferred engineered macrophage-based therapy in melanoma

Adoptive transfer of genetically or nanoparticle-engineered macrophages represents a promising cell therapy modality for treatment of solid tumor. However, the therapeutic efficacy is suboptimal without achieving a complete tumor regression, and the underlying mechanism remains elusive. Here, we discover a subpopulation of cancer cells with upregulated CD133 and programmed death-ligand 1 in mouse melanoma, resistant to the phagocytosis by the transferred macrophages. Compared to the CD133-PD-L1- cancer cells, the CD133+PD-L1+ cancer cells express higher transforming growth factor-β signaling molecules to foster a resistant tumor niche, that restricts the trafficking of the transferred macrophages by stiffened extracellular matrix, and inhibits their cell-killing capability by immunosuppressive factors. The CD133+PD-L1+ cancer cells exhibit tumorigenic potential. The CD133+PD-L1+ cells are further identified in the clinically metastatic melanoma. Hyperthermia reverses the resistance of CD133+PD-L1+ cancer cells through upregulating the ‘eat me’ signal calreticulin, significantly improving the efficacy of adoptive macrophage therapy. Our findings demonstrate the mechanism of resistance to adoptive macrophage therapy, and provide a de novo strategy to counteract the resistance.

Doxorubicin-Conjugated Nanoparticles for Potential Use as Drug Delivery Systems.

Doxorubicin (DOX) is one of the most widely used chemotherapy drugs in the treatment of both solid and liquid tumors in patients of all age groups. However, it is likely to produce several side effects that include doxorubicin cardiomyopathy. Nanoparticles (NPs) can offer targeted delivery and release of the drug, potentially increasing treatment efficiency and alleviating side effects. This makes them a viable vector for novel drug delivery systems. Currently, DOX is commonly conjugated to NPs by non-covalent conjugation-physical entrapping of the drug using electrostatic interactions, van der Waals forces, or hydrogen bonding. The reported downside of these methods is that they provide a low drug loading capacity and a higher drug leakage possibility. In comparison to this, the covalent conjugation of DOX via amide (typically formed by coupling carboxyl groups on DOX with amine groups on the nanoparticle or a linker, often facilitated by carbodiimide reagents), hydrazone (which results from the reaction between hydrazines and carbonyl groups, offering pH-sensitive cleavage for controlled release), or disulfide bonds (formed through the oxidation of thiol groups and cleavable by intracellular reducing agents such as glutathione) is more promising as it offers greater bonding strength. This review covers the covalent conjugation of DOX to three different types of NPs-metallic, silica/organosilica, and polymeric-including their corresponding release rates and mechanisms.

A Strategy for Simultaneous Engineering of Interspecies Cross-Reactivity, Thermostability, and Expression of a Bispecific 5T4 x CD3 DART® Molecule for Treatment of Solid Tumors.

Background: Bispecific antibodies represent a promising class of biologics for cancer treatment. However, their dual specificity and complex structure pose challenges in the engineering process, often resulting in molecules with good functional but poor physicochemical properties. Method: To overcome limitations in the properties of an anti-5T4 x anti-CD3 (α5T4 x αCD3) DART molecule, a phage-display method was developed, which succeeded in simultaneously engineering cross-reactivity to the cynomolgus 5T4 ortholog, improving thermostability and the elevating expression level. Results: This approach generated multiple DART molecules that exhibited significant improvements in all three properties. The lead DART molecule demonstrated potent in vitro and in vivo anti-tumor activity. Although its clearance in human FcRn-transgenic mice was comparable to that of the parental molecule, faster clearance was observed in cynomolgus monkeys. The lead α5T4 x αCD3 DART molecule displayed no evidence of off-target binding or polyspecificity, suggesting that the increased affinity for the target may account for its accelerated clearance in cynomolgus monkeys. Conclusions: This may reflect target-mediated drug disposition (TMDD), a potential limitation of targeting 5T4, despite its limited expression in healthy tissues.

Supramolecular Combination Chemotherapy: Directly Inducing Immunogenic Cell Death To Inhibit Tumor Metastasis via Host-Guest Interactions.

Tumor metastasis is a difficult clinical problem to solve due to tumor heterogeneity and the emergence of antiapoptotic clones driven by tumor evolution. Clinical combination chemotherapy remains a standard treatment for solid metastasis tumors but with worse treatment efficiency. It is worth exploring a high-efficiency and low-side-effect therapeutic method to solve solid metastases. Herein, we fabricate a supramolecular combination chemotherapeutic system based on host-guest interactions using a cucurbit[8]uril complex (CB[8]-lobaplatin-oxaliplatin, CLO). We explored whether CLO can induce colorectal cancer cell death by activating immunogenic cell death (ICD) to inhibit cancer cell migration in a safe and effective manner. CLO inhibits the viability of human colorectal cancer cells (HCT116) at only 10 μM and alleviates the cytotoxicity induced by lobaplatin-oxaliplatin (LO) in normal colorectal cells (NCM460). Interestingly, CLO can trigger ICD in colorectal tumor cells, and our results verified the upregulations of high mobility group box 1 (HMGB1) and adenosine triphosphate (ATP) release and cell surface calreticulin (CRT) exposure. Besides, we found that CLO can inhibit tumor migration both in vivo and in vitro, and bio-AFM characterization of tumor cellular surface also confirmed this phenomenon. To further investigate the underlying mechanisms of the antitumor effects of CLO, quantitative proteomics was employed, and the results indicated that the citrate cycle (TCA cycle), protein processing in the endoplasmic reticulum, cGMP-PKG signaling pathway, p53 signaling pathway, chemical carcinogenesis, and necroptosis signaling pathway might contribute to CLO-induced antitumor effects. Collectively, our study suggests that the supramolecular combination chemotherapeutic system based on CB[8] host-guest complex can activate ICD to inhibit metastasis in antitumor strategy and exhibits a remarkable potential for supramolecular immunotherapy.

Enforced E-selectin ligand installation enhances homing and efficacy of adoptively transferred T cells.

Adoptive T-cell transfer has revolutionized the treatment of hematological malignancies. However, this approach has had very limited success in treating solid tumors, largely due to inadequate infiltration of vascularly administered T cells at tumor sites. The shear-resistant interaction between endothelial E-selectin and its cognate ligand expressed on leukocytes, sialyl Lewis X (sLeX), is an essential prerequisite for extravasation of circulating leukocytes. Here, we report that enforced E-selectin ligand expression (enforced sLeX display) on antigen-specific T cells can be achieved by fucosylating cells via cell surface treatment with the human α1-3-fucosyltransferase, FUT6 ("exofucosylation"), or via Golgi-targeted FUT6 overexpression ("Golgi-fucosylation"). However, despite comparable E-selectin binding, only sLeX-modified T cells engendered by exofucosylation, not by Golgi-fucosylation, exhibited enhanced parenchymal infiltration of target malignant sites. This heightened homing yielded significantly improved therapeutic efficacy in various murine syngeneic and xenograft cancer models, including subcutaneous solid tumors, lymphoma and leukemia, as well as lung and bone marrow metastases. Therefore, exofucosylation represents a promising strategy to improve the efficacy of adoptive T-cell therapy, particularly in the treatment of solid tumors and metastatic disease.

The chiisanoside derivatives present in the leaves of Acanthopanax sessiliflorus activate autophagy through the LRP6/GSK3β axis and thereafter inhibit oxidative stress, thereby counteracting cisplatin-induced ototoxicity

IntroductionCisplatin is extensively employed in the treatment of multiple solid malignant tumors. Nevertheless, side effects such as cisplatin-induced ototoxicity (CIO) pose obstacles to tumor therapy.The important natural product chiisanoside from Acanthopanax sessiliflorus has abundant activity against CIO.MethodsIn this study, 26 chiisanoside derivatives were screened, and compound 19 demonstrated significant protective activity against CIO damage. A cisplatin—induced HEI—OC1 cell injury model and a mouse ototoxicity model were established. The regulatory effects were revealed through transcriptome sequencing, and the protein expression levels were analyzed by molecular docking, ELISA, Western blotting, and immunofluorescence.ResultsIt was found that compound 19 inhibited cell apoptosis, alleviated abnormal hearing and spiral ganglion damage. Transcriptome sequencing revealed its regulatory effects. Compound 19 treatment increased autophagy levels, thereby alleviating mitochondrial dysfunction and reducing the accumulation of reactive oxygen species (ROS).In-depth studies have found that the autophagy inhibitor 3-methyladenine (3-MA) weakens the regulatory effect of compound 19 on autophagy and inhibits the clearance of damaged cells, resulting in oxidative stress damage, apoptosis and necrosis. By knocking down LRP6, it was found that the protective effect of compound 19 was eliminated, the autophagy level was significantly reduced, oxidative stress and ROS production were induced, and apoptosis after cisplatin exposure was promoted. Finally, the inhibitor LiCl was used to suppress the expression of GSK3β. It was found that inhibiting GSK3β could protect cells from cisplatin-induced damage by activating autophagy.DiscussionThese findings suggest that compound 19 is capable of preventing ototoxicity by activating autophagy via the LRP6/GSK3β axis and consequently inhibiting oxidative stress, offering a new approach for treating CIO and sensorineural hearing loss.

Recent Advances in Nanocarrier-mediated Combination Drug Therapy for Tackling Solid-resistant Tumors.

Cancer is a group of dynamic diseases characterized by uncontrollable growth and spread of cells. The heterogenic nature of cancer hinders the abolishment of cancer resulting in a narrow therapeutic index, the capacity of drug efflux, multidrug resistance, and unacceptable side effects. The major challenge in the treatment of malignancies is multidrug resistance (MDR). A novel platform, nanoscale delivery system, concluding desirable applications for the treatment of cancer with targeted and controlled release of drugs, reducing the number of side effects and systemic toxicity. Recent studies emphasize that combining 2 or more nanocarrier-mediated therapies may produce complementary therapeutic effects, perhaps resulting in improved outcomes of cancer current therapies like deterioration of drug resistance. Therefore, in this article, we scrutinize the recent advancement addressing combination therapy by combining nanoparticles with anticancer drugs. It briefly concludes a thorough overview of cancer, tumor or solid resistant tumors, the mechanism of resistant tumors, current therapies for the treatment of solid tumors, and their challenges. It also covers various types of nanoparticles used in cancer treatment, the usage of nanocarriers in resistant tumors, and nanocarrier-based combinatorial therapy for the treatment of resistant tumors as well as its benefits. However, this approach still needs to be improved for clinical applications.

Zinc nanoparticles from oral supplements accumulate in renal tumours and stimulate antitumour immune responses.

A successful therapeutic outcome in the treatment of solid tumours requires efficient intratumoural drug accumulation and retention. Here we demonstrate that zinc gluconate in oral supplements assembles with plasma proteins to form ZnO nanoparticles that selectively accumulate into papillary Caki-2 renal tumours and promote the recruitment of dendritic cells and cytotoxic CD8+ T cells to tumour tissues. Renal tumour targeting is mediated by the preferential binding of zinc ions to metallothionein-1X proteins, which are constitutively overexpressed in Caki-2 renal tumour cells. This binding event further upregulates intracellular metallothionein-1X expression to induce additional nanoparticle binding and retention. In both tumour animal models and human renal tumour samples, we show that ZnO nanoparticles actively cross the vascular wall to achieve high intratumoural accumulation. We further explore this feature of ZnO nanoparticles for the delivery of chemotherapeutics to mouse and rabbit cancer models. Our findings demonstrate that ZnO nanoparticles derived from supplements can serve as a multifunctional drug delivery and cancer immunotherapy platform.