Improve Cancer Therapy Research Articles

METB-08. CIRCULAR EXTRACHROMOSOMAL DNA IS ASSOCIATED WITH POOR SURVIVAL IN CHILDHOOD CANCER TYPES

Abstract BACKGROUND Circular extrachromosomal DNA (ecDNA) is a common form of oncogene amplification in aggressive cancers and a promising target for improved cancer therapy. The frequency and diversity of ecDNA has been described in different types of adult cancers and in selected childhood cancer types such as neuroblastoma and medulloblastoma. However, the frequency of ecDNA and its association with survival has not been comprehensively analyzed across the spectrum of pediatric cancers. METHODS We performed a pediatric pan-cancer study of ecDNA in which we mined large pediatric cancer genomics repositories and reconstructed ecDNA sequence structures from whole genome sequencing data. RESULTS We analyzed a retrospective cohort of 1684 tumor biopsies from 1506 different patients, covering all major childhood cancers, many of which occur exclusively in children, including rare embryonal tumor types. The fraction of patients with ecDNA-positive tumors was 10%, varying significantly by tumor type. Aggressive tumor types had particularly high incidences of ecDNA, including embryonal tumors with multilayered rosettes (n = 6, 67%), osteosarcoma (n = 55, 47%), rhabdomyosarcoma (n = 38, 39%), and neuroblastoma (n = 111, 30%). Survival analysis revealed that ecDNA amplifications are significantly associated with poor outcome. Furthermore, we catalogued known and potentially novel oncogenes that are recurrently amplified on ecDNA in pediatric cancers and showed that ecDNA often evolves during disease progression. CONCLUSIONS These results reveal childhood tumor types in which ecDNA is widely prevalent and highlight patient populations that could potentially benefit from future therapies targeting mechanisms of ecDNA biogenesis and function.

Strengthened binding affinity of bispecific antibody nanoplatforms improved the anti-tumor efficacy

Dual receptor targeting (DRT) strategies use bispecific antibodies to simultaneously target two distinct disease mediators and thereby overcome major escape mechanisms evident in mono-targeted therapy. DRT enhances the binding affinity between the ligand and receptors and the specific targeted delivery of nanoparticles (NPs) into cancer cells. In this study we developed anti-EGFR cetuximab (CTX) and Herceptin (HER) decorated poly(lactic-co-glycolic acid) (PLGA) NPs for the targeted delivery of docetaxel (DTX), which we call DRT-DTX-PLGA-NPs, and we quantified their binding affinity with EGFR and HER2 positive cancer cells.The binding affinity assay indicated that dual conjugation of CTX and HER on PLGA-NPsenhanced the binding affinity between the NPs and cells additively in terms of affinity and synergistically in terms of adhesion energy, compared with PLGA-NPs conjugated with CTX and HER. Furthermore, the DRT-DTX-PLGA-NPs exhibited higher cellular uptake and higher cancer cell cytotoxicity than the single receptor-targeted NPs. In SW480 xenograft mice, the DRT-DTX-PLGA-NPs were more concentrated and retained at the tumor site due to their enhanced binding affinity, and as a result, tumor volume and tumor weight were significantly inhibited compared with tumors treated with the single-ligand targeted NPs.Therefore, DRT-NPs have the potential to improve cancer therapy by providing high affinity between NPs and cells and improving selectivity compared with single-ligand-targeted NPs.

Reprogrammed IDO-Induced Immunosuppressive Microenvironment Synergizes with Immunogenic Magnetothermodynamics for Improved Cancer Therapy.

Indoleamine 2,3-dioxygenase (IDO), highly expressed in hepatocellular carcinoma (HCC), plays a pivotal role in creating an immune-suppressive tumor microenvironment. Inhibiting IDO activity has emerged as a promising immunotherapeutic strategy; however, the delivery of IDO inhibitors to the tumor site is constrained, limiting their therapeutic efficacy. In this study, we developed a magnetic vortex nanodelivery system for the targeted delivery of the IDO inhibitor NLG919, integrated with magnetic hyperthermia therapy to reverse the immune-suppressive microenvironment of liver cancer and inhibit tumor growth. This system comprises thermoresponsive polyethylenimine-coated ferrimagnetic vortex-domain iron oxide nanorings (PI-FVIOs) loaded with NLG919 (NLG919/PI-FVIOs). Under thermal effects, NLG919 can be precisely released from the delivery system, counteracting IDO-mediated immune suppression and synergizing with NLG919/PI-FVIOs-mediated magnetothermodynamic (MTD) therapy-induced immunogenic cell death (ICD), resulting in effective HCC suppression. In vivo studies demonstrate that this combination therapy significantly inhibits tumor growth and metastasis by enhancing the accumulation of cytotoxic T lymphocytes and suppressing regulatory T cells within the tumor. Overall, our findings reveal that NLG919/PI-FVIOs can induce a potent antitumor immune response by disrupting the IDO pathway and activating the ICD, offering a promising therapeutic avenue for HCC treatment.

The Polarization of Tumor-Associated Macrophages as an Effective Therapeutic Strategy: A Comprehensive Analysis

The complex interplay between tumors and their microenvironment presents challenges in cancer therapy, sparking interest in novel immunotherapeutic strategies. Current therapeutic approaches lack consistency and pose significant risks to patients. Tumor-associated macrophages (TAMs) play a pivotal role in tumor progression or inhibition, depending on their polarization state. This comprehensive analysis explores the potential of selectively repolarizing TAMs towards an anti-tumor phenotype as an effective therapeutic strategy. Nanoparticle-based delivery systems, such as polymeric, lipid-based, and inorganic nanoparticles, offer promising TAM targeting and repolarization avenues. These strategies demonstrate the ability to shift TAMs from a pro-tumoral M2 phenotype to an anti-tumoral M1 phenotype, resulting in significant anti-tumor effects. These processes have been both in vivo and in vitro, depending on the progress of the process. Nanoparticles, for example, have primarily been in vitro, but some have reached the in vivo stage. Despite the complexity of tumor immunology, the repolarization of TAMs emerges as a promising and versatile immunotherapeutic approach with reduced adverse effects compared to traditional treatments. This study underscores the importance of continued research and development in TAM repolarization, paving the way for future advancements and improved cancer therapies.

Nanosuspensions for improved Cancer Therapy: A Comprehensive Review

Cancer continues to be a major cause of sickness and death in the world's health. Conventional cancer treatments, such radiation and chemotherapy, frequently have drawbacks like poor solubility, limited absorption, and non-specific targeting, which can result in systemic toxicity and decreased efficacy. To get over these restrictions and improve cancer therapy, nanosuspensions—submicron colloidal dispersions of drug particles stabilized by polymers and/or surfactants—have become a viable new approach. This review provides a comprehensive overview of nanosuspensions, including their preparation methods, characterization techniques, and therapeutic applications in cancer treatment. The potential advantages of nanosuspensions over conventional formulations, such as improved solubility, enhanced bioavailability, and tumor-targeted delivery, are discussed in detail. The potential advantages of nanosuspensions over conventional formulations, such as improved solubility, enhanced bioavailability, and tumor-targeted delivery, are discussed in detail. Recent advances in nanosuspension technology, including the development of stimuli-responsive and multifunctional nanosuspensions, are also highlighted. Recent advances in nanosuspension technology, including the development of stimuli-responsive and multifunctional nanosuspensions, are also highlighted. Finally, the challenges and future directions of nanosuspensions in cancer therapy are explored.

Poly(2-(dimethylamino)ethyl methacrylate)-Grafted Amphiphilic Block Copolymer Micelles Co-Loaded with Quercetin and DNA.

The synergistic effect of drug and gene delivery is expected to significantly improve cancer therapy. However, it is still challenging to design suitable nanocarriers that are able to load simultaneously anticancer drugs and nucleic acids due to their different physico-chemical properties. In the present work, an amphiphilic block copolymer comprising a biocompatible poly(ethylene glycol) (PEG) block and a multi-alkyne-functional biodegradable polycarbonate (PC) block was modified with a number of poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA) side chains applying the highly efficient azide-alkyne "click" chemistry reaction. The resulting cationic amphiphilic copolymer with block and graft architecture (MPEG-b-(PC-g-PDMAEMA)) self-associated in aqueous media into nanosized micelles which were loaded with the antioxidant, anti-inflammatory, and anticancer drug quercetin. The drug-loaded nanoparticles were further used to form micelleplexes in aqueous media through electrostatic interactions with DNA. The obtained nanoaggregates-empty and drug-loaded micelles as well as the micelleplexes intended for simultaneous DNA and drug codelivery-were physico-chemically characterized. Additionally, initial in vitro evaluations were performed, indicating the potential application of the novel polymer nanocarriers as drug delivery systems.

Mechanical shear flow regulates the malignancy of colorectal cancer cells.

Colorectal cancer (CRC) is notable for its high mortality and high metastatic characteristics. The shear force generated by bloodstream provides mechanical signals regulating multiple responses of cells, including metastatic cancer cells, dispersing in blood vessels. We, therefore, studied the effect of shear flow on circulating CRC cells in the present study. The CRC cell line SW620 was subjected to shear flow of 12.5 dynes/cm2 for 1 and 2 h separately. Resulting elevated caspase-9 and -3 indicated that shear flow initiated the apoptosis of SW620. Enlarged cell size associated with a higher level of cyclin D1 was coincident with the flow cytometric results indicating that the cell cycle was arrested at the G1 phase. An elevated phosphor-eNOSS1177 increased the production of nitric oxide and led to reactive oxygen species-mediated oxidative stress. Shear flow also regulated epithelial-mesenchymal transition (EMT) by increasing E-cadherin and ZO-1 while decreasing Snail and Twist1. The migration and invasion of sheared SW620 were also substantially decreased. Further investigations showed that mitochondrial membrane potential was significantly decreased, whereas mitochondrial mass and ATP production were not changed. In addition to the shear flow of 12.5 dynes/cm2, the expressions of EMT were compared at lower (6.25 dynes/cm2) and at higher (25 dynes/cm2) shear flow. The results showed that lower shear flow increased mesenchymal characteristics and higher shear flow increased epithelial characteristics. Shear flow reduces the malignancy of CRC in their metastatic dispersal that opens up new ways to improve cancer therapies by applying a mechanical shear flow device.

Therapeutic potentials of FexMoyS-PEG nanoparticles in colorectal cancer: a multimodal approach via ROS-ferroptosis-glycolysis regulation

Improving cancer therapy by targeting the adverse tumor microenvironment (TME) rather than the cancer cells presents a novel and potentially effective strategy. In this study, we introduced FexMoyS nanoparticles (NPs), which act as sequential bioreactors to manipulate the TME. FexMoyS NPs were synthesized using thermal decomposition and modified with polyethylene glycol (PEG). Their morphology, chemical composition, and photothermal properties were characterized. The capability to produce ROS and deplete GSH was evaluated. Effects on CRC cells, including cell viability, apoptosis, and glycolysis, were tested through various in vitro assays. In vivo efficacy was determined using CRC-bearing mouse models and patient-derived xenograft (PDX) models. The impact on the MAPK signaling pathway and tumor metabolism was also examined. The FexMoyS NPs showed efficient catalytic activity, leading to increased ROS production and GSH depletion, inducing ferroptosis, and suppressing glycolysis in CRC cells. In vivo, the NPs significantly inhibited tumor growth, particularly when combined with NIR light therapy, indicating a synergistic effect of photothermal therapy and chemodynamic therapy. Biosafety assessments revealed no significant toxicity in treated mice. RNA sequencing suggested that the NPs impact metabolism and potentially immune processes within CRC cells. FexMoyS NPs present a promising multifaceted approach for CRC treatment, effectively targeting tumor cells while maintaining biosafety. The nanoparticles exhibit potential for clinical translation, offering a new avenue for cancer therapy.

Glutathione S-transferase omega class 1 (GSTO1)-associated large extracellular vesicles are involved in tumor-associated macrophage-mediated cisplatin resistance in bladder cancer.

Bladder cancer poses a significant challenge to chemotherapy due to its resistance to cisplatin, especially at advanced stages. Understanding the mechanisms behind cisplatin resistance is crucial for improving cancer therapy. The enzyme glutathione S-transferase omega class 1 (GSTO1) is known to be involved in cisplatin resistance in colon cancer. This study focused on its role in cisplatin resistance in bladder cancer. Our analysis of protein expression in bladder cancer cells stimulated by secretions from tumor-associated macrophages (TAMs) showed a significant increase in GSTO1. This prompted further investigation into the role of GSTO1 in bladder cancer. We found a strong correlation between GSTO1 expression and cisplatin resistance. Mechanistically, GSTO1 triggered the release of large extracellular vesicles (EVs) that promoted cisplatin efflux, thereby reducing cisplatin-DNA adduct formation and enhancing cisplatin resistance. Inhibition of EV release effectively counteracted the cisplatin resistance associated with GSTO1. In conclusion, GSTO1-mediated EV release may contribute to cisplatin resistance caused by TAMs in bladder cancer. Strategies to target GSTO1 could potentially improve the efficacy of cisplatin in treating bladder cancer.

Therapeutic Potential of Chlorogenic Acid in Chemoresistance and Chemoprotection in Cancer Treatment.

Chemotherapeutic drugs are indispensable in cancer treatment, but their effectiveness is often lessened because of non-selective toxicity to healthy tissues, which triggers inflammatory pathways that are harmful to vital organs. In addition, tumors' resistance to drugs causes failures in treatment. Chlorogenic acid (5-caffeoylquinic acid, CGA), found in plants and vegetables, is promising in anticancer mechanisms. In vitro and animal studies have indicated that CGA can overcome resistance to conventional chemotherapeutics and alleviate chemotherapy-induced toxicity by scavenging free radicals effectively. This review is a summary of current information about CGA, including its natural sources, biosynthesis, metabolism, toxicology, role in combatting chemoresistance, and protective effects against chemotherapy-induced toxicity. It also emphasizes the potential of CGA as a pharmacological adjuvant in cancer treatment with drugs such as 5-fluorouracil, cisplatin, oxaliplatin, doxorubicin, regorafenib, and radiotherapy. By analyzing more than 140 papers from PubMed, Google Scholar, and SciFinder, we hope to find the therapeutic potential of CGA in improving cancer therapy.

Current advances in cancer treatment: A comprehensive review of therapeutic strategies and emerging innovations

Cancer stands as a pressing global health crisis, claiming one in every six lives across the world. The treatment of cancer has evolved into a remarkably intricate endeavour. In recent years, there have been significant advancements in the field of cancer treatment, alongside the longstanding methods of surgery, chemotherapy, and radiotherapy. In the realm of oncology, there has been a surge of innovative treatments, encompassing stem cell therapy, targeted therapy, ablation therapy, nanoparticles, natural antioxidants, radionics, chemo dynamic therapy, sonodynamic therapy, and ferroptosis-based therapy. Contemporary oncology is predominantly dedicated to the progression of cancer nanomedicines, with notable promise found in stem cell therapy, offering the potential to rejuvenate and mend afflicted tissues at both primary and metastatic cancer sites. Nanoparticles have ushered in new avenues for both diagnosis and treatment. Targeted therapy presents a groundbreaking strategy that hinders the proliferation and dissemination of particular cancer cells, while minimizing harm to healthy ones. Ablation therapy, characterized by its minimally invasive nature, enables the elimination of cancer using methods like controlled burning or freezing, eliminating the necessity for open surgery. In the ongoing pursuit of improved cancer therapies, numerous innovative technologies are currently undergoing clinical trials, and some have already gained approval. This review provides a comprehensive update on the recent advancements and breakthroughs in the realm of cancer treatment.

Sequential release of drugs from dual-delivery plasmonic nanogels containing lipid-gated mesoporous silica-coated gold nanorods

Nanosystems that enable the sequential delivery of various drugs with different targets are desired for improved cancer therapy. However, current strategies are mainly dependent on the tumour microenvironment, such as low pH or enzyme-triggered release. In this work, a nanosystem design strategy for near infrared (NIR) light-triggered sequential delivery based on lipid-gated mesoporous silica-coated gold nanorods and chitosan/alginate nanogels was developed. The mesoporous silica particles (99 ± 11 nm) were loaded with methotrexate, and further coated with a thermoresponsive phospholipid bilayer that works as gatekeeper. These particles were then incorporated in a chitosan/alginate nanogel matrix containing doxorubicin. The plasmonic nanogels exhbited high loading efficiencies of ∼90 % and ∼85 for methotrexate and doxorubicin, respectively. Notably, this system displayed average hydrodynamic diameters near 300 nm, low polidispersity, highly negative zeta potential (∼−30 mV), and a sustained release of both drugs under acidic and neutral conditions. Upon NIR laser irradiation, an enhanced release of both drugs was observed, with doxorubicin exhibiting a faster release rate than methotrexate under acidic conditions. This design strategy of NIR-triggered sequential delivery holds promise for different drug combinations against multiple targets in tumour microenvironment in the field of multimodal cancer therapy.

Improving Cancer Therapy: Design, Synthesis, and Evaluation of Carboplatin-Based Nanoliposomes against Breast Cancer Cell Lines

Objective: Cancer poses a significant challenge to modern medicine, with breast carcinoma being one of the most prevalent forms of the disease. Carboplatin is a commonly used chemotherapy drug for treating breast cancer, but its efficacy can be limited due to its poor water solubility and associated side effects. This study intended to enhance the therapeutic potency of carboplatin by encapsulating it within liposomal nanocarriers. Methods: We fabricated nanoscale liposomes loaded with carboplatin via a technique called reverse phase evaporation, and examined their physical attributes. We also studied the toxicity of these nanoliposomes on MDA-MB 231 breast cancer cells. Results: Our findings indicated that the liposomal nanoparticles possessed a negative zeta potential of -18.2 mV and an average size of 278 nm. The drug loading level was 2.2%, while the efficiency of drug encapsulation reached 58.5%. Of note, the cytotoxicity of carboplatin in its nanoliposomal form was markedly more potent against the MDA-MB 231 breast cancer cell line than the free drug (p-value less than 0.05). Conclusion: Our findings suggest that carboplatin-loaded liposomal nanocarriers could potentially serve as an advanced chemotherapeutic approach for the treatment of breast cancer, offering enhanced efficacy and reduced side effects compared to conventional carboplatin therapy. Further research is warranted to explore this novel delivery system’s benefits fully.

Global DNA Methylation Level in Tumour and Margin Samples in Relation to Human Papilloma Virus and Epstein-Barr Virus in Patients with Oropharyngeal and Oral Squamous Cell Carcinomas.

Aberrant DNA methylation is a common epigenetic modification in cancers, including oropharyngeal squamous cell carcinoma (OPSCC) and oral squamous cell carcinoma (OSCC). Therefore, the analysis of methylation levels appears necessary to improve cancer therapy and prognosis. The enzyme-linked immunosorbent assay (ELISA) was used to analyse global DNA methylation levels in OPSCC and OSCC tumours and the margin samples after DNA isolation. HPV detection was conducted by hybridisation using GenoFlow HPV Array Test Kits (DiagCor Bioscience Inc., Hong Kong, China). EBV detection was performed using real-time PCR with an EBV PCR Kit (EBV/ISEX/100, GeneProof, Brno, Czech Republic). OPSCC tumour samples obtained from women showed lower global DNA methylation levels than those from men (1.3% vs. 3.5%, p = 0.049). The margin samples from OPSCC patients with HPV and EBV coinfection showed global DNA methylation lower than those without coinfection (p = 0.042). G3 tumours from OSCC patients had significantly lower levels of global DNA methylation than G2 tumours (0.98% ± 0.74% vs. 3.77% ± 4.97%, p = 0.010). Additionally, tumours from HPV-positive OSCC patients had significantly lower global DNA methylation levels than those from HPV-negative patients (p = 0.013). In the margin samples, we observed a significant negative correlation between global DNA methylation and the N stage of OSCC patients (rS = -0.33, p = 0.039). HPV-positive OPSCC patients had higher global DNA methylation levels than HPV-positive OSCC patients (p = 0.015). We confirmed that methylation could be changed in relation to viral factors, such as HPV and EBV, as well as clinical and demographical parameters.

Specific photodamage on HT-29 cancer cells leads to endolysosomal failure and autophagy blockage by cathepsin depletion

Endolysosomes perform a wide range of cellular functions, including nutrient sensing, macromolecule digestion and recycling, as well as plasma membrane repair. Because of their high activity in cancerous cells, endolysosomes are attractive targets for the development of novel cancer treatments. Light-activated compounds termed photosensitizers (PS) can catalyze the oxidation of specific biomolecules and intracellular organelles. To selectively damage endosomes and lysosomes, HT-29 colorectal cancer cells were incubated with nanomolar concentrations of meso-tetraphenylporphine disulfonate (TPPS2a), an amphiphilic PS taken up via endocytosis and activated by green light (522 nm, 2.1 J.cm−1). Several cellular responses were characterized by a combination of immunofluorescence and immunoblotting assays. We showed that TPPS2a photosensitization blocked autophagic flux without extensive endolysosomal membrane rupture. Nevertheless, there was a severe functional failure of endolysosomes due to a decrease in CTSD (cathepsin D, 55%) and CTSB (cathepsin B, 52%) maturation. PSAP (prosaposin) processing (into saposins) was also considerably impaired, a fact that could be detrimental to glycosphingolipid homeostasis. Therefore, photosensitization of HT-29 cells previously incubated with a low concentration of TPPS2a promotes endolysosomal dysfunction, an effect that can be used to improve cancer therapies.

Sequential catalytic nanomedicinal utilization for synergistic drug delivery application in cancer nanotechnology

Cancer is the major cause of the increase in the deah rate globally, with an escalating number of cases every year. However, early detection of cancer and its treatment have remained a key challenge. The rapid advancement of nanotechnology toward nanomedicine holds considerable potential for improving cancer therapy techniques. The concept of “nanocatalytic medicine” has emerged due to the rapid proliferation of scientific investigations concerning the biomedical applications of nanocatalysts, which are anticipated to advance the field. This emerging catalytic therapeutic approach is expected to have a bigger impact on the discipline of nanomedicine.The goal of introducing drug delivery systems is to enhance the therapeutic effect or reduce drug toxicity. This manuscript explores an in-depth analysis of the rationale for developing nanomedicine products for cancer therapy. In addition, numerous techniques for the delivery of drugs to tumor cells have been introduced. Following this, catalytic-based nanomedicine employs a diverse array of nanoparticles, which has the potential to be extraordinarily beneficial in the treatment of cancer. This article offers a succinct synopsis of recent advancements in co-delivery agents and nanocarriers, including the characterization of nanocarriers and the successful implementations of drug-delivery cases in synergistic systems.

Neil 1 deficiency facilitates chemoresistance through upregulation of RAD18 expression in ovarian cancer stem cells

Over the past decades, cancer stem cells (CSCs) have emerged as a critical subset of tumor cells associated with tumor recurrence and resistance to chemotherapy. Understanding the mechanisms underlying CSC-mediated chemoresistance is imperative for improving cancer therapy outcomes. This study delves into the regulatory role of NEIL1, a DNA glycosylase, in chemoresistance in ovarian CSCs.We first observed a decreased expression of NEIL1 in ovarian CSCs, suggesting its potential involvement in CSC regulation. Using pan-cancer analysis, we confirmed the diminished NEIL1 expression in ovarian tumors compared to normal tissues. Furthermore, NEIL1 downregulation correlated with an increase in stemness markers and enrichment of CSCs, highlighting its role in modulating CSC phenotype.Further mechanistic investigation revealed an inverse correlation between NEIL1 and RAD18 expression in ovarian CSCs. NEIL1 depletion led to heightened RAD18 expression, promoting chemoresistance possibly via enhancing Translesion DNA Synthesis (TLS)-mediated DNA lesion bypass. Moreover, dowregulation of NEIL1 results in reduced DNA damage accumulation and suppressed apoptosis in ovarian cancer.Overall, our findings unveil a novel mechanism involving NEIL1 and RAD18 in regulating chemoresistance in ovarian CSCs. Targeting this NEIL1-RAD18 axis may offer promising therapeutic strategies for combating chemoresistance and improving ovarian cancer treatment outcomes.

An Epic Advancement in Targeting Macrophages for Cancer Therapy Approach.

Macrophages are immune cells with high heterogeneity and plasticity, crucial for recognizing and eliminating foreign substances, including cancer cells. However, cancer cells can evade the immune system by producing signals that cause macrophages to switch to a pro-tumor phenotype, promoting tumor growth and progression. Tumor-associated macrophages, which infiltrate into tumor tissue, are important immune cells in the tumor microenvironment and can regulate cancer's growth, invasion, and metastasis by inhibiting tumor immunity. This review article highlights the characteristics of tumor-associated macrophages and their role in the occurrence and development of cancer. It outlines how reprogramming macrophages towards an anti-tumor phenotype can improve the response to cancer therapy. Explore the intricate process of engineered nanoparticles serving as carriers for immunostimulatory molecules, activating macrophages to instigate an anti-tumor response. Finally, it summarizes several studies demonstrating targeting macrophages is a potential in preclinical cancer models. Several challenges must be addressed in developing effective macrophage-targeted therapies, such as the heterogeneity of macrophage subtypes and their plasticity. Further research is needed to understand the mechanisms underlying macrophage function in the tumor microenvironment and identify novel targets for macrophage-directed therapies. Targeting macrophages is a promising and innovative approach to improving cancer therapy and patient outcomes.

Therapeutic Implications of Dietary Polyphenols-Loaded Nanoemulsions in Cancer Therapy.

Cancer is one of the major causes of death worldwide, even the second foremost cause related to non-communicable diseases. Cancer cells typically possess several cellular and biological processes including, persistence, propagation, differentiation, cellular death, and expression of cellular-type specific functions. The molecular picture of carcinogenesis and progression is unwinding, and it appears to be a tangled combination of processes occurring within and between cancer cells and their surrounding tissue matrix. Polyphenols are plant secondary metabolites abundant in fruits, vegetables, cereals, and other natural plant sources. Natural polyphenols have implicated potential anticancer activity by various mechanisms involved in their antitumor action, including modulation of signaling pathways majorly related to cellular proliferation, differentiation, relocation, angiogenesis, metastatic processes, and cell death. The applications of polyphenols have been limited due to the hydrophobic nature and lower oral bioavailability that could be possibly overcome through encapsulating them into nanocarrier-mediated delivery systems, leading to improved anticancer activity. Nanoemulsions (NEs) possess diverse feasible properties, including greater surface area, modifiable surficial charge, higher half-life, site-specific targeting, and formulation imaging capability necessary to create a practical therapeutic impact, and have drawn increased attention in cancer therapy research. This review has summarized and discussed the basic concepts, classification, delivery approaches, and anticancer mechanism of various polyphenols and polyphenols-encapsulated nanoemulsions with improved cancer therapy.

Abstract 5240: Novel CD3-Fusion Receptor enables combination of T-cell engagers and allogeneic CAR T cells to promote enhanced antitumor activity and overcome antigen escape

Abstract Chimeric antigen receptor (CAR) T cells have shown remarkable clinical success in the treatment of hematologic malignancies. However, the durability of response of CAR T therapy can be impaired by heterogenous expression of the CAR-specific target antigen (1° Ag) on tumors. In combination with a CAR, T-cell engagers (TCEs) that target additional tumor antigen (2° Ag) can be a unique approach to address tumor heterogeneity and overcome antigen escape. Engineered induced pluripotent stem cell (iPSC) master cell lines are a renewable source material from which iPSC-derived CAR T (CAR-iT) cells can be manufactured and administered in an off-the-shelf manner. In developing allogeneic CAR-iT cells, the T-cell receptor (TCR) must be eliminated to prevent graft-versus-host disease. However, the absence of TCR expression leads to loss of surface CD3 and a corresponding loss of TCE compatibility. Here we discuss a novel CD3ε fusion receptor (CD3-FR) with a modified transmembrane and endodomain, which allows for CD3 surface expression on TCR-less T cells and effective combination of off-the-shelf allogeneic CAR-T cells and TCEs. CAR+ CD3-FR+ iPSCs were differentiated into CAR-iT cells, uniformly expressing both modalities (>95% CAR+, >90% CD3ε+) and absent of TCR. To demonstrate that CD3-FR+ CAR-iT cells can elicit TCE-dependent activity, 1° Ag- (CD19-)/2° Ag+ (EpCAM+) target cells were used in cytotoxicity assays. As shown, CD3-FR- CAR-iT cells failed to kill 1° Ag- target cells. In contrast, CD3-FR+ CAR-iT cells demonstrated potent activity toward the target cells (>80% cytolysis) but only in the presence of the TCE targeting 2° Ag. To test the ability of CD3-FR+ CAR-iT cells to mitigate antigen escape, we used a tumor cell population heterogenous for the CAR-specific target (50% 1° Ag-) but homogenous for TCE-specific target (100% 2° Ag+). In co-culture assays, CD3-FR- CAR-iT cells failed to prevent tumor cell growth due to 1° Ag- tumor escape. However, CD3-FR+ CAR-iT cells in the presence of TCE exhibited robust control (80% cytolysis) of the heterogenous tumor, mitigating 1° Ag- tumor escape via targeting of 2° Ag. Next, we tested the ability of CD3-FR+ CAR-iT cells to control heterogeneous tumor in vivo in a disseminated leukemia model. As expected, CD3-FR+ CAR-iT cells exhibited significantly better tumor growth inhibition in the presence of TCE (p-value <0.005) compared to controls lacking the CD3-FR modality. Ex vivo analysis of tumor in the bone marrow confirmed 1° Ag- tumor escape in the control treated mice, but not in mice treated with CD3-FR+ CAR-iT and TCE targeting 2° Ag. Taken together, these studies present a novel opportunity to leverage a novel CD3 fusion receptor and enable combination of TCEs with engineered off-the-shelf CAR T-cell products, uniquely harnessing two potent therapeutic modalities for improving cancer therapy. Citation Format: Dan Lu, Eigen Peralta, Hui-Yi Chu, Soo Park, Masanao Tsuda, Earl Avramis, Matthew Denholtz, Alec Witty, Tom Lee, Bahram Valamehr. Novel CD3-Fusion Receptor enables combination of T-cell engagers and allogeneic CAR T cells to promote enhanced antitumor activity and overcome antigen escape [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5240.