Conditions In Tumor Microenvironment Research Articles

Sequential Ultrasound-Triggered and Hypoxia-Sensitive Nanoprodrug for Cascade Amplification of Sonochemotherapy.

Hypoxia, the typical and conspicuous characteristic of most solid tumors, worsens the tumor invasiveness and metastasis. Here, we engineered a sequential ultrasound (US)/hypoxia-sensitive sonochemotherapeutic nanoprodrug by initially synthesizing the hypoxia-activated azo bond-containing camptothecin (CPT) prodrug (CPT2-Azo) and then immobilizing it into the mesopores of sonosensitizer-integrated metal organic frameworks (MOF NPs). Upon entering the hypoxic tumor microenvironment (TME), the structure of CPT2-Azo immobilized MOFs (denoted as MCA) was ruptured and the loaded nontoxic CPT2-Azo prodrug was released from the MOF NPs. Under US actuation, this sonochemotherapeutic nanoprodrug not only promoted sonosensitizer-mediated sonodynamic therapy (SDT) via the conversion of oxygen into cytotoxic reactive oxygen species (ROS) but also aggravated hypoxia in the TME by elevating oxygen consumption. The exacerbated hypoxia in turn served as a positive amplifier to boost the activation of CPT2-Azo, and the controllable release of toxic chemotherapeutic drug (CPT), and compensated the insufficient treatment efficacy of SDT. In vitro and in vivo evaluations confirmed that sequential SDT and tumor hypoxia-activated sonochemotherapy promoted the utmost of tumor hypoxia and thereby contributed to the augmented antitumor efficacy, resulting in conspicuous apoptotic cell death and noteworthy tumor suppression in vivo. Our work provides a distinctive insight into the exploitation of the hypoxia-activated sonochemotherapeutic nanoprodrug that utilizes the hypoxic condition in TME, a side effect of SDT, to initiate chemotherapy, thus causing a significantly augmented treatment outcome compared to conventional SDT.

Glutathione-Triggered catalytic response of Copper-Iron mixed oxide Nanoparticles. Leveraging tumor microenvironment conditions for chemodynamic therapy

Heterogeneous catalysis has emerged as a promising alternative for the development of new cancer therapies. In addition, regarding the tumor microenvironment as a reactor with very specific chemical features has provided a new perspective in the search for catalytic nanoarchitectures with specific action against chemical species playing a key role in tumor metabolism. One of these species is glutathione (GSH), whose depletion is the cornerstone of emerging strategies in oncology, since this metabolite plays a pivotal regulatory role as antioxidant agent, dampening the harmful effects of intracellular reactive oxidative species (ROS). Herein, we present copper-iron oxide spinel nanoparticles that exhibit a versatile and selective catalytic response to reduce GSH levels while generating ROS in a cascade reaction. We demonstrate a clear correlation between GSH depletion and apoptotic cell death in tumor cells in the presence of the copper-iron nanocatalyst. Furthermore, we also provide a novel analytical protocol, alternative to state-of-the-art commercial kits, to accurately monitoring the concentration of GSH intracellular levels in both tumor and healthy cells. We observe a selective action of the nanoparticles, with lower toxicity in healthy cell lines, whose intrinsic GSH levels are lower, and intense apoptosis in tumor cells accompanied by a fast reduction of GSH levels.

Enhanced Chemodynamic Therapy by Cu-Fe Peroxide Nanoparticles: Tumor Microenvironment-Mediated Synergistic Fenton Reaction.

An urgent need in chemodynamic therapy (CDT) is to achieve high Fenton catalytic efficiency at small doses of CDT agents. However, simple general promotion of the Fenton reaction increases the risk of damaging normal cells along with the cancer cells. Therefore, a tailored strategy to selectively enhance the Fenton reactivity in tumors, for example, by taking advantage of the characteristics of the tumor microenvironment (TME), is in high demand. Herein, a heterogeneous CDT system based on copper-iron peroxide nanoparticles (CFp NPs) is designed for TME-mediated synergistic therapy. CFp NPs degrade under the mildly acidic conditions of TME, self-supply H2O2, and the released Cu and Fe ions, with their larger portions at lower oxidation states, cooperatively facilitate hydroxyl radical production through a highly efficient catalytic loop to achieve an excellent tumor therapeutic efficacy. This is distinct from previous heterogeneous CDT systems in that the synergism is closely coupled with the Cu+-assisted conversion of Fe3+ to Fe2+ rather than their independent actions. As a result, almost complete ablation of tumors at a minimal treatment dose is demonstrated without the aid of any other therapeutic modality. Furthermore, CFp NPs generate O2 during the catalysis and exhibit a TME-responsive T1 magnetic resonance imaging contrast enhancement, which are useful for alleviating hypoxia and in vivo monitoring of tumors, respectively.

Impact of cancer metabolism on therapy resistance – Clinical implications

Despite an increasing arsenal of anticancer therapies, many patients continue to have poor outcomes due to the therapeutic failures and tumor relapses. Indeed, the clinical efficacy of anticancer therapies is markedly limited by intrinsic and/or acquired resistance mechanisms that can occur in any tumor type and with any treatment. Thus, there is an urgent clinical need to implement fundamental changes in the tumor treatment paradigm by the development of new experimental strategies that can help to predict the occurrence of clinical drug resistance and to identify alternative therapeutic options. Apart from mutation-driven resistance mechanisms, tumor microenvironment (TME) conditions generate an intratumoral phenotypic heterogeneity that supports disease progression and dismal outcomes. Tumor cell metabolism is a prototypical example of dynamic, heterogeneous, and adaptive phenotypic trait, resulting from the combination of intrinsic [(epi)genetic changes, tissue of origin and differentiation dependency] and extrinsic (oxygen and nutrient availability, metabolic interactions within the TME) factors, enabling cancer cells to survive, metastasize and develop resistance to anticancer therapies. In this review, we summarize the current knowledge regarding metabolism-based mechanisms conferring adaptive resistance to chemo-, radio-and immunotherapies as well as targeted therapies. Furthermore, we report the role of TME-mediated intratumoral metabolic heterogeneity in therapy resistance and how adaptations in amino acid, glucose, and lipid metabolism support the growth of therapy-resistant cancers and/or cellular subpopulations. We also report the intricate interplay between tumor signaling and metabolic pathways in cancer cells and discuss how manipulating key metabolic enzymes and/or providing dietary changes may help to eradicate relapse-sustaining cancer cells. Finally, in the current era of personalized medicine, we describe the strategies that may be applied to implement metabolic profiling for tumor imaging, biomarker identification, selection of tailored treatments and monitoring therapy response during the clinical management of cancer patients.

A Tumor Microenvironment-Triggered and Photothermal-Enhanced Nanocatalysis Multimodal Therapy Platform for Precise Cancer Therapy

The tumor microenvironment (TME)-triggered therapeutic strategy not only provides effective and economical methods for cancer treatment but also minimizes the side effects on normal tissues. However, anticancer species generated by TME-triggered chemical reactions in situ within cancer cells are insufficient to inhibit tumor growth. This study reports the construction of a TME-triggered and photothermal (PT)-enhanced nanocatalysis platform that is based on cancer cell (MCF-7) membrane-camouflaged hollow porous Cu7S4 nanospheres (HPCu7S4@MCF-7) for efficient cancer therapy. HPCu7S4 exhibits strong absorption in the near-infrared region with a high PT conversion efficiency (∼30%). After coating with a cell membrane, HPCu7S4@MCF-7, which possesses a high ability to recognize and target cancer cells, can not only be used as a PT agent for PT therapy (PTT) but can also catalyze the generation of •OH and H2S under TME conditions to facilitate chemodynamic therapy (CDT) and gas therapy (GT), respectively. Moreover, NIR irradiation enhances the generation of more •OH and H2S to improve the therapeutic efficiency. Both in vitro and in vivo results demonstrate a high therapeutic efficiency of HPCu7S4@MCF-7-based PTT in combination with TME-triggered and PT-enhanced CDT and GT, which will open a new approach for constructing multimodal therapeutic strategies for potential use in the clinic.

Immunostimulatory multi-interfacial bimetallic phosphide nanoparticles as photo-enhanced cascade nanozyme for cancer therapy

Nanozyme has been widely explored for tumor catalytic therapy. Nevertheless, highly efficient and specific cancer therapy with nanozyme is still challenging under the strict condition of tumor microenvironment (TME). Herein, we fabricate a bimetallic phosphide nanoparticle (CuFeP) with multiphase interfaces as a photo-enhanced cascade nanozyme for efficient immunostimulatory cancer therapy. The CuFeP has structural, atomic and electric coupling with multi-interfacial heterojunction to promote the interfacial electron transfer, and the bimetallic redox couple of Cu+/2+ and Fe0/2+/3+ to synergistically improve the cascade catalysis of peroxidase (POD) and glutathione peroxidase (GPX), thereby inducing lethal cellular oxidative damage. Moreover, the excellent photothermal efficiency of 66.9% assists in catalysis in view of thermodynamics. Finally, the synergetic catalysis triggers immune cell death (ICD) process, which promotes maturation of dendritic cells (DCs), activation of cytotoxic and helper T cells, and excretion of proinflammatory cytokines to boost antitumor immunity in vivo. This study provides an enlightenment for the design of efficient therapeutic nanozyme to conquer cancer.

Achieving NIR Light-Mediated Tumor-Specific Fenton Reaction-Assisted Oncotherapy by Using Magnetic Nanoclusters.

As an emerging strategy for oncotherapy, Fenton chemistry can efficiently improve the conversion from endogenous H2O2 into highly toxic ·OH in the whole high-performance therapeutic process. Although promising, the efficiency of Fenton reaction in tumor regions is highly limited by the inefficient delivery of Fenton reagents and the restrictive conditions of tumor microenvironment. One promising strategy against the above limitations is to specifically increase the temperature around the tumor regions. In this study, a novel NIR light-mediated tumor-specific nanoplatform based on magnetic iron oxide nanoclusters (MNCs) was rationally designed and well developed for photothermally enhanced Fenton reaction-assisted oncotherapy. MNCs could accumulate into the tumor regions with the help of an external magnet field to enable T2-weighted magnetic resonance (MR) imaging of tumors and MR imaging-guided combined antitumor therapy. Our well-prepared MNCs also revealed excellent photothermal effect upon a NIR light irradiation, promising their further important role as a photothermal therapy (PTT) agent. More importantly, heat induced by the PTT of MNCs could accelerate the release of Fe from MNCs and enhance the efficiency of Fenton reaction under H2O2-enriched acidic tumor microenvironment. Results based on long-term toxicity investigations demonstrated the overall safety of MNCs after intravenous injection. This work therefore introduced a novel nanoplatform based on MNCs that exerted a great antitumor effect via photothermally enhanced tumor-specific Fenton chemistry.

Asymmetrically coating Pt nanoparticles on magnetic silica nanospheres for target cell capture and therapy.

AJanus cargo has been developedvia the combination of magnetic mesoporous silica (MMS) with asymmetric decoration of Pt nanoparticles (PtNPs). Mesoporous morphology of MMS provides plenty of space for loading photosensitizers and targeting agents; the magnetic feature endows the as-formed nanospheres with satisfactory isolation function in removal of low abundant target cells. The excellent catalytic ability of PtNPs can effectively alleviate the hypoxia condition of tumor microenvironment via the decomposition of hydrogen peroxide (H2O2), as well as an O2-drived nanomotor for highly efficient drug release. Using CCRF-CEM as the model target cell, the Janus cargo is demonstrated to possess significantly improved performance in cell capture and photodynamic therapy. Specially, owing to the patchy Pt decoration, the loaded photosensitizers exhibit a more efficient release behavior. More importantly, asymmetric O2-emission from one side of the nanocargo acts as a driving force, which could effectively accelerate the motion ability of cargo in cell media, thus leading to an enhanced therapeutic effect compared withthe traditionally symmetric nanocargo. This Janus cargo would offer a new paradigm to design highly efficient drug carrier for gaining an improved photodynamic therapy in hypoxic cancer cells.

The Tumor Microenvironment-Dependent Transcription Factors AHR and HIF-1α Are Dispensable for Leukemogenesis in the Eµ-TCL1 Mouse Model of Chronic Lymphocytic Leukemia.

Simple SummaryChronic lymphocytic leukemia (CLL) is the most common leukemia in Western countries, mostly affecting the elderly. The survival of leukemic cells depends on multiple soluble factors and on the stimulation of the BCR signaling pathway. Microenvironment-dependent transcription factors also contribute to CLL biology. Here, we generated new transgenic murine conditional knock-out models of CLL to study the role of the two transcription factors HIF-1α and AHR. Unexpectedly, we observed that both factors are dispensable for leukemia development in these models.Chronic lymphocytic leukemia (CLL) is the most frequent leukemia in the elderly and is characterized by the accumulation of mature B lymphocytes in peripheral blood and primary lymphoid organs. In order to proliferate, leukemic cells are highly dependent on complex interactions with their microenvironment in proliferative niches. Not only soluble factors and BCR stimulation are important for their survival and proliferation, but also the activation of transcription factors through different signaling pathways. The aryl hydrocarbon receptor (AHR) and hypoxia-inducible factor (HIF)-1α are two transcription factors crucial for cancer development, whose activities are dependent on tumor microenvironment conditions, such as the presence of metabolites from the tryptophan pathway and hypoxia, respectively. In this study, we addressed the potential role of AHR and HIF-1α in chronic lymphocytic leukemia (CLL) development in vivo. To this end, we crossed the CLL mouse model Eµ-TCL1 with the corresponding transcription factor-conditional knock-out mice to delete one or both transcription factors in CD19+ B cells only. Despite AHR and HIF-1α being activated in CLL cells, deletion of either or both of them had no impact on CLL progression or survival in vivo, suggesting that these transcription factors are not crucial for leukemogenesis in CLL.

Novel Characterization of Myeloid-Derived Suppressor Cells in Tumor Microenvironment.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of cells generated in various pathologic conditions, which have been known to be key components of the tumor microenvironment (TME) involving in tumor immune tolerance. So MDSCs have been extensively researched recently. As its name suggests, immunosuppression is the widely accepted function of MDSCs. Aside from suppressing antitumor immune responses, MDSCs in the TME also stimulate tumor angiogenesis and metastasis, thereby promoting tumor growth and development. Therefore, altering the recruitment, expansion, activation, and immunosuppression of MDSCs could partially restore antitumor immunity. So, this view focused on the favorable TME conditions that promote the immunosuppressive effects of MDSCs and contribute to targeted therapies with increased precision for MDSCs.

PH/ROS Dual-Responsive Polymer–Drug-Based Nanocarriers: Click-Reaction Preparation and Fluorescence Imaging-Guided Chemotherapy and Photodynamic Therapy

In the past decades, polymer-drug conjugates of anticancer agents have gained much attention due to their enhanced aqueous solubility, improved pharmacokinetics, and better drug utilization than their conventional insoluble counterparts. Several polymer-drug conjugates have entered the third phase of clinical trials yet suffer from inherent deficiencies, including uncontrolled drug release and unclear degradation mechanisms. In this study, a pH/reactive oxygen species (ROS) dual-responsive PEG-doxorubicin (DOX) conjugate (denoted as TPD) was synthesized through acyl alkynyl-amine click reaction by PEG dipropiolate (PEGB), amine-terminated thioketal (TKL), and doxorubicin (DOX). Due to the generated ene-amine and thioketal in the backbone, the prepared amphiphilic TPD not only has a high drug loading ratio for photosensitizer chlorin e6 (Ce6) but also has the sensitivity to the acidic tumor microenvironment (TME) and ROS. Considering the complex conditions of TME, the prepared TPD@Ce6 nanoparticles (NPs) might respond to the relatively low pH and release Ce6 initially, and upon laser radiation, Ce6 produces abundant singlet oxygen (1O2) to achieve a programmable accelerated release of DOX and more Ce6 at the tumor site. In addition, the NIR fluorescence of DOX could monitor drug delivery and controlled release. The developed TPD@Ce6 NPs can realize the targeted tumor in combination therapy with negligible cytotoxicity on normal tissues.

Supramolecular micelles as multifunctional theranostic agents for synergistic photodynamic therapy and hypoxia-activated chemotherapy

Photodynamic therapy (PDT), where a photosensitizer (under light irradiation) converts molecular oxygen to singlet oxygen to elicit programmed cell death, is a promising cancer treatment modality with a high temporal and spatial resolution. However, only limited cancer treatment efficacy has been achieved in clinical PDT due to the hypoxic conditions of solid tumor microenvironment that limits the generation of singlet oxygen, and PDT process often leads to even more hypoxic microenvironment due to the consumption of oxygens during therapy. Herein, we designed novel supramolecular micelles to co-deliver photosensitizer and hypoxia-responsive prodrug to improve the overall therapeutic efficacy. The supramolecular micelles (CPC) were derived from a polyethylene glycol (PEG) system dually tagged with hydrophilic cucurbit[7]uril (CB[7]) and hydrophobic Chlorin e6 (Ce6), respectively on each end, for synergistic antitumor therapy via PDT of Ce6 and chemotherapy of a hypoxia-responsive prodrug, banoxantrone (AQ4N), loaded into the cavity of CB[7]. In addition, CPC was further modularly functionalized by folate (FA) via strong host-guest interaction between folate-amantadine (FA-ADA) and CB[7] to produce a novel nanoplatform, AQ4N@CPC-FA, for targeted delivery. AQ4N@CPC-FA exhibited enhanced cellular uptake, negligible cytotoxicity and good biocompatibility, and improved intracellular reactive oxygen species (ROS) generation efficiency. More importantly, in vivo evaluation of AQ4N@CPC-FA revealed a synergistic antitumor efficacy between PDT of Ce6 and hypoxia-activated chemotherapy of AQ4N (that can be converted to chemotherapeutic AQ4 for tumor chemotherapy in response to the strengthened hypoxic tumor microenvironment during PDT treatment). This study not only provides a new nanoplatform for synergistic photodynamic-chemotherapeutic treatment, but also offers important new insights to design and development of multifunctional supramolecular drug delivery system. Statement of significancePhotodynamic therapy (PDT) has exhibited a variety of advantages for cancer phototherapy as compared to traditional chemotherapy. However, the unsatisfactory therapeutic efficacy by PDT alone as a result of the enhanced tumor hypoxia during PDT has limited its clinical application. Herein, we designed multifunctional supramolecular micelles to co-deliver photosensitizer and hypoxia-responsive prodrug to improve the overall therapeutic efficacy. The supramolecular micelles are biocompatible and possess strong red absorption, controlled drug release profile, and ultimately enhanced therapeutic outcome via PDT-chemotherapy. This study not only provides a new nanoplatform for synergistic photodynamic-chemotherapeutic treatment of cancer, but also offers important new insights to design and development of multifunctional supramolecular drug delivery tool for multi-modality cancer therapy.

Explainable Artificial Intelligence Reveals Novel Insight into Tumor Microenvironment Conditions Linked with Better Prognosis in Patients with Breast Cancer.

Simple SummaryOver the past decade, there has been a significant increase in the number of omics datasets that provide unprecedented opportunities to systematically characterize the underlying biological mechanisms involved in cancer evolution and to understand how the tumor microenvironment contributes to this evolution. Novel techniques in artificial intelligence (AI) can help determine areas of therapeutic need, enhance clinical trial interpretation, identify novel targets, and generate accurate predictions that are impossible with traditional statistical techniques. However, a major criticism of incorporating the highly accurate and nonlinear AI models into medical fields is the notion that AI is essentially a “black box”. We resolved this overarching problem with explainable artificial intelligence (XAI) to determine prognoses in patients with breast cancer and reveal valuable information about conditions in the tumor microenvironment that are associated with enhanced prognosis and patient survival. The benefits of using XAI in the development of new targeted therapies would be significant.We investigated the data-driven relationship between immune cell composition in the tumor microenvironment (TME) and the ≥5-year survival rates of breast cancer patients using explainable artificial intelligence (XAI) models. We acquired TCGA breast invasive carcinoma data from the cbioPortal and retrieved immune cell composition estimates from bulk RNA sequencing data from TIMER2.0 based on EPIC, CIBERSORT, TIMER, and xCell computational methods. Novel insights derived from our XAI model showed that B cells, CD8+ T cells, M0 macrophages, and NK T cells are the most critical TME features for enhanced prognosis of breast cancer patients. Our XAI model also revealed the inflection points of these critical TME features, above or below which ≥5-year survival rates improve. Subsequently, we ascertained the conditional probabilities of ≥5-year survival under specific conditions inferred from the inflection points. In particular, the XAI models revealed that the B cell fraction (relative to all cells in a sample) exceeding 0.025, M0 macrophage fraction (relative to the total immune cell content) below 0.05, and NK T cell and CD8+ T cell fractions (based on cancer type-specific arbitrary units) above 0.075 and 0.25, respectively, in the TME could enhance the ≥5-year survival in breast cancer patients. The findings could lead to accurate clinical predictions and enhanced immunotherapies, and to the design of innovative strategies to reprogram the breast TME.

Drug Repurposing of Pantoprazole and Vitamin C Targeting Tumor Microenvironment Conditions Improves Anticancer Effect in Metastatic Castration-Resistant Prostate Cancer.

The effective and economical therapeutic strategy for metastatic castration-resistant prostate cancer (mCRPC) is still requested from patients, who are not available for Lu-177 or Ra-223 treatment. Drug repurposing as a cost-effective and time-saving alternative to traditional drug development has been increasingly discussed. Proton pump inhibitors (PPIs) such as pantroprazole, which are commonly used as antacids, have also been shown to be effective in cancer chemoprevention via induction of apoptosis in multiple cancer cell lines. Vitamin C is an essential micronutrient for human body, has been proposed as a potential anti-cancer agent. In this context, have we investigated the combination of vitamin C and pantoprazole for the management of metastatic castration-resistant prostate cancer (mCRPC). Six chosen human adenocarcinoma cell lines were used to investigate the influence of pantoprazole on the microenvironment of cancer cells (extracellular pH and production of exosomes). Tumor growth and tumor 18F-FDG uptake in PC3 xenografts were analyzed following varied treatment. Our in vitro Results have suggested that pantoprazole enhanced the cytotoxic activity of vitamin C by regulating pH values and production of exosomes in cancer cells. Moreover, the synergistic effect of pantoprazole and vitamin C was pH-dependent since pantoprazole was more effective at a slightly acidic pH. In vivo, the combined treatment using pantoprazole and vitamin C produced better therapeutic outcomes than treatment with vitamin C or pantoprazole alone, as demonstrated via tumor growth and uptake of 18F-FDG. Therefore, we suggest that pantoprazole combined with vitamin C could be as a possible strategy to manage mCRPC.

A biocompatible theranostic agent based on stable bismuth nanoparticles for X-ray computed tomography/magnetic resonance imaging-guided enhanced chemo/photothermal/chemodynamic therapy for tumours

Cancer is a leading cause of death worldwide and seriously threatens the health of humans. The current clinical treatments for cancer are not efficient and always lead to significant side effects. Herein, a biocompatible and powerful theranostic agent (Bi@mSiO2@MnO2/DOX) is fabricated using a facile stepwise reaction method. The Bi nanoparticles (NPs) are coated by mesoporous silica to protect the Bi NPs from oxidation, which guarantees the stable photothermal effect of the Bi NPs. When the Bi@mSiO2@MnO2/DOX nanocomposites (NCs) accumulate in the tumour site, hyperthermia is generated by Bi NPs under near-infrared (NIR) light irradiation for photothermal therapy (PTT), and the generated heat triggers the release of DOX for chemotherapy in the tumour. In addition, the MnO2 of the NCs responsively catalyses endogenous H2O2 to generate O2, raising the oxygen level to enhance the effect of chemotherapy in the tumour microenvironment (TME), and consumes glutathione (GSH) to produce Mn2+ for magnetic resonance (MR) imaging. Under acidic TME conditions, H2O2 and Mn2+ also produce toxic hydroxyl radical (·OH) for chemodynamic therapy (CDT). Furthermore, the Bi NPs can also be used as excellent contrast agents for X-ray computed tomography (CT) imaging of tumours with a high CT value (6.865 HU mM−1). The Bi@mSiO2@MnO2/DOX NCs exhibit a powerful theranostic performance for CT/MR imaging-guided enhanced PTT/CDT/chemotherapy, which opens a new prospect to rationally design theranostic agents for tumour imaging.

Abstract 1870: Novel conditionally active bispecific T cell engagers targeting solid tumors

Abstract The use of CD3/target bispecific molecules has great therapeutic potential in oncology. This potential, however, is diminished due to severe cytokine release effects as well as serious on-target off-tumor toxicities. Conditionally Active Biologic (CAB) technology is a proprietary platform that generates bispecific antibodies which have no or very little binding to CD3 and to the tumor target antigen (TAA) in healthy tissue (normal physiological conditions), but have strong binding in the context of diseased tissues (tumor microenvironment) based on the glycolytic tumor metabolism (including Warburg effect). Using our CAB technology, we have developed dual-CAB (CAB TAA x CAB CD3) bispecific antibodies targeting two well-established tumor associated antigens, B7H3 and Nectin4. These dual-CAB bispecific antibodies were developed so that they bind to recombinant CD3 and TAA as well as to CD3 and TAA expressing cells under in vitro tumor microenvironment conditions, but not in physiologic conditions. In vitro characterization and in vivo efficacy data of the dual-CAB TAA x CD3 bispecific antibodies targeting B7H3 and Nectin4 will be presented. The CAB technology allows the generation of a new class of potent T-cell engagers with increased safety margin and therapeutic index in the clinic. Citation Format: Haizhen Liu, Jing Wang, Ana Paula G. Cugnetti, Charles Xing, Christina Wheeler, Matthew Lucas, Cathy Chang, Gerhard Frey, William Boyle, Jay Short. Novel conditionally active bispecific T cell engagers targeting solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1870.

Chemo-mechanistic multi-scale model of a three-dimensional tumor microenvironment to quantify the chemotherapy response of cancer.

Exploring efficient chemotherapy would benefit from a deeper understanding of the tumor microenvironment (TME) and its role in tumor progression. As in vivo experimental methods are unable to isolate or control individual factors of the TME, and in vitro models often cannot include all the contributing factors, some questions are best addressed with mathematical models of systems biology. In this study, we establish a multi-scale mathematical model of the TME to simulate three-dimensional tumor growth and angiogenesis and then implement the model for an array of chemotherapy approaches to elucidate the effect of TME conditions and drug scheduling on controlling tumor progression. The hyperglycemic condition as the most common disorder for cancer patients is considered to evaluate its impact on cancer response to chemotherapy. We show that combining antiangiogenic and anticancer drugs improves the outcome of treatment and can decrease accumulation of the drug in normal tissue and enhance drug delivery to the tumor. Our results demonstrate that although both concurrent and neoadjuvant combination therapies can increase intratumoral drug exposure and therapeutic accuracy, neoadjuvant therapy surpasses this, especially against hyperglycemia. Our model provides mechanistic explanations for clinical observations of tumor progression and response to treatment and establishes a computational framework for exploring better treatment strategies.

Exploiting a New Approach to Destroy the Barrier of Tumor Microenvironment: Nano-Architecture Delivery Systems.

Recent findings suggest that tumor microenvironment (TME) plays an important regulatory role in the occurrence, proliferation, and metastasis of tumors. Different from normal tissue, the condition around tumor significantly altered, including immune infiltration, compact extracellular matrix, new vasculatures, abundant enzyme, acidic pH value, and hypoxia. Increasingly, researchers focused on targeting TME to prevent tumor development and metastasis. With the development of nanotechnology and the deep research on the tumor environment, stimulation-responsive intelligent nanostructures designed based on TME have attracted much attention in the anti-tumor drug delivery system. TME-targeted nano therapeutics can regulate the distribution of drugs in the body, specifically increase the concentration of drugs in the tumor site, so as to enhance the efficacy and reduce adverse reactions, can utilize particular conditions of TME to improve the effect of tumor therapy. This paper summarizes the major components and characteristics of TME, discusses the principles and strategies of relevant nano-architectures targeting TME for the treatment and diagnosis systematically.

Multi-sensitive curcumin-loaded nanomicelle based on ABC-CBA block copolymer for sustained drug delivery

A type of multi-sensitive ABC-CBA block copolymer with thermal, glutathione and pH-responsive bonds was synthesized via ring opening polymerization along with cationic ring opening mechanisms. In continuum, the synthesized copolymer strands self-assembled into nanomicelles. The linear copolymer is comprised poly (methoxy ethylene glycol)-b-poly (2-ethyl-2-oxazoline)-b-poly (ε-caprolactone)-cystamine (i.e. [mPEG-b-PEtOz-PCL]2-Cys) and the curcumin was encapsulated inside the micelles mostly through hydrophobic interaction. The H-NMR, FTIR and GPC analysis were applied to identify the composition structure of the copolymer. The critical micelle concentration (CMC) value was achieved favorably 0.01 mg/mL for the synthesized copolymer. The morphology and particle size of solid nanocarrier were characterized by DLS, Zeta potential, AFM, TEM, and SEM micrographs. The drug loading content for the curcumin was attained 13.3% (w/w), and the entrapment efficacy of the drug in nanocarrier was obtained 79 percent. The in vitro release profile of the drug-loaded micelle was investigated by exposure to different pH, temperature and reduction circumstances, stimulated by tumor microenvironment conditions. The cell viability assay of the drug-loaded nanocarrier demonstrates high cytotoxicity toward HDF cells, while the drug-free nanocarrier has trifling toxicity and good biocompatibility. Therefore, according to the pleasant output of the research, this novel nanomicelle based on ABC-CBA block copolymer can be carried out effectively as an efficient nanocarrier in targeted drug delivery.

Evaluation of Combination Strategies for the A2AR Inhibitor AZD4635 Across Tumor Microenvironment Conditions via a Systems Pharmacology Model.

BackgroundAdenosine receptor type 2 (A2AR) inhibitor, AZD4635, has been shown to reduce immunosuppressive adenosine effects within the tumor microenvironment (TME) and to enhance the efficacy of checkpoint inhibitors across various syngeneic models. This study aims at investigating anti-tumor activity of AZD4635 alone and in combination with an anti-PD-L1-specific antibody (anti-PD-L1 mAb) across various TME conditions and at identifying, via mathematical quantitative modeling, a therapeutic combination strategy to further improve treatment efficacy.MethodsThe model is represented by a set of ordinary differential equations capturing: 1) antigen-dependent T cell migration into the tumor, with subsequent proliferation and differentiation into effector T cells (Teff), leading to tumor cell lysis; 2) downregulation of processes mediated by A2AR or PD-L1, as well as other immunosuppressive mechanisms; 3) A2AR and PD-L1 inhibition by, respectively, AZD4635 and anti-PD-L1 mAb. Tumor size dynamics data from CT26, MC38, and MCA205 syngeneic mice treated with vehicle, anti-PD-L1 mAb, AZD4635, or their combination were used to inform model parameters. Between-animal and between-study variabilities (BAV, BSV) in treatment efficacy were quantified using a non-linear mixed-effects methodology.ResultsThe model reproduced individual and cohort trends in tumor size dynamics for all considered treatment regimens and experiments. BSV and BAV were explained by variability in T cell-to-immunosuppressive cell (ISC) ratio; BSV was additionally driven by differences in intratumoral adenosine content across the syngeneic models. Model sensitivity analysis and model-based preclinical study simulations revealed therapeutic options enabling a potential increase in AZD4635-driven efficacy; e.g., adoptive cell transfer or treatments affecting adenosine-independent immunosuppressive pathways.ConclusionsThe proposed integrative modeling framework quantitatively characterized the mechanistic activity of AZD4635 and its potential added efficacy in therapy combinations, across various immune conditions prevailing in the TME. Such a model may enable further investigations, via simulations, of mechanisms of tumor resistance to treatment and of AZD4635 combination optimization strategies.