Engineering multifunctional nanoplatforms with high therapeutic benefits has become a promising strategy for intractable cancer treatment. A novel polyphenol‐based nanocomplex was designed to evoke ...highly efficacious cancer immunosurveillance while localizing therapy on the primary tumor and to minimize systemic side effects. This nanocomplex is prepared via metal–polyphenol coordination by encapsulating a natural polyphenol, gossypol, and a newly synthesized polyphenol derivative, polyethylene glycol‐Chlorin e6 (Ce6). The combination of gossypol from cotton and the photosensitizer Ce6 can induce chemotherapeutic/photodynamic immunogenic cancer cell death upon laser irradiation, which is supported by a rich maturation of dendritic cells, concentrated secretion of inflammatory cytokines, and significant inhibition of distant untreated tumors. Finally, an assistance of the programmed‐cell‐death ligand‐1 checkpoint‐blockade immunotherapy can enhance the anti‐tumor immune stimulation of our nanoplatform to a higher level.
A naturally occurring polyphenol, gossypol, and a self‐synthesized polyphenol derivative, PEG‐Ce6 polyphenol, coordinate to Fe2+ and thereby form a nanoplatform for the combination of photodynamic therapy and chemotherapy. This nanoplatform‐based combination therapy could significantly enhance the treatment efficacy of PD‐L1 checkpoint‐blockade immunotherapy.
Cancer immunotherapy aimed at boosting cancer-specific immunoresponses to eradicate tumor cells has evolved as a new treatment modality. Nanoparticles incorporating antigens and immunomodulatory ...agents can activate immune cells and modulate the tumor microenvironment to enhance anti-tumor immunity. The nanotechnology approach has been demonstrated to be superior to standard formulations in in-vivo settings. In this article, we focus on recent advances made within the last 5 years in nanoparticle-based cancer immunotherapy, including peptide- and nucleic acid-based nanovaccines, nanomedicines containing an immunoadjuvant to activate anti-tumor immunity, nanoparticle delivery of immune checkpoint inhibitors and the combination of the above approaches. Encouraging results and new emerging nanotechnologies in drug delivery promise the continuous growth of this field and ultimately clinical translation of enhanced immunotherapy of cancer.
The schematic illustration of various nanoparticle delivery systems for cancer immunotherapy. Display omitted
Microfluidic culture has the potential to revolutionize cancer diagnosis and therapy. Indeed, several microdevices are being developed specifically for clinical use to test novel cancer therapeutics. ...To be effective, these platforms need to replicate the continuous interactions that exist between tumor cells and non-tumor cell elements of the tumor microenvironment through direct cell-cell or cell-matrix contact or by the secretion of signaling factors such as cytokines, chemokines and growth factors. Given the challenges of personalized or precision cancer therapy, especially with the advent of novel immunotherapies, a critical need exists for more sophisticated
ex vivo
diagnostic systems that recapitulate patient-specific tumor biology with the potential to predict response to immune-based therapies in real-time. Here, we present details of a method to screen for the response of patient tumors to immune checkpoint blockade therapy, first reported in Jenkins
et al. Cancer Discovery
, 2018,
8
, 196-215, with updated evaluation of murine- and patient-derived organotypic tumor spheroids (MDOTS/PDOTS), including evaluation of the requirement for 3D microfluidic culture in MDOTS, demonstration of immune-checkpoint sensitivity of PDOTS, and expanded evaluation of tumor-immune interactions using RNA-sequencing to infer changes in the tumor-immune microenvironment. We also examine some potential improvements to current systems and discuss the challenges in translating such diagnostic assays to the clinic.
Microfluidic culture has the potential to revolutionize cancer diagnosis and therapy.
Hematological malignancies (HM) are a collection of malignant transformations originating from cells in the primary or secondary lymphoid organs. Leukemia, lymphoma, and multiple myeloma comprise the ...three major types of HM. Current treatment consists of bone marrow transplantation, radiotherapy, immunotherapy and chemotherapy. Although, many chemotherapeutic drugs are clinically available for the treatment of HM, the use of these agents is limited due to dose-related toxicity and lack of specificity to tumor tissue. Moreover, the poor pharmacokinetic profile of most of the chemotherapeutics requires high dosage and frequent administration to maintain therapeutic levels at the target site, both increasing adverse effects. This underlines an urgent need for a suitable drug delivery system to improve efficacy, safety, and pharmacokinetic properties of conventional therapeutics. Nanomedicines have proven to enhance these properties for anticancer therapeutics. The most extensively studied nanomedicine systems are lipid-based nanoparticles and polymeric nanoparticles. Typically, nanomedicines are small sub-micron sized particles in the size range of 20-200 nm. The biocompatible and biodegradable nature of nanomedicines makes them attractive vehicles to improve drug delivery. Their small size allows them to extravasate and accumulate at malignant sites passively by means of the enhanced permeability and retention (EPR) effect, resulting from rapid angiogenesis and inflammation. Moreover, the specificity to the target tissue can be further enhanced by surface modification of nanoparticles. This review describes currently available therapies as well as limitations and potential advantages of nanomedicine formulations for treatment of various types of HM. Additionally, recent investigational and approved nanomedicine formulations and their limited applications in HM are discussed.
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•Secondary lymphoid organ microenvironment is crucial for progression of HM.•Conventional (chemo)therapeutics lack specificity towards malignant sites.•Nanomedicines could improve the therapeutic index of drugs for HM.•Nanomedicine properties make them ideal for targeting specifically infiltrated sites.
Magenkarzinome sind in Deutschland bei Frauen für 2,4% und bei Männern für 3,5% der Krebsneuerkrankungen verantwortlich und gehen mit einer hohen Letalitätsrate einher. In der Therapie wird zwischen ...einer lokalen und einer metastasierten Tumorerkrankung unterschieden. Neue Behandlungsverfahren wie Immuntherapie und zielgerichtete Therapie halten in beiden Fällen Einzug in die derzeitigen Therapiestrategien und verbessern damit die Prognose der Patient*innen.
Cytokines were the first modern immunotherapies to produce durable responses in patients with advanced cancer, but they have only modest efficacy and limited tolerability
. In an effort to identify ...alternative cytokine pathways for immunotherapy, we found that components of the interleukin-18 (IL-18) pathway are upregulated on tumour-infiltrating lymphocytes, suggesting that IL-18 therapy could enhance anti-tumour immunity. However, recombinant IL-18 previously did not demonstrate efficacy in clinical trials
. Here we show that IL-18BP, a high-affinity IL-18 decoy receptor, is frequently upregulated in diverse human and mouse tumours and limits the anti-tumour activity of IL-18 in mice. Using directed evolution, we engineered a 'decoy-resistant' IL-18 (DR-18) that maintains signalling potential but is impervious to inhibition by IL-18BP. Unlike wild-type IL-18, DR-18 exerted potent anti-tumour effects in mouse tumour models by promoting the development of poly-functional effector CD8
T cells, decreasing the prevalence of exhausted CD8
T cells that express the transcriptional regulator of exhaustion TOX, and expanding the pool of stem-like TCF1
precursor CD8
T cells. DR-18 also enhanced the activity and maturation of natural killer cells to effectively treat anti-PD-1 resistant tumours that have lost surface expression of major histocompatibility complex class I molecules. These results highlight the potential of the IL-18 pathway for immunotherapeutic intervention and implicate IL-18BP as a major therapeutic barrier.
Drug discovery and efficacy in cancer treatments are limited by the inability of pre‐clinical models to predict successful outcomes in humans. Limitations remain partly due to their lack of a ...physiologic tumor microenvironment (TME), which plays a considerable role in drug delivery and tumor response to therapy. Chemotherapeutics and immunotherapies rely on transport through the vasculature, via the smallest capillaries and stroma to the tumor, where passive and active transport processes are at play. Here, a 3D vascularized tumor on‐chip is used to examine drug delivery in a relevant TME within a large bed of perfusable vasculature. This system demonstrates highly localized pathophysiological effects of two tumor spheroids (Skov3 and A549), which cause significant changes in vessel density and barrier function. Paclitaxel (Taxol) uptake is examined through diffusivity measurements, functional efflux assays, and accumulation of the fluorescent‐conjugated drug within the TME. Due to vascular and stromal contributions, differences in the response of vascularized tumors to Taxol (shrinkage and CD44 expression) are apparent compared with simpler models. This model specifically allows for examination of spatially resolved tumor‐associated endothelial dysfunction, likely improving the representation of in vivo drug distribution, and has potential for development into a more predictable model of drug delivery.
A vascularized human tumor on‐chip examines chemotherapeutic drug delivery in a more relevant tumor microenvironment. Tumors dramatically alter the local vascular and stromal landscape and can contribute to the negative impacts of chemotherapeutic treatment on vascular transport. This model has the potential for development into a relevant pre‐clinical model, where tumor‐endothelial and tumor‐stromal interactions are considered in drug‐delivery.
T cell immunotherapy holds significant challenges in solid tumors, mainly due to the T cells’ low activation and the decreased synthesis–release of therapeutic proteins, including perforin and ...granzyme B, which are present in lysosomes. In this study, a lysosome‐targeting nanoparticle (LYS‐NP) is developed by way of a mineralized metal–organic framework (MOF) coupled with a lysosome‐targeting aptamer (CD63‐aptamer) to enhance the antitumor effect of T cells. The MOF synthesized from Zn2+ and dimethylimidazole has good protein encapsulation and acid sensitivity, and is thus an ideal lysosomal delivery vector. Calcium carbonate (CaCO3) is used to induce MOF mineralization, improve the composite material's stability in encapsulating therapeutic protein, and provide calcium ions with synergistic effects. Before mineralization, perforin and granzyme B—T cell‐needed therapeutic proteins for tumors—are preloaded with the MOF. Moreover, T cells are pretreated with processed tumor‐specific antigens to activate or produce memory before reprogramming the lysosomes, facilitating the T cell receptor (TCR) for release of the therapeutic proteins. Using T cells recombined by LYS‐NPs, a significant enhancement of breast cancer control is confirmed.
Lysosome‐targeted drug‐loaded nanoparticles (LYS‐NPs) composed of CD63‐aptamers coupled with mineralized metal–organic frameworks are developed. Using the degradation of the LYS‐NPs in lysosomes, therapeutic proteins and Ca2+ are stored in the lysosomes of T cells. Next, they are released when the T cell receptor (TCR) of the T cells binds to tumor cells. These elements possess a powerful ability for cancer immunotherapy.
As an essential component of immunotherapy, monoclonal antibodies (mAbs) have emerged as a class of powerful therapeutics for treatment of a broad range of diseases. For central nervous system (CNS) ...diseases, however, the efficacy remains limited due to their inability to enter the CNS. A platform technology is reported here that enables effective delivery of mAbs to the CNS for brain tumor therapy. This is achieved by encapsulating the mAbs within nanocapsules that contain choline and acetylcholine analogues; such analogues facilitate the penetration of the nanocapsules through the brain–blood barrier and the delivery of mAbs to tumor sites. This platform technology uncages the therapeutic power of mAbs for various CNS diseases that remain poorly treated.
A bioinspired platform technology is developed, which enables effective delivery of monoclonal antibodies to the central nervous system for brain tumor therapy via intravenous administration. This platform technology uncages the therapeutic power of mAbs for various CNS diseases that remain poorly treated.
Immunotherapy is known to be clinically beneficial for cancer patients and in many cases represents the new standard of care. Because of this success, the interest in integrating nanomedicine with ...cancer immunotherapy to further improve clinical response and toxicity profiles has grown. However, unlike conventional systemic therapies, which are directly cytotoxic to tumour cells, cancer immunotherapy relies on the host's immune system to generate tumouricidal effects. As such, proper design of cancer immune nanomedicine requires scrutiny of tumours' intrinsic and extrinsic factors that may impact host antitumour immunity. Here, we highlight key parameters that differentiate cancer immunotherapy from conventional cytotoxic agents, and we discuss their implications for designing preclinical cancer immune nanomedicine studies. We emphasize that these factors, including intratumoural genomic heterogeneity, commensal diversity, sexual dimorphism and biological ageing, which were largely ignored in traditional cancer nanomedicine experiments, should be carefully considered and incorporated into cancer immune nanomedicine investigations given their critical involvement in shaping the body's antitumour immune responses.
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