Near-infrared photoimmunotherapy (NIR-PIT) on cholangiocarcinoma using a novel catheter device with light emitting diodes.

Near-infrared photoimmunotherapy (NIR-PIT) is a novel therapy for cancers that uses NIR light and antibody-photosensitizer (IR700) conjugates. However, it is difficult to deliver NIR light into the bile duct for cholangiocarcinoma (CCA) from the conventional extracorporeal apparatus. Thus, in this study, we developed a dedicated catheter with light emitting diodes (LEDs) that supersedes conventional external irradiation devices; we investigated the therapeutic effect of NIR-PIT for CCA using the novel catheter. The new catheter was designed to be placed in the bile duct and a temperature sensor was attached to the tip of the catheter to avoid thermal burn. An anti-epidermal growth factor receptor (EGFR) antibody, Panitumumab-IR700 conjugate or anti-human epidermal growth factor receptor type 2 (HER2) antibody, Trastuzumab-IR700 conjugate, was used with EGFR- or HER2-expressing cell lines, respectively. The in vitro efficacy of NIR-PIT was confirmed in cultured cells; the capability of the new catheter for NIR-PIT was then tested in a mouse tumor model. NIR-PIT via the developed catheter treated CCA xenografts in mice. NIR-PIT had an effect in Panitumumab-IR700 conjugate- and Trastuzumab-IR700 conjugate-treated CCA cells that depended on the receptor expression level. Tumor growth was significantly suppressed in mice treated with NIR-PIT using the novel catheter compared with controls (P < .01). NIR-PIT was an effective treatment for EGFR- and HER2-expressing CCA cells, and the novel catheter with mounted LEDs was useful for NIR-PIT of CCA.

Laser Treatment of Pancreatic Cancer with Immunostimulating Interstitial Laser Thermotherapy Protocol: Safety and Feasibility Results From Two Phase 2a Studies.

PURPOSE: Ablative techniques have emerged as new potential therapeutic options for patients with locally advanced pancreatic cancer (LAPC). We explored the safety and feasibility of using TRANBERG|Thermal Therapy System (Clinical Laserthermia Systems AB, Lund, Sweden) in feedback mode for immunostimulating Interstitial Laser Thermotherapy (imILT) protocol, the newest ablative technique introduced for the treatment of LAPC. METHODS: The safety and feasibility results after the use of imILT protocol treatment in 15 patients of a prospective series of postsystemic therapy LAPC in two high-volume European institutions, the General and Pancreatic Unit of the Pancreas Institute, of the University of Verona, Italy, and the Department of Surgical Oncology of the Institut Paoli-Calmettes of Marseille, France, were assessed. RESULTS: The mean age was 66 ± 5 years, with a mean tumor size of 34.6 (±8) mm. The median number of cycles of pre-imILT chemotherapy was 6 (6-12). The procedure was performed in 13 of 15 (86.6%) cases; indeed, in two cases, the procedure was not performed; in one, the procedure was considered technically demanding; in the other, liver metastases were found intraoperatively. In all treated cases, the procedure was completed. Three late pancreatic fistulas developed over four overall adverse events (26.6%) and were attributed to imILT. Mortality was nil. A learning curve is necessary to interpret and manage the laser parameters. CONCLUSIONS: Safety, feasibility, and device handling outcomes of using TRANBERG|Thermal Therapy System with temperature probes in feedback mode and imILT protocol on LAPC were not satisfactory. The metastatic setting may be appropriate to evaluate the hypothetic abscopal effect.#NCT02702986 and #NCT02973217.

In vitro humanized 3D microfluidic chip for testing personalized immunotherapeutics for head and neck cancer patients.

OBJECTIVES: Immunotherapy and personalized medicine therapeutics are emerging as promising approaches in the management of head and neck squamous cell carcinoma (HNSCC). In spite of that, there is yet no assay that could predict individual response to immunotherapy. METHODS: We manufactured an in vitro 3D microfluidic chip to test the efficacy of immunotherapy. The assay was first tested using a tongue cancer cell line (HSC-3) embedded in a human tumour-derived matrix "Myogel/fibrin" and immune cells from three healthy donors. Next, the chips were used with freshly isolated cancer cells, patients' serum and immune cells. Chips were loaded with different immune checkpoint inhibitors, PD-L1 antibody and IDO 1 inhibitor. Migration of immune cells towards cancer cells and the cancer cell proliferation rate were evaluated. RESULTS: Immune cell migration towards HSC-3 cells was cancer cell density dependent. IDO 1 inhibitor induced immune cells to migrate towards cancer cells both in HSC-3 and in two HNSCC patient samples. Efficacy of PD-L1 antibody and IDO 1 inhibitor was patient dependent. CONCLUSION: We introduced the first humanized in vitro microfluidic chip assay to test immunotherapeutic drugs against HNSCC patient samples. This assay could be used to predict the efficacy of immunotherapeutic drugs for individual patients.

Harnessing nanoparticles for immune modulation.

Recent approaches using nanoparticles engineered for immune regulation have yielded promising results in preclinical models of disease. The number of nanoparticle therapies is growing, fueled by innovations in nanotechnology and advances in understanding of the underlying pathogenesis of immune-mediated diseases. In particular, recent mechanistic insight into the ways in which nanoparticles interact with the mononuclear phagocyte system and impact its function during homeostasis and inflammation have highlighted the potential of nanoparticle-based therapies for controlling severe inflammation while concurrently restoring peripheral immune tolerance in autoimmune disease. Here we review recent advances in nanoparticle-based approaches aimed at immune-modulation, and discuss these in the context of concepts in polymeric nanoparticle development, including particle modification, delivery and the factors associated with successful clinical deployment.

Nanoparticle-Based Phototriggered Cancer Immunotherapy and Its Domino Effect in the Tumor Microenvironment.

Immune system evasion by cancer cells is one of the hallmarks of cancers, and it occurs with the support of tumor-associated immune cells (TICs) in the tumor microenvironment that increase the growth and invasiveness of tumor cells. With recent advancements in the development of novel near-infrared (NIR)-responsive nanoparticles, specifically eradicating TICs or inducing an inflammatory immune response by activating killer T cells has become possible. This review will discuss the mechanisms and applications of phototriggered immunotherapy in detail. In addition, various nanoparticles employed in phototriggered immunotherapy for cancer treatment will be covered. Furthermore, the challenges and future directions of phototriggered nanoparticle development for anticancer immunotherapy will be briefly discussed.

Design of virus-based nanomaterials for medicine, biotechnology, and energy.

This review provides an overview of recent developments in "chemical virology." Viruses, as materials, provide unique nanoscale scaffolds that have relevance in chemical biology and nanotechnology, with diverse areas of applications. Some fundamental advantages of viruses, compared to synthetically programmed materials, include the highly precise spatial arrangement of their subunits into a diverse array of shapes and sizes and many available avenues for easy and reproducible modification. Here, we will first survey the broad distribution of viruses and various methods for producing virus-based nanoparticles, as well as engineering principles used to impart new functionalities. We will then examine the broad range of applications and implications of virus-based materials, focusing on the medical, biotechnology, and energy sectors. We anticipate that this field will continue to evolve and grow, with exciting new possibilities stemming from advancements in the rational design of virus-based nanomaterials.

Enhanced Cancer Immunotherapy by Microneedle Patch-Assisted Delivery of Anti-PD1 Antibody.

Despite recent advances in melanoma treatment through the use of anti-PD-1 (aPD1) immunotherapy, the efficacy of this method remains to be improved. Here we report an innovative self-degradable microneedle (MN) patch for the sustained delivery of aPD1 in a physiologically controllable manner. The microneedle is composed of biocompatible hyaluronic acid integrated with pH-sensitive dextran nanoparticles (NPs) that encapsulate aPD1 and glucose oxidase (GOx), which converts blood glucose to gluconic acid. The generation of acidic environment promotes the self-dissociation of NPs and subsequently results in the substantial release of aPD1. We find that a single administration of the MN patch induces robust immune responses in a B16F10 mouse melanoma model compared to MN without degradation trigger or intratumoral injection of free aPD1 with the same dose. Moreover, this administration strategy can integrate with other immunomodulators (such as anti-CTLA-4) to achieve combination therapy for enhancing antitumor efficacy.

Selective cytopheretic inhibitory device with regional citrate anticoagulation and portable sorbent dialysis.

Selective cytopheretic inhibitory device (SCD) therapy is an immunomodulatory treatment provided by a synthetic biomimetic membrane in an extracorporeal circuit, which has shown promise in preclinical large animal models of severe sepsis as well as in clinical trials treating patients with acute kidney injury and multiple organ failure. During SCD therapy, citrate is administered to lower ionized calcium levels in blood for anticoagulation and inhibition of leukocyte activation. Historically, citrate has been known to interfere with sorbent dialysis, therefore, posing a potential issue for the use of SCD therapy with a portable dialysis system. This sorbent dialysis SCD (sorbent SCD) would be well suited for battlefield and natural disaster applications where the water supply for standard dialysis is limited, and the types of injuries in those settings would benefit from SCD therapy. In order to explore the compatibility of sorbent and SCD technologies, a uremic porcine model was tested with the Allient sorbent dialysis system (Renal Solutions Incorporated, Fresenius Medical Care, Warrendale, PA, USA) and concurrent SCD therapy with regional citrate anticoagulation. The hypothesis to be assessed was whether the citrate load required by the SCD could be metabolized prior to recirculation from systemic blood back into the therapeutic circuit. Despite the fact that the sorbent SCD maintained urea clearance without any adverse hematologic events, citrate load for SCD therapy caused an interaction with the sorbent column resulting in elevated, potentially toxic aluminum levels in dialysate and in systemic blood. Alternative strategies to implement sorbent-SCD therapy will be required, including development of alternate urease-sorbent column binding chemistry or further changes to the sorbent-SCD therapeutic circuit along with determining the minimum citrate concentration required for efficacious SCD treatment.

[The efficacy of polychromatic visible and infrared radiation used for the postoperative immunological rehabilitation of patients with breast cancer].

The immunological rehabilitation of the patients with oncological problems after the completion of standard anti-tumour therapy remains a topical problem in modern medicine. The up-to-date phototherapeutic methods find the increasingly wider application for the treatment of such patients including the use of monochromatic visible (VIS) and near infrared (nIR) radiation emitted from lasers and photodiodes. The objective of the present study was to substantiate the expediency of postoperative immune rehabilitation of the patients with breast cancer (BC) by means of irradiation of the body surface with polychromatic visible (pVIS) in combination with polychromatic infrared (pIR) light similar to the natural solar radiation without its minor UV component. The study included 19 patients with stage I--II BC at the mean age of 54.0 +/- 4.28 years having the infiltrative-ductal form of the tumour who had undergone mastectomy. These patients were randomly allocated to two groups, one given the standard course of postoperative rehabilitation (control), the other (study group) additionally treated with pVIS + pIR radiation applied to the lumbar-sacral region from days 1 to 7 after surgery. A Bioptron-2 phototherapeutic device, Switzerland, was used for the purpose (480-3400 nm, 40 mW/cm2, 12 J/cm2, with the light spot diameter of 15 cm). The modern standard immunological methods were employed. It was found that mastectomy induced changes of many characteristics of cellular and humoral immunity; many of them in different patients were oppositely directed. These changes were apparent within the first 7 days postoperatively. The course of phototherapy (PT) was shown to prevent the postoperative decrease in the counts of monocytes and natural killer (NK) cells, the total amount of CD3+ -T-lymphocytes (LPC), CD4+ -T-helpers, activated T-lymphocytes (CD3+ HLA-DR+ cells) and IgA levels as well as intracellular digestion rate of neutrophil-phagocyted bacteria. Moreover PT promoted faster normalization of postoperative leukocytosis and activation of cytotoxic CD8+ -T-LPC, reduced the elevated concentration of immune complexes in blood. Among the six tested cytokines, viz. IL-1beta, TNF-alpha, IL-6, IL-10, IFN-alpha, and IFN-gamma, only the latter two underwent significant elevation of their blood concentrations (IL-6 within 1 day) and IFN-gamma (within 7 days after mastectomy). The course of PT resulted in the decrease of their levels to the initial values. The follow-up of the treated patients during 4 years revealed neither recurrence of the disease nor the appearance of metastases.

Molecular surgery for the treatment of malignant tumors: bioincompatible material apheresis for cancer therapy?

Controlled immunological shock, induced by bioincompatible material apheresis for cancer (BIC MAC) therapy, produces an immunoactive status in experimental subjects. However, in order to provide a safe, painless, effective, and reproducible BIC MAC therapy, it is mandatory to provide general anesthesia with endotracheal intubation not only during apheresis procedures of 1-h duration but also for an additional 5 h. Using this procedure, there was no mortality experienced during animal experiments. Also, there were no procedurally related physical or sensory abnormalities demonstrated. This general anesthesia of 6 h covered not only the initial 30 min of the hypotension and hypoxic stages but also the recovery stages to hemodynamically normalize the experimental animals. After 6 h, the accumulated leukocytes in the lung are released back to the systemic circulation. In general, granulocytes decreased almost 100% while lymphocytes decreased only 40-50%. During these 6 h, increases of cytokines (tumor necrosis factor-α, interleukin-6, etc.) sometimes up to 1000 times occurred. After the 6-h procedure, leukocytes returned nearly to preoperative levels but tended to be continuously increased. After the fourth day, leukocyte counts more than doubled. These cellular and humoral activations were normalized after 2 weeks. These studies were conducted on six normal mongrel dogs. Currently, similar studies are planned to be conducted on tumor-bearing experimental animals. This procedurally induced immunoactivation by apheresis may be able to produce effective apoptosis in malignant tumor cells.

Comprehensive screening for antigens overexpressed on carcinomas via isolation of human mAbs that may be therapeutic.

Although several murine mAbs that have been humanized became useful therapeutic agents against a few malignancies, therapeutic Abs are not yet available for the majority of the human cancers because of our lack of knowledge of which antigens (Ags) can become useful targets. In the present study we established a procedure for comprehensive identification of such Ags through the extensive isolation of human mAbs that may become therapeutic. Using the phage-display Ab library we isolated a large number of human mAbs that bind to the surface of tumor cells. They were individually screened by immunostaining, and clones that preferentially and strongly stained the malignant cells were chosen. The Ags recognized by those clones were isolated by immunoprecipitation and identified by MS. We isolated 2,114 mAbs with unique sequences and identified 21 distinct Ags highly expressed on several carcinomas. Of those 2,114 mAbs 356 bound specifically to one of the 21 Ags. After preparing complete IgG(1) Abs the in vitro assay for Ab-dependent cell-mediated cytotoxicity (ADCC) and the in vivo assay in cancer-bearing athymic mice were performed to examine antitumor activity. The mAbs converted to IgG(1) revealed effective ADCC as well as antitumor activity in vivo. Because half of the 21 Ags showed distinct tumor-specific expression pattern and the mAbs isolated showed various characteristics with strong affinity to the Ag, it is likely that some of the Ags detected will become useful targets for the corresponding carcinoma therapy and that several mAbs will become therapeutic agents.

Soluble Antigen Arrays Efficiently Deliver Peptides and Arrest Spontaneous Autoimmune Diabetes.

Antigen-specific immunotherapy (ASIT) offers a targeted treatment of autoimmune diseases that selectively inhibits autoreactive lymphocytes, but there remains an unmet need for approaches that address the limited clinical efficacy of ASIT. Soluble antigen arrays (SAgAs) deliver antigenic peptides or proteins in multivalent form, attached to a hyaluronic acid backbone using either hydrolysable linkers (hSAgAs) or stable click chemistry linkers (cSAgAs). They were evaluated for the ability to block spontaneous development of disease in a nonobese diabetic mouse model of type 1 diabetes (T1D). Two peptides, a hybrid insulin peptide and a mimotope, efficiently prevented the onset of T1D when delivered in combination as SAgAs, but not individually. Relative to free peptides administered at equimolar dose, SAgAs (particularly cSAgAs) enabled a more effective engagement of antigen-specific T cells with greater persistence and induction of tolerance markers, such as CD73, interleukin-10, programmed death-1, and KLRG-1. Anaphylaxis caused by free peptides was attenuated using hSAgA and obviated using cSAgA platforms. Despite similarities, the two peptides elicited largely nonoverlapping and possibly complementary responses among endogenous T cells in treated mice. Thus, SAgAs offer a novel and promising ASIT platform superior to free peptides in inducing tolerance while mitigating risks of anaphylaxis for the treatment of T1D.

Implantable optical fibers for immunotherapeutics delivery and tumor impedance measurement.

Immune checkpoint blockade antibodies have promising clinical applications but suffer from disadvantages such as severe toxicities and moderate patient-response rates. None of the current delivery strategies, including local administration aiming to avoid systemic toxicities, can sustainably supply drugs over the course of weeks; adjustment of drug dose, either to lower systemic toxicities or to augment therapeutic response, is not possible. Herein, we develop an implantable miniaturized device using electrode-embedded optical fibers with both local delivery and measurement capabilities over the course of a few weeks. The combination of local immune checkpoint blockade antibodies delivery via this device with photodynamic therapy elicits a sustained anti-tumor immunity in multiple tumor models. Our device uses tumor impedance measurement for timely presentation of treatment outcomes, and allows modifications to the delivered drugs and their concentrations, rendering this device potentially useful for on-demand delivery of potent immunotherapeutics without exacerbating toxicities.

Pathological environment directed in situ peptidic supramolecular assemblies for nanomedicines.

Peptidic self-assembly provides a powerful method to build biomedical materials with integrated functions. In particular, pathological environment instructed peptidic supramolecular have gained great progress in treating various diseases. Typically, certain pathology related factors convert hydrophilic precursors to corresponding more hydrophobic motifs to assemble into supramolecular structures. Herein, we would like to review the recent progress of nanomedicines based on the development of instructed self-assembly against several specific disease models. Firstly we introduce the cancer instructed self-assembly. These assemblies have exhibited great inhibition efficacy, as well as enhanced imaging contrast, against cancer models both in vitro and in vivo. Then we discuss the infection instructed peptidic self-assembly. A number of different molecular designs have demonstrated the potential antibacterial application with satisfied efficiency for peptidic supramolecular assemblies. Further, we discuss the application of instructed peptidic self-assembly for other diseases including neurodegenerative disease and vaccine. The assemblies have succeeded in down-regulating abnormal Aß aggregates and immunotherapy. In summary, the self-assembly precursors are typical two-component molecules with (1) a self-assembling motif and (2) a cleavable trigger responsive to the pathological environment. Upon cleavage, the self-assembly occurs selectively in pathological loci whose targeting capability is independent from active targeting. Bearing the novel targeting regime, we envision that the pathological conditions instructed peptidic self-assembly will lead a paradigm shift on biomedical materials.

Activatable Polymer Nanoenzymes for Photodynamic Immunometabolic Cancer Therapy.

Tumor immunometabolism contributes substantially to tumor proliferation and immune cell activity, and thus plays a crucial role in the efficacy of cancer immunotherapy. Modulation of immunometabolism to boost cancer immunotherapy is mostly based on small-molecule inhibitors, which often encounter the issues of off-target adverse effects, drug resistance, and unsustainable response. In contrast, enzymatic therapeutics can potentially bypass these limitations but has been less exploited. Herein, an organic polymer nanoenzyme (SPNK) with near-infrared (NIR) photoactivatable immunotherapeutic effects is reported for photodynamic immunometabolic therapy. SPNK is composed of a semiconducting polymer core conjugated with kynureninase (KYNase) via PEGylated singlet oxygen (1 O2 ) cleavable linker. Upon NIR photoirradiation, SPNK generates 1 O2 not only to exert photodynamic effect to induce the immunogenic cell death of cancer, but also to unleash KYNase and trigger its activity to degrade the immunosuppressive kynurenine (Kyn). Such a combinational effect mediated by SPNK promotes the proliferation and infiltration of effector T cells, enhances systemic antitumor T cell immunity, and ultimately permits inhibition of both primary and distant tumors in living mice. Therefore, this study provides a promising photodynamic approach toward remotely controlled enzymatic immunomodulation for improved anticancer therapy.

Immunotherapy-on-Chip Against an Experimental Sepsis Model.

Lipopolysaccharide (LPS) is commonly used in murine sepsis models, which are largely associated with immunosuppression and collapse of the immune system. After adapting the LPS treatment to the needs of locally bred BALB/c mice, the present study explored the protective role of Micrococcus luteus peptidoglycan (PG)-pre-activated vaccine-on-chip technology in endotoxemia. The established protocol consisted of five daily intraperitoneal injections of 0.2 µg/g LPS, allowing longer survival, necessary for a therapeutic treatment application. A novel immunotherapy technology, the so-called vaccine-on-chip, consists of a 3-dimensional laser micro-textured silicon (Si) scaffold loaded with macrophages and activated in vitro with 1 µg/ml PG, which has been previously shown to exert a mild immunostimulatory activity upon subcutaneous implantation. The LPS treatment significantly decreased CD4 + and CD8 + cells, while increasing CD11b + , Gr1 + , CD25 + , Foxp3 + , and class II + cells. These results were accompanied by increased arginase-1 activity in spleen cell lysates and C-reactive protein (CRP), procalcitonin (PCT), IL-6, TNF-a, IL-10, and IL-18 in the serum, while acquiring severe sepsis phenotype as defined by the murine sepsis scoring. The in vivo application of PG pre-activated implant significantly increased the percentage of CD4 + and CD8 + cells, while decreasing the percentage of Gr1 + , CD25 + , CD11b + , Foxp3 + cells, and arginase-1 activity in the spleen of LPS-treated animals, as well as all serum markers tested, allowing survival and rescuing the severity of sepsis phenotype. In conclusion, these results reveal a novel immunotherapy technology based on PG pre-activated micro-texture Si scaffolds in LPS endotoxemia, supporting thus its potential use in the treatment of septic patients.

Elucidating the interaction dynamics between microswimmer body and immune system for medical microrobots.

The structural design parameters of a medical microrobot, such as the morphology and surface chemistry, should aim to minimize any physical interactions with the cells of the immune system. However, the same surface-borne design parameters are also critical for the locomotion performance of the microrobots. Understanding the interplay of such parameters targeting high locomotion performance and low immunogenicity at the same time is of paramount importance yet has so far been overlooked. Here, we investigated the interactions of magnetically steerable double-helical microswimmers with mouse macrophage cell lines and splenocytes, freshly harvested from mouse spleens, by systematically changing their helical morphology. We found that the macrophages and splenocytes can recognize and differentially elicit an immune response to helix turn numbers of the microswimmers that otherwise have the same size, bulk physical properties, and surface chemistries. Our findings suggest that the structural optimization of medical microrobots for the locomotion performance and interactions with the immune cells should be considered simultaneously because they are highly entangled and can demand a substantial design compromise from one another. Furthermore, we show that morphology-dependent interactions between macrophages and microswimmers can further present engineering opportunities for biohybrid microrobot designs. We demonstrate immunobots that can combine the steerable mobility of synthetic microswimmers and the immunoregulatory capability of macrophages for potential targeted immunotherapeutic applications.

Oxygen-ozone (O2-O3) immunoceutical therapy for patients with COVID-19. Preliminary evidence reported.

OBJECTIVE: This study evaluated the potential efficacy of a novel approach to treat COVID-19 patients, using an oxygen-ozone (O2-O3) mixture, via a process called Oxygen-Ozone- Immunoceutical Therapy. The methodology met the criteria of a novel, promising approach to treat successfully elderly COVID-19 patients, particularly when hospitalized in intensive care units (ICUs) Experimental design: We investigated the therapeutic effect of 4 cycles of O2-O3 in 50 hospitalized COVID-19 subjects suffering from acute respiratory disease syndrome (ARDS), aged more than 60 years, all males and undergoing non invasive mechanical ventilation in ICUs. RESULTS: Following O2-O3 treatment a significant improvement in inflammation and oxygenation indexes occurred rapidly and within the first 9 days after the treatment, despite the expected 14-20 days. A significant reduction of inflammatory and thromboembolic markers (CRP, IL-6, D-dimer) was observed. Furthermore, amelioration in the major respiratory indexes, such as respiratory and gas exchange markers (SatO2%, PaO2/FiO2 ratio), was reported. CONCLUSION: Our results show that O2-O3 treatment would be a promising therapy for COVID-19 patients. It leads patients to a fast recovery from ARDS via the improvement of major respiratory indexes and blood gas parameters, following a relatively short time of dispensed forced ventilation (about one to two weeks). This study may encourage the scientific community to further investigate and evaluate the proposed method for the treatment of COVID-19 patients.

Role of Nanobiotechnology in Drug Delivery.

This chapter is a brief overview of use of nanobiotechnology in drug delivery. Several types of nanoparticles are available. Nanoparticulate formulations of normally used drugs have increased efficacy due to improved absorption and require lower dosage with less side effects than standard formulations. Nanobiotechnology also facilitates targeted drug delivery of anticancer drugs, which is important for the management of cancer. Nanoparticles also facilitate crossing of biological barriers in the human body for drug delivery to targeted organs, for example, crossing the blood-brain barrier to reach the brain. Nanobiotechnology applications in delivery of biological therapies are expanding in areas such as cell and gene therapies, siRNAs, and monoclonal antibodies. Some nanoparticles can carry more than one therapeutic molecule enabling multimodal therapy and combination with physical modalities such as radiotherapy in cancer. Nanorobotics is developing with applications in drug delivery, particularly for cancer. Other anticipated developments in this area include use of nanotechnology for creating intelligent drug release devices.

Dissecting the immunosuppressive tumor microenvironments in Glioblastoma-on-a-Chip for optimized PD-1 immunotherapy.

Programmed cell death protein-1 (PD-1) checkpoint immunotherapy efficacy remains unpredictable in glioblastoma (GBM) patients due to the genetic heterogeneity and immunosuppressive tumor microenvironments. Here, we report a microfluidics-based, patient-specific 'GBM-on-a-Chip' microphysiological system to dissect the heterogeneity of immunosuppressive tumor microenvironments and optimize anti-PD-1 immunotherapy for different GBM subtypes. Our clinical and experimental analyses demonstrated that molecularly distinct GBM subtypes have distinct epigenetic and immune signatures that may lead to different immunosuppressive mechanisms. The real-time analysis in GBM-on-a-Chip showed that mesenchymal GBM niche attracted low number of allogeneic CD154+CD8+ T-cells but abundant CD163+ tumor-associated macrophages (TAMs), and expressed elevated PD-1/PD-L1 immune checkpoints and TGF-ß1, IL-10, and CSF-1 cytokines compared to proneural GBM. To enhance PD-1 inhibitor nivolumab efficacy, we co-administered a CSF-1R inhibitor BLZ945 to ablate CD163+ M2-TAMs and strengthened CD154+CD8+ T-cell functionality and GBM apoptosis on-chip. Our ex vivo patient-specific GBM-on-a-Chip provides an avenue for a personalized screening of immunotherapies for GBM patients.