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    Delivery technologies for cancer immunotherapy. Riley Rachel S,June Carl H,Langer Robert,Mitchell Michael J Nature reviews. Drug discovery Immunotherapy has become a powerful clinical strategy for treating cancer. The number of immunotherapy drug approvals has been increasing, with numerous treatments in clinical and preclinical development. However, a key challenge in the broad implementation of immunotherapies for cancer remains the controlled modulation of the immune system, as these therapeutics have serious adverse effects including autoimmunity and nonspecific inflammation. Understanding how to increase the response rates to various classes of immunotherapy is key to improving efficacy and controlling these adverse effects. Advanced biomaterials and drug delivery systems, such as nanoparticles and the use of T cells to deliver therapies, could effectively harness immunotherapies and improve their potency while reducing toxic side effects. Here, we discuss these research advances, as well as the opportunities and challenges for integrating delivery technologies into cancer immunotherapy, and we critically analyse the outlook for these emerging areas. 10.1038/s41573-018-0006-z
    Improving cancer immunotherapy through nanotechnology. Goldberg Michael S Nature reviews. Cancer The 2018 Nobel Prize in Physiology or Medicine was awarded to pioneers in the field of cancer immunotherapy, as the utility of leveraging a patient's coordinated and adaptive immune system to fight the patient's unique tumour has now been validated robustly in the clinic. Still, the proportion of patients who respond to immunotherapy remains modest (~15% objective response rate across indications), as tumours have multiple means of immune evasion. The immune system is spatiotemporally controlled, so therapies that influence the immune system should be spatiotemporally controlled as well, in order to maximize the therapeutic index. Nanoparticles and biomaterials enable one to program the location, pharmacokinetics and co-delivery of immunomodulatory compounds, eliciting responses that cannot be achieved upon administration of such compounds in solution. The convergence of cancer immunotherapy, nanotechnology, bioengineering and drug delivery is opportune, as each of these fields has matured independently to the point that it can now be used to complement the others substantively and rationally, rather than modestly and empirically. As a result, unmet needs increasingly can be addressed with deductive intention. This Review explores how nanotechnology and related approaches are being applied to augmenting both endogenous leukocytes and adoptively transferred ones by informing specificity, influencing localization and improving function. 10.1038/s41568-019-0186-9
    Nanomedicine-Based Immunotherapy for the Treatment of Cancer Metastasis. Zhang Pengcheng,Zhai Yihui,Cai Ying,Zhao Yuliang,Li Yaping Advanced materials (Deerfield Beach, Fla.) Metastasis is the leading cause of cancer-associated death, with poor prognosis even after extensive treatment. The dormancy of metastatic cancer cells during dissemination or after colony formation is one major reason for treatment failure, as most drugs target cells of active proliferation. Immunotherapy has shown great potential in cancer therapy because the activity of effector cells is less affected by the metabolic status of cancer cells. In addition, metastatic cells out of immunosuppressive tumor microenvironment (TME) are more susceptible to immune clearance, although these cells can achieve immune surveillance evasion via strategies such as platelet and macrophage recruitment. Since nanomaterials themselves or their carried drugs have the capability to modulate the immune system, a great amount of focus has been placed on nanomedicine strategies that leverage immune cells participating the metastatic cascade. These nanomedicines successfully inhibit the tumor metastasis and prolong the survival of model animals. Immune cells that are involved in the metastasis cascade are first summarized and then recent and inspiring strategies and nanomaterials in this growing field are highlighted. 10.1002/adma.201904156
    Engineering Macrophages for Cancer Immunotherapy and Drug Delivery. Xia Yuqiong,Rao Lang,Yao Huimin,Wang Zhongliang,Ning Pengbo,Chen Xiaoyuan Advanced materials (Deerfield Beach, Fla.) Macrophages play an important role in cancer development and metastasis. Proinflammatory M1 macrophages can phagocytose tumor cells, while anti-inflammatory M2 macrophages such as tumor-associated macrophages (TAMs) promote tumor growth and invasion. Modulating the tumor immune microenvironment through engineering macrophages is efficacious in tumor therapy. M1 macrophages target cancerous cells and, therefore, can be used as drug carriers for tumor therapy. Herein, the strategies to engineer macrophages for cancer immunotherapy, such as inhibition of macrophage recruitment, depletion of TAMs, reprograming of TAMs, and blocking of the CD47-SIRPα pathway, are discussed. Further, the recent advances in drug delivery using M1 macrophages, macrophage-derived exosomes, and macrophage-membrane-coated nanoparticles are elaborated. Overall, there is still significant room for development in macrophage-mediated immune modulation and macrophage-mediated drug delivery, which will further enhance current tumor therapies against various malignant solid tumors, including drug-resistant tumors and metastatic tumors. 10.1002/adma.202002054
    Recent Advances in Engineered Materials for Immunotherapy-Involved Combination Cancer Therapy. Liang Jun-Long,Luo Guo-Feng,Chen Wei-Hai,Zhang Xian-Zheng Advanced materials (Deerfield Beach, Fla.) Immunotherapy that can activate immunity or enhance the immunogenicity of tumors has emerged as one of the most effective methods for cancer therapy. Nevertheless, single-mode immunotherapy is still confronted with several critical challenges, such as the low immune response, the low tumor infiltration, and the complex immunosuppression tumor microenvironment. Recently, the combination of immunotherapy with other therapeutic modalities has emerged as a powerful strategy to augment the therapeutic outcome in fighting against cancer. In this review, recent research advances of the combination of immunotherapy with chemotherapy, phototherapy, radiotherapy, sonodynamic therapy, metabolic therapy, and microwave thermotherapy are summarized. Critical challenges and future research direction of immunotherapy-based cancer therapeutic strategy are also discussed. 10.1002/adma.202007630
    Leveraging self-assembled nanobiomaterials for improved cancer immunotherapy. Cancer cell Nanomaterials and targeted drug delivery vehicles improve the therapeutic index of drugs and permit greater control over their pharmacokinetics, biodistribution, and bioavailability. Here, nanotechnologies applied to cancer immunotherapy are discussed with a focus on current and next generation self-assembling drug delivery systems composed of lipids and/or polymers. Topics covered include the fundamental design, suitability, and inherent properties of nanomaterials that induce anti-tumor immune responses and support anti-cancer vaccination. Established active and passive targeting strategies as well as newer "indirect" methods are presented together with insights into how nanocarrier structure and surface chemistry can be leveraged for controlled delivery to the tumor microenvironment while minimizing off-target effects. 10.1016/j.ccell.2022.01.006
    Mesoporous Silica as a Versatile Platform for Cancer Immunotherapy. Nguyen Thanh Loc,Choi Youngjin,Kim Jaeyun Advanced materials (Deerfield Beach, Fla.) Immunotherapy has been recognized for decades as a promising therapeutic method for cancer treatment. To enhance host immune responses against cancer, antigen-presenting cells (APCs; e.g., dendritic cells) or T cells are educated using immunomodulatory agents including tumor-associated antigens and adjuvants, and manipulated to induce a cascading adaptive immune response targeting tumor cells. Mesoporous silica materials are promising candidates to improve cancer immunotherapy based on their attractive properties that include high porosity, high biocompatibility, facile surface modification, and self-adjuvanticity. Here, the recent progress on mesoporous-silica-based immunotherapies based on two material forms is summarized: 1) mesoporous silica nanoparticles (MSNs), which can be internalized into APCs, and 2) micrometer-sized mesoporous silica rods (MSRs) that can form a 3D space to recruit APCs. Subcutaneously injected MSN-based cancer vaccines can be taken up by peripheral APCs or by APCs in lymphoid organs to educate the immune system against cancer cells. MSR cancer vaccines can recruit immune cells into the MSR scaffold to induce cancer-specific immunity. Both vaccine systems successfully stimulate the adaptive immune response to eradicate cancer in vivo. Thus, mesoporous silica has potential value as a material platform for the treatment of cancer or infectious diseases. 10.1002/adma.201803953
    Improving cancer immunotherapy using nanomedicines: progress, opportunities and challenges. Martin John D,Cabral Horacio,Stylianopoulos Triantafyllos,Jain Rakesh K Nature reviews. Clinical oncology Multiple nanotherapeutics have been approved for patients with cancer, but their effects on survival have been modest and, in some examples, less than those of other approved therapies. At the same time, the clinical successes achieved with immunotherapy have revolutionized the treatment of multiple advanced-stage malignancies. However, the majority of patients do not benefit from the currently available immunotherapies and many develop immune-related adverse events. By contrast, nanomedicines can reduce - but do not eliminate - the risk of certain life-threatening toxicities. Thus, the combination of these therapeutic classes is of intense research interest. The tumour microenvironment (TME) is a major cause of the failure of both nanomedicines and immunotherapies that not only limits delivery, but also can compromise efficacy, even when agents accumulate in the TME. Coincidentally, the same TME features that impair nanomedicine delivery can also cause immunosuppression. In this Perspective, we describe TME normalization strategies that have the potential to simultaneously promote the delivery of nanomedicines and reduce immunosuppression in the TME. Then, we discuss the potential of a combined nanomedicine-based TME normalization and immunotherapeutic strategy designed to overcome each step of the cancer-immunity cycle and propose a broadly applicable 'minimal combination' of therapies designed to increase the number of patients with cancer who are able to benefit from immunotherapy. 10.1038/s41571-019-0308-z
    Stimuli-Responsive Nanoparticles for Controlled Drug Delivery in Synergistic Cancer Immunotherapy. Zhang Jin,Lin Yandai,Lin Zhe,Wei Qi,Qian Jiaqi,Ruan Renjie,Jiang Xiancai,Hou Linxi,Song Jibin,Ding Jianxun,Yang Huanghao Advanced science (Weinheim, Baden-Wurttemberg, Germany) Cancer immunotherapy has achieved promising clinical progress over the recent years for its potential to treat metastatic tumors and inhibit their recurrences effectively. However, low patient response rates and dose-limiting toxicity remain as major dilemmas for immunotherapy. Stimuli-responsive nanoparticles (srNPs) combined with immunotherapy offer the possibility to amplify anti-tumor immune responses, where the weak acidity, high concentration of glutathione, overexpressions of enzymes, and reactive oxygen species, and external stimuli in tumors act as triggers for controlled drug release. This review highlights the design of srNPs based on tumor microenvironment and/or external stimuli to combine with different anti-tumor drugs, especially the immunoregulatory agents, which eventually realize synergistic immunotherapy of malignant primary or metastatic tumors and acquire a long-term immune memory to prevent tumor recurrence. The authors hope that this review can provide theoretical guidance for the construction and clinical transformation of smart srNPs for controlled drug delivery in synergistic cancer immunotherapy. 10.1002/advs.202103444
    Tumor-activated carrier-free prodrug nanoparticles for targeted cancer Immunotherapy: Preclinical evidence for safe and effective drug delivery. Advanced drug delivery reviews As immunogenic cell death (ICD) inducers initiating antitumor immune responses, certain chemotherapeutic drugs have shown considerable potential to reverse the immunosuppressive tumor microenvironment (ITM) into immune-responsive tumors. The application of these drugs in nanomedicine provides a more enhanced therapeutic index by improving unfavorable pharmacokinetic (PK) profiles and inefficient tumor targeting. However, the clinical translation of conventional nanoparticles is restricted by fundamental problems, such as risks of immunogenicity and potential toxicity by carrier materials, premature drug leakage in off-target sites during circulation, low drug loading contents, and complex structure and synthetic processes that hinder quality control (QC) and scale-up industrial production. To address these limitations, tumor-activated carrier-free prodrug nanoparticles (PDNPs), constructed only by the self-assembly of prodrugs without any additional carrier materials, have been widely investigated with distinct advantages for safe and more effective drug delivery. In addition, combination immunotherapy based on PDNPs with other diverse modalities has efficiently reversed the ITM to immune-responsive tumors, potentiating the response to immune checkpoint blockade (ICB) therapy. In this review, the trends and advances in PDNPs are outlined, and each self-assembly mechanism is discussed. In addition, various combination immunotherapies based on PDNPs are reviewed. Finally, a physical tumor microenvironment remodeling strategy to maximize the potential of PDNPs, and key considerations for clinical translation are highlighted. 10.1016/j.addr.2022.114177
    Adverse Events Following Cancer Immunotherapy: Obstacles and Opportunities. Pauken Kristen E,Dougan Michael,Rose Noel R,Lichtman Andrew H,Sharpe Arlene H Trends in immunology Oncology has recently undergone a revolutionary change with widespread adoption of immunotherapy for many cancers. Immunotherapy using monoclonal antibodies against checkpoint molecules, including programmed death (PD)-1, PD ligand (PD-L)1, and cytotoxic T lymphocyte-associated antigen (CTLA)-4, is effective in a significant subset of patients. However, immune-related adverse events (irAEs) have emerged as frequent complications of checkpoint blockade, likely due to the physiological role of checkpoint pathways in regulating adaptive immunity and preventing autoimmunity. As immunotherapy becomes more common, a better understanding of the etiology of irAEs and ways to limit these events is needed. At the same time, studying these new therapy-related disorders provides an opportunity to better understand naturally occurring human autoimmune and inflammatory disorders, with the potential to improve therapies for cancer and autoimmune diseases. 10.1016/j.it.2019.04.002
    Top 10 Challenges in Cancer Immunotherapy. Hegde Priti S,Chen Daniel S Immunity Cancer immunotherapy is a validated and critically important approach for treating patients with cancer. Given the vast research and clinical investigation efforts dedicated to advancing both endogenous and synthetic immunotherapy approaches, there is a need to focus on crucial questions and define roadblocks to the basic understanding and clinical progress. Here, we define ten key challenges facing cancer immunotherapy, which range from lack of confidence in translating pre-clinical findings to identifying optimal combinations of immune-based therapies for any given patient. Addressing these challenges will require the combined efforts of basic researchers and clinicians, and the focusing of resources to accelerate understanding of the complex interactions between cancer and the immune system and the development of improved treatment options for patients with cancer. 10.1016/j.immuni.2019.12.011