Efficient Nanovaccine Delivery in Cancer Immunotherapy Guizhi Zhu,† Fuwu Zhang,† Qianqian Ni,† Gang Niu,† and Xiaoyuan Chen*,† †
Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH), Bethesda, Maryland 20892, United States ABSTRACT: Vaccines hold tremendous potential for cancer immunotherapy by treating the immune system. Subunit vaccines, including molecular adjuvants and cancer-associated antigens or cancer-specific neoantigens, can elicit potent antitumor immunity. However, subunit vaccines have shown limited clinical benefit in cancer patients, which is in part attributed to inefficient vaccine delivery. In this Perspective, we discuss vaccine delivery by synthetic nanoparticles or naturally derived nanoparticles for cancer immunotherapy. Nanovaccines can efficiently codeliver adjuvants and multiepitope antigens into lymphoid organs and into antigen-presenting cells, and the intracellular release of vaccine and crosspresentation of antigens can be fine-tuned via nanovaccine engineering. Aside from peptide antigens, antigen-encoding mRNA for cancer immunotherapy delivered by nanovaccine will also be discussed.
T
in vivo for immune modulation. In this Perspective, we will primarily discuss exogenous nanovaccines.
he immune system in cancer patients is hampered by multitier immune suppressive mechanisms, and cancer immunotherapy aims to treat the cancer by treating the hampered immune system. The past few decades have witnessed breakthroughs in cancer immunotherapy, such as interleukin-2,1 immune checkpoint inhibitors,2,3 and engineered chimeric antigen receptor T cells (CAR-T),4 as well as many others are in the pipeline. In addition to working as a monotherapy, vaccines can also complement other cancer therapy modalities by exploiting synergistic signaling pathways. Unlike live attenuated pathogens, which are used for prophylaxis against many infectious diseases, attenuated or processed live tumor cells or lysates have shown marginal efficacy for cancer therapy at best. Alternatively, subunit antigens, which contain the minimal determinant epitopes of protein antigen, have been extensively pursued for nearly two decades due to their advantages such as defined chemistry and ease of manufacturing and storage. However, most subunit vaccines have failed to yield sufficient clinical outcomes for cancer therapy, due in large part to inefficient vaccine delivery. Nanovaccines are being pursued for efficient vaccine delivery in cancer immunotherapy (Figure 1).5−12 For cancer immunotherapy, nanovaccines have multifaceted unique characteristics, such as efficient delivery to secondary lymphoid organs such as lymph nodes (LNs) and penetration of tissue barriers, tailor-designed codelivery of antigen and adjuvant, efficient intracellular vaccine delivery, and tunable intracellular vaccine release and antigen cross-presentation in antigenpresenting cells (APCs). To execute nanovaccine-based cancer therapy, exogenous nanovaccines can be administered into the body to enable uptake by endogenous phagocytic cells (e.g., dendritic cells [DCs], macrophages, monocytes, neutrophils), stimulate innate and adaptive immune cells, and elicit immunity; alternatively, isolated immune cells (e.g., DCs) can be treated with nanovaccines ex vivo, followed by injection of treated cells © XXXX American Chemical Society
Nanovaccines are being pursued recently for efficient vaccine delivery in cancer immunotherapy. THE PASSENGERS: MOLECULAR ADJUVANTS AND CANCER ANTIGENS Both adjuvant and antigen are essential to induce optimal antitumor immunity. Adjuvants induce robust innate and adaptive immunity and potentiate antigen-specific immune responses. Although soluble subunit antigens alone are marginally immunogenic, administration of adjuvant together with subunit antigen may dramatically potentiate the immunogenicity. Nanovaccines have been developed for LN-targeted delivery of molecular adjuvants, including pathogen-associated molecular patterns (PAMPs), which can recognize pattern recognition receptors (PRR) on many immune cells and trigger immune responses. Pathogen-associated molecular patterns that can be delivered by nanovaccine include cytosine-phosphate-guanosine oligonucleotides [CpG (TLR9a)],13,14 R848 (TLR7/8a),9,15 monophosphoryl lipid A (TLR4a),16 and cyclic di-GMP (cdGMP, an agonist of stimulator of interferon, IFN, genes, STING).17,18 Similarly, nanovaccines can deliver cancer antigen to LNs to induce antigen-specific T-cell response. Subunit tumor antigen, which is the minimal determinant epitope of tumor antigen, has proven efficacious for tumor immunotherapy. In the past two decades, subunit tumor-associated antigen (TAA) has been extensively explored preclinically and clinically, with varying degrees of success. The intrinsic drawbacks of TAA include that
A
DOI: 10.1021/acsnano.7b00978 ACS Nano XXXX, XXX, XXX−XXX
Perspective
www.acsnano.org
ACS Nano
Perspective
Figure 1. Schematic depiction of nanovaccine-based vaccine delivery for cancer immunotherapy. Nanovaccines can be loaded with both adjuvant and multiepitope antigens on the surface (as depicted) or inside nanocarriers. Locally administered nanovaccines efficiently codeliver adjuvant and tumor antigen to secondary lymphoid organs (lymph node is depicted as an example) for efficient antigen presentation and induction of robust antitumor T-cell response.
TAA-specific T cells are depleted to evade autoimmunity because of negative selection during development; TAA often induces weak avidity of T-cell response, which can be suppressed by immunoediting; and TAA is prone to induce autoimmunity. In contrast, neoantigen, a class of tumor-specific antigen that is generated from somatic mutations in tumors but not in healthy tissue, has emerged as a promising path to personalized cancer immunotherapy that may overcome some challenges of TAA.8,19 Clinical observations suggest that the load of neoantigencorresponding genetic mutations correlates with the responsiveness of the tumor to immunotherapy such as checkpoint blockade,20−22 which further implies that the load of neoantigen could be a pivotal parameter to predict patients’ responsiveness to other immunotherapies. However, despite the presence of neoantigen, the immune system is often skewed by the tumor such that neoantigen-specific immune responses are suppressed. Therefore, delivery of exogenous neoantigen may potentiate neoantigen-specific immune responses to improve tumor immunotherapy. Technological advancements in high-throughput exosome sequencing, mass spectrometry, bioinformatics, and peptide manufacturing have facilitated the identification of cancer neoantigens and the production of synthetic neoantigen peptides within a reasonable time course, making it possible to use synthetic neoantigen as a cancer vaccine. Like TAA, the delivery of synthetic neoantigen peptide can also be improved by nanotechnology.8
Vaccines have tremendous potential for cancer immunotherapy, either as a monotherapy or more often in combination with other therapeutic modalities such as immunotherapy, chemotherapy, radiotherapy, and surgery. subunit vaccines rapidly diffuse into the peripheral blood vessels due to their relatively small molecular sizes, leading to systemic dissemination of vaccine; however, limited delivery to secondary lymphoid organs occurs, and, consequently, these vaccines have limited therapeutic efficacy. Depot-forming water-in-oil emulsions that can potentiate the immunogenicity of antigen, such as Montanide, have been used in over 100 federally registered clinical trials. However, the underlying working mechanism of Montanide was not fully understood, and the clinical outcomes of Montanide have been suboptimal. A recent report found that when mice were vaccinated with Montanide-emulsified short subunit cancer antigen, the majority of antigen-specific T cells, which play a key role in tumor immunotherapy, were sequestered in the vaccine injection depot, leading to T cell apoptosis rather than tumor infiltration.23 To improve the therapeutic efficacy of vaccines, nanovaccines have been explored for LN-targeted vaccine delivery. Due to the pressure gradient between the blood and lymphatic vessels, lymphatic drainage drives efficient delivery of interstitial nanoparticles via the lymphatics to LNs. Among all draining LNs, tumor-draining LNs have been found to be particularly interesting for nanovaccine delivery in tumor immunotherapy. On the one hand, tumor draining LNs are immunosuppressive due to immune regulation coordinated by the
THE VEHICLE: NANOMATERIALS FOR LYMPH NODE-TARGETED VACCINE DELIVERY Nanovaccines improve the efficiency of vaccine delivery to LNs by modulating the immune responses coordinated by LN-residing lymphocytes. Intramuscularly or subcutaneously administered B
DOI: 10.1021/acsnano.7b00978 ACS Nano XXXX, XXX, XXX−XXX
ACS Nano
Perspective
efficacious cancer immunotherapy. In nature, biomolecules such as IgG and albumin have long in vivo half-lives in circulation (>20 days in humans), due in part to recycling from degradation in endosomes. Inspired by this long half-life, molecular vaccines that can bind with endogenous albumin, which has multiple binding sites and is a natural carrier for versatile biomolecules and drugs,29,30 provide an attractive alternative to exogenous nanovaccines. For example, an albumin-binding lipid-conjugated cancer vaccine has dramatically outperformed free vaccines to elicit T cell response and inhibit tumor progression.29 Another type of naturally derived nanomaterial, HDL nanomaterials, have intrinsically low immunogenicity and have been extensively explored from bench to bedside. A synthetic HDL nanodisc, which was made of phospholipids and apolipoprotein A1 (ApoA1)-mimetic peptides, has been developed for LN-targeted delivery of CpG adjuvant and neoantigen in cancer immunotherapy.8 Cell-membrane-cloaking nanoparticles represent another interesting approach to the development of naturally derived nanovaccines. Cell-membrane-cloaking nanoparticles transplant the intact biomolecular signature of cell membranes onto the surface of synthetic nanoparticles, thus taking advantage of the low immunogenicity and good biocompatibility of host cell membranes. Among biomedical applications, cancer therapeutic nanovaccines have been created by coating synthetic nanoparticles with cancer cell membranes or erythrocyte membranes.31,32 Further, subcellular vesicles, which are prepared by disrupting cancer cells that inherited the antigen repertoire of the parent cancer cell and can be additionally loaded with adjuvant, provide another insightful approach to cancer vaccination.33
upstream tumor; on the other hand, these LNs are readily exposed to the whole set of tumor-specific neoantigen, and the immune microenvironment can be markedly stimulated by injected nanovaccine at the ipsilateral side of the tumor.24 The efficiency of LN-targeted nanovaccine delivery may depend on a collection of factors including size, electronic charge, hydrophobicity, and elasticity. Generally speaking, small nanoparticles (100 nm) can more often be taken up by interstitial migratory at the injection site, and these APCs then carry internalized nanovaccine to draining LNs.6,25 Various synthetic nanoparticles have been studied for vaccine delivery, and, recently, naturally derived nanoparticles have been explored as alternative nanovehicles for vaccine delivery due to their potential for increased patient safety and ease of large-scale manufacturing. Synthetic Nanovaccines As Delivery Vehicles. Synthetic nanoparticles studied for vaccine delivery primarily include organic and inorganic nanoparticles. For example, spherical nucleic acids with a gold nanoparticle core and a shell of CpG, a Toll-like receptor 9 (TLR9) agonist, were developed for efficient delivery of immunomodulatory agents, which led to inhibition of tumor growth.26 Organic nanoparticles made of lipids or polymers offer a wide variety of nanocarriers for vaccine delivery. For example, liposomes encapsulated with cdGMP, a potentially robust immunostimulatory adjuvant, dramatically enhanced the efficiency of LN-targeted delivery.18,27 This increased efficiency is remarkable for the development of cyclic dinucleotides as vaccine adjuvants, as the delivery of free cyclic dinucleotides into LNs has been difficult due to their small molecular size, hydrophilicity, and susceptibility of nuclease degradation. Moreover, by engineering a polymer nanoparticle based on N-(2-hydroxypropyl)methacrylamide (HPMA) with TLR7/8a, TLR7/8a was delivered into LNs with ∼400-fold higher efficiency than free TLR7/8a, making it a promising nanoplatform for cancer vaccine delivery.15 By combining inorganic components and organic scaffolds, we have developed a DNAinorganic hybrid nanovaccine that integrates polymeric CpG with safe inorganic components; the resulting nanovaccine had an extremely high payload capacity of CpG, resisted chemical and thermal denaturation, and significantly delayed tumor progression.7,28 Naturally Derived Nanovaccines As Delivery Vehicles. Compared with synthetic nanovehicles, naturally derived nanomaterials share an attractive featuregood biocompatibility with the host body. Various approaches have been exploited to develop naturally derived nanomaterials, such as in vivoassembled nanocomplexes of exogenous vaccine and endogenous protein, high-density lipoprotein (HDL) nanoparticles, as well as cell-membrane-cloaking nanoparticles. Designer exogenous molecular vaccines have been assembled in vivo with endogenous biomolecules into nanocomplexes. Compared to exogenous nanocarriers, chemically and pharmacologically defined molecular vaccines are attractive because of their relatively facile manufacturing, quality control, and formulation of the good manufacturing practice (GMP) grade. By forming nanovaccines in vivo, this approach takes advantage of both the easy production of molecular vaccines and the ability of nanovaccines to promote efficient LN-targeted delivery and to prolong the bioavailability of molecular vaccines in LNs for
TEAMING UP PASSENGERS: NANOVACCINES CODELIVER ADJUVANT AND MULTI-EPITOPE ANTIGEN Codelivery of antigen and adjuvant to APCs by nanovaccines confers efficient antigen cross-presentation and robust T-cell response for tumor immunotherapy. Antigen and adjuvant can be codelivered to the same APCs on the same or separate nanocarriers. Nanoparticles can also be fine-tuned to be loaded with both antigen and adjuvant at a specified ratio. Because antigen-specific immunity presents selection pressure on the tumor, the tumor evolves to down-regulate the expression of the same antigen on tumor cells. Therefore, for optimal tumor immunotherapy, it is important to deliver multiepitope antigens to induce a broad spectrum of T-cell responses. Nanovaccines can codeliver multiepitope antigens. For example, sHDL nanodiscs were designed to codeliver CpG adjuvant and neoantigen, leading to a 31-fold greater antigen-specific T-cell response in comparison to Montanide and eradication of most established tumors in combination with immune checkpoint inhibitors against programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4).8 The abovementioned nanodiscs can also deliver multiepitope antigens, which launched relatively broad T-cell responses and enhanced the rate of complete regression in the immunotherapy of aggressive B16F10 murine melanoma. PASSPORT TO CELLS: INTRACELLULAR DELIVERY OF NANOVACCINES Many molecular adjuvants used for vaccines are derived from the PAMP’s “danger signals” in pathogens, which rapidly elicit host immunity through recognition of PRRs on APCs and potentiate the immunogenicity of antigens for cancer immunotherapy. C
DOI: 10.1021/acsnano.7b00978 ACS Nano XXXX, XXX, XXX−XXX
ACS Nano
Perspective
in the reductive environment of the APC endosome, which leads to robust CD8+ T-cell responses compared to antigen conjugated on nanocarriers via a noncleavable linker.39 Furthermore, technologies that enhance the disruption of phagosomal compartments, via the proton sponge effect, are promising for the direct delivery of antigen into cytosol, so as to skew antigen presentation to the MHC class I pathway for CD8+ T-cell response.
The intracellular delivery of these adjuvants is essential to bind to intracellular PRRs and subsequently to activate downstream signaling pathways for optimal immunomodulation. By mimicking microbial pathogens in many ways, nanovaccines generally enter APCs more efficiently than do free molecular vaccines, making nanovaccines promising for efficient intracellular adjuvant delivery. A large panel of nanovaccines have demonstrated efficient intracellular delivery of molecular adjuvants. For example, CpG can be delivered via nanovaccine into the endolysosome of APCs,8,26 where CpG is recognized by TLR9 and stimulates the immunostimulatory pathway.34 Similarly, cyclic dinucleotides can also be delivered efficiently into cytosol via nanocarriers,17,18 so that these cytosolic agonists can bind to their receptor, STING, and stimulate the production of cytokines including type I interferon.35 The enhanced efficiency of intracellular adjuvant delivery can be attributed to its unique characteristics such as multivalent adjuvant binding to receptors (if adjuvant is coated on the surface of nanovaccine), typically higher cell uptake efficiency of nanoparticles than free molecular agents, and shielding of the hydrophobicity and negative charges of adjuvant by encapsulating adjuvant inside nanoparticles. Intracellular delivery of antigen is also pivotal for eliciting robust antigen-specific T-cell responses in cancer immunotherapy. Unlike adjuvant, antigen typically does not have any receptors on the APC surface that can facilitate binding and intracellular delivery. Yet, antigen often needs to be internalized into APCs to be processed by intracellular protease machinery (except for minimal determinant epitopes of subunit antigen) and transported into specialized intracellular compartment to bind with major histocompatibility complex (MHC) molecules for antigen presentation.10,36 Antigen can be presented by MHC class I or MHC class II molecules to CD8+ T cells or CD4+ T cells, respectively. By the MHC class I antigen-presentation pathway, intracellular nonself or transformed proteins are degraded into small peptides by the cytosolic proteasome, are translocated by the transporters associated with antigen processing (TAP) into the endoplasmic reticulum (ER) lumen, and bind with MHC I, which is expressed on all nucleated cells as well as platelets. The epitope-MHC I complexes are then transported to APC surfaces for antigen presentation to CD8+ T cells. The MHC class I pathway enables the immune system to destroy cells with intracellular nonself or transformed proteins in the case of infection or cancer. The MHC class II pathway is harnessed by the immune system to eliminate extracellular soluble nonself antigen. In the MHC class II pathway, extracellular nonself proteins are internalized by APCs, degraded in the endocytic pathway, and then bind with MHC II, which is expressed mainly on APCs, and the epitope-MHC II complexes are then transported to the APC surface and present the epitopes to CD4+ T cells. In contrast to extracellular soluble antigen, antigens on extracellular micro/nanoparticles or microbes internalized by APCs undergo a process known as cross-presentation, in which antigens on internalized particles are intracellularly processed, loaded onto MHC I, and presented to CD8+ T cells.37,38 Inspired by these findings, nanovaccines have been extensively explored for the delivery of antigens for crosspresentation and elicitation of CD8+ T-cell responses, which are pivotal for cancer immunotherapy. It is intriguing that the pathway of antigen cross-presentation can be finely engineered specifically for CD8 + T-cell responses or CD4+ T-cell responses.39,40 For example, when antigen is conjugated to poly(propylene sulfide) (PPS) nanoparticles via a disulfide linker, the antigen is released when the disulfide bond is cleaved
A RISING STAR: MRNA VACCINES DELIVERED BY NANOVACCINES Compared with peptide antigens, DNA vaccines, and viral vaccines, antigen-encoding in vitro transcribed (IVT) mRNA vaccines have key advantages, including low immunogenicity and risk of latent viral infection and potent T-cell response when mRNA is translated into protein in cytosol.41−44 For optimal immune response, antigen-encoding mRNA needs to be delivered to DCs, the professional APCs. Transfecting DCs ex vivo with mRNA and then administering these DCs back into the body involves a complex manipulation process that hinders its widespread clinical application, however the safety and efficacy have been demonstrated. Therefore, in vivo delivery of mRNA to DCs is required for practical mRNA-based vaccination, but is confronted with some challenges. First, unmodified mRNA is susceptible to ubiquitous nucleases. Second, the negative charge of mRNA, like any nucleic acids, makes cellular uptake relatively inefficient. Third, internalized mRNA needs to escape the endosome to reach the cytosol for antigen translation. Although direct intranodal injection of naked mRNA yields an antitumor T-cell response, the efficacy is at best moderate, and the complex procedure also hampers the clinical application of this approach.45 Alternatively, nanotechnology holds unique advantages to address these challenges for the delivery of mRNA vaccines.46,47 mRNA-carrying nanovaccines can protect mRNA from degradation by RNase and facilitate uptake by DCs; in addition, nanoparticles can also be engineered to escape the endosome by the proton sponge effect. For example, by complexation of liposome and neoantigen-based mRNA, mRNA− lipoplex (RNA−LPX) was developed, and the intravenous injected RNA−LPX resulted in efficient mRNA delivery to lymphoid DCs, leading to subsequent induction of potent neoantigen-specific T-cell responses in mice and in human melanoma patients.46,47 Remarkably, simply by gene engineering, one mRNA can be synthesized to encode multiepitope cancer-specific neoantigens, thus achieving a broad spectrum of antitumor T-cell responses upon intracellular neoantigen translation. CONCLUSIONS AND OUTLOOK Vaccines have tremendous potential for cancer immunotherapy, either as monotherapies or more often in combination with other therapeutic modalities such as immunotherapy, chemotherapy, radiotherapy, and surgery. Chemically defined subunit vaccines can elicit antigen-specific T-cell responses and are relatively easy to manufacture on large scales. However, currently, subunit vaccines have shown limited therapeutic efficacy in humans, which is in part attributed to the poor efficiency of vaccine delivery. Therefore, novel technologies, including nanotechnologies, that can efficiently deliver subunit vaccine to secondary lymphoid organs to improve the therapeutic efficacy of vaccines are promising. For example, nanovaccines can avoid the otherwise rapid dissemination into the blood circulation and can be D
DOI: 10.1021/acsnano.7b00978 ACS Nano XXXX, XXX, XXX−XXX
ACS Nano
Perspective
are a promising platform that can play a pivotal role in cancer immunotherapy.
drained efficiently into LNs by the lymphatics, which provides a prolonged time window for the nanovaccine to interact with LN-residing lymphocytes. Nanovaccines can also codeliver cancer antigen and adjuvant or multiepitope antigens to induce a broad anticancer T-cell response with minimal immune tolerance. Further, nanovaccines can be internalized efficiently by APCs, which present antigen to T cells; inside APCs, the nanovaccine can be engineered precisely to release adjuvant and antigen at desired intracellular compartments for optimal cancer immunotherapy. Nanovaccines are also expected to facilitate the evaluation and application of cancer therapeutic neoantigen and IVT-mRNA antigen, which are two classes of antigens that have recently been extensively explored for cancer immunotherapy. Derived from somatic mutations in tumors, neoantigen is expressed exclusively in tumor cells but not healthy cells. Despite the extremely low frequency of neoantigen, recent technological advancements in mass spectrometry, exosome, and bioinformatic analysis and prediction provide powerful momentum to mine sparse neoantigen from complex cell proteome. Due to the intrinsic randomness of somatic mutations, the mutatome of each patient is often unique, as suggested by current clinical observations. This makes neoantigen ideal for personalized cancer immunotherapy. However, due to immunosuppression in the tumor microenvironment and the low frequency of natural neoantigen, the repertoire of neoantigen-specific T cells is often small. Delivery of exogenous neoantigen, by nanovaccine for example, may expand the repertoire of tumor-specific T cells and improve therapeutic efficacy. Despite the overall promise of neoantigenbased nanovaccine for cancer immunotherapy, there are a few challenges. First, a large cohort of patients was found to have extremely rare neoantigens, especially in cancers such as glioblastoma, pancreatic, and breast.48 Strategies to increase the tumor neoantigen load in these patients may subsequently potentiate immunotherapy. In this regard, synergistic combination of immunotherapy with mutation-prone therapies, such as radiotherapy and some chemotherapies, will likely increase cancer therapeutic efficacy. Second, using current technology, it takes three months, at best, to identify and to manufacture synthetic neoantigen peptides for vaccination. Even though patients can be treated first by other regimens before neoantigen vaccination, it is highly desirable to shorten this duration for optimal therapeutic outcome. The IVT-mRNA vaccine is another emerging candidate enthusiastically pursued for cancer immunotherapy, yet the delivery of naked mRNA, like other therapeutic nucleic acids such as siRNA and plasmids, can be a daunting challenge. Nanomaterials show promise in improving the efficiency of IVT-mRNA delivery by protecting mRNA from nuclease degradation, enhancing mRNA delivery to lymphoid organs, such as LNs and spleens, and facilitating intracellular delivery of mRNA to APCs. A few pharmaceutical companies have started to explore mRNA vaccines extensively for applications including cancer immunotherapy, and a number of ongoing related clinical trials will likely unveil the potential and the challenges more specifically in the near future. In small animals, a good number of nanovaccines have shown the ability to induce antitumor immunity and can be combined with many other therapeutic modalities for synergistic cancer therapy. It is expected that in the next few years, more types of nanovaccines can be manufactured on large scales and at GMP grade, and GMP-produced nanovaccines can be tested in humans for safety and therapeutic efficacy. Overall, nanovaccines
AUTHOR INFORMATION Corresponding Author
*E-mail:
[email protected]. ORCID
Xiaoyuan Chen: 0000-0002-9622-0870 Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS This work was supported by intramural research program of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH). REFERENCES (1) Rosenberg, S. A. IL-2: The First Effective Immunotherapy for Human Cancer. J. Immunol. 2014, 192, 5451−5458. (2) Sharma, P.; Allison, J. P. The Future of Immune Checkpoint Therapy. Science 2015, 348, 56−61. (3) Yao, S.; Zhu, Y.; Chen, L. Advances in Targeting Cell Surface Signalling Molecules for Immune Modulation. Nat. Rev. Drug Discovery 2013, 12, 130−146. (4) Gill, S.; June, C. H. Going Viral: Chimeric Antigen Receptor T-Cell Therapy for Hematological Malignancies. Immunol. Rev. 2015, 263, 68− 89. (5) Moon, J. J.; Huang, B.; Irvine, D. J. Engineering Nano- and Microparticles To Tune Immunity. Adv. Mater. 2012, 24, 3724−3746. (6) Irvine, D. J.; Hanson, M. C.; Rakhra, K.; Tokatlian, T. Synthetic Nanoparticles for Vaccines and Immunotherapy. Chem. Rev. 2015, 115, 11109−11146. (7) Zhu, G.; Liu, Y.; Yang, X.; Kim, Y.-H. H.; Zhang, H.; Jia, R.; Liao, H.-S. S.; Jin, A.; Lin, J.; Aronova, M.; Leapman, R.; Nie, Z.; Niu, G.; Chen, X. DNA-Inorganic Hybrid Nanovaccine for Cancer Immunotherapy. Nanoscale 2016, 8, 6684−6692. (8) Kuai, R.; Ochyl, L. J.; Bahjat, K. S.; Schwendeman, A.; Moon, J. J. Designer Vaccine Nanodiscs for Personalized Cancer Immunotherapy. Nat. Mater. 2016, DOI: 10.1038/nmat4822. (9) Nguyen, D. N.; Mahon, K. P.; Chikh, G.; Kim, P.; Chung, H.; Vicari, A. P.; Love, K. T.; Goldberg, M.; Chen, S.; Krieg, A. M.; Chen, J.; Langer, R.; Anderson, D. G. Lipid-Derived Nanoparticles for Immunostimulatory RNA Adjuvant Delivery. Proc. Natl. Acad. Sci. U. S. A. 2012, 109, E797−E803. (10) Hubbell, J. A.; Thomas, S. N.; Swartz, M. A. Materials Engineering for Immunomodulation. Nature 2009, 462, 449−460. (11) Jeanbart, L.; Swartz, M. A. Engineering Opportunities in Cancer Immunotherapy. Proc. Natl. Acad. Sci. U. S. A. 2015, 112, 14467−14472. (12) Shao, K.; Singha, S.; Clemente-Casares, X.; Tsai, S.; Yang, Y.; Santamaria, P. Nanoparticle-Based Immunotherapy for Cancer. ACS Nano 2015, 9, 16−30. (13) Klinman, D. M. Immunotherapeutic Uses of CpG Oligodeoxynucleotides. Nat. Rev. Immunol. 2004, 4, 249−258. (14) Krieg, A. M. Therapeutic Potential of Toll-Like Receptor 9 Activation. Nat. Rev. Drug Discovery 2006, 5, 471−484. (15) Lynn, G. M.; Laga, R.; Darrah, P. A.; Ishizuka, A. S.; Balaci, A. J.; Dulcey, A. E.; Pechar, M.; Pola, R.; Gerner, M. Y.; Yamamoto, A.; Buechler, C. R.; Quinn, K. M.; Smelkinson, M. G.; Vanek, O.; Cawood, R.; Hills, T.; Vasalatiy, O.; Kastenmüller, K.; Francica, J. R.; Stutts, L.; et al. In Vivo Characterization of the Physicochemical Properties of Polymer-Linked TLR Agonists that Enhance Vaccine Immunogenicity. Nat. Biotechnol. 2015, 33, 1201−1210. (16) Zhang, Z.; Tongchusak, S.; Mizukami, Y.; Kang, Y. J.; Ioji, T.; et al. Induction of Anti-Tumor Cytotoxic T Cell Responses Through PLGA− Nanoparticle Mediated Antigen Delivery. Biomaterials 2011, 32, 3666− 3678. E
DOI: 10.1021/acsnano.7b00978 ACS Nano XXXX, XXX, XXX−XXX
ACS Nano
Perspective
(17) Fu, J.; Kanne, D. B.; Leong, M.; Glickman, L. H.; McWhirter, S. M.; Lemmens, E.; Mechette, K.; Leong, J. J.; Lauer, P.; Liu, W.; Sivick, K. E.; Zeng, Q.; Soares, K. C.; Zheng, L.; Portnoy, D. A.; Woodward, J. J.; Pardoll, D. M.; Dubensky, T. W.; Kim, Y. STING Agonist Formulated Cancer Vaccines Can Cure Established Tumors Resistant to PD-1 Blockade. Sci. Transl. Med. 2015, 7, 283ra52. (18) Hanson, M. C.; Crespo, M. P.; Abraham, W.; Moynihan, K. D.; Szeto, G. L.; Chen, S. H.; Melo, M. B.; Mueller, S.; Irvine, D. J. Nanoparticulate STING Agonists are Potent Lymph Node-Targeted Caccine Adjuvants. J. Clin. Invest. 2015, 125, 2532−2546. (19) Schumacher, T. N.; Schreiber, R. D. Neoantigens in Cancer Immunotherapy. Science 2015, 348, 69−74. (20) Van Allen, E. M.; Miao, D.; Schilling, B.; Shukla, S. A.; Blank, C.; Zimmer, L.; Sucker, A.; Hillen, U.; Foppen, M. H.; Goldinger, S. M.; Utikal, J.; Hassel, J. C.; Weide, B.; Kaehler, K. C.; Loquai, C.; Mohr, P.; Gutzmer, R.; Dummer, R.; Gabriel, S.; Wu, C. J.; et al. Genomic Correlates of Response to CTLA-4 Blockade in Metastatic Melanoma. Science 2015, 350, 207−211. (21) Snyder, A.; Makarov, V.; Merghoub, T.; Yuan, J.; Zaretsky, J. M.; Desrichard, A.; Walsh, L. A.; Postow, M. A.; Wong, P.; Ho, T. S.; Hollmann, T. J.; Bruggeman, C.; Kannan, K.; Li, Y.; Elipenahli, C.; Liu, C.; Harbison, C. T.; Wang, L.; Ribas, A.; Wolchok, J. D.; et al. Genetic Basis for Clinical Response to CTLA-4 Blockade in Melanoma. N. Engl. J. Med. 2014, 371, 2189−2199. (22) Gubin, M. M.; Zhang, X.; Schuster, H.; Caron, E.; Ward, J. P.; Noguchi, T.; Ivanova, Y.; Hundal, J.; Arthur, C. D.; Krebber, W.-J.; Mulder, G. E.; Toebes, M.; Vesely, M. D.; Lam, S. S. K.; Korman, A. J.; Allison, J. P.; Freeman, G. J.; Sharpe, A. H.; Pearce, E. L.; Schumacher, T. N.; et al. Checkpoint Blockade Cancer Immunotherapy Targets Tumour-Specific Mutant Antigens. Nature 2014, 515, 577−581. (23) Hailemichael, Y.; Dai, Z.; Jaffarzad, N.; Ye, Y.; Medina, M.; Huang, X.-F.; Dorta-Estremera, S.; Greeley, N.; Nitti, G.; Peng, W.; Liu, C.; Lou, Y.; Wang, Z.; Ma, W.; Rabinovich, B.; Schluns, K.; Davis, R.; Hwu, P.; Overwijk, W. Persistent Antigen at Vaccination Sites Induces TumorSpecific CD8+ T Cell Sequestration, Dysfunction and Deletion. Nat. Med. 2013, 19, 465−472. (24) Thomas, S. N.; Vokali, E.; Lund, A. W.; Hubbell, J. A.; Swartz, M. A. Targeting the Tumor-Draining Lymph Node with Adjuvanted Nanoparticles Reshapes the Anti-Tumor Immune Response. Biomaterials 2014, 35, 814−824. (25) Reddy, S. T.; van der Vlies, A. J.; Simeoni, E.; Angeli, V.; Randolph, G. J.; O’Neil, C. P.; Lee, L. K.; Swartz, M. A.; Hubbell, J. A. Exploiting Lymphatic Transport and Complement Activation in Nanoparticle Vaccines. Nat. Biotechnol. 2007, 25, 1159−1164. (26) Radovic-Moreno, A. F.; Chernyak, N.; Mader, C. C.; Nallagatla, S.; Kang, R. S.; Hao, L.; Walker, D. A.; Halo, T. L.; Merkel, T. J.; Rische, C. H.; Anantatmula, S.; Burkhart, M.; Mirkin, C. A.; Gryaznov, S. M. Immunomodulatory Spherical Nucleic Acids. Proc. Natl. Acad. Sci. U. S. A. 2015, 112, 3892−3897. (27) Koshy, S. T.; Cheung, A. S.; Gu, L.; Graveline, A. R.; Mooney, D. J. Liposomal Delivery Enhances Immune Activation by STING Agonists for Cancer Immunotherapy. Adv. Biosystems 2017, 1, 1600013. (28) Zhang, L.; Zhu, G.; Mei, L.; Wu, C.; Qiu, L.; Cui, C.; Liu, Y.; Teng, I. T. T.; Tan, W. Self-Assembled DNA Immunonanoflowers as Multivalent CpG Nanoagents. ACS Appl. Mater. Interfaces 2015, 7, 24069−24074. (29) Liu, H.; Moynihan, K. D.; Zheng, Y.; Szeto, G. L.; Li, A. V.; Huang, B.; Van Egeren, D. S.; Park, C.; Irvine, D. J. Structure-Based Programming of Lymph-Node Targeting in Molecular Vaccines. Nature 2014, 507, 519−522. (30) Sand, K. M.; Bern, M.; Nilsen, J.; Noordzij, H. T.; Sandlie, I.; Andersen, J. T. Unraveling the Interaction between FcRn and Albumin: Opportunities for Design of Albumin-Based Therapeutics. Front. Immunol. 2015, 5, 682. (31) Guo, Y.; Wang, D.; Song, Q.; Wu, T.; Zhuang, X.; Bao, Y.; Kong, M.; Qi, Y.; Tan, S.; Zhang, Z. Erythrocyte Membrane-Enveloped Polymeric Nanoparticles as Nanovaccine for Induction of Antitumor Immunity against Melanoma. ACS Nano 2015, 9, 6918−6933.
(32) Fang, R. H.; Hu, C.-M. J. M.; Luk, B. T.; Gao, W.; Copp, J. A.; Tai, Y.; O’Connor, D. E.; Zhang, L. Cancer Cell Membrane-Coated Nanoparticles for Anticancer Vaccination and Drug Delivery. Nano Lett. 2014, 14, 2181−2188. (33) Cheung, A. S.; Koshy, S. T.; Stafford, A. G.; Bastings, M. M. C.; Mooney, D. J. Adjuvant-Loaded Subcellular Vesicles Derived From Disrupted Cancer Cells for Cancer Vaccination. Small 2016, 12, 2321− 2333. (34) Leifer, C. A.; Kennedy, M. N.; Mazzoni, A.; Lee, C.; Kruhlak, M. J.; Segal, D. M. TLR9 is Localized in the Endoplasmic Reticulum Prior to Stimulation. J. Immunol. 2004, 173, 1179−1183. (35) Barber, G. N. STING: Infection, Inflammation and Cancer. Nat. Rev. Immunol. 2015, 15, 760−70. (36) Mellman, I.; Steinman, R. M. Dendritic Cells: Specialized and Regulated Antigen Processing Machines. Cell 2001, 106, 255−258. (37) Guermonprez, P.; Saveanu, L.; Kleijmeer, M.; Davoust, J.; van Endert, P.; Amigorena, S. ER−Phagosome Fusion Defines an MHC Class I Cross-Presentation Compartment in Dendritic Cells. Nature 2003, 425, 397−402. (38) Burgdorf, S.; Schölz, C.; Kautz, A.; Tampé, R.; Kurts, C. Spatial and Mechanistic Separation of Cross-Presentation and Endogenous Antigen Presentation. Nat. Immunol. 2008, 9, 558−566. (39) Hirosue, S.; Kourtis, I. C.; van der Vlies, A. J.; Hubbell, J. A.; Swartz, M. A. Antigen Delivery to Dendritic Cells by Poly (Propylene Sulfide) Nanoparticles with Disulfide Conjugated Peptides: CrossPresentation and T Cell Activation. Vaccine 2010, 28, 7897−7906. (40) Scott, E. A.; Stano, A.; Gillard, M.; Maio-Liu, A. C.; Swartz, M. A.; Hubbell, J. A. Dendritic Cell Activation and T Cell Priming with Adjuvant- and Antigen-Loaded Oxidation-Sensitive Polymersomes. Biomaterials 2012, 33, 6211−6219. (41) Schlake, T.; Thess, A.; Fotin-Mleczek, M.; Kallen, K.-J. Developing mRNA-Vaccine Technologies. RNA Biol. 2012, 9, 1319− 1330. (42) Benteyn, D.; Heirman, C.; Bonehill, A.; Thielemans, K.; Breckpot, K. mRNA-Based Dendritic Cell Vaccines. Expert Rev. Vaccines 2015, 14, 161−176. (43) Sahin, U.; Karikó, K.; Türeci, Ö . mRNA-Based Therapeutics Developing a New Class of Drugs. Nat. Rev. Drug Discovery 2014, 13, 759−780. (44) Li, J.; Wang, W.; He, Y.; Li, Y.; Yan, E. Z.; Zhang, K.; Irvine, D. J.; Hammond, P. T. Structurally Programmed Assembly of Translation Initiation Nanoplex for Superior mRNA Delivery. ACS Nano 2017, DOI: 10.1021/acsnano.6b08447. (45) Kreiter, S.; Selmi, A.; Diken, M.; Koslowski, M.; Britten, C. M.; Huber, C.; Türeci, Ö .; Sahin, U. Intranodal Vaccination with Naked Antigen-Encoding RNA Elicits Potent Prophylactic and Therapeutic Antitumoral Immunity. Cancer Res. 2010, 70, 9031−9040. (46) Kranz, L. M.; Diken, M.; Haas, H.; Kreiter, S.; Loquai, C.; Reuter, K. C.; Meng, M.; Fritz, D.; Vascotto, F.; Hefesha, H.; Grunwitz, C.; Vormehr, M.; Hüsemann, Y.; Selmi, A.; Kuhn, A. N.; Buck, J.; Derhovanessian, E.; Rae, R.; Attig, S.; Diekmann, J.; et al. Systemic RNA Delivery to Dendritic Cells Exploits Antiviral Defence for Cancer Immunotherapy. Nature 2016, 534, 396−401. (47) Kreiter, S.; Vormehr, M.; van de Roemer, N.; Diken, M.; Löwer, M.; Diekmann, J.; Boegel, S.; Schrörs, B.; Vascotto, F.; Castle, J. C.; Tadmor, A. D.; Schoenberger, S. P.; Huber, C.; Türeci, Ö .; Sahin, U. Mutant MHC Class II Epitopes Drive Therapeutic Immune Responses to Cancer. Nature 2015, 520, 692−696. (48) Alexandrov, L. B.; Nik-Zainal, S.; Wedge, D. C.; Aparicio, S. A. J. R.; Behjati, S.; Biankin, A. V.; Bignell, G. R.; Bolli, N.; Borg, A.; BørresenDale, A.-L.; Boyault, S.; Burkhardt, B.; Butler, A. P.; Caldas, C.; Davies, H. R.; Desmedt, C.; Eils, R.; Eyfjörd, J.; Foekens, J. A.; Greaves, M.; et al. Signatures of Mutational Processes in Human Cancer. Nature 2013, 500, 415−421.
F
DOI: 10.1021/acsnano.7b00978 ACS Nano XXXX, XXX, XXX−XXX
