Synthetic 3D scaffolds for cancer immunotherapy

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ScienceDirect Synthetic 3D scaffolds for cancer immunotherapy Armand Kurum1, Min Gao2 and Li Tang1,2 Recent clinical success of systemic cancer immunotherapy has paved the way for the next-generation therapeutics. Nevertheless, cancer immunotherapies, in particular combination therapies, are associated in some cases with severe side effects and low response rates. Synthetic scaffolds have emerged as a promising platform to deliver immunotherapeutic agents locally. Placed at strategic locations of the body, scaffolds can reduce side effects while increasing the concentration of the agent at the site of interest. Moreover, scaffolds can mimic the context, in which biochemical cues are presented in vivo to enhance cell modulation. Recent research has focused on designing threedimensional (3D) scaffolds with specific properties to modulate the antitumor response at various stages of the cancer immunity cycle. As the number of immunotherapies in clinical trials is soaring, it is essential to critically evaluate the role that scaffolds can play in improving the safety and efficacy of existing and future therapies. Addresses 1 Institute of Materials Science & Engineering, E´cole Polytechnique Fe´de´rale de Lausanne (EPFL), Lausanne, CH-1015, Switzerland 2 Institute of Bioengineering, E´cole Polytechnique Fe´de´rale de Lausanne (EPFL), Lausanne, CH-1015, Switzerland Corresponding author: Tang, Li ([email protected])

Current Opinion in Biotechnology 2020, 65:1–8 This review comes from a themed issue on Pharmaceutical biotechnology Edited by Lana Kandalaft and Michele Graciotti

https://doi.org/10.1016/j.copbio.2019.11.010 0958-1669/ã 2019 Elsevier Ltd. All rights reserved.

Introduction Immunotherapy has led to robust and durable responses in a fraction of cancer patients and become one of the mainstays in the therapeutic arsenal against cancer. Successful clinical strategies have been rapidly developed in recent years to target various immune cells and stages of the immune response. For example, cancer vaccines are used to induce or expand antigen-specific immune responses [1]; autologous T cells have been genetically engineered ex vivo to express tumor-specific chimeric antigen receptors (CARs) for adoptive cell www.sciencedirect.com

transfer into patients [2]; intratumoral T cells can be reactivated by checkpoint blockade therapies, which inhibit specific surface receptors such as programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyteassociated protein 4 (CTLA-4), to overcome immunosuppression in the tumor microenvironment (TME) and enhance antitumor immunity [3]. Some of these therapies are routinely used today in the clinic and have transformed the standard of care for a variety of malignancies. Nevertheless, systemic cancer immunotherapy has the risk to perturb the body immune homeostasis and generate autoimmune side effects with potentially life-threatening consequences. In addition, poor T-cell trafficking, infiltration, and proliferation at the tumor site have hindered the progress of immunotherapy against solid tumors. Novel delivery strategies of immunotherapeutic agents can circumvent off-target effects of these therapies and improve both safety and treatment outcomes [4]. In particular, biomaterial 3D scaffolds can be used to localize soluble immunotherapeutic agents at the tumor site, thus avoiding systemic exposure, control their pharmacokinetics, and increase their local concentration [5]. Moreover, scaffolds can be designed to support cellular immunotherapies by exhibiting biochemical, structural, and mechanical characteristics promoting cell survival, activation, and expansion [6]. These artificial niches can be used to modulate cells in vivo, promote multicellular interactions, and generate antitumor immunity [7,8]. It has become increasingly evident that efficacy of immunotherapies can be improved by targeting multiple steps of the cancer immunity [9]. Scaffolds can provide a platform for the co-delivery of a variety of therapeutic agents and enable synergistic antitumor responses. In this Review, we will discuss recent advances in the field of scaffold-supported immunotherapies for cancer. These strategies are examined according to the various stages of the antitumor immune responses, including induction of tumor-reactive immunity, tumor infiltration of T cells, and modulation of the TME against immunosuppression (Figure 1). We also emphasize therapies targeting multiple aspects of the cancer immunity and discuss the use of scaffolds to synergize these multi-pronged strategies.

Inducing tumor-reactive T cell immunity T cells have a critical role in antitumor immunity. CD8+ cytotoxic T cells (CTLs) have been intensively studied and targeted [10], as they can identify and destroy tumor cells, while CD4+ T-helper cells have also emerged as key players in antitumor immunity [11]. In general, providing a sufficient number of tumor-reactive T cells is paramount Current Opinion in Biotechnology 2020, 65:1–8

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Figure 1

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Overview of 3D scaffold-based immunotherapy in the context of the cancer immune response. DC: dendritic cell. PD-1: programmed cell death protein 1. aPD-1: antibody against programmed cell death protein 1. PD-L1: programmed cell death protein ligand 1. TCR: T cell receptor. pMHC: peptide-major histocompatibility complex.

to mounting a successful antitumor response [12]. Nevertheless, antitumor immunity is often prevented due to immune tolerance to self-antigens [13]. Strategies have been designed to overcome tolerance at different points of the antitumor response, including cancer vaccines that stimulate endogenous cellular immune responses, and adoptive transfer of ex vivo expanded T cells. These therapies have been used in the clinic and exhibited different levels of success. Endogenous T cell response through vaccination

In a typical process of vaccination against cancer, immature dendritic cells (DCs) migrate to the site of infection to capture antigens, and subsequently present these antigenic peptides on their surface in complex with a major histocompatibility complex (MHC) [14]. In the lymph node, naive T cells are activated by mature DCs and expanded into CTLs to elicit an antitumor response. Strategies aiming at transplanting antigen-pulsed DCs into patients to generate an antitumor response have been disappointing, Current Opinion in Biotechnology 2020, 65:1–8

due to the low viability of the transplanted DCs, less than 10%, and their limited homing, 0.5%–2.0%, to the lymph nodes, resulting in low vaccination efficacy [7,15]. These issues may contribute to explaining the modest improvement in median survival exhibited by Sipuleucel-T therapy, a DC-based cancer vaccine [16]. However, in contrast to ex vivo manipulation, DCs can be modulated in vivo. 3D porous scaffolds are ideal tools for cell modulation owing to the spatiotemporal control over the release of loaded cargo and their high surface area. 3D scaffolds have been designed to recruit DCs in vivo through sustained release of cytokines, such as granulocyte-macrophage colony-stimulating factor (GM-CSF) [17,18]. At the scaffold, DCs are presented with tumor-associated antigens (TAAs), such as ovalbumin (OVA) [19], or whole tumor cell lysates [20], together with immunostimulatory adjuvants, such as cytosine-phosphodiester-guanine (CpG), a Tolllike receptor 9 (TLR9) agonist [21], or stimulator of interferon genes (STING) agonists [22]. For example, a methacrylated (MA)-alginate with CpG could recruit four www.sciencedirect.com

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times more DCs than blank alginate group [17]. The Mooney group encapsulated GM-CSF and CpG oligodeoxynucleotide into polylactide-co-glycolide (PLG) matrices to elicit plasmacytoid DCs and CD8+ DCs [23]. In a subsequent study, inorganic mesoporous silica rods (MSRs) were used to form macroporous structures in vivo and provide a 3D cellular microenvironment to host immune cells [24]. The adsorption of polyethylene glycol (PEG) [25] or poly(ethylenimine) (PEI) [24] on MSRs enhanced cell adhesion and infiltration compared to bare MSRs. Mice bearing TC-1 tumors and treated with MSR-PEI vaccine displayed enhanced DC activation and prolonged survival (Figure 2a). When rechallenged with TC-1 tumor 6 months later, surviving mice exhibited strong immunological memory (Figure 2a). In an effort to increase loading efficiency and prolong the release of loaded agents compared to the above-mentioned systems, Sinha et al. modified alginate with graphene and obtained a 3D scaffold that could activate DCs for up to 30 days [19]. Despite the positive results obtained in preclinical studies, many of these examples rely on whole tumor lysates, which require surgical procedure and lengthy preparation [26]. In an attempt to bypass ex vivo tumor lysis, Wang et al. used local radiotherapy, which eliminated tumor cells and promoted the release of neoantigens, in combination with sustained release of CpG and anti-CTLA-4 at the tumor site [27]. In a different study, Ye et al. used photothermal therapy to promote

tumor-antigen uptake by DCs [28]. They designed a microneedle patch containing vaccine adjuvants and melanin. Upon irradiation with near-infrared light, melanin locally generated heat which promoted tumor-antigen uptake by DCs. These preclinical studies highlight the immense potential that scaffolds hold for cancer vaccines. Nevertheless, it remains to be seen whether these strategies will translate to meaningful clinical results. Exogenous T cell response through ACT

In contrast to cancer vaccines, which rely on endogenous T cell response, adoptive cell therapy (ACT) provides patients with ex vivo expanded T cells. Bypassing in vivo activation of T cells offers multiple advantages, such as the lack of immunosuppressive environment and the opportunity to engineer T cells to express CARs or produce effector molecules, such as immunostimulant cytokines. However, generating sufficient numbers of T cells (up to 1011) for ACT remains technically challenging [30]. Artificial antigen-presenting cells (aAPCs), such as commercially available Dynabeads, are commonly used today to expand T cells, representing a convenient alternative to autologous DCs. These aAPCs exhibit the three canonical signals: antigen presentation by the MHC (Signal 1), co-stimulation (Signal 2), along with soluble cytokines (Signal 3). Nevertheless, these polystyrene microspheres have characteristics that differ significantly

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(a) Top: Schematic illustration of a cancer vaccine using PEI-modified mesoporous silica microrods (MSR-PEI). Bottom: Survival curves of mice treated with MSR E7 vaccine, MSR-PEI E7 vaccine, or untreated. Surviving mice were rechallenged with E7-expressing TC-1 tumors 6 months after the first inoculation. PEI: Polyethylenimine. E7: oncoprotein of human papilloma virus. Adapted with permission from Ref. [24]. (b) Top: Schematic illustration of an artificial antigen presenting cell system using lipid-coated mesoporous silica microrods (APC-ms) used to expand T cells ex vivo. Bottom: APC-ms expands primary mouse T cells approximately 6 times more than Dynabeads by day 13. Dynabeads-to-cell-ratio of 25:1. APC-ms concentration of 333 mg/mL, coated with 10 nM of activating stimulus, and loaded with 40 mM of IL-2. Fraction of lipid presenting activation stimulus: 0.1%mol. TCR: T cell receptor. aCD3: agonist antibody to CD3. aCD28: agonist antibody to CD28. Adapted with permission from Ref. [29]. www.sciencedirect.com

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from APCs, including high material stiffness and lack of ligand mobility. Biomaterial approaches have been actively developed to study and better recapitulate physicochemical properties of APCs. In particular, the mechanical properties [31,32], shape [33], and topography [34] of the antigen-presenting surface, the type of ligands [35] and their spatial presentation [36,37], as well as the spatiotemporal control of cytokine release [38,39] have been shown to influence T cell activation. Macroscale scaffolds represent an attractive platform for ex vivo T cell activation as they can be engineered to exhibit large surface area containing high density of biochemical cues and tunable physicochemical properties. A composite scaffold of bundled carbon nanotubes coated with SIINFEKL-MHC I complex and CD28 agonist antibody (anti-CD28) was shown to increase in vitro expansion of OT1 T cells by a factor of 1.5 compared to Dynabeads by day 14 [40]. This increase was attributed to the highly clustered antigen presentation on the surface of the carbon bundles. Interestingly, paracrine release of interleukin 2 (IL-2) from polylactic-co-glycolic acid (PLGA) nanoparticles attached to the carbon surface further increased T cell proliferation by a factor of 1.5. More recently, an artificial system composed of MSRs coated with a lipid bilayer and functionalized with T cell activation cues, including peptide-MHC complex or anti-CD3 antibody along with CD28 antibody, showed a four to ten-fold increased expansion of primary mouse and human T cells compared to Dynabeads at similar activation cue concentration and resulted in similar T cell phenotypes (Figure 2b) [29]. While Dynabeads and the carbon nanotubes system rely on high density of activation cues to provide TCR clustering, this new system mimics the lipid bilayer of cells and enables dynamic antigen reorganization on the surface of the APC. Interestingly, dosage of activating stimuli was shown to influence the CD4/CD8 ratio and affect mouse and human T cells in a different manner [29]. Polymeric systems have also been widely used as platforms to activate T cells [41]. For example, taking inspiration from recent development in the biophysical aspect of T cell activation, a hyaluronic acid-based 2D matrix was engineered to exhibit various stiffnesses, activating cue density, and extracellular matrix proteins [42]. In another study, a poly(e-caprolactone)-polydimethylsiloxane scaffold composed of electrospun microfibers and coated with anti-CD3/CD28 antibodies was shown to increase T cell expansion by a factor of four compared to Dynabeads [43]. Faster T cell ex vivo expansion is key to the widespread use of ACT in the clinic. The evidence presented here suggests that biomimetic scaffolds can provide a significant improvement compared to the current golden standard, that is, Dynabeads. In addition, better control of the phenotype of ex vivo expanded T cells provides an opportunity to evaluate the impact of T cell quality for ACT, as opposed to solely focusing on quantity. Current Opinion in Biotechnology 2020, 65:1–8

Enhancing tumor infiltration of T cells ACT has been highly successful in treating hematologic malignancies [30]. However, it has had to date limited efficacy in the treatment of most solid tumors due to the low tumor infiltration of T cells, lack of persistence in cell number and function, and immunosuppression in the TME. Hence, increasing both the number of T cells [44,45] and their functionality [46] at the tumor site is essential to ACT. 3D scaffolds are an interesting vehicle by which T cells can be localized at the tumor site and provided with an adequate environment for in vivo expansion and maintenance of their effector functions. Early evidence that scaffolds could act as a reservoir for lymphocytes was shown using a chitosan-based thermoreversible hydrogel [47]. Encapsulated T cells could migrate from the gel and retained their antitumor activity in vitro. A variety of injectable T cell reservoirs were developed, such as another chitosan-based hydrogel [48] and a polyisocyanopeptide (PIC)-based hydrogel [49]. The potential of T cell transplantation in vivo using 3D scaffolds for cancer therapy was first demonstrated by Stephan et al. in a breast cancer resection model and an unresectable ovarian carcinoma model [8] (Figure 3a). The authors developed an implantable, macroscale alginate scaffold coated with collagen-mimicking peptides and containing silica microparticles presenting stimulatory antibodies and IL-15 superagonist. Transplanted T cells exhibited high proliferation capacity, in vivo persistence, and a non-exhausted phenotype, unlike cells injected intratumorally, and were shown to successfully eradicate tumor cells. This approach succeeded in preventing tumor relapse and eliciting tumor regression in the breast cancer and ovarian carcinoma models respectively. In both cases, intratumorally injected T cells only provided marginal improvements. Interestingly, this approach required neither lymphodepletion nor bolus injection of cytokines. In a follow-up study, CAR-T cells were co-delivered along with a STING agonist in a pancreatic cancer model [50]. While the implanted CAR-T cells alone were unable to completely cure the tumor-bearing mice likely due to the heterogeneity of the pancreatic tumor, the reported new approach combining CAR-T cells with the STING agonist eliminated both tumor and metastases in 40% of treated mice, and elicited a systemic immunity in surviving mice. Collectively, these studies suggest that macroscale scaffolds represent a promising tool for the local delivery of adoptively transferred T cells and the facile combination of multiple therapeutic modalities.

Overcoming immunosuppression in tumor microenvironment Immunosuppression in the TME is one of the major barriers to cancer immunotherapy. Various factors contribute to the immunosuppressive environment, including soluble cytokines, such as transforming growth factor beta (TGF-b) [52], cellular agents, such as regulatory www.sciencedirect.com

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(a) Top: Schematic illustration of a scaffold containing T cells which is placed in the tumor resection bed. T cells are released from the gel and can target residual tumor cells. Bottom: Representative picture of a section of tumor tissue and scaffold. Tumor cells are labelled with CellTracker Orange, scaffold with Hilyte Fluor 647, and the tumor resection cavity expresses luciferase. Scale bar: 100 mm. Adapted with permission from Ref. [8]. (b) Top: schematic illustration of fibrin gel spraying and in situ gelation. Antibody against CD47 (aCD47) is released from the gel and the pH value within the tumor is increased due to the reaction between calcium carbonate (CaCO3) and hydrogen ions. Bottom: 50% percent of tumorbearing mice treated with aCD47 + CaCO3 in fibrin gel survived for 40 days. Adapted with permission from Ref. [51].

T cells (Tregs) [53], tumor-associated macrophages (TAMs) [54], and myeloid-derived suppressor cells (MDSCs) [55], as well as chemical and nutrient factors, such as hypoxia [56,57] and glucose deprivation [58]. Modulation of the TME to reverse the suppressive state is a promising strategy for enhancing cancer immunotherapy. Gemcitabine (GEM), a widely used clinical chemotherapy, was shown to deplete MDSCs [59]. A 3D porous scaffold containing antigens from tumor lysates, polyinosinic:polycytidylic acid (poly(I:C)), and GEM showed great efficacy in curing mice bearing subcutaneous 4T1 breast tumors [60]. Similar combination strategies were also explored with checkpoint blockade antibodies. For instance, a reactive oxygen species (ROS)-degradable hydrogel was designed to co-deliver GEM and antibodies against programmed cell death protein ligand 1 (PD-L1) [61]. In this elegant design, the gel served as a scavenger of ROS, which can be harmful to immune cells, to enhance the general immune response in the tumor and promote elimination of 4T1 breast and B16F10 melanoma tumors. Surgery is the most common cancer treatment modality but the subsequent tissue repair process can enhance metastasis [22]. To address this issue, Chen et al. developed an in situ sprayed fibrin gel for post-surgical cancer treatment containing calcium carbonate nanoparticles [51] (Figure 3b). These particles could raise the pH value in the TME by scavenging hydrogen ions, causing inflammation within the tumor resection site. In addition, concurrent release of www.sciencedirect.com

anti-CD47 antibody increased phagocytosis of cancer cells by macrophages. These examples highlight how scaffolds can be leveraged to locally modulate the TME to improve therapy outcomes, while restricting the effects of the therapeutic agents to the area of interest.

Discussion and futures directions The soaring number of clinical trials of cancer immunotherapy in the past five years is a good indicator of the high promise that these therapies hold for patients. However, some of the major challenges in each modality of immunotherapy, such as low response rate, persist. We have highlighted in this Review some most recent examples showing the role synthetic 3D scaffolds can play in reducing off-target effects and unleashing the full potential of immunotherapies. These encouraging preclinical studies pave the way for the next generation of scaffoldenabled cancer immunotherapy for enhanced safety and efficacy. Future development of 3D scaffolds for cellular immunotherapy will require precise physicochemical properties better mimicking the physiological environment and tailored to a specific cell type [32,62]. Combination therapies, combining different immunotherapeutic modalities or other conventional therapies, have been shown to be an effective way of achieving higher response rates and durable cures in the clinic. Scaffolds offer an interesting platform for evaluating such combination therapies and identifying potential synergistic effects [50,61]. Therefore, robust and highly Current Opinion in Biotechnology 2020, 65:1–8

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versatile 3D scaffolds adapted to the delivery of various therapeutic agents are highly desired. In general, successful clinical translation of these synthetic 3D scaffold remains challenging and requires a full spectrum of considerations. To date, clinical translation of scaffoldbased immunotherapies has been limited. Of note, an implantable vaccine for melanoma named WDVAX is currently in Phase I clinical trial (NCT01753089) and was licensed to Novartis in 2018. This product is formulated with Food and Drug Administration (FDA)-approved compounds, including PLGA, which has certainly contributed to a faster translation to the clinic. Following in the footsteps of this promising therapy and drawing on decades of development of toolbox in tissue engineering and pharmaceutical implants will help researchers and engineers to design systems which will be clinically relevant and get into the clinic more rapidly.

Author contributions A.K., M.G. and L.T. planned and wrote the review.

Conflict of interest statement Nothing declared.

Acknowledgements The authors thank Swiss National Science Foundation (Project grant 315230_173243), the Foundation Pierre Mercier pour la science, ISREC Foundation with a donation from the Biltema Foundation, Swiss Cancer League (no. KFS-4600-08-2018) and E´cole Polytechnique Fe´de´rale de Lausanne (EPFL). A.K. has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 754354. M.G. is supported by the China Science Council (CSC) (File No. 201808320453). Elements from Figures 1, 2, and 3 were modified from Servier Medical Art, licensed under a Creative Common Attribution 3.0 Generic License. http://smart.servier.com/.

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43. Dang AP, De Leo S, Bogdanowicz DR, Yuan DJ, Fernandes SM, Brown JR, Lu HH, Kam LC: Enhanced activation and expansion of T cells using mechanically soft elastomer fibers. Adv Biosyst 2018:1-6. 1700167. 44. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C, Tosolini M, Camus M, Berger A, Wind P et al.: Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science (80-) 2006, 313:1960-1964. 45. Deschoolmeester V, Baay M, Van Marck E, Weyler J, Vermeulen P, Lardon F, Vermorken JB: Tumor infiltrating lymphocytes: aAn intriguing player in the survival of colorectal cancer patients. BMC Immunol 2010, 11:1-12. 46. Thommen DS, Schumacher TN: T cell dysfunction in cancer. Cancer Cell 2018, 33:547-562. 47. Tsao CT, Kievit FM, Ravanpay A, Erickson AE, Jensen MC, Ellenbogen RG, Zhang M: Thermoreversible poly(ethylene glycol)-g-chitosan hydrogel as a therapeutic T lymphocyte depot for localized glioblastoma immunotherapy. Biomacromolecules 2014, 15:2656-2662. 48. Monette A, Ceccaldi C, Assaad E, Lerouge S, Lapointe R: Chitosan thermogels for local expansion and delivery of tumor-specific T lymphocytes towards enhanced cancer immunotherapies. Biomaterials 2016, 75:237-249. 49. Weiden J, Voerman D, Do¨len Y, Das RK, Van Duffelen A, Hammink R, Eggermont LJ, Rowan AE, Tel J, Figdor CG: Injectable biomimetic hydrogels as tools for efficient T Cell expansion and delivery. Front Immunol 2018, 9:1-15. 50. Smith TT, Moffett HF, Stephan SB, Opel CF, Dumigan AG, Jiang X, Pillarisetty VG, Pillai SPS, Wittrup KD, Stephan MT:  Biopolymers codelivering engineered T cells and STING agonists can eliminate heterogeneous tumors. J Clin Invest 2017, 127:2176-2191 This paper addresses the issue of tumor heterogeneity using a therapy combining local delivery of CAR-T cells and STING to elicit a potent immune response against tumor cells not recognized by the adoptively transferred cells. 51. Chen Q, Wang C, Zhang X, Chen G, Hu Q, Li H, Wang J, Wen D, Zhang Y, Lu Y et al.: In situ sprayed bioresponsive immunotherapeutic gel for post-surgical cancer treatment. Nat Nanotechnol 2019, 14:89-97. 52. Tormoen GW, Crittenden MR, Gough MJ: Role of the immunosuppressive microenvironment in immunotherapy. Adv Radiat Oncol 2018, 3:520-526. 53. Zou W: Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol 2006, 6:295-307. 54. Binnewies M, Roberts EW, Kersten K, Chan V, Fearon DF, Merad M, Coussens LM, Gabrilovich DI, Ostrand-Rosenberg S, Hedrick CC et al.: Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat Med 2018, 24:541-550. 55. Lindau D, Gielen P, Kroesen M, Wesseling P, Adema GJ: The immunosuppressive tumour network: myeloid-derived suppressor cells, regulatory T cells and natural killer T cells. Immunology 2012, 138:105-115. 56. Huang Y, Kim BYS, Chan CK, Hahn SM, Weissman IL, Jiang W: Improving immune–vascular crosstalk for cancer immunotherapy. Nat Rev Immunol 2018, 18:195-203. 57. De Palma M, Biziato D, Petrova TV: Microenvironmental regulation of tumour angiogenesis. Nat Rev Cancer 2017, 17:457-474. 58. Li X, Wenes M, Romero P, Huang SCC, Fendt SM, Ho PC: Navigating metabolic pathways to enhance antitumour immunity and immunotherapy. Nat Rev Clin Oncol 2019, 16:425-441. 59. Le HK, Graham L, Cha E, Morales JK, Manjili MH, Bear HD: Gemcitabine directly inhibits myeloid derived suppressor cells in BALB/c mice bearing 4T1 mammary carcinoma and augments expansion of T cells from tumor-bearing mice. Int Immunopharmacol 2009, 9:900-909. Current Opinion in Biotechnology 2020, 65:1–8

8 Pharmaceutical biotechnology

60. Phuengkham H, Song C, Um SH, Lim YT: Implantable Synthetic  immune niche for spatiotemporal modulation of tumorderived immunosuppression and systemic antitumor immunity: postoperative immunotherapy. Adv Mater 2018, 30:1-9 This paper combines spatiotemporal modulation of the tumor microenvironment with a cancer vaccine to activate antitumor immunity and prevent tumor metastasis and cancer recurrence. 61. Wang C, Wang J, Zhang X, Yu S, Wen D, Hu Q, Ye Y, Bomba H, Hu X,  Liu Z et al.: In situ formed reactive oxygen species–responsive

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scaffold with gemcitabine and checkpoint inhibitor for combination therapy. Sci Transl Med 2018, 10:1-12 The authors present an ingenious reactive oxygen species (ROS) hydrogel containing aPD1 and gemcitabine. Interestingly, the gel serves both as a delivery vehicle and tumor microenvironment modulator. 62. Mennens SFB, Bolomini-Vittori M, Weiden J, Joosten B, Cambi A, Van Den Dries K: Substrate stiffness influences phenotype and function of human antigen-presenting dendritic cells. Sci Rep 2017, 7:1-14.

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