The gut microbiota produces metabolites such as short-chain fatty acids (SCFAs) that regulate the energy homeostasis and impact on immune cell function of the host. Recently, innovative approaches ...based on the oral administration of SCFAs have been discussed for therapeutic modification of inflammatory immune responses in autoimmune diseases. So far, most studies have investigated the SCFA-mediated effects on CD4
T cells and antigen presenting cells. Here we show that butyrate and, to a lesser degree, propionate directly modulate the gene expression of CD8
cytotoxic T lymphocytes (CTLs) and Tc17 cells. Increased IFN-γ and granzyme B expression by CTLs as well as the molecular switch of Tc17 cells towards the CTL phenotype was mediated by butyrate independently of its interaction with specific SCFA-receptors GPR41 and GPR43. Our results indicate that butyrate strongly inhibited histone-deacetylases (HDACs) in CD8
T cells thereby affecting the gene expression of effector molecules. Accordingly, the pan-HDAC inhibitors trichostatin A (TSA) and sodium valproate exerted similar influence on CD8
T cells. Furthermore, higher acetate concentrations were also able to increase IFN-γ production in CD8
T lymphocytes by modulating cellular metabolism and mTOR activity. These findings might have significant implications in adoptive immunotherapy of cancers and in anti-viral immunity.
The large-scale genetic profiling of tumours can identify potentially actionable molecular variants for which approved anticancer drugs are available
. However, when patients with such variants are ...treated with drugs outside of their approved label, successes and failures of targeted therapy are not systematically collected or shared. We therefore initiated the Drug Rediscovery protocol, an adaptive, precision-oncology trial that aims to identify signals of activity in cohorts of patients, with defined tumour types and molecular variants, who are being treated with anticancer drugs outside of their approved label. To be eligible for the trial, patients have to have exhausted or declined standard therapies, and have malignancies with potentially actionable variants for which no approved anticancer drugs are available. Here we show an overall rate of clinical benefit-defined as complete or partial response, or as stable disease beyond 16 weeks-of 34% in 215 treated patients, comprising 136 patients who received targeted therapies and 79 patients who received immunotherapy. The overall median duration of clinical benefit was 9 months (95% confidence interval of 8-11 months), including 26 patients who were experiencing ongoing clinical benefit at data cut-off. The potential of the Drug Rediscovery protocol is illustrated by the identification of a successful cohort of patients with microsatellite instable tumours who received nivolumab (clinical benefit rate of 63%), and a cohort of patients with colorectal cancer with relatively low mutational load who experienced only limited clinical benefit from immunotherapy. The Drug Rediscovery protocol facilitates the defined use of approved drugs beyond their labels in rare subgroups of cancer, identifies early signals of activity in these subgroups, accelerates the clinical translation of new insights into the use of anticancer drugs outside of their approved label, and creates a publicly available repository of knowledge for future decision-making.
In the past few years mRNA molecules have become an attractive class of new drugs with numerous opportunities. mRNA therapeutics holds great potential for the treatment of a variety of diseases and ...is an emerging field both in academia and in the pharma industry. Among the various mRNA-based therapeutic approaches, immunotherapy is one of the pioneering and most advanced therapy to date. Immune cells manipulation using mRNA is commonly used for vaccination purposes, but its potential is much broader. In this review, we discuss the promise of mRNA delivery to leukocytes. We aim to provide an overview of the main progress in this field, as well as the challenges in expanding the scope of mRNA therapy for different therapeutic applications. We also discuss the main technological developments for overcoming mRNA therapy limitations, including mRNA rational design and delivery platforms.
Display omitted
•mRNA-based therapies have gained much progress in recent years.•Among these therapies, mRNA-based immunotherapy is the most common.•Here we review the main progress of mRNA delivery to leukocytes.•We include well-studied modalities as well as promising applications.•We discuss the main hurdles of this field and the suggested solutions.
Cancer immunotherapy based on genetically redirecting T cells has been used successfully to treat B cell malignancies
. In this strategy, the T cell genome is modified by integration of viral vectors ...or transposons encoding chimaeric antigen receptors (CARs) that direct tumour cell killing. However, this approach is often limited by the extent of expansion and persistence of CAR T cells
. Here we report mechanistic insights from studies of a patient with chronic lymphocytic leukaemia treated with CAR T cells targeting the CD19 protein. Following infusion of CAR T cells, anti-tumour activity was evident in the peripheral blood, lymph nodes and bone marrow; this activity was accompanied by complete remission. Unexpectedly, at the peak of the response, 94% of CAR T cells originated from a single clone in which lentiviral vector-mediated insertion of the CAR transgene disrupted the methylcytosine dioxygenase TET2 gene. Further analysis revealed a hypomorphic mutation in this patient's second TET2 allele. TET2-disrupted CAR T cells exhibited an epigenetic profile consistent with altered T cell differentiation and, at the peak of expansion, displayed a central memory phenotype. Experimental knockdown of TET2 recapitulated the potency-enhancing effect of TET2 dysfunction in this patient's CAR T cells. These findings suggest that the progeny of a single CAR T cell induced leukaemia remission and that TET2 modification may be useful for improving immunotherapies.
Immunotherapy has exhibited enormous practice in the treatment of melanoma because of the intrinsic properties of tumor. Tumor can downmodulate immune function via multiple mechanisms such as immune ...checkpoint pathways. The PD-L1 monoclonal antibodies that block the PD1/PD-L1 pathway, which induced tumor cells to evade an immune attack, can delay tumor growth efficiently with inevitable disadvantages such as low selectivity and systemic toxicity. Nanomedicine is clearly an approach that holds tremendous potential for addressing the shortcomings and assisting delivery of drugs with proper biodistribution. Herein, we developed a smart nanoplatform with precisely active targeting liposome co-loaded chemotherapy and immunotherapy drugs for synergistic antitumor effects while decreasing systemic toxicity. Immunoliposomes have stable pharmaceutical properties and show a significant antitumor effect in vivo and in vitro. Cellular uptake in vitro and biodistribution in vivo demonstrated that immunoliposomes could be delivered and accumulated more in tumor tissues. These immunoliposomes exhibited effective tumor inhibition and prolonged survival time due to activation of tumor-specific CD8+ T cell and highly selective tumor killing. In addition, safety evaluation of liposomes also demonstrated their increased tumor accumulation and decreased systemic toxicity. Hence, this smart pH-sensitive nanoplatform has promising potential for clinical applications and possibly provides a well-controlled design for combination of chemotherapy with various immunotherapies for further exploration.
Display omitted
•Preparation of immunoliposomes that co-loaded DTX and PD-L1 antibody•Immunoliposomes show precisely active targeting and effective therapeutic effect•Killing tumor cell directly while switching off immunosuppression•Increased tumor accumulation and decreased systemic toxicity by nanotechnology
Checkpoint blockade immunotherapy (CBI) awakes a host innate immune system and reactivates cytotoxic T cells to elicit durable response in some cancer patients. Now, a cationic nanoscale ...metal–organic framework, W‐TBP, is used to facilitate tumor antigen presentation by enabling immunogenic photodynamic therapy (PDT) and promoting the maturation of dendritic cells (DCs). Comprised of dinuclear WVI secondary building units and photosensitizing 5,10,15,20‐tetra(p‐benzoato)porphyrin (TBP) ligands, cationic W‐TBP mediates PDT to release tumor associated antigens and delivers immunostimulatory CpG oligodeoxynucleotides to DCs. The enhanced antigen presentation synergizes with CBI to expand and reinvigorate cytotoxic T cells, leading to superb anticancer efficacy and robust abscopal effects with >97 % tumor regression in a bilateral breast cancer model.
A metal–organic framework, W‐TBP, is used to facilitate tumor antigen presentation by enabling immunogenic photodynamic therapy (PDT) and promoting the maturation of dendritic cells (DCs). The enhanced antigen presentation synergizes with checkpoint blockade immunotherapy to expand and reinvigorate cytotoxic T cells, leading to 97 % tumor regression in a bilateral breast cancer model.
Solid cancers are able to escape immune surveillance and are resistant to current treatment in immunotherapy. Recent evidence indicates the critical role of the stimulator of interferon genes (STING) ...pathway in antitumor immunity. STING-targeted activation is extensively investigated as a new strategy for cancer therapy. Previously, we reported a safe and efficacious STING-activating nanovaccine to boost systemic tumor-specific T cell responses in multiple tumor models. Local radiotherapy has been reported to not only reduce tumor burden but also enhance local antitumor immunity in a STING-dependent manner. In this study, we demonstrate that combination of these two modalities leads to a synergistic response with long-term regression of large established tumors in two mouse tumor models. The percentage of CD8+ T cells increased significantly in primary tumors after combination therapy. Mechanistically, the augmented T cell responses of radiotherapy and nanovaccine is STING pathway dependent. Furthermore, nanovaccine synergizes with radiotherapy to achieve a better therapeutic effect in distal tumors. These findings suggest that combination of local radiotherapy with systemic PC7A nanovaccine offers a useful strategy to improve the therapeutic outcome of late stage solid cancers.
Display omitted
Melanoma remains one of the most challenging malignant tumor related deaths worldwide and alternative approaches to efficiently treat melanoma are eagerly needed. Anti-PD1 antibody (aPD1) ...immunotherapy is the most significant and impactful therapy for melanoma by immune checkpoint inhibition and T cell stimulation to mediate tumor killing. But the clinical remission rate of aPD1 immunotherapy is limited in melanoma. Here we show a potent combination of aPD1 and photothermal therapy (PTT) by effective delivery of a multifunctional phase-transformation nanocarrier to melanoma tumor. We successfully synthesized multifunctional nanoparticles (NPs) encapsulated with aPD1, iron oxide and perfluoropentane (PFP) in lactic-co-glycolic acid (PLGA) shell modified with poly ethylene glycol (PEG) and Gly-Arg-Gly-Asp-Ser (GRGDS) peptides (GOP@aPD1). In vitro, GOP@aPD1 NPs were characterized for particle size and drug-loading efficiency. The NPs were also tested for photothermal property, optical droplet vaporization (ODV) capacity and the ability of aPD1 release profile. In vivo, GOP@aPD1 NPs were systemically administered to melanoma-bearing mice demonstrated no toxicity and accumulation at tumor site. When mediated with PTT, this synergistic treatment achieved enhanced antitumor efficacy, due to combination of the effective aPD1 release and increased CD8+ T cell infiltration in tumor site. In conclusion, GOP@aPD1 NPs combined with PTT could potentiate the efficacy of aPD1 not only by tumor-targeted delivery of aPD1 but also by activating the immune system in the tumor microenvironment, which is a highly effective approach to treat melanoma.
Display omitted
•PTT-mediated phase-transformation nanoparticles with encapsulation of aPD1 were developed.•The nanoparticles had the ability to target melanoma and could increase the dose of aPD1 in tumor tissue.•The nanoparticles combined with PTT induced immunogenic environment in tumors and sensitized tumors to aPD1 therapy.
Immunosuppressive tumors generally exhibit poor response to immune checkpoint blockade based cancer immunotherapy. Rationally designed hybrid nanoreactors are now presented that have integrated ...functions as Fenton catalysts and glutathione depletion agents for amplifying the immunogenic cell death and activating immune cells. A simple physical mixture of nanoreactors and chemodrugs in combination with immune checkpoint blockades show synergistically and concurrently enhanced chemo‐immunotherapy efficacy, inhibiting the growth of both treated primary immunosuppressive tumors and untreated distant tumors. The off‐the‐shelf strategy uses tumor antigens generated in situ and avoids cargo loading, and is thus a substantial advance in personalized nanomedicine for clinical translation.
A hybrid nanoreactor based on dendritic mesoporous silica nanoparticles containing copper and tetrasulfide that can trigger Fenton's reaction and glutathione depletion has been developed for simultaneously amplifying immunogenic cell death and activating the immune system. It exhibits excellent synergism with immune checkpoint blockades for treating immunosuppressive tumors by concurrently enhanced chemo/immunotherapy.
Display omitted
Tumor-associated macrophage (TAM)-related immunotherapy is a greatly promising strategy that involves altering the immunosuppressive tumor microenvironment with the immunomodulator ...imiquimod (R837) for enhanced cancer therapy. However, the function of R837 is seriously limited due to poor water solubility and a lack of targeting ability. Here, we developed two types of targeting polymer micelles to separately deliver R837 and the anticancer drug doxorubicin (DOX) to TAMs and tumor cells via intratumoral injection and intravenous injection, respectively, for enhanced cancer chemo-immunotherapy against breast cancer. After these micelles accumulated in the tumor tissues, the immunostimulating micelles released R837, which bound to the TLR-7 receptor on the lysosomal membrane within the TAM, stimulating the maturation of the TAM, thereby causing an antitumor immune response and relieving the immunosuppressive effect in the tumor microenvironment. Simultaneously, the chemotherapeutic micelles released DOX in the cytoplasm of the tumor cells, directly inducing cell death. As a result, a synergistic combination of chemotherapy and immunotherapy was achieved through these nanomedicines, which separately activated the antitumor immune response and inhibited tumor cell growth. Therefore, this strategy is a new avenue for the development of targeting nanomedicines for combination chemo-immunotherapy against malignant cancer.
PDF
