Combination of AAV-delivered tumor suppressor PTEN with anti-PD-1 loaded depot gel for enhanced antitumor immunity

Recent clinical studies have shown that mutation of phosphatase and tensin homolog deleted on chromosome 10(PTEN)gene in cancer cells may be associated with immunosuppressive tumor microenvironment(TME)and poor response to immune checkpoint blockade(ICB)therapy.Therefore,efficiently restoring PTEN gene expression in cancer cells is critical to improving the responding rate to ICB therapy.Here,we screened an adeno-associated virus(AAV)capsid for efficient PTEN gene delivery into B16F10 tumor cells.We demonstrated that intratumorally injected AAV6-PTEN successfully restored the tumor cell PTEN gene expression and effectively inhibited tumor progression by inducing tumor cell immunogenic cell death(ICD)and increasing immune cell infiltration.Moreover,we developed an anti-PD-1 loaded phospholipid-based phase separation gel(PPSG),which formed an in situ depot and sustainably release anti-PD-1 drugs within 42 days in vivo.In order to effectively inhibit the recurrence of melanoma,we further applied a triple therapy based on AAV6-PTEN,PPSG^(@anti-PD-1)and CpG,and showed that this triple therapy strategy enhanced the synergistic antitumor immune effect and also induced robust immune memory,which completely rejected tumor recurrence.We anticipate that this triple therapy could be used as a new tumor combination therapy with stronger immune activation capacity and tumor inhibition efficacy.

Bacteria-Mediated Synergistic Cancer Therapy:Small Microbiome Has a Big Hope

The use of bacteria to specifically migrate to cancerous tissue and elicit an antitumor immune response provides a promising platform against cancer with significantly high potency.With dozens of clinical trials underway,some researchers hold the following views:“humans are nearing the first commercial live bacteria therapeutic.”However,the facultative anaerobe Salmonella typhimurium VNP20009,which is particularly safe and shows anticancer effects in preclinical studies,had failed in a phase I clinical trial due to low tumor regression and undesired dose-dependent side effects.This is almost certain to disappoint people’s inflated expectations,but it is noted that recent stateof-the-art research has turned attention to bacteria-mediated synergistic cancer therapy(BMSCT).In this review,the foundation of bacteria-mediated bio-therapy is outlined.Then,we summarize the potential benefits and challenges of bacterial bio-therapy in combination with different traditional anticancer therapeutic modalities(chemotherapy,photothermal therapy,reactive oxygen and nitrogen species therapy,immunotherapy,or prodrug-activating therapy)in the past 5 years.Next,we discuss multiple administration routes of BMSCT,highlighting potentiated antitumor responses and avoidance of potential side effects.Finally,we envision the opportunities and challenges for BMSCT development,with the purpose of inspiring medicinal scientists to widely utilize the microbiome approach in patient populations.

Oncolytic virus therapy in cancer: A current review

In view of the advancement in the understanding about the most diverse types of cancer and consequently a relentless search for a cure and increased survival rates of cancer patients,finding a therapy that is able to combat the mechanism of aggression of this disease is extremely important.Thus,oncolytic viruses(OVs)have demonstrated great benefits in the treatment of cancer because it mediates antitumor effects in several ways.Viruses can be used to infect cancer cells,especially over normal cells,to present tumor-associated antigens,to activate“danger signals”that generate a less immune-tolerant tumor microenvironment,and to serve transduction vehicles for expression of inflammatory and immunomodulatory cytokines.The success of therapies using OVs was initially demonstrated by the use of the genetically modified herpes virus,talimogene laherparepvec,for the treatment of melanoma.At this time,several OVs are being studied as a potential treatment for cancer in clinical trials.However,it is necessary to be aware of the safety and possible adverse effects of this therapy;after all,an effective treatment for cancer should promote regression,attack the tumor,and in the meantime induce minimal systemic repercussions.In this manuscript,we will present a current review of the mechanism of action of OVs,main clinical uses,updates,and future perspectives on this treatment.

Inducing immunogenic cell death in immuno-oncological therapies

Immunotherapy has revolutionized cancer treatment and substantially improved patient outcomes with respect to multiple types of tumors.However,most patients cannot benefit from such therapies,mainly due to the intrinsic low immunogenicity of cancer cells(CCs)that allows them to escape recognition by immune cells of the body.Immunogenic cell death(ICD),which is a form of regulated cell death,engages in a complex dialogue between dying CCs and immune cells in the tumor microenvironment(TME),ultimately evoking the damage-associated molecular pattern(DAMP)signals to activate tumor-specific immunity.The ICD inducers mediate the death of CCs and improve both antigenicity and adjuvanticity.At the same time,they reprogram TME with a“cold-warmhot”immune status,ultimately amplifying and sustaining dendritic cell-and T cell-dependent innate sensing as well as the antitumor immune responses.In this review,we discuss how to stimulate ICD based upon the biological properties of CCs that have evolved under diverse stress conditions.Additionally,we highlight how this dynamic interaction contributes to priming tumor immunogenicity,thereby boosting anticancer immune responses.We believe that a deep understanding of these ICD processes will provide a framework for evaluating its vital role in cancer immunotherapy.

Angiotensin-converting enzyme 2 connects COVID-19 with cancer and cancer immunotherapy

The coronavirus disease 2019(COVID-19)pandemic caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)has resulted in more than two million deaths.Underlying diseases,including cancer,are high-risk factors for severe COVID-19 outcomes.Angiotensin-converting enzyme 2(ACE2),as a SARS-CoV-2 host cell receptor,plays a crucial role in SARS-CoV-2 invading human cells.ACE2 also has significant associations with cancer.Recent studies showed that ACE2 was inversely correlated with the activities of multiple oncogenic pathways and tumor progression phenotypes,and was positively correlated with antitumor immune response and survival prognosis in diverse cancers,suggesting a potential protective role of ACE2 in cancer progression.Positive expression of ACE2 is also correlated with programmed death-ligand 1(PD-L1)in cancer.The positive associations of ACE2 expression with antitumor immune signatures and PD-L1 expression indicate that ACE2 expression is a positive predictor for the response to immune checkpoint inhibitors(ICIs).This was evidenced in multiple cancer cohorts treated with ICIs.Thus,ACE2 may build potential connections between COVID-19 and cancer and cancer immunotherapy.The potential connections suggest that ACE2 inhibitors may not be a good option for treating COVID-19 patients with cancer,particularly in cancer patients who are receiving immunotherapy.Furthermore,the relationships between ACE2,COVID-19,and cancer are worth confirming by more experimental and clinical data,considering that many cancer patients are at high risk for COVID-19.

Distinct T helper cell-mediated antitumor immunity:T helper 2 cells in focus

The adaptive arm of the immune system is crucial for appropriate antitumor immune responses.It is generally accepted that clusters of differentiation 4^(+)(CD4^(+))T cells,which mediate T helper(Th)1 immunity(type 1 immunity),are the primary Th cell subtype associated with tumor elimination.In this review,we discuss evidence showing that antitumor immunity and better prognosis can be associated with distinct Th cell subtypes in experimental mouse models and humans,with a focus on Th2 cells.The aim of this review is to provide an overview and understanding of the mechanisms associated with different tumor outcomes in the face of immune responses by focusing on the(1)site of tumor development,(2)tumor properties(i.e.,tumor metabolism and cytokine receptor expression),and(3)type of immune response that the tumor initially escaped.Therefore,we discuss how low-tolerance organs,such as lungs and brains,might benefit from a less tissue-destructive immune response mediated by Th2 cells.In addition,Th2 cells antitumor effects can be independent of CD8^(+)T cells,which would circumvent some of the immune escape mechanisms that tumor cells possess,like low expression of major histocompatibility-I(MHC-I).Finally,this review aims to stimulate further studies on the role of Th2 cells in antitumor immunity and briefly discusses emerging treatment options.

Photosynthetic microorganisms coupled photodynamic therapy for enhanced antitumor immune effect

The ideal photodynamic therapy(PDT)should effectively remove the primary tumor,and produce a stronger immune memory effect to inhibit the tumor recurrence and tumor metastasis.However,limited by the hypoxic and immunosuppressive microenvironment,the PDT efficiency is apparently low.Here,Chlorella(Chl.)is exploited to enhance local effect by producing oxygen to reverse hypoxia,and release adjuvants to reverse immunosuppressive microenvironment to enhance abscopal effect afterwards.Results from different animal models indicated that Chl.could enhance local effect and PDT related immune response.Ultimately,Chl.coupled PDT elicited anti-tumor effects toward established primary tumors(inhibition rate:90%)and abscopal tumors(75%),controlled the challenged tumors(100%)and alleviated metastatic tumors(90%).This Chl.coupled PDT strategy can also produce a stronger anti-tumor immune memory effect.Overall,this Chl.coupled PDT strategy generates enhanced local tumor killing,boosts PDT-induced immune responses and promotes anti-tumor immune memory effect,which may be a great progress for realizing systemic effect of PDT.

Nanovaccines for cancer immunotherapy:Current knowledge and future perspectives

Cancer immunotherapy harnesses the immune system to attack tumors and has received extensive attention in recent years.Cancer vaccines as an important branch of immunotherapy are designed for delivering tumor antigens to antigen-presenting cells(APCs)to stimulate a strong immune response to against tumors,representing a potentially therapeutic and prophylactic effect with the long-term anticancer benefits.Nevertheless,the disappointing outcomes of their clinical use might be attributed to dilemma in antigen selection,immunogenicity,lymph nodes(LNs)targeting ability,lysosomal escape ability,immune evasion,etc.Nanotechnology,aiming to overcome these barriers,has been utilized in cancer vaccine development for decades.Numerous preclinical and clinical studies demonstrate positive results in nanomaterials-based cancer vaccines with considerable improvement in the vaccine efficacy.In this review,we systematically introduced the characteristics of nanovaccines and highlighted the different types of nanomaterials used for cancer vaccine design.In addition,the opportunities and challenges of the emerging nanotechnology-based cancer vaccines were discussed.

The immune-chemo-embolization effect of temperature sensitive gold nanomedicines against liver cancer

Although transcatheter arterial chemo-embolization(TACE)plays a key role on clinical treatment of hepatocellular carcinoma(HCC),it was greatly limited by the poor synergistic effect between chemotherapeutics and physical embolization to tumor-feeding arteries.In the present work,a temperature sensitive polymer poly(N-isopropylacrylamide-b-methacrylic acid)(PNA),which was modified with gold nanoparticles(AuNP@PNA),was successfully used to encapsulate doxorubicin(DOX)by electrostatic binding with their carboxyl groups.The resultant gold nanomedicines(AuNP@PNA/DOX)exhibited temperature responsive sol-gel phase transition,favorable shear thinning effect and X-ray angiography.By in vivo evaluation of vascular embolization on VX2-tumor-bearing rabbits,AuNP@PNA/DOX exhibited far better antitumor efficacy than Lipiodol/DOX,on either tumor growth inhibition,proliferation,apoptosis,necrosis or anti-metastasis.Owing to sufficient embolization to tumor vascular networks,AuNP@PNA/DOX down-regulated the expression levels of HIF-1α,VEGF and MMP-9,and prompted more efficient activation on CD3+/CD8+T cells and the related cytokines,suggesting the synergistic effect between AuNP@PNA and DOX on the improvement of post-operative tumor immunosuppressive microenvironment.With their favorable pharmcokinetics and biocompatibility,AuNP@PNA/DOX is promising to be developed as a multi-functional artery-imaging/embolic agent with immune-chemo-embolization for enhancing TACE efficacy on HCC.

Stimuli-responsive nano vehicle enhances cancer immunotherapy by coordinating mitochondria-targeted immunogenic cell death and PD-L1 blockade

Induction of immunogenic cell death promotes antitumor immunity against cancer. However, majority of clinically-approved drugs are unable to elicit sufficient ICD. Here, our study revealed that mitochondria-targeted delivery of doxorubicin(DOX) massively amplified ICD via substantial generation of reactive oxygen species(ROS) after mitochondrial damage. The underlying mechanism behind increased ICD was further demonstrated to be ascribed to two pathways:(1) ROS elevated endoplasmic reticulum(ER) stress, leading to surface exposure of calreticulin;(2) ROS promoted release of various mitochondriaassociated damage molecules including mitochondrial transcription factor A. Nevertheless, adaptive upregulation of PD-L1 was found after such ICD-inducing treatment. To overcome such immunosuppressive feedback,we developed a tumor stimuli-responsive nano vehicle to simultaneously exert mitochondrial targeted ICD induction and PD-L1 blockade. The nano vehicle was self-assembled from ICD-inducing copolymer and PD-L1 blocking copolymer, and possessed long-circulating property which contributed to better tumor accumulation and mitochondrial targeting. As a result, the nano vehicle remarkably activated antitumor immune responses and exhibited robust antitumor efficacy in both immunogenic and non-immunogenic tumor mouse models.

Cancer-cell-biomimetic nanoparticles systemically eliminate hypoxia tumors by synergistic chemotherapy and checkpoint blockade immunotherapy

Checkpoint blockade-based immunotherapy has shown unprecedented effect in cancer treatments,but its clinical implementation has been restricted by the low host antitumor response rate.Recently,chemotherapy is well recognized to activate the immune system during some chemotherapeutics-mediated tumor eradication.The enhancement of immune response during chemotherapy might further improve the therapeutic efficiency through the synergetic mechanism.Herein,a synergistic antitumor platform(designated as BMS/RA@CC-Liposome)was constructed by utilizing CT26 cancer-cell-biomimetic nanoparticles that combined chemotherapeutic drug(RA-V)and PD-1/PD-L1 blockade inhibitor(BMS-202)to remarkably enhance antitumor immunity.In this study,the cyclopeptide RA-V as chemotherapeutic drugs directly killing tumor cells and BMS-202 as anti-PD agents eliciting antitumor immune responses were co-encapsulated in a pH-sensitive nanosystem.To achieve the cell-specific targeting drug delivery,the combination therapy nanosystem was functionalized with cancer cell membrane camouflage.The biomimetic drug delivery system perfectly disguised as endogenous substances,and realized elongated blood circulation due to anti-phagocytosis capability.Moreover,the BMS/RA@CC-Liposome also achieved the selective targeting of CT26 cells by taking advantage of the inherent homologous adhesion property of tumor cells.The in vitro and in vivo experiments revealed that the BMS/RA@CC-Liposome realized PD-1/PD-L1 blockade-induced immune response,RA-V-induced PD-L1 down-regulation and apoptosis in cancer cells.Such a system combining the advantages of chemotherapy and checkpoint blockade-based immunotherapy to create an immunogenic tumor microenvironment systemically,demonstrated improved therapeutic efficacy against hypoxic tumor cells and offers an alternative strategy based on the immunology of the PD-1/PD-L1 pathway.