A Review on Nano-Based Drug Delivery System for Cancer Chemoimmunotherapy

Although notable progress has been made on novel cancer treatments,the overall survival rate and therapeutic effects are still unsatisfactory for cancer patients.Chemoimmunotherapy,combining chemotherapeutics and immunotherapeutic drugs,has emerged as a promising approach for cancer treatment,with the advantages of cooperating two kinds of treatment mechanism,reducing the dosage of the drug and enhancing therapeutic effect.Moreover,nano-based drug delivery system(NDDS)was applied to encapsulate chemotherapeutic agents and exhibited outstanding properties such as targeted delivery,tumor microenvironment response and site-specific release.Several nanocarriers have been approved in clinical cancer chemotherapy and showed significant improvement in therapeutic efficiency compared with traditional formulations,such as liposomes(Doxil R,Lipusu R),nanoparticles(Abraxane R)and micelles(Genexol-PM R).The applications of NDDS to chemoimmunotherapy would be a powerful strategy for future cancer treatment,which could greatly enhance the therapeutic efficacy,reduce the side effects and optimize the clinical outcomes of cancer patients.Herein,the current approaches of cancer immunotherapy and chemoimmunotherapy were discussed,and recent advances of NDDS applied for chemoimmunotherapy were further reviewed.

Prognostic significance of plasma interleukin-6/-8 in pancreatic cancer patients receiving chemoimmunotherapy

AIM: To investigate the association of plasma levels of interleukin(IL)-6 and-8 with Wilms' tumor 1(WT1)-specific immune responses and clinical outcomes in patients with pancreatic ductal adenocarcinoma(PDA) treated with dendritic cells(DCs) pulsed with three types of major histocompatibility complex classⅠand Ⅱ-restricted WT1 peptides combined with chemotherapy.METHODS: During the entire treatment period, plasma levels of IL-6 and-8 were analyzed by ELISA. The induction of WT1-specific immune responses was assessed using the WT1 peptide-specific delayed-type hypersensitivity(DTH) test.RESULTS: Three of 7 patients displayed strong WT1-DTH reactions throughout long-term vaccination with significantly decreased levels of IL-6/-8 after vaccinations compared with the levels prior to treatment. Moreover, overall survival(OS) was significantly longer in PDA patients with low plasma IL-6 levels(< 2 pg/m L) after 5 vaccinations than in patients with high plasma IL-6 levels(≥ 2 pg/m L)(P = 0.025). After disease progression, WT1-DTH reactions decreased severely and were ultimately negative at the terminal stage of cancer. The decreased levels of IL-6/-8 observed throughout long-term vaccination were associated with WT1-specific DTH reactions and long-term OS.CONCLUSION: Prolonged low levels of plasma IL-6/-8 in PDA patients may be a prognostic marker for the clinical outcomes of chemoimmunotherapy.

A pH/ROS dual-responsive system for effective chemoimmunotherapy against melanoma via remodeling tumor immune microenvironment

Chemotherapeutics can induce immunogenic cell death(ICD)in tumor cells,offering new possibilities for cancer therapy.However,the efficiency of the immune response generated is insufficient due to the inhibitory nature of the tumor microenvironment(TME).Here,we developed a pH/reactive oxygen species(ROS)dual-response system to enhance chemoimmunotherapy for melanoma.The system productively accumulated in tumors by specific binding of phenylboronic acid(PBA)to sialic acids(SA).The nanoparticles(NPs)rapidly swelled and released quercetin(QUE)and doxorubicin(DOX)upon the stimulation of tumor microenvironment(TME).The in vitro and in vivo results consistently demonstrated that the NPs improved anti-tumor efficacy and prolonged survival of mice,significantly enhancing the effects of the combination.Our study revealed DOX was an ICD inducer,stimulating immune responses and promoting maturation of dendritic cells(DCs).Additionally,QUE served as a TME regulator by inhibiting the cyclooxygenase-2(COX2)-prostaglandin E2(PGE2)axis,which influenced various immune cells,including increasing cytotoxic T cells(CLTs)infiltration,promoting M1 macrophage polarization,and reducing regulatory T cells(Tregs)infiltration.The combination synergistically facilitated chemoimmunotherapy efficacy by remodeling the immunosuppressive microenvironment.This work presents a promising strategy to increase anti-tumor efficiency of chemotherapeutic agents.

Activation of autophagy by in situ Zn^(2+) chelation reaction for enhanced tumor chemoimmunotherapy

Chemotherapy can induce a robust T cell antitumor immune response by triggering immunogenic cell death(ICD),a process in which tumor cells convert from nonimmunogenic to immunogenic forms.However,the antitumor immune response of ICD remains limited due to the low immunogenicity of tumor cells and the immunosuppressive tumor microenvironment.Although autophagy is involved in activating tumor immunity,the synergistic role of autophagy in ICD remains elusive and challenging.Herein,we report an autophagy amplification strategy using an ion-chelation reaction to augment chemoimmunotherapy in cancer treatments based on zinc ion(Zn^(2+))-doped,disulfiram(DSF)-loaded mesoporous silica nanoparticles(DSF@Zn-DMSNs).Upon pH-sensitive biodegradation of DSF@Zn-DMSNs,Zn2+and DSF are coreleased in the mildly acidic tumor microenvironment,leading to the formation of toxic Zn2+chelate through an in situ chelation reaction.Consequently,this chelate not only significantly stimulates cellular apoptosis and generates damage-associated molecular patterns(DAMPs)but also activates autophagy,which mediates the amplified release of DAMPs to enhance ICD.In vivo results demonstrated that DSF@Zn-DMSNs exhibit strong therapeutic efficacy via in situ ion chelation and possess the ability to activate autophagy,thus enhancing immunotherapy by promoting the infiltration of T cells.This study provides a smart in situ chelation strategy with tumor microenvironment-responsive autophagy amplification to achieve high tumor chemoimmunotherapy efficacy and biosafety.

Macrophage-camouflaged epigenetic nanoinducers enhance chemoimmunotherapy in triple negative breast cancer

Chemoimmunotherapy has been approved as standard treatment for triple-negative breast cancer(TNBC),but the clinical outcomes remain unsatisfied.Abnormal epigenetic regulation is associated with acquired drug resistance and T cell exhaustion,which is a critical factor for the poor response to chemoimmunotherapy in TNBC.Herein,macrophage-camouflaged nanoinducers co-loaded with paclitaxel(PTX)and decitabine(DAC)(P/D-mMSNs)were prepared in combination with PD-1 blockade therapy,hoping to improve the efficacy of chemoimmunotherapy through the demethylation of tumor tissue.Camouflage of macrophage vesicle confers P/D-mMSNs with tumor-homing properties.First,DAC can achieve demethylation of tumor tissue and enhance the sensitivity of tumor cells to PTX.Subsequently,PTX induces immunogenic death of tumor cells,promotes phagocytosis of dead cells by dendritic cells,and recruits cytotoxic T cells to infiltrate tumors.Finally,DAC reverses T cell depletion and facilitates immune checkpoint blockade therapy.P/D-mMSNs may be a promising candidate for future drug delivery design and cancer combination therapy in TNBC.

Co-delivery of gemcitabine and paclitaxel plus NanoCpG empowers chemoimmunotherapy of postoperative“cold”triple-negative breast cancer

Triple-negative breast cancer(TNBC)due to lack of clear target and notorious“cold”tumor microenvironment(TME)is one of the most intractable and lethal malignancies.Tuning“cold”TME into“hot”becomes an emerging therapeutic strategy to TNBC.Herewith,we report that integrin-targeting micellar gemcitabine and paclitaxel(ATN-mG/P,ATN sequence:Ac-PhScNK-NH2)cooperating with polymersomal CpG(NanoCpG)effectively“heated up”and treated TNBC.ATN-mG/P exhibited greatly boosted apoptotic activity in 4T1 cells,induced potent immunogenic cell death(ICD),and efficiently stimulated maturation of bone marrow-derived dendritic cells(BMDCs).Remarkably,in a postoperative TNBC model,ATN-mG/P combining with NanoCpG promoted strong anti-cancer immune responses,showing a greatly augmented proportion of mature DCs and CD8^(+)T cells while reduced immune-suppressive myeloid-derived suppressor cells(MDSCs)and regulatory T cells(T_(reg)),which led to complete inhibition of lung metastasis and 60%mice tumor-free.The co-delivery of gemcitabine and paclitaxel at desired ratio in combination with NanoCpG provides a unique platform for potent chemoimmunotherapy of“cold”tumors like TNBC.

Intratumoral CD103^(+)CD8^(+)T cells predict response to neoadjuvant chemoimmunotherapy in advanced head and neck squamous cell carcinoma

Background Immune cell heterogenicity is known to determine the therapeutic response to cancer progression.Neoadjuvant chemoimmunotherapy(NACI)has shown clinical benefits in some patients with advanced head and neck squamous cell carcinoma(HNSCC),but the underlying mechanism behind this clinical response is unknown.The efficacy of NACI needs to be potentiated by identifying accurate biomarkers to predict clinical responses.Here,we attempted to identify molecules predicting NACI response in advanced HNSCC.Methods We performed combined single-cell RNA sequencing(scRNA-seq)and multiplex immunofluorescence(mIHC)staining with tumor samples derived from NACI-treated HNSCC patients to identify a new tumor-infiltrating cell(TIL)subtype,CD103^(+)CD8^(+)TILs,associated with clinical response,while both in vitro and in vivo assays were carried out to determine its antitumor efficiency.The regulatory mechanism of the CD103^(+)CD8^(+)TILs population was examined by performing cell-cell interaction analysis of the scRNA-seq data and spatial analysis of the mIHC images.Results We established intratumoral CD103^(+)CD8^(+)TILs density as a determinant of NACI efficacy in cancers.Our scRNA-seq results indicated that the population of CD103^(+)CD8^(+)TILs was dramatically increased in the responders of NACI-treated HNSCC patients,while mIHC analysis confirmed the correlation between intratumoral CD103^(+)CD8^(+)TILs density and NACI efficacy in HNSCC patients.Further receiver operating characteristic curve analysis defined this TIL subset as a potent marker to predict patient response to NACI.Functional assays showed that CD103^(+)CD8^(+)TILs were tumor-reactive T cells,while programmed cell death protein-1(PD-1)blockade enhanced CD103^(+)CD8^(+)TILs cytotoxicity against tumor growth in vivo.Mechanistically,targeting the triggering receptor expressed on myeloid cells 2-positive(TREM2^(+))macrophages might enhance the population of CD103^(+)CD8^(+)TILs and facilitate antitumor immunity during NACI treatment.Conclusions Our study highlights the impact of intratumoral CD103^(+)CD8^(+)TILs density on NACI efficacy in different cancers,while the efforts to elevate its population warrant further clinical investigation.

Time-limited,Combined Regimen in Chronic Lymphocytic Leukemia:A Promising Strategy to Achieve a Drug Holiday

Chemoimmunotherapy(CIT)is defined as standard first line treatment for chronic lymphocytic leukemia(CLL)patients while patients with unfavorable biological characteristics such as unmutated immunoglobulin heavy chain(UM-IGHV)and TP53 aberration failed to benefit from it.The emergency of the small molecular targeted agents including Bruton’s tyrosine kinase(BTK)inhibitor(BTKi)leads to a brand-new era,from a CIT to a chemo-free era in CLL.However,the treatment of target agents is not enough to attain a deep remission and high rate of complete remission(CR),especially in patients with high risks.The long duration brought about problems,such as cost,drug resistance and toxicity.To benefit CLL in progression free survival(PFS)and long-term remission,exploration of time-limited therapies,mainly with BTKi plus CIT and BCL2i based combination therapy has become a mainstream in clinical trials.The time-limited combination therapy shed light on the promising potentiality to attain sustainable deep remission and partly overcame the risk factors,although long term follow-up is required to consolidate the conclusion.In this review,we intend to introduce key results of clinical trials with combination therapy,discuss the achievements and limitations and put forward future direction for clinical trial design in this field.

Impact of COVID-19 in patients with lymphoid malignancies

The first cases of coronavirus disease 2019(COVID-19)were detected in Wuhan,China,in December 2019.Since this time a concerted global effort of research and observational data gathering has meant that a great deal has been learnt about the impact of COVID-19 in patients with lymphoid malignancies.Approximately onethird of patients with lymphoid malignancies who acquire COVID-19 and have it severely enough to require hospital assessment will die from this infection.Major risk factors for a poor outcome are age and co-morbidities,but when these are taken into account lymphoma patients have a slightly greater than 2-fold increased risk compared to the general population.Notably,despite early concerns regarding the particular vulnerability of lymphoma patients due to the immunosuppressive effects of therapy,active treatment,including B-cell depleting agents such as rituximab,do not appear to be associated with an increased risk of a poorer outcome.Indeed,some treatments such as ibrutinib may be beneficial due to their modulation of the potential fatal hyperinflammatory phase of infection.There are risks associated with hemopoietic stem cell transplantation,but the collective experience is that these can be minimized by preventive strategies and that the majority of transplant recipients with COVID-19 infection will survive.Many questions remain including those regarding the outcome of COVID-19 infection in the rarer lymphoid malignancies and the efficacy of COVID-19 vaccines in lymphoma patients.This review aims to discuss these issues and present a summary of the current knowledge of the impact of COVID-19 in lymphoid malignancies.

GSH-responsive camptothecin prodrug-based hybrid micellar nanoparticles enable antitumor chemo-immunotherapy by PD-L1 knockdown

The combinational chemo-immunotherapy as a novel treatment strategy has been widely studied and applied in clinic to enhance antitumor therapeutic efficacy and relieve side effects.RNA interference(RNAi)targeting PD-L1 via inhibiting novo production of PD-L1 will overcome the innate and adaptive PD-L1 expression during chemotherapy,thus enable sustained and efficient immune checkpoint blockade(ICB)to active antitumor immune response.Herein,we designed a glutathione(GSH)-responsive camptothecin(CPT)prodrug-based hybrid micellar nanoparticles(siPD-L1@HM-CPT)to achieve synergistic antitumor chemoimmunotherapy by PD-L1 knockdown.siPD-L1@HM-CPT derived from the one-step loading PD-L1 siRNA(siPD-L1)into the CPT prodrug-based hybrid micelles(HM-CPT)which were co-assembled from biodegradable polyphosphoesters-based prodrug CPT-ss-PAEEP15 and stabilizer DSPE-PEG,showed high loading efficiency,GSH-responsive drug release,and excellent stability and biosafety.siPD-L1@HM-CPT achieved simultaneously the co-delivery of CPT and siPD-L1 in vitro and in vivo,high accumulation at the tumor sites,and rapid intracellular release to promote antitumor efficacy via sensitizing CPT chemotherapy,inducing strong immunogenic cell death(ICD)and sustained ICB to improve intratumoral CD8+T cells infiltration.In addition,the antitumor immunity response limited by the differentiated immunogenicity,intrinsic PD-L1 expression,and intracellular GSH level was facilitated by efficient ICD and ICB from silencing PD-L1 and synergistic CPT chemosensitization in our experimental B16-F10 and 4T1 tumor models.Our study might offer a perspective on designing novel co-delivery nanoparticles by convenient and controllable preparation for antitumor chemo-immunotherapy.

Neoadjuvant immunotherapy for non-small cell lung cancer:State of the art

Lung cancer mortality has decreased over the past decade and can be partly attributed to advances in targeted therapy and immunotherapy.Immune checkpoint inhibitors(ICIs)have rapidly evolved from investigational drugs to standard of care for the treatment ofmetastatic non-small cell lung cancer(NSCLC).In particular,antibodies that block inhibitory immune checkpoints,such as programmed cell death protein 1(PD-1)and programmed cell death 1 ligand 1(PD-L1),have revolutionized the treatment of advanced NSCLC,when administered alone or in combination with chemotherapy.Immunotherapy is associated with higher response rates,improved overall survival(OS),and increased tolerability compared with conventional cytotoxic chemotherapy.These benefits may increase the utility of immunotherapy and its combinational use with chemotherapy in the neoadjuvant treatment of patients with NSCLC.Early findings from various ongoing clinical trials suggest that neoadjuvant ICIs alone or combined with chemotherapy may significantly reduce systemic recurrence and improve long-term OS or cure rates in resectable NSCLC.Here we further summarize the safety and efficacy of various neoadjuvant treatment regimens including immunotherapy from ongoing clinical trials and elaborate the role of neoadjuvant immunotherapy in patients with resectable NSCLC.In addition,we discuss several unresolved challenges,including the evaluations to assess neoadjuvant immunotherapy response,the role of adjuvant treatment after neoadjuvant immunotherapy,the efficacy of treatment for oncogenic-addicted tumors,and predictive biomarkers.We also provide our perspective on ways to overcome current obstacles and establish neoadjuvant immunotherapy as a standard of care.

Cytosolic delivery of the immunological adjuvant PolyⅠ:C and cytotoxic drug crystals via a carrier-free strategy significantly amplifies immune response

Co-delivery of chemotherapeutics and immunostimulant or chemoimmunotherapy is an emerging strategy in cancer therapy.The precise control of the targeting and release of agents is critical in this methodology.This article proposes the asynchronous release of the chemotherapeutic agents and immunostimulants to realize the synergistic effect between chemotherapy and immunotherapy.To obtain a proof-of-concept,a co-delivery system was prepared via a drug-delivering-drug(DDD)strategy for cytosolic co-delivery of Poly I:C,a synthetic ds RNA analog to activate RIG-I signaling,and PTX,a commonly used chemotherapeutics,in which pure PTX nanorods were sequentially coated with Poly I:C and mannuronic acid via stimulating the RIG-I signaling axis.The co-delivery system with a diameter of 200 nm enables profound immunogenicity of cancer cells,exhibiting increased secretion of cytokines and chemokines,pronounced immune response in vivo,and significant inhibition of tumor growth.Also,we found that intracellularly sustained release of cytotoxic agents could elicit the immunogenicity of cancer cells.Overall,the intracellular asynchronous release of chemotherapeutics and immunomodulators is a promising strategy to promote the immunogenicity of cancer cells and augment the antitumor immune response.

Epstein-Barr virus-associated post-transplant lymphoproliferative disorders:beyond chemotherapy treatment

Post-transplant lymphoproliferative disorder(PTLD)is a rare but life-threatening complication of both allogeneic solid organ(SOT)and hematopoietic cell transplantation(HCT).The histology of PTLD ranges from benign polyclonal lymphoproliferation to a lesion indistinguishable from classic monoclonal lymphoma.Most commonly,PTLDs are Epstein-Barr virus(EBV)positive and result from loss of immune surveillance over EBV.Treatment for PTLD differs from the treatment for typical non-Hodgkin lymphoma because prognostic factors are different,resistance to treatment is unique,and there are specific concerns for organ toxicity.While recipients of HCT have a limited time during which they are at risk for this complication,recipients of SOT have a lifelong requirement for immunosuppression,so approaches that limit compromising or help restore immune surveillance are of high interest.Furthermore,while EBV-positive and EBV-negative PTLDs are not intrinsically resistant to chemotherapy,the poor tolerance of chemotherapy in the post-transplant setting makes it essential to minimize potential treatment-related toxicities and explore alternative treatment algorithms.Therefore,reduced-toxicity approaches such as single-agent CD20 monoclonal antibodies or bortezomib,reduced dosing of standard chemotherapeutic agents,and non-chemotherapy-based approaches such as cytotoxic T cells have all been explored.Here,we review the chemotherapy and non-chemotherapy treatment landscape for PTLD.

Checkpoint immunotherapy for NK/T cell lymphoma—Time for a showdown?

Editor’s note A commentary on“Combination of anti-PD-1 antibody with P-GEMOX as a potentially effective immunochemotherapy for advanced natural killer/T cell lymphoma”.Extranodal natural killer/T-cell lymphoma(ENKTL)is an uncommon and aggressive subtype of non-Hodgkin lymphoma with a geographic distribution unique to East Asia and Latin America.

Immunogenic-cell-killing and immunosuppression-inhibiting nanomedicine

Combining chemo-therapeutics with immune checkpoint inhibitors facilitates killing cancer cells and activating the immune system through inhibiting immune escape.However,their treatment effects remain limited due to the compromised accumulation of both drugs and inhibitors in certain tumor tissues.Herein,a new poly(acrylamide-co-acrylonitrile-co-vinylimidazole-co-bis(2-methacryloyl)oxyethyl disulfide)(PAAVB)polymer-based intelligent platform with controllable upper critical solution temperature(UCST)was used for the simultaneous delivery of paclitaxel(PTX)and curcumin(CUR).Additionally,a hyaluronic acid(HA)layer was coated on the surface of PAAVB NPs to target the CD44-overexpressed tumor cells.The proposed nanomedicine demonstrated a gratifying accumulation in tumor tissue and uptake by cancer cells.Then,the acidic microenvironment and high level of glutathione(GSH)in cancer cells could spontaneously decrease the UCST of polymer,leading to the disassembly of the NPs and rapid drug release at body temperature without extra-stimuli.Significantly,the released PTX and CUR could induce the immunogenic cell death(ICD)to promote adaptive anti-tumor immunogenicity and inhibit immunosuppression through suppressing the activity of indoleamine 2,3-dioxygenase 1(IDO1)enzyme respectively.Therefore,the synergism of this intelligent nanomedicine can suppress primary breast tumor growth and inhibit their lung metastasis.