Erratum: A Novel Pak1/ATF2/miR-132 Signaling Axis Is Involved in the Hematogenous Metastasis of Gastric Cancer Cells.

[This corrects the article DOI: 10.1016/j.omtn.2017.07.005.].

Erythrocyte-Leveraged Oncolytic Virotherapy (ELeOVt): Oncolytic Virus Assembly on Erythrocyte Surface to Combat Pulmonary Metastasis and Alleviate Side Effects.

Despite being a new promising tool for cancer therapy, intravenous delivery of oncolytic viruses (OVs) is greatly limited by poor tumor targeting, rapid clearance in the blood, severe organ toxicity, and cytokine release syndrome. Herein, a simple and efficient strategy of erythrocyte-leveraged oncolytic virotherapy (ELeOVt) is reported, which for the first time assembled OVs on the surface of erythrocytes with up to near 100% efficiency and allowed targeted delivery of OVs to the lung after intravenous injection to achieve excellent treatment of pulmonary metastases while greatly improving the biocompatibility of OVs as a drug. Polyethyleneimine (PEI) as a bridge to assemble OVs on erythrocytes also played an important role in promoting the transfection of OVs. It is found that ELeOVt approach significantly prolonged the circulation time of OVs and increased the OVs distribution in the lung by more than tenfold, thereby significantly improving the treatment of lung metastases while reducing organ and systemic toxicity. Taken together, these findings suggest that the ELeOVt provides a biocompatible, efficient, and widely available approach to empower OVs to combat lung metastasis.

Progress in oncolytic viruses modified with nanomaterials for intravenous application.

In oncolytic virus (OV) therapy, a critical component of tumor immunotherapy, viruses selectively infect, replicate within, and eventually destroy tumor cells. Simultaneously, this therapy activates immune responses and mobilizes immune cells, thereby eliminating residual or distant cancer cells. However, because of OVs' high immunogenicity and immune clearance during circulation, their clinical applications are currently limited to intratumoral injections, and their use is severely restricted. In recent years, numerous studies have used nanomaterials to modify OVs to decrease virulence and increase safety for intravenous injection. The most commonly used nanomaterials for modifying OVs are liposomes, polymers, and albumin, because of their biosafety, practicability, and effectiveness. The aim of this review is to summarize progress in the use of these nanomaterials in preclinical experiments to modify OVs and to discuss the challenges encountered from basic research to clinical application.

FN1 mRNA 3'-UTR supersedes traditional fibronectin 1 in facilitating the invasion and metastasis of gastric cancer through the FN1 3'-UTR-let-7i-5p-THBS1 axis.

Background: Current clinical treatments for gastric cancer (GC), particularly advanced GC, lack infallible therapeutic targets. The 3'-untranslated region (3'-UTR) has attracted increasing attention as a drug target. Methods: In vitro and in vivo experiments were conducted to determine the function of FN1 3'-UTR and FN1 protein in invasion and metastasis. RNA pull-down assay and high-throughput sequencing were used to screen the factors regulated by FN1 3'-UTR and construct the regulatory network. Western blotting and polymerase chain reaction were used to examine the correlation of intermolecular expression levels. RNA-binding protein immunoprecipitation was used to verify the correlation between FN1 3'-UTR and target mRNAs. Results: The FN1 3'-UTR may have stronger prognostic implications than the FN1 protein in GC patients. Upregulation of FN1 3'-UTR significantly promoted the invasive and metastatic abilities of GC cells to a greater extent than FN1 protein in vitro and in vivo. A novel regulatory network was constructed based on the FN1 3'-UTR-let-7i-5p-THBS1 axis, wherein FN1 3'-UTR displayed stronger oncogenic effects than the FN1 protein. Conclusions: FN1 3'-UTR may be a better therapeutic target for constructing targeted drugs in GC than the FN1 protein.

Virus-Protein Corona Replacement Strategy to Improve the Antitumor Efficacy of Intravenously Injected Oncolytic Adenovirus.

Intravenous administration of oncolytic adenoviruses (OVs) is a hopeful tumor therapeutic modality. However, the sharp clearance of OVs by the immune system dampens its effectiveness. Many studies have attempted to extend the circulation of intravenously administered OVs, almost all by preventing OVs from binding to neutralizing antibodies and complements in the blood, but the results have not been satisfactory. In contrast to previous conclusions, we found that the key to improving the circulation of OVs is to prevent the formation of the virus-protein corona rather than simply preventing the binding of neutralizing antibodies or complements to OVs. After identifying the key protein components of the virus-protein corona, we proposed a virus-protein corona replacement strategy, where an artificial virus-protein corona was formed on OVs to completely prevent the interaction of OVs with key virus-protein corona components in the plasma. It was found that this strategy dramatically prolonged the circulation time of OVs by over 30 fold and increased the distribution of OVs in tumors by over 10-fold, resulting in superior antitumor efficacy in primary and metastatic tumor models. Our finding provides a perspective on intravenous delivery of OVs, shifting the focus of future studies from preventing OV binding with neutralization antibodies and complements to preventing OVs from interacting with key virus-protein corona components in the plasma.

Adverse events of PD-(L)1 inhibitors plus anti-VEGF(R) agents compared with PD-(L)1 inhibitors alone for cancer patients: a systematic review and meta-analysis.

Background: Anti-PD-(L)1 antibody monotherapy or in combination with VEGF(R) blockade has been applied widely for cancer treatment. Whether combination therapy increases irAEs still remains controversial. Methods: A systematic review and meta-analysis comparing PD-(L)1 and VEGF(R) blockade combination therapy with PD-(L)1 inhibitors alone was performed. Phase II or III randomized clinical trials reporting irAEs or trAEs were included. The protocol was registered with PROSPERO, CRD42021287603. Results: Overall, 77 articles were included in the meta-analysis. A total of 31 studies involving 8,638 participants were pooled and an incidence for PD-(L)1 inhibitor monotherapy with any grade and grade ≥3 irAEs of 0.25 (0.20, 0.32) and 0.06 (0.05, 0.07), respectively, were reported. Two studies with 863 participants pooled for PD-(L)1 and VEGF(R) blockade showed that an incidence of any grade and grade ≥3 irAEs were 0.47 (0.30, 0.65) and 0.11 (0.08, 0.16), respectively. Regarding pairwise comparisons for irAEs, only one study was included, indicating no significant difference between the two regimens in terms of colitis, hyperthyroidism, and hypothyroidism for any grade and grade ≥3, while there was a trend of higher incidence for any grade hyperthyroidism under the combination therapy. The incidence of reactive cutaneous capillary endothelial proliferation (RCCEP) was as high as 0.80 under camrelizumab monotherapy. Conclusion: Total incidences of any grade and grade ≥3 irAEs were higher in the combination treatment group. Direct comparisons indicated no significant difference between the two regimens for any grade and grade ≥3 specific irAEs. RCCEP and thyroid disorders need to be paid attention to clinically. Moreover, trials with direct comparisons are needed and the safety profiles of the two regimens should be further explored. Exploration of the mechanism of action and regulatory management of adverse events should be enhanced. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=287603, identifier CRD42021287603.

Self-assembled short peptides: Recent advances and strategies for potential pharmaceutical applications.

Self-assembled short peptides have intrigued scientists due to the convenience of synthesis, good biocompatibility, low toxicity, inherent biodegradability and fast response to change in the physiological environment. Therefore, it is necessary to present a comprehensive summary of the recent advances in the last decade regarding the construction, route of administration and application of self-assembled short peptides based on the knowledge on their unique and specific ability of self-assembly. Herein, we firstly explored the molecular mechanisms of self-assembly of short peptides, such as non-modified amino acids, as well as Fmoc-modified, N-functionalized, and C-functionalized peptides. Next, cell penetration, fusion, and peptide targeting in peptide-based drug delivery were characterized. Then, the common administration routes and the potential pharmaceutical applications (drug delivery, antibacterial activity, stabilizers, imaging agents, and applications in bioengineering) of peptide drugs were respectively summarized. Last but not least, some general conclusions and future perspectives in the relevant fields were briefly listed. Although with certain challenges, great opportunities are offered by self-assembled short peptides to the fascinating area of drug development.

Engineered bacterial outer membrane vesicles encapsulating oncolytic adenoviruses enhance the efficacy of cancer virotherapy by augmenting tumor cell autophagy.

Oncolytic adenovirus (Ad) infection promotes intracellular autophagy in tumors. This could kill cancer cells and contribute to Ads-mediated anticancer immunity. However, the low intratumoral content of intravenously delivered Ads could be insufficient to efficiently activate tumor over-autophagy. Herein, we report bacterial outer membrane vesicles (OMVs)-encapsulating Ads as microbial nanocomposites that are engineered for autophagy-cascade-augmented immunotherapy. Biomineral shells cover the surface antigens of OMVs to slow their clearance during in vivo circulation, enhancing intratumoral accumulation. After entering tumor cells, there is excessive H2O2 accumulation through the catalytic effect of overexpressed pyranose oxidase (P2O) from microbial nanocomposite. This increases oxidative stress levels and triggers tumor autophagy. The autophagy-induced autophagosomes further promote Ads replication in infected tumor cells, leading to Ads-overactivated autophagy. Moreover, OMVs are powerful immunostimulants for remolding the immunosuppressive tumor microenvironment, facilitating antitumor immune response in preclinical cancer models in female mice. Therefore, the present autophagy-cascade-boosted immunotherapeutic method can expand OVs-based immunotherapy.

Inhibition of Tumor Metastasis by Liquid-Nitrogen-Shocked Tumor Cells with Oncolytic Viruses Infection.

Despite the superior tumor lytic efficacy of oncolytic viruses (OVs), their systemic delivery still faces the challenges of limited circulating periods, poor tumor tropism, and spontaneous antiviral immune responses. Herein, a virus-concealed tumor-targeting strategy enabling OVs' delivery toward lung metastasis via systemic administration is described. The OVs can actively infect, be internalized, and cloak into tumor cells. Then the tumor cells are subsequently treated with liquid-nitrogen-shocking to eliminate the pathogenicity. Such a Trojan Horse-like vehicle avoids virus neutralization and clearance in the bloodstream and facilitates tumor-targeted delivery for more than 110-fold virus enrichment in the tumor metastasis. In addition, this strategy can serve as a tumor vaccine and initiate endogenous adaptive antitumor effects through increasing the memory T cells and modulating the tumor immune microenvironment, including reducing the M2 macrophage, downregulating Treg cells, and priming T cells.

Oncolytic Virus-Driven Biotherapies from Bench to Bedside.

With advances in cancer biology and an ever-deepening understanding of molecular virology, oncolytic virus (OV)-driven therapies have developed rapidly and become a promising alternative to traditional cancer therapies. In recent years, satisfactory results for oncolytic virus therapy (OVT) are achieved at both the cellular and organismal levels, and efforts are being increasingly directed toward clinical trials. Unfortunately, OVT remains ineffective in these trials, especially when performed using only a single OV reagent. In contrast, integrated approaches, such as using immunotherapy, chemotherapy, or radiotherapy, alongside OVT have demonstrated considerable efficacy. The challenges of OVT in clinical efficacy include the restricted scope of intratumoral injections and poor targeting of intravenous administration. Further optimization of OVT delivery is needed before OVs become a viable therapy for tumor treatment. In this review, the development process and antitumor mechanisms of OVs are introduced. The advances in OVT delivery routes to provide perspectives and directions for the improvement of OVT delivery are highlighted. This review also discusses the advantages and limitations of OVT monotherapy and combination therapy through the lens of recent clinical trials and aims to chart a course toward safer and more effective OVT strategies.

Drug conjugate-based anticancer therapy - Current status and perspectives.

Drug conjugates are conjugates comprising a tumor-homing carrier tethered to a cytotoxic agent via a linker that are designed to deliver an ultra-toxic payload directly to the target cancer cells. This strategy has been successfully used to increase the therapeutic efficacy of cytotoxic agents and reduce their toxic side effects. Drug conjugates are being developed worldwide, with the potential to revolutionize current cancer treatment strategies. Antibody-drug conjugates (ADCs) have developed rapidly, and 14 of them have received market approval since the first approval event by the Food and Drug Administration in 2000. However, there are some limitations in the use of antibodies as carriers. Other classes of drug conjugates are emerging, such as targeted drugs conjugated with peptides (peptide-drug conjugates, PDCs) and polymers (polymer-drug conjugates, PolyDCs) with the remaining constructs similar to those of ADCs. These novel drug conjugates are gaining attention because they overcome the limitations of ADCs. This review summarizes the current state and advancements in knowledge regarding the design, constructs, and clinical efficacy of different drug conjugates.

Boarding Oncolytic Viruses onto Tumor-Homing Bacterium-Vessels for Augmented Cancer Immunotherapy.

Oncolytic viruses (OVs) have been widely used as anticancer therapeutics because of their systemic immune responses during viral replication. However, the low enrichment of OVs within tumors and limited immune activation have hindered their clinical application. Herein, we proposed the concept of bacteria-assisted targeting of OVs to tumors, with liposome-cloaked oncolytic adenoviruses (OAs) conjugated onto tumor-homing Escherichia coli BL21 (designated as E. coli-lipo-OAs) for enhanced cancer immunotherapy. Notably, the enrichment of OAs transported by self-propelled bacterial microbe vehicles in E. coli-lipo-OAs in a nonsmall cell lung tumor can be potentiated by more than 170-fold compared with that of intravenously injected bare OAs. In vivo studies further revealed that E. coli-lipo-OAs administered intravenously significantly enhanced antitumor immunity through bacterial-viral-augmented immune responses. Our findings suggest that the self-driving microbe vehicle as a systemic delivery system for OVs can be a potent platform for developing future anticancer biotherapeutics at the clinical level.

Emerging systemic delivery strategies of oncolytic viruses: A key step toward cancer immunotherapy.

Oncolytic virotherapy (OVT) is a novel type of immunotherapy that induces anti-tumor responses through selective self-replication within cancer cells and oncolytic virus (OV)-mediated immunostimulation. Notably, talimogene laherparepvec (T-Vec) developed by the Amgen company in 2015, is the first FDA-approved OV product to be administered via intratumoral injection and has been the most successful OVT treatment. However, the systemic administration of OVs still faces huge challenges, including in vivo pre-existing neutralizing antibodies and poor targeting delivery efficacy. Recently, state-of-the-art progress has been made in the development of systemic delivery of OVs, which demonstrates a promising step toward broadening the scope of cancer immunotherapy and improving the clinical efficacy of OV delivery. Herein, this review describes the general characteristics of OVs, focusing on the action mechanisms of OVs as well as the advantages and disadvantages of OVT. The emerging multiple systemic administration approaches of OVs are summarized in the past five years. In addition, the combination treatments between OVT and traditional therapies (chemotherapy, thermotherapy, immunotherapy, and radiotherapy, etc.) are highlighted. Last but not least, the future prospects and challenges of OVT are also discussed, with the aim of facilitating medical researchers to extensively apply the OVT in the cancer therapy.

Integrative analysis-based identification and validation of a prognostic immune cell infiltration-based model for patients with advanced gastric cancer.

BACKGROUNDS: Advanced gastric cancer (GC) remains difficult to conduct individualized prognostic evaluations owing to the highly heterogeneous nature and the low level of immune cell infiltration (ICI) within GC tumors. This study thus sought to develop a model capable of classifying GC patients according to the degree of tumor ICI and gauging prognosis. METHODS: The degree of ICI in GC patients from the GSE15459, GSE57303, and GSE62254 datasets were estimated, and these values were used to group patients via an unsupervised clustering approach, after which ICI cluster-related genes were identified the association with prognosis through Cox and LASSO regression analyses. The primary risk genes were then verified by immunohistochemical staining of GC tumor tissue samples. RESULTS: 570 patients were clustered into three clusters and 289 ICI cluster-related genes were identified. A prognostic model based on the expression of six crucial ICI risk genes (CXCL11, RBPMS2, LOC400043, JCHAIN, CT83, and ORM1) wa constructed. Patients identified as being high risk based upon the model have poorer clinical features and survival outcomes compared to the other patients. Adjuvant intervention was found to be more beneficial for patients expressing high levels of RBPMS2, JCHAIN, or ORM1. Furthermore, patients expressing low levels of JCHAIN or CT83 in GC tumor tissues were verified to exhibit a significantly better prognosis in a CMU cohort. CONCLUSION: Advanced GC patients were successfully grouped into clusters based on the degree of intratumoral ICI, and a prognostic evaluation model based on 6 ICI risk genes was developed and validated.

Decision-making of adjuvant therapy in pT1N1M0 gastric cancer: Should radiotherapy be added to chemotherapy? A propensity score-matched analysis.

Background: Early gastric cancer (EGC) with metastatic lymph nodes (mLNs) has a relatively higher recurrence rate and poorer prognosis than EGC without mLNs. However, the postoperative treatment directions of pT1N1M0 vary from different guidelines. This study attempted to confirm the value of postoperative treatments in pT1N1M0 GC patients. Methods: Overall, 379 patients with pT1N1M0 GC following gastrectomy from 2000 to 2016 were selected from the Surveillance, Epidemiology, and End Results (SEER) database. Propensity score-matched (PSM) analysis was used to reduce bias. Overall survival was analyzed by Kaplan-Meier method and the log-rank test. Cox proportional hazards regression analyses were used to confirm the independent prognostic factors. Results: Before matching, the results of survival analyses indicated that adjuvant chemotherapy (ACT) and chemoradiotherapy (ACRT) could significantly prolong the survival time of the cohort (P < 0.05). After PSM analysis, 136 patients remained and ACRT maintained significance in the survival analysis (P = 0.018). Furthermore, patients with well or moderately differentiated GC (HR = 0.226, P =0.018) or intestinal type GC (HR = 0.380, P = 0.040) achieved a significantly superior prognosis with ACRT, compared to patients receiving ACT. Conclusion: The survival benefit of ACRT and ACT for pT1N1M0 GC patients following gastrectomy was confirmed in the SEER cohort. RT added to ACT might be recommended according to Lauren's classification and tumor grade in clinical decision making.

Localized Free Radicals Burst Triggered by NIR-II Light for Augmented Low-Temperature Photothermal Therapy.

As a novel treatment modality of tumors, hypothermal hyperthermia employed relatively lower temperature (<45 °C) to damage cancer cells with mild toxicity to normal tissues. However, beyond that inducible heat resistance of tumor cells, the discounted therapeutic effect of low temperature hyperthermia was also ascribed to poor penetration of exogenous light stimulation and low accumulation of photothermal agents in tumor sites. Herein, we constructed a multifunctional in situ hydrogel of sodium alginate (ALG) via Ca2+ coordinated with ALG to encapsulate the photothermal agent of Ink and azo initiator of 2,2'-azobis[2-(2-imidazolin-2-yl)propane]dihydrochloride (AIPH) for effective tumor treatment. The designed ALG hydrogel was used to improve the therapeutic effect by increased accumulation of Ink and AIPH and avoid potential side-effects caused by the unexpected spread to the surrounding normal tissues. After injection, local low temperature stimulation was generated with near-infrared-II irradiation by a 1064 nm laser, triggering rapid decomposition of AIPH to produce alkyl radicals. The synergistic low temperature photothermal therapy and cytotoxic-free radicals enhanced the apoptosis of tumor cells via physical heat damage and lipid peroxidation. Thus, remarkable inhibition of tumor growth was observed in a subcutaneous colorectal cancer with negligible side effects. Furthermore, the formulation could also exert strong photoacoustic signals, which were utilized to monitor the stability of the composite hydrogel.

Novel immune-risk score of gastric cancer: A molecular prediction model combining the value of immune-risk status and chemosensitivity.

Gastric cancer is still one of the most common and deadly malignancies in the world. Not all patients could benefit from chemotherapy or chemoradiotherapy due to tumor heterogeneity. Therefore, identifying different subgroups of patients is an important trend for obtaining more effective responses. However, few molecular classifications associated with chemosensitivity are based on immune-risk status. In this study, we obtained six key immune-related genes. Using these genes, we constructed a molecular model related to immune-risk status and calculated an individual immune-risk score. The score showed great efficiency and stability in predicting prognosis and identifying different subgroups where persons could benefit from postoperative adjuvant therapy. The patients could be divided into different risk groups based on the immune-related score. For patients in the low-risk group, both postoperative chemoradiotherapy and chemotherapy could significantly improve prognosis on overall survival (OS) and disease-free survival (DFS) (DFS, P < 0.001 and P = 0.041, respectively; OS, P < 0.001, P = 0.006, respectively) and chemoradiotherapy was significantly superior than simple chemotherapy (DFS, P = 0.031; OS, P = 0.027). For patients with an intermediate-risk score, postoperative chemoradiotherapy showed a statistically significant survival advantage over no anticancer treatment (P = 0.004 and P = 0.002, respectively), while chemotherapy did not. Compared with no adjuvant treatment, neither postoperative chemoradiotherapy nor chemotherapy made significant difference for patients in the high-risk group. Combining the value of immune-risk status and chemosensitivity, the immune-risk score could not only offer us prognostic evaluation and adjuvant treatment guidance, but also improve our understanding about the binding point between chemotherapy or chemoradiotherapy and the immune system, which may be helpful for further expanding the application of immunotherapy.

A Proposal of a Personalized Surveillance Strategy for Gastric Cancer: A Retrospective Analysis of 9191 Patients.

BACKGROUND: In gastric cancer, various surveillance strategies are suggested in international guidelines. The current study is intended to evaluate the current strategies and provide more personalized proposals for personalized cancer medicine. MATERIALS AND METHODS: In the aggregate, 9191 patients with gastric cancer after gastrectomy from 1998 to 2009 were selected from the Surveillance, Epidemiology, and End Results database. Disease-specific survival was analyzed by Kaplan-Meier method and the log-rank test. Cox proportional hazards regression analyses were used to confirm the independent prognostic factors. As well, hazard ratio (HR) curves were used to compare the risk of death over time. Conditional survival (CS) was applied to dynamically assess the prognosis after each follow-up. RESULTS: Comparisons from HR curves on different stages showed that earlier stages had distinctly lower HR than advanced stages. The curve of stage IIA was flat and more likely the same as that of stage I while that of stage IIB is like that of stage III with an obvious peak. After estimating CS at intervals of three months, six months, and 12 months in different periods, stages I and IIA had high levels of CS all along, while there were visible differences among CS levels of stages IIB and III. CONCLUSIONS: The frequency of follow-up for early stages, like stages I and IIA, could be every six months or longer in the first three years and annually thereafter. And those with unfavorable conditions, such as stages IIB and III, could be followed up much more frequently and sufficiently than usual.

Combined CB2 receptor agonist and photodynamic therapy synergistically inhibit tumor growth in triple negative breast cancer.

Triple negative breast cancer (TNBC) is the deadliest form of breast cancer because it is more aggressive, diagnosed at later stage and more likely to develop local and systemic recurrence. Many patients do not experience adequate tumor control after current clinical treatments involving surgical removal, chemotherapy and/or radiotherapy, leading to disease progression and significantly decreased quality of life. Here we report a new combinatory therapy strategy involving cannabinoid-based medicine and photodynamic therapy (PDT) for the treatment of TNBC. This combinatory therapy targets two proteins upregulated in TNBC: the cannabinoid CB2 receptor (CB2R, a G-protein coupled receptor) and translocator protein (TSPO, a mitochondria membrane receptor). We found that the combined CB2R agonist and TSPO-PDT treatment resulted in synergistic inhibition in TNBC cell and tumor growth. This combinatory therapy approach provides new opportunities to treat TNBC with high efficacy. In addition, this study provides new evidence on the therapeutic potential of CB2R agonists for cancer.