Publications by authors named "Baorui Liu"

223 Publications

Tumor eradicated by combination of imiquimod and OX40 agonist for in situ vaccination.

Cancer Sci 2021 Sep 19. Epub 2021 Sep 19.

The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.

Various cancer vaccines have been developed to generate and amplify antigen-specific T cell responses against malignancy. Among them, in situ vaccination is one of the most practical types as it can trigger immune responses without previous antigen identification. Here we reported a novel in situ vaccine by intratumoral injection of imiquimod and OX40 agonist. In mice bearing hepatic carcinoma, both the injected tumor and the noninjected tumor in the distant lesion of the same mice were suppressed after vaccination. Further studies found that this in situ vaccine triggered systemic tumor-specific responses, with one-fold increase of effector memory T cells properties and stronger toxicity of lymphocytes in spleen. Besides, we found that imiquimod upregulated the expression of OX40 on CD4 T cells and thus enhanced the effectiveness of OX40 agonist. Five immune-positive-related pathways were activated after vaccination. This in situ vaccine caused little harm to normal organs and provided long-term protection against the same syngeneic tumor rechallenge. Due to its effectiveness, feasibility and safety, this strategy could potentially be applied to various types of late-stage solid tumors and worthy of further clinical research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cas.15145DOI Listing
September 2021

A dual-targeted molecular therapy of PP242 and cetuximab plays an anti-tumor effect through EGFR downstream signaling pathways in colorectal cancer.

J Gastrointest Oncol 2021 Aug;12(4):1625-1642

The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.

Background: Epidermal growth factor receptor (EGFR) and its downstream Ras-mitogen-activated protein kinase kinase (MAPKK, MEK)-extracellular regulated protein kinase (ERK) signaling pathway and phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt)-mammalian target of rapamycin (mTOR) signaling pathway play important roles in the pathogenesis of colorectal cancer (CRC). The combination therapy of anti-EGFR and anti-mTOR needs to be explored.

Methods: Here we combined the anti-EGFR monoclonal antibody cetuximab (CTX) with the mTOR inhibitor PP242 in CRC cell lines and mouse xenograft models and discussed the changes of EGFR downstream signaling pathways of CRC cell lines.

Results: In HT-29 cells and Caco-2 cells, combined application of CTX and PP242 significantly inhibited the proliferation of CRC cells in vivo and in vitro. In BRAF wild-type Caco-2 cells, combined application of CTX and PP242 inhibited the activation of the EGFR and its downstream signaling pathways.

Conclusions: Our research further demonstrates the effectiveness of the combined application of CTX and PP242 in inhibiting CRC cell lines from the perspective of cell proliferation, cell cycle, apoptosis, and mouse xenografts. We revealed that the combined application of CTX and PP242 can inhibit tumor growth and proliferation by inhibiting the phosphorylation of key molecules in EGFR downstream MEK-ERK and MEK 4/7 (MKK)-c-Jun N-terminal kinase (JNK) signaling pathways in BRAF wild-type CRC cells. In addition, we found that in BRAF mutant CRC cells, the monotherapy of PP242 resulted in negative feedback increased EGFR phosphorylation rates, accompanied by significant up-regulation of downstream MEK and ERK phosphorylation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/jgo-21-467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8421906PMC
August 2021

Identification of a peptide binding to cancer antigen Kita-kyushu lung cancer antigen 1 from a phage-display library.

Cancer Sci 2021 Aug 12. Epub 2021 Aug 12.

The Comprehensive Cancer Center of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.

Kita-kyushu lung cancer antigen 1 (KK-LC-1) is a kind of cancer-testis antigen with anti-tumor potential for clinical application. As a class of small-molecule antigen conjugate, tumor-targeting peptides have broad application prospects in gastric cancer diagnosis, imaging, and biological treatment. Here, we screened specific cyclic nonapeptides from a phage-display library. The targeting peptide with the best affinity was selected and further verified in ex vivo tissue sections. Finally, enrichment of targeting peptides in tumor tissues was observed in vivo, and the dynamic biodistribution process was also observed with micro-positron emission tomography (micro-PET)/computed tomography (CT) imaging. Studies showed that the specific cyclic nonapeptide had a high binding capacity for KK-LC-1 protein. It has a strong affinity and specificity for KK-LC-1-expressing positive tumor cells. Targeting peptides were significantly enriched at tumor sites in vivo, with very low normal tissue background. These findings demonstrated that the KK-LC-1 targeting peptide has high clinical potential.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cas.15109DOI Listing
August 2021

Advanced HCC Patient Benefit From Neoantigen Reactive T Cells Based Immunotherapy: A Case Report.

Front Immunol 2021 13;12:685126. Epub 2021 Jul 13.

Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing, China.

Advanced hepatocellular carcinoma (HCC) is a highly lethal disease, mainly due to the late stage at diagnosis and its rapid progression. Although patients with advanced HCC can choose targeted therapy or chemotherapy, overall, the treatment response rate is extremely low and the average survival time is one year more or less. But the application of immunotherapy have led to a paradigm shift in the treatment of HCC,such as TILs (tumor infiltrating lymphocytes),Checkpoint blockade (immune Checkpoint blockade), CAR-T(chimeric antigen receptor T cells) and TCR-T (engineered t-cell receptor T cells). And recent data indicate neoantigens generated when tumors mutate are the main target of tumor-specific TILs, and they are also the main antigens mediating tumor regression in TILs treatment. Moreover, numerous evidences have revealed that radiotherapy lead to massive release of tumor antigens, which may increase the effectiveness of immunotherapy. Based on the above theory, we used neoantigen reactive T cells combined with tomotherapy to treat a patient with advanced HCC (Clinical Trial Study Registration Number: NCT03199807), who reached a long time progress free survival.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2021.685126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8315135PMC
July 2021

Deep Penetration of Nanolevel Drugs and Micrometer-Level T Cells Promoted by Nanomotors for Cancer Immunochemotherapy.

J Am Chem Soc 2021 Aug 28;143(31):12025-12037. Epub 2021 Jul 28.

The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing University, Nanjing 210008, China.

The ability of nanomotors to promote the deep penetration of themselves and the loaded drugs in diseased tissues has been proposed and confirmed. However, whether such motion behavior of the nanomotors can also promote deep penetration of micrometer-sized immune cells in the diseased microenvironment, which is important for the immunotherapy of some diseases, has not been mentioned. Herein, we construct a nitric oxide (NO)-driven nanomotor that can move in the tumor microenvironment, focusing on its motion behavior and the role of NO, the beneficial product released during movement from this kind of nanomotor, in regulating the infiltration behavior and activity of immune cells. It can be found that the drug-loaded nanomotors with both NO-releasing ability and motility can promote the normalization of the tumor vasculature system and the degradation of the intrinsic extracellular matrix (ECM), which can significantly improve the tumor infiltration ability of T cells in vivo. The efficiency of T-cell infiltration in tumor tissue in vivo increased from 2.1 to 28.2%. Both subcutaneous and intraperitoneal implantation tumor models can validate the excellent antitumor effect of drug-loaded NO-driven nanomotors. This combination of motility of the power source from nanomotors and their physiological function offers a design idea for therapeutic agents for the future immunotherapy of many diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jacs.1c03071DOI Listing
August 2021

gene status in gastric signet-ring cell carcinoma patients and acts as biomarker of MEK inhibitor.

J Gastrointest Oncol 2021 Jun;12(3):1020-1030

The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing, China.

Background: Signet-ring cell carcinoma (SRCC) is a specific subtype of stomach cancer with unique epidemiology. Here, we sought to explore the role of in SRCC.

Methods: status was studied both in The Cancer Genome Atlas (TCGA) and internal cohorts. Immunohistochemistry (IHC) and fluorescence hybridization (FISH) were performed in formalin-fixed and paraffin-embedded (FFPE) samples. We explored patients' survival and clinicopathological characteristics in terms of mutation and expression. We also explored status and drug response curve of MEK/mTOR inhibitors in SRCC cell lines.

Results: Patients with mutations and copy number variation (CNV) showed higher mRNA level compared to non-mutant cases (P=0.003 and P<0.001). In internal cohort, 15 samples harbored mutations. Survival analysis showed that these patients had significantly lower overall survival (OS) (P=0.048). We further analyzed 75 patients with sufficient FFPE samples. Eight patients showed mutations and one patient showed amplification. The median OS was 12.5 months for patients with mutation, and 19.5 months for patients without mutation (P=0.005). Positive expression of as shown by IHC was detected in majority of SRCC samples, which was higher than our intestinal cohort (28% 12.6%, P=0.033). We further explored the correlation between status and drug sensitivity in 4 SRCC cell lines. SNU601 and SNU668, which harbored mutation, were hypersensitive to MEK and mTOR inhibitors than wide type cell lines KATO-III and NUGC-4.

Conclusions: Our findings demonstrate that gene plays an important role in SRCC and reveals therapeutic potential of targeting tumors by inhibiting MEK and mTOR pathways.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/jgo-20-617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8261324PMC
June 2021

Heterogeneity response to afatinib in gastric cancer patient with uncommon epidermal growth factor receptor (EGFR) mutations: a case report.

Ann Transl Med 2021 May;9(9):814

The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing, China.

Despite concerted efforts that have been made to characterize and understand the genomic landscape of gastric cancer (GC), only HER2 has been validated as a molecular target for GC treatment. Identifying new valid therapeutic targets is important for the treatment of this disease. The present report describes a Chinese male with a history of smoking two packs per day, who did not have a family history of cancer or other hereditary diseases, we discovered a small painless lump in the right groin in February 2018. Histopathology revealed a primary gastric adenocarcinoma. Positron emission tomography-computed tomography (PET-CT) showed multiple hypermetabolic nodules in the right upper lung, greater curvature of the stomach, and muscles. The patient had received treatment included oxaliplatin, docetaxel, and tegafur for two cycles, and second-line therapy of irinotecan and capecitabine, inguinal mass excision followed by concurrent radio-chemotherapy. However, the disease rapidly progressed. Whole exome sequencing (WES) showed uncommon epidermal growth factor receptor (EGFR) mutation of G719S + L861Q. The following EGFR tyrosine kinase inhibitors (TKIs) afatinib demonstrated partial response. Two months after targeted therapy, gastroscopy indicated rapid progression. With subsequent gastric specimen WES analysis, secondary MET amplification was found. The patient received local radiotherapy for gastric lesions as well as oral administration of apatinib. However, the disease rapidly progressed. A month later, he died of hepatic encephalopathy caused by obstructive jaundice combined with pulmonary and biliary tract infection. The present study indicated that afatinib might be a beneficial therapeutic option for a subset of GC patients with rare EGFR mutation in their tumors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/atm-20-7312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246221PMC
May 2021

Prognostic Nomograms Based on Three Lymph Node Classification Systems for Resected Gastric Adenocarcinoma: A Large Population-Based Cohort Study and External Validation.

Ann Surg Oncol 2021 Jul 9. Epub 2021 Jul 9.

The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School & Clinical Cancer Institute of Nanjing University, Nanjing, China.

Backgrounds: The optimal lymph node classification system for prognostic assessment in gastric adenocarcinoma (GAC) patients who undergo lymph node dissection remains unclear. Therefore, this study aimed to compare prognostic nomograms based on AJCC N stage, lymph node ratio (LNR), and log odds of metastatic lymph nodes (LODDS) to evaluate the prognosis and differentiate risk subgroups of patients with resected GAC.

Patients And Methods: We collected 4633 patients with resected stage I-III GAC receiving chemotherapy from the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2015. Independent prognostic factors were selected by Cox regression analyses, based on which nomograms were constructed. External validation was performed in 228 cases from Nanjing Drum Tower Hospital. Kaplan-Meier survival analysis was used to evaluate the effect of postoperative radiotherapy (PORT) for different lymph node classifications.

Results: Multivariate analysis indicated that age, grade, primary site, T stage, N stage, LNR, LODDS, and radiotherapy were independent predictors. Good discrimination power and high consistency of calibration plots were obtained from the LODDS system nomogram. The LODDS classification could more precisely differentiate risk subgroups and improve the discrimination of the resected GAC prognosis. A user-friendly webserver of LODDS system was built based on the nomogram for convenient clinical application.

Conclusions: The LODDS seems to be the most reliable lymph node classification in predicting the prognosis of patients with resected GAC and should be recommended in clinical prognostic assessment. Incorporating LODDS into the staging system will enable clinicians to more accurately predict prognosis and guide radiotherapy regimen decisions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1245/s10434-021-10299-1DOI Listing
July 2021

ASO Visual Abstract: Prognostic Nomograms Based on Three-Lymph-Node Classification Systems for Resected Gastric Adenocarcinoma: A Large Population-Based Cohort Study and External Validation.

Ann Surg Oncol 2021 Jul 8. Epub 2021 Jul 8.

The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School and Clinical Cancer Institute of Nanjing University, Nanjing, 210008, China.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1245/s10434-021-10348-9DOI Listing
July 2021

Identification of a Glypican-3 Binding Peptide From a Phage-Displayed Peptide Library for PET Imaging of Hepatocellular Carcinoma.

Front Oncol 2021 4;11:679336. Epub 2021 Jun 4.

The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.

Tumor-targeting peptides functioned as molecular probes are essential for multi-modality imaging and molecular-targeting therapy in caner theronostics. Here, we performed a phage-displayed bio-panning to identify a specific binding peptide targeting Glypican-3 (GPC-3), a promising biomarker in hepatocellular carcinoma (HCC). After screening in the cyclic peptide library, a candidate peptide named F3, was isolated and showed specific binding to HCC cell lines. In a bio-distribution study, higher accumulation of F3 peptide was observed in HepG-2 tumors compared to PC-3 tumors in xenograft models. After labeling with radioactive Ga, the F3 peptide tracer enabled the specific detection of tumors in HCC tumor models with PET imaging. More importantly, the expression of GPC-3 in human tissue samples may be distinguished by an F3 fluorescent peptide probe indicating its potential for clinical application. This cyclic peptide targeting GPC-3 has been validated, and may be an alternative to serve as an imaging probe or a targeting domain in the drug conjugate.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2021.679336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8212053PMC
June 2021

Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2-3 study.

Lancet Oncol 2021 07 15;22(7):977-990. Epub 2021 Jun 15.

Live Surgery Ward, Peking Union Medical College Hospital, Beijing, China.

Background: China has a high burden of hepatocellular carcinoma, and hepatitis B virus (HBV) infection is the main causative factor. Patients with hepatocellular carcinoma have a poor prognosis and a substantial unmet clinical need. The phase 2-3 ORIENT-32 study aimed to assess sintilimab (a PD-1 inhibitor) plus IBI305, a bevacizumab biosimilar, versus sorafenib as a first-line treatment for unresectable HBV-associated hepatocellular carcinoma.

Methods: This randomised, open-label, phase 2-3 study was done at 50 clinical sites in China. Patients aged 18 years or older with histologically or cytologically diagnosed or clinically confirmed unresectable or metastatic hepatocellular carcinoma, no previous systemic treatment, and a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 were eligible for inclusion. In the phase 2 part of the study, patients received intravenous sintilimab (200 mg every 3 weeks) plus intravenous IBI305 (15 mg/kg every 3 weeks). In the phase 3 part, patients were randomly assigned (2:1) to receive either sintilimab plus IBI305 (sintilimab-bevacizumab biosimilar group) or sorafenib (400 mg orally twice daily; sorafenib group), until disease progression or unacceptable toxicity. Randomisation was done using permuted block randomisation, with a block size of six, via an interactive web response system, and stratified by macrovascular invasion or extrahepatic metastasis, baseline α-fetoprotein, and ECOG performance status. The primary endpoint of the phase 2 part of the study was safety, assessed in all patients who received at least one dose of study drug. The co-primary endpoints of the phase 3 part of the study were overall survival and independent radiological review committee (IRRC)-assessed progression-free survival according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT03794440. The study is closed to new participants and follow-up is ongoing for long-term outcomes.

Findings: Between Feb 11, 2019 and Jan 15, 2020, we enrolled 595 patients: 24 were enrolled directly into the phase 2 safety run-in and 571 were randomly assigned to sintilimab-bevacizumab biosimilar (n=380) or sorafenib (n=191). In the phase 2 part of the trial, 24 patients received at least one dose of the study drug, with an objective response rate of 25·0% (95% CI 9·8-46·7). Based on the preliminary safety and activity data of the phase 2 part, in which grade 3 or worse treatment-related adverse events occurred in seven (29%) of 24 patients, the randomised phase 3 part was started. At data cutoff (Aug 15, 2020), the median follow-up was 10·0 months (IQR 8·5-11·7) in the sintilimab-bevacizumab biosimilar group and 10·0 months (8·4-11·7) in the sorafenib group. Patients in the sintilimab-bevacizumab biosimilar group had a significantly longer IRRC-assessed median progression-free survival (4·6 months [95% CI 4·1-5·7]) than did patients in the sorafenib group (2·8 months [2·7-3·2]; stratified hazard ratio [HR] 0·56, 95% CI 0·46-0·70; p<0·0001). In the first interim analysis of overall survival, sintilimab-bevacizumab biosimilar showed a significantly longer overall survival than did sorafenib (median not reached [95% CI not reached-not reached] vs 10·4 months [8·5-not reached]; HR 0·57, 95% CI 0·43-0·75; p<0·0001). The most common grade 3-4 treatment-emergent adverse events were hypertension (55 [14%] of 380 patients in the sintilimab-bevacizumab biosimilar group vs 11 [6%] of 185 patients in the sorafenib group) and palmar-plantar erythrodysaesthesia syndrome (none vs 22 [12%]). 123 (32%) patients in the sintilimab-bevacizumab biosimilar group and 36 (19%) patients in the sorafenib group had serious adverse events. Treatment-related adverse events that led to death occurred in six (2%) patients in the sintilimab-bevacizumab biosimilar group (one patient with abnormal liver function, one patient with both hepatic failure and gastrointestinal haemorrhage, one patient with interstitial lung disease, one patient with both hepatic faliure and hyperkalemia, one patient with upper gastrointestinal haemorrhage, and one patient with intestinal volvulus) and two (1%) patients in the sorafenib group (one patient with gastrointestinal haemorrhage and one patient with death of unknown cause).

Interpretation: Sintilimab plus IBI305 showed a significant overall survival and progression-free survival benefit versus sorafenib in the first-line setting for Chinese patients with unresectable, HBV-associated hepatocellular carcinoma, with an acceptable safety profile. This combination regimen could provide a novel treatment option for such patients.

Funding: Innovent Biologics.

Translation: For the Chinese translation of the abstract see Supplementary Materials section.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1470-2045(21)00252-7DOI Listing
July 2021

The Efficacy and Safety of Hypofractionated Radiation Therapy With Tomotherapy for Advanced or Recurrent Hepatocellular Carcinoma.

Front Oncol 2021 31;11:559112. Epub 2021 May 31.

Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, China.

The effects of radiotherapy on hepatocellular carcinoma (HCC) still remain to be further proved. The dose of radiotherapy is generally 2Gy*25f. In the current study, we prospectively investigated the clinical outcomes of advanced or recurrent HCC patients who received hypofractionated radiotherapy at a dose of 5Gy*10f with tomotherapy. A study involving hypofractionated radiotherapy (5Gy*10f) based on TOMO was conducted in HCC patients with Child-Pugh grade A or B who were unsuitable candidates for resection or radiofrequency ablation or with residual disease after transarterial chemoembolization (TACE). The prescription dose was 50 grays in 10 fractions. From Sep. 2016 and Dec. 2017, 65 patents were evaluated with a median follow-up of 24 months (range: 7-41 months). 10 patients were treatment-naïve (failure to undergo surgery or intervention due to the presence of a portal or portal branch tumor thrombus), 15 patients were treated for residual HCC after TACE as salvage therapy, and 40 cases were treated for recurrent HCC. The median overalls survival (OS) of these patients was 18 months. Among them, 27 patients classified as BCLC stage B had a median OS of 22 months. Moreover, 28 patients classified as BCLC stage C had a median OS of 14 months. None of the patients experienced recurrence in the area of radiotherapy. The local control rate of primary tumor at 3 months, 6 months, 1 year and 2 years was 100%. The 3-month survival rate was 100%, the 6-month survival rate was 100%, the 1-year survival rate was 75.4%, and the 2-year survival rate was 43%. In addition, 14 patients had the opportunity to continue the treatment of PD-1 antibody after the disease progression, and their prognosis was not surprisingly better compared with the patients who did not receive PD-1 antibody treatment (NR . 15 months, P=0.04). No serious side effect was found in all patients during and after radiotherapy. Hypofractionated radiotherapy (5Gy*10f) based on TOMO achieved high local control rate and OS with tolerable toxicities for HCC patients. TOMO therapy could be used to effectively against HCC in treatment-naive, intrahepatic failure, residual disease, and recurrent settings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2021.559112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8201615PMC
May 2021

Beta2-microglobulin(B2M) in cancer immunotherapies: Biological function, resistance and remedy.

Cancer Lett 2021 Oct 12;517:96-104. Epub 2021 Jun 12.

The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School & Clinical Cancer Institute of Nanjing University, Nanjing, 210008, China. Electronic address:

Cancer immunotherapies have made much headway during the past decades. Techniques including the immune checkpoint inhibition (ICI) and adoptive cell therapy (ACT) have harvested impressive efficacy and provided far-reaching tools for treating cancer patients. However, due to inadequate priming of the immune system, a certain subgroup of patients remains resistant to cancer immunotherapies during or after the treatment. β2-microglobulin (B2M) is an important subunit of major histocompatibility complex (MHC) class I which exerts substantive biological functions in tumorigenesis and immune control. Accumulating evidence has shown that alterations of B2M gene and B2M proteins contribute to poor reaction to cancer immunotherapies by dampening antigen presentation. Here, we discuss the basic biological functions of B2M, its distribution in a spectrum of cancers, and current understanding of its role in ICI, cancer vaccines and chimeric antigen receptor T cell (CAR-T) therapies. Furthermore, we summarize some promising therapeutic strategies to improve the efficacy inhibited by B2M defects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.canlet.2021.06.008DOI Listing
October 2021

Bifunctional iRGD-anti-CD3 enhances antitumor potency of T cells by facilitating tumor infiltration and T-cell activation.

J Immunother Cancer 2021 05;9(5)

The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University, Nanjing, China

Background: Poor infiltration and limited activation of transferred T cells are fundamental factors impeding the development of adoptive cell immunotherapy in solid tumors. A tumor-penetrating peptide iRGD has been widely used to deliver drugs deep into tumor tissues. CD3-targeting bispecific antibodies represent a promising immunotherapy which recruits and activates T cells.

Methods: T-cell penetration was demonstrated in tumor spheroids using confocal microscope, and in xenografted tumors by histology and in vivo real-time fluorescence imaging. Activation and cytotoxicity of T cells were assessed by flow cytometry and confocal microscope. Bioluminescence imaging was used to evaluate in vivo antitumor effects, and transmission electron microscopy was used for mechanistic studies.

Results: We generated a novel bifunctional agent iRGD-anti-CD3 which could immobilize iRGD on the surface of T cells through CD3 engaging. We found that iRGD-anti-CD3 modification not only facilitated T-cell infiltration in 3D tumor spheroids and xenografted tumor nodules but also induced T-cell activation and cytotoxicity against target cancer cells. T cells modified with iRGD-anti-CD3 significantly inhibited tumor growth and prolonged survival in several xenograft mouse models, which was further enhanced by the combination of programmed cell death protein 1 (PD-1) blockade. Mechanistic studies revealed that iRGD-anti-CD3 initiated a transport pathway called vesiculovacuolar organelles in the endothelial cytoplasm to promote T-cell extravasation.

Conclusion: Altogether, we show that iRGD-anti-CD3 modification is an innovative and bifunctional strategy to overcome major bottlenecks in adoptive cell therapy. Moreover, we demonstrate that combination with PD-1 blockade can further improve antitumor efficacy of iRGD-anti-CD3-modified T cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jitc-2020-001925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126316PMC
May 2021

Lipophilic recombinant-protein insertion endows lymphocytes with enhanced targeting-infiltration ability in EGFR positive cancer.

Cell Immunol 2021 Jul 5;365:104376. Epub 2021 May 5.

The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing, China. Electronic address:

Adoptive T cell transfer is one of the most promising ways to combat solid tumors. However, the weak infiltration of T cells into tumor sites has restricted their antitumor efficacy. To overcome this obstacle, we used the lipophilic protein painting strategy to improve tumor targeting and penetrating capacity of lymphocytes for the first time. We synthesized the lipid anchor consisting of a bispecific recombinant protein iRGD-antiEGFR and DSPE-PEG derivates, then successfully inserted it into the membranes of T cells. This surface modification was non-invasive and could efficiently improve the infiltration ability of T cells into multicellular spheroids and tumor masses. The surface modified T cells also displayed superior antitumor activities in EGFR-positive tumor xenografts via systematic infusion. Moreover, the permeability and antitumor efficacy of these surface painted T cells could be remarkably enhanced when used in combination with local low-dose irradiation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cellimm.2021.104376DOI Listing
July 2021

Gene fusion neoantigens: Emerging targets for cancer immunotherapy.

Cancer Lett 2021 05 4;506:45-54. Epub 2021 Mar 4.

The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School & Clinical Cancer Institute of Nanjing University, Nanjing, 210008, China. Electronic address:

Tumor neoantigens play an important role in current cancer immunotherapies. The most commonly studied class of tumor neoantigens contains those derived from single-nucleotide variants (SNVs) and insertions or deletions (Indels). However, gene fusions are also ideal sources of tumor neoantigens, as they can form new open reading frames (ORFs). Compared with SNV and Indel (SNV&Indel) neoantigens, fusion gene neoantigens tend to be more immunogenic, have more targets per mutation, and are more broadly shared across different cancer types. As a result, they are an important class of tumor neoantigens and emerging targets for cancer immunotherapies, with uses as prognostic biomarkers of immune checkpoint blockade (ICB) and in the development of tumor vaccines, adoptive cell therapies and tumor immune microenvironment modulation. In this review, we introduce the chromosomal basis and characteristics of gene fusions. Then, we summarize the predictive tools, mutation burden and immunogenicity of gene fusion neoantigens. Further, we discuss applications and future improvements of gene fusion neoantigens with respect to current cancer immunotherapies and novel developments in cancer treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.canlet.2021.02.023DOI Listing
May 2021

Combined delivery of salinomycin and docetaxel by dual-targeting gelatinase nanoparticles effectively inhibits cervical cancer cells and cancer stem cells.

Drug Deliv 2021 Dec;28(1):510-519

The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing, China.

Intra-tumor heterogeneity is widely accepted as one of the key factors, which hinders cancer patients from achieving full recovery. Especially, cancer stem cells (CSCs) may exhibit self-renewal capacity, which makes it harder for complete elimination of tumor. Therefore, simultaneously inhibiting CSCs and non-CSCs in tumors becomes a promising strategy to obtain sustainable anticancer efficacy. Salinomycin (Sal) was reported to be critical to inhibit CSCs. However, the poor bioavailability and catastrophic side effects brought about limitations to clinical practice. To solve this problem, we previously constructed gelatinase-stimuli nanoparticles composed of nontoxic, biocompatible polyethylene glycol-polycaprolactone (PEG-PCL) copolymer with a gelatinase-cleavable peptide Pro-Val-Gly-Leu-Iso-Gly (PVGLIG) inserted between the two blocks of the copolymer. By applying our "smart" gelatinase-responsive nanoparticles for Sal delivery, we have demonstrated specific accumulation in tumor, anti-CSCs ability and reduced toxicity of Sal-NPs in our previous study. In the present study, we synthesized Sal-Docetaxel-loaded gelatinase-stimuli nanoparticles (Sal-Doc NP) and confirmed single emulsion as the optimal method of producing Sal-Doc NPs (Sal-Doc SE-NP) in comparison with nanoprecipitation. Sal-Doc SE-NPs inhibited both CSCs and non-CSCs in mice transplanted with cervical cancer, and might be associated with enhanced restriction of epithelial-mesenchymal transition (EMT) pathway. Besides, the tumorigenic capacity and growing speed were obviously suppressed in Sal-Doc-SE-NPs-treated group in rechallenge experiment. Our results suggest that Sal-Doc-loaded gelatinase-stimuli nanoparticles could be a promising strategy to enhance antitumor efficacy and reduce side effects by simultaneously suppressing CSCs and non-CSCs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/10717544.2021.1886378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935125PMC
December 2021

Case Report: Neoadjuvant PD-1 Blockade Plus Concurrent Chemoradiotherapy in Unresectable Locally Advanced Gastric Cancer Patients.

Front Oncol 2020 5;10:554040. Epub 2021 Feb 5.

The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing, China.

Programmed death 1(PD-1) blockade has shown promising efficacy in advanced gastric cancer. Here, we performed a retrospective analysis of three patients with locally advanced gastric cancer who received adjuvant PD-1 plus chemoradiotherapy as neoadjuvant treatment. Neoadjuvant sintilimab plus concurrent chemoradiotherapy had an acceptable side-effect profile. All three patients underwent surgical gastrectomy after a median of 3.9 months. A major pathological response occurred in two resected tumors and a pathologic complete response was observed in one patient. Our results suggest that PD-1 blockade combined with chemoradiotherapy is a promising strategy as a neoadjuvant therapy in patients with unresectable locally advanced gastric cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2020.554040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901487PMC
February 2021

Combination Therapy with iRGD-antiCD3 and PD-1 Blockade Enhances Antitumor Potency of Cord Blood-Derived T Cells.

Onco Targets Ther 2021 5;14:835-844. Epub 2021 Feb 5.

The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, Jiangsu, 210008, People's Republic of China.

Background: T cell-redirecting bispecific antibodies (BsAbs) are emerging as a potent cancer therapy that crosslinks tumor cells and T cells by simultaneously binding to tumor-associated antigen and CD3ε. However, immune inhibitory molecules can be remarkably upregulated after BsAbs treatment, leading to a suppressive tumor microenvironment and treatment resistance. This can be partially reversed by combination with immune checkpoint inhibitors. In our previous work, we successfully constructed the recombinant protein iRGD-antiCD3 and demonstrated that it promoted antitumor efficacy of transferred T cells by promoting T cell activation and infiltration.

Methods: We detected the levels of both PD-1 and PD-L1 as resistance to iRGD-antiCD3 treatment. Using cord blood-derived T cells, we assessed the activation and effects of iRGD-antiCD3 combined with PD-1 as evidenced by activation markers, Th1/Th2-cytokines, and killing capability against tumor cells in vitro. Moreover, to better mimic the physiological characteristics of in vivo solid tumors, we generated 3D spheroids from target cell lines. Spheroids were stained with a Viability/Cytotoxicity Assay Kit and examined by confocal microscopy to study the in vitro antitumor effect of T cells co-administered with combination iRGD-antiCD3 and PD-1 blockade. The mouse peritoneal metastatic gastric tumor model was employed. The synergistic antitumor effect and safety profiles in vivo were evaluated by tumor and body weight of tumor-bearing mice.

Results: We found that expression of both PD-1 and PD-L1 were increased as resistance to iRGD-antiCD3 treatment. We found that PD-1 blockade partially restored T cell activation as evidenced by elevated activation markers, Th1-cytokines, and killing capability against tumor cells in vitro. The combination of PD-1 blockade consistently and significantly increased cord blood-derived T cell cytotoxicity against 3D tumor spheroids. In vivo, we observed synergistic antitumor activity without obvious side effects.

Conclusion: These results demonstrated that combining iRGD-antiCD3 with PD-1 blockade could further improve antitumor efficacy of T cells, and this strategy holds great potential for the treatment of solid malignancies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/OTT.S291086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873023PMC
February 2021

Highly expressed Claudin18.2 as a potential therapeutic target in advanced gastric signet-ring cell carcinoma (SRCC).

J Gastrointest Oncol 2020 Dec;11(6):1431-1439

The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing, China.

Background: Advanced gastric signet-ring cell carcinoma (SRCC) is a specific type of malignant gastric cancer (GC) with distinct poorer survival. Claudin18.2 (CLDN18.2) is a promising neo-biomarker for the treatment of GC. Clinical trials of CLDN18.2-targeted antibody and T cell-based immunotherapy providing promising prospects for the treatment of GC. The effect of antibody therapy depended on the expression rate of CLDN18.2 has been found in clinical trials. This study aimed to determine the prevalence and the therapeutic value of CLDN18.2 in advanced gastric SRCC.

Methods: Expression of CLDN18.2 in 105 formalin-fixed, paraffin-embedded (FFPE) tumor tissues was detected by immunohistochemistry (IHC) and evaluated according to FAST criteria. Next-generation sequencing (NGS) using 416 pan-cancer genes panel was performed to characterize the genomic landscape in 61 advanced gastric SRCC patients. Fisher's exact test was used to determine gene differences in different CLDN18.2 expression levels.

Results: A total number of 105 advanced gastric SRCC samples were analyzed, of which 95.2% (100/105) were positive stained. Moderate-to-strong CLDN18.2 expression was observed in 64.8% (68/105) of all samples. In particularly, 21.0% (22/105) samples had positive staining in more than 90% tumor cells. No significance was found between CLDN18.2 expression and overall survival (OS). NGS results showed that single nucleotide variations (SNVs) could be frequently found in TP53 (26.2%), CDH1 (19.7%), MED12 (18.0%), PKHD1 (18.0%) and ARID1A (11.5%), besides, copy number variations (CNVs) were rich in NOTCH1 (18.0%) and FLT4 (9.8%) in SRCC samples. Moreover, SNVs in GRIN2A was found in 20% of the patients who had CLDN18.2 staining in <40% of tumor cells (P=0.043), indicating CLDN18.2 expression might be related to the aberration of GRIN2A in advanced gastric SRCC.

Conclusions: The highly expressed CLDN18.2 among advanced gastric SRCC patients that we found certified the value of CLDN18.2-targeted therapy in this specific type of GC. In addition, Analyses between CLDN18.2 expression and genetic abnormalities provided novel therapeutic options for advanced gastric SRCC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/jgo-20-344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7807267PMC
December 2020

[Corrigendum] Tumor‑penetrating peptide fused EGFR single‑domain antibody enhances radiation responses following EGFR inhibition in gastric cancer.

Oncol Rep 2021 01 4;45(1):404-405. Epub 2020 Nov 4.

The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, Jiangsu 210008, P.R. China.

Following the publication of the above article, the authors noticed that data shown in certain of the panels in Figs. 4 and 5 were selected incorrectly and presented wrongly in these figures. Essentially, in Fig. 4, the data shown for the Tunel, anti‑EGFR‑iRGD and Tunel, anti‑EGFR‑iGRD+IR data panels (i.e., the panels in the third row, columns 2 and 4), were chosen incorrectly, and in Fig. 5, the data panel for the Lung, IR experiment (fourth row, third column) was selected incorrectly. The revised versions of Figs. 4 and 5, featuring all the correct data panels, are shown on the next page. Furthermore, the results were re‑analyzed based on the correct data. The errors made in the compilation of these Figures did not affect the overall conclusions reported in the paper. The authors are grateful to the Editor of Oncology Reports for allowing them the opportunity to publish this Corrigendum, and apologize to the readership for any inconvenience caused. [the original article was published in Oncology Reports 40: 1583-1591, 2018; DOI: 10.3892/or.2018.6532].
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3892/or.2020.7834DOI Listing
January 2021

The efficacy of treating patients with non-metastatic gastric linitis plastica using surgery with chemotherapy and/or radiotherapy.

Ann Transl Med 2020 Nov;8(21):1433

Division of Surgical Oncology, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Background: To explore the efficacy of treatment strategies for non-metastatic gastric linitis plastica (GLP).

Methods: Patients with non-metastatic GLP from 2004 to 2014 were identified from the National Cancer Database (NCDB). We compared overall survival (OS) of those patients who received different treatments, including surgery alone, a combination of surgery with chemotherapy and/or radiotherapy (S + C/R), chemotherapy and/or radiotherapy (C/R), and no treatment.

Results: The cohort included 474 patients with non-metastatic GLP. Overall, the median survival was significantly different among four groups (13.90 months in S + C/R, 8.38 months in surgery alone, 8.94 months in C/R and 2.50 months in no treatment). Then, we compared the efficacy of surgery alone and surgery with postoperative chemotherapy and/or radiotherapy (S + post C/R). When the tumor size was greater than 8 cm in stage III patients, S + post C/R was associated with a better survival benefit than surgery alone. S + post C/R also conferred an obvious survival advantage compared to surgery alone for R0 patients with positive lymph nodes and patients with positive margins.

Conclusions: Surgery plays the fundamental role in improving the OS of patients with non-metastatic GLP. S + post C/R would benefit patients in stage III with large-sized tumors (>8 cm), patients with negative margins and positive lymph nodes, and/or patients with positive margins.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/atm-20-2785bDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723551PMC
November 2020

MicroRNA-200c Nanoparticles Sensitized Gastric Cancer Cells to Radiotherapy by Regulating PD-L1 Expression and EMT.

Cancer Manag Res 2020 27;12:12215-12223. Epub 2020 Nov 27.

The Comprehensive Cancer Centre of Drum Tower Hospital, Nanjing University Medical School & Clinical Cancer Institute of Nanjing University, Nanjing, People's Republic of China.

Introduction: Immuno-checkpoint inhibitors (ICIs) in advanced gastric cancer either as monotherapy or in combining strategies are rapidly evolving but still in early phase. Various efforts have been made to provide insights into regulating immune checkpoint molecule programmed cell death ligand-1 (PD-L1) expression to improve ICIs efficacy. The aim of this study was to investigate the effect and potential mechanism of miR-200c nanoparticles combined with radiotherapy in gastric cancer cells.

Methods: We prepared miR-200c-loaded nanoparticles (miR-200c NPs) to achieve targeted delivery of miR-200c to AGS cells. The roles of miR-200c NPs and radiotherapy in regulating the viability of AGS cells were assessed by CCK-8 toxicity test and Annexin V-FITC/PI apoptosis kit. Flow cytometry was used to analyze expression of PD-L1 and CD44 on the surface of AGS cells treated by miR-200c NPs and/or ionizing radiation. Enzyme-linked immunosorbent assay (ELISA) was used to test the level of transforming growth factor-beta 1 (TGF-β1) secreted by AGS cells. The cooperation mechanism between miR-200c NPs and radiotherapy was also explored in vitro.

Results: Compared with naked miR-200c mimics, miR-200c NPs significantly downregulated PD-L1 expression of gastric cancer cells. The combination of miR-200c NPs and radiotherapy showed significantly synergistic inhibitory effect on gastric cancer cells by inhibiting immune escape mediated by PD-L1, reversing EMT phenotype as well as abrogating cancer stem cells (CSCs)-associated properties of tumor cells.

Conclusion: MiR-200c NPs sensitized gastric cancer cells to radiotherapy by regulating PD-L1 expression and EMT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/CMAR.S279978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7707438PMC
November 2020

CDK5 Inhibition Abrogates TNBC Stem-Cell Property and Enhances Anti-PD-1 Therapy.

Adv Sci (Weinh) 2020 Nov 15;7(22):2001417. Epub 2020 Oct 15.

State Key Laboratory of Pharmaceutical Biotechnology and The Comprehensive Cancer Center Nanjing Drum Tower Hospital The Affiliated Hospital of Nanjing University Medical School Nanjing University Nanjing 210046 P. R. China.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, in which the higher frequency of cancer stem cells (CSCs) correlates with the poor clinical outcome. An aberrant activation of CDK5 is found to associate with TNBC progression closely. CDK5 mediates PPAR phosphorylation at its Ser 273, which induces CD44 isoform switching from CD44s to CD44v, resulting in an increase of stemness of TNBC cells. Blocking CDK5/pho-PPAR significantly reduces CD44v+ BCSCs population in tumor tissues, thus abrogating metastatic progression in TNBC mouse model. Strikingly, diminishing stemness transformation reverses immunosuppressive microenvironment and enhances anti-PD-1 therapeutic efficacy on TNBC. Mechanistically, CDK5 switches the E3 ubiquitin ligase activity of PPAR and directly protects ESRP1 from a ubiquitin-dependent proteolysis. This finding firstly indicates that CDK5 blockade can be a potent strategy to diminish stemness transformation and increase the response to PD-1 blockade in TNBC therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/advs.202001417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675186PMC
November 2020

Anti-PD-1 therapy plus chemotherapy showed superior and durable survival benefit in a patient with small cell esophageal cancer: A case report.

Thorac Cancer 2021 01 11;12(2):264-267. Epub 2020 Nov 11.

The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing, China.

The prognosis of the small cell esophageal cancer (SCEC) patient in our study was poor due to lack of treatment options which were limited to surgery and chemotherapies, with a median overall survival (OS) of only 11.1 months according to previous studies. Herein, we adopted the regimen of immunotherapy plus chemotherapy, which exerted superior and durable benefit (OS > 19 months) in the patient in our study. Immunotherapy plus chemotherapy might therefore be a reasonable option for selected SCEC patients. In addition, well-designed trials for better evidence are required to verify the findings in this study.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/1759-7714.13735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812062PMC
January 2021

Association of Sex, Age, and Eastern Cooperative Oncology Group Performance Status With Survival Benefit of Cancer Immunotherapy in Randomized Clinical Trials: A Systematic Review and Meta-analysis.

JAMA Netw Open 2020 08 3;3(8):e2012534. Epub 2020 Aug 3.

Division of Hematology, Mayo Clinic, Rochester, Minnesota.

Importance: Sex, age, and Eastern Cooperative Oncology Group (ECOG) performance status (PS) may affect immune response. However, the association of these factors with the survival benefit of cancer immunotherapy with immune checkpoint inhibitors (ICIs) remains unclear.

Objective: To assess the potential sex, age, and ECOG PS differences of immunotherapy survival benefit in patients with advanced cancer.

Data Sources: PubMed, Web of Science, Embase, and Scopus were searched from inception to August 31, 2019.

Study Selection: Published randomized clinical trials comparing overall survival (OS) in patients with advanced cancer treated with ICI immunotherapy vs non-ICI control therapy were included.

Data Extraction And Synthesis: Pooled OS hazard ratio (HR) and 95% CI for patients of different sex, age (<65 and ≥65 years) or ECOG PS (0 and ≥1) were calculated separately using a random-effects model, and the heterogeneity between paired estimates was assessed using an interaction test by pooling study-specific interaction HRs. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline.

Main Outcomes And Measures: The difference in survival benefit of ICIs between sex, age (<65 vs ≥65 years), and ECOG PS (0 vs ≥1), as well as the difference stratified by cancer type, line of therapy, agent of immunotherapy, and immunotherapy strategy in the intervention arm.

Results: Thirty-seven phase 2 or 3 randomized clinical trials involving 23 760 patients were included. An OS benefit of immunotherapy was found for both men (HR, 0.75; 95% CI, 0.71-0.81) and women (HR, 0.79; 95% CI, 0.72-0.88); for both younger (<65 years: HR, 0.77; 95% CI, 0.71-0.83) and older (≥65 years: HR, 0.78; 95% CI, 0.72-0.84) patients; and for both patients with ECOG PS 0 (HR, 0.81; 95% CI, 0.73-0.90) and PS greater than or equal to 1 (HR, 0.79; 95% CI, 0.74-0.84). No significant difference of relative benefit from immunotherapy over control therapy was found in patients of different sex (P = .25, I2 = 19.02%), age (P = .94, I2 = 15.57%), or ECOG PS (P = .74, I2 = 0%). No significant difference was found in subgroup analyses by cancer type, line of therapy, agent of immunotherapy, and immunotherapy strategy in the intervention arm.

Conclusions And Relevance: This meta-analysis found no evidence of an association of sex, age (<65 vs ≥65 years), or ECOG PS (0 vs ≥1) with cancer immunotherapy survival benefit. This finding suggests that the use of ICIs in advanced cancer should not be restricted to certain patients in sex, age, or ECOG PS categories.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamanetworkopen.2020.12534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414387PMC
August 2020

Effectiveness and Safety of Apatinib in Patients with Advanced or Metastatic Adenocarcinoma of Stomach or Gastroesophageal Junction: A Prospective Observation Study.

Onco Targets Ther 2020 20;13:4457-4464. Epub 2020 May 20.

Department of Oncology, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research and The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, People's Republic of China.

Background: Apatinib showed promising efficacy in the treatment of advanced or metastatic gastric cancer (mGC) in previous clinical studies. However, the real-world data are limited, and this study aimed to assess the effectiveness and safety of apatinib for the treatment of advanced or mGC in this setting.

Methods: In this prospective observational study, progression-free survival (PFS), overall survival (OS), overall response rate (ORR), disease control rate (DCR) and treatment-related adverse events (AEs) were recorded and evaluated. Univariate and multivariate analyses were conducted to explore potential biomarkers which might be related to the effectiveness.

Results: A total of 321 mGC patients from 47 centers in China were enrolled between July 1, 2015, and March 1, 2018. Thirty-two patients achieved partial response, 155 patients achieved stable disease, and 115 patients had progressive disease, and no CR was achieved, illustrating an ORR of 10.60% and a DCR of 61.92%. The median PFS and OS were 4.0 and 8.2 months, respectively. Multivariate Cox analysis showed that the potential biomarkers associated with longer PFS were combination regimens plus taxel/docetaxel, and apatinib initial dosage ≥500mg, occurrence of AEs of leukopenia, and hand-foot syndrome. Main AEs were proteinuria (17.1%), hypertension (15.9%), and handfoot syndrome (8.7%).

Conclusion: The present prospective observational study showed favorable effectiveness and safety of apatinib in real-world patients with advanced or metastatic GC in China. (A prospective, multi-center, non-intervention study of apatinib in the treatment of advanced gastric cancer-Trial Registry Number: ChiCTR-OPN-15006601).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/OTT.S232287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246318PMC
May 2020

Superior Antitumor Efficacy of IFN-α2b-Incorporated Photo-Cross-Linked Hydrogels Combined with T Cell Transfer and Low-Dose Irradiation Against Gastric Cancer.

Int J Nanomedicine 2020 27;15:3669-3680. Epub 2020 May 27.

The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing, People's Republic of China.

Introduction: The exhaustion and poor homing of activated lymphocytes are critical obstacles in adoptive cell immunotherapy for solid tumors. In order to effectively deliver immune cells into tumors, we encapsulated interferon-α2b (IFN-α2b) into macroporous hydrogels as an enhancement factor and utilized low-dose irradiation (LDI) as a tumoral attractor of T cells.

Methods: Hydroxypropyl cellulose hydrogels were prepared by irradiation techniques, and the cross-sectional microstructure was characterized by scanning electron microscopy. The synergistic antitumor mechanism of combination of IFN-α2b and CIK cells was evaluated by detecting the expression of activation marker CD69 on CIK cell surface and IFN-γ production by CIK cells. The in vivo antitumor activity of IFN-α2b-incorporated hydroxypropyl cellulose hydrogels combined with CIK and radiation was evaluated in an MKN-45 xenografted nude mice model.

Results: The bioactivity of IFN-α2b was well maintained in ultraviolet-reactive, rapidly cross-linkable hydroxypropyl cellulose hydrogels. In vitro studies demonstrated IFN-α2b-activated T cells, as evidenced by upregulating early activation marker CD69 and secretion inflammatory cytokine IFN-γ. In vivo real-time image showed our hydrogels kept a higher amount of drug delivery at the tumor site for a long time compared with free drug injection. Low-dose irradiation promoted T cell accumulation and infiltration in subcutaneous tumors. Combination of IFN-α2b-loaded hydrogels (Gel-IFN) with T cells and LDI exhibited higher efficacy to eradicate human gastric cancer xenograted tumors with less proliferating cells and more necrotic regions compared with IFN-α2b or T cells alone.

Discussion: HPC hydrogels kept the activity of IFN-α2b and stably release of IFN-α2b to stimulate T cells for a long time. At the same time, low-dose radiation recruits T cells into tumors. This innovative integration mode of IFN-α2b-loaded hydrogels and radiotherapy offers a potent strategy to improve the therapeutic outcome of T cell therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/IJN.S249174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261665PMC
July 2020

Study on Properties Prediction and Braiding Optimization of Axial Braided Carbon/Carbon Composite.

Materials (Basel) 2020 Jun 5;13(11). Epub 2020 Jun 5.

Science and Technology on Reliability and Environment Engineering Laboratory, Beijing Institute of Structure and Environment Engineering, Beijing 100076, China.

It is well established that the microstructure has significant effects on the properties of axial braided C/C composites. In this study, a method coupling the homogenization method and finite element method (FEM) was proposed to predict the relationship between the microstructure characteristics and macroscopic properties. Based on the representative volume element (RVE) model, the periodic displacement boundary condition was introduced to predict the equivalent elastic properties of the RVE and component of C/C composite material, and the coefficient of thermal expansion (CTE) of the material was predicted by the energy prediction method. The predicted results were in good agreement with experimental results. By predicting the thermal and mechanical properties of the materials with different braiding spacing and fiber rod diameter, the variation of the properties with braiding spacing and fiber rod diameter was obtained. The research methods and results in this paper could provide important references for the optimization and rational application of composite materials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ma13112588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7321628PMC
June 2020

Prominent Enhancement of Cisplatin Efficacy with Optimized Methoxy Poly(ethylene glycol)-Polycaprolactone Block Copolymeric Nanoparticles.

J Biomed Nanotechnol 2020 Mar;16(3):335-343

Chemotherapy has been one of the major standard treatments for a variety of cancers. cis-Dichlorodiamminoplatiunum (II) (cisplatin, CDDP), as one of the anticancer agents, demonstrated excellent efficacy against tumor and has been an indispensable component in chemotherapy, chemoradiation, chemo-molecular targeted therapy and chemo-immunotherapy. However, its therapeutic concentration was limited since its inevitable toxicity. Previously, we have constructed CDDPloaded nanoparticles (NPs) with mixture of poly(ethyleneglycol)-polycaprolactone (PEG-PCL) and polycarprolactone (HOPCL) by a facile method. The most optimal proportion of the two copolymers was selected through a series of physical, chemical, cytological and histological evaluations. In the present study, we explored the mechanisms of NPs and observed the in vivo antitumor effect after administrating CDDP-loaded PEG-PCL NPs. Positron emission tomography as well as computed tomography (PET/CT) were adopted for detecting tumoral metabolic activity. Images from fluorescence microscope revealed superior cellular uptake of CDDP-loaded NPs with rhodamine B aggregated intracellularly in cancer cells. Similar apoptotic rates between free CDDP group and CDDP-loaded NPs group was measured by flow cytometry. Tumor volumes and murine weights confirmed the superiority of CDDP-loaded NPs in therapeutic efficacy as compared with free CDDP. Blood tests showed milder side effects in CDDP-loaded nanoparticle group. PET/CT images illustrated less uptake intensity of FDG in mice received CDDP-loaded NPs than free CDDP. Our results suggest that PEG-PCL/PCL NPs could be a promising antitumor drug carrier for CDDP delivery with solid efficacy and minor side effects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1166/jbn.2020.2892DOI Listing
March 2020
-->