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Volume 30,Issue 4,2023 Table of Contents
2023, 30(4):275-285.
DOI: 10.3872/j.issn.1007-385X.2023.04.001
Abstract:
CRISPR gene editing technologies have had a revolutionary impact on many disciplines and fields, and have also greatly changed research methods of tumor biotherapy and promoted the formation of new therapeutic strategies. In tumor researches, gene editing accelerated the discovery of potential targets in biotherapeutic tumor cells and immune cells, promoted new editing strategies of "tumor cell normalization" therapy through targeting oncogene，tumor suppressor gene, epigenetic molecular, drug resistance gene etc. It also promoted the iteration of adoptive cellular therapies of CAR-T/TCR-T cells to "universal" and "off-the-shelf" therapies, and greatly accelerated the clinical application of cell therapies such as that of CAR-T cells. With the development of more accurate gene editing systems, the continuous progress of gene delivery strategies, the development of multi-target editing, site-specific insertion and in vivo spatio-temporal editing, the off-target effect of gene editing can be further reduced, the safety and accessibility improved and the cost controlled. In the future, gene editing will be more widely used in tumor biotherapy, and is expected to achieve new breakthroughs in the treatment of solid tumors.
CRISPR gene editing technologies have had a revolutionary impact on many disciplines and fields, and have also greatly changed research methods of tumor biotherapy and promoted the formation of new therapeutic strategies. In tumor researches, gene editing accelerated the discovery of potential targets in biotherapeutic tumor cells and immune cells, promoted new editing strategies of "tumor cell normalization" therapy through targeting oncogene，tumor suppressor gene, epigenetic molecular, drug resistance gene etc. It also promoted the iteration of adoptive cellular therapies of CAR-T/TCR-T cells to "universal" and "off-the-shelf" therapies, and greatly accelerated the clinical application of cell therapies such as that of CAR-T cells. With the development of more accurate gene editing systems, the continuous progress of gene delivery strategies, the development of multi-target editing, site-specific insertion and in vivo spatio-temporal editing, the off-target effect of gene editing can be further reduced, the safety and accessibility improved and the cost controlled. In the future, gene editing will be more widely used in tumor biotherapy, and is expected to achieve new breakthroughs in the treatment of solid tumors.
2023, 30(4):286-295.
DOI: 10.3872/j.issn.1007-385X.2023.04.002
Abstract:
Glioma are the most common primary tumors in the brain, accounting for 81% of central nervous system malignancies. The current standard of care for patients with glioma is still surgical resection and postoperative radiochemotherapy. However, the prognosis of glioma is very poor with a median survival of only 15 months due to its highly aggressive nature, molecular heterogeneity,reproducibility of resistant cancer stem after therapy, and difficulty in crossing the blood-brain barrier (BBB) for chemotherapeutic agents to reach sufficiently high therapeutic levels. In recent years, the emerging oncolytic viruses (OVs) immunotherapy in the treatment of glioma has received much attention and made some progress. Nevertheless, multiple challenges still exist, such as crossing BBB, immune "cold" microenvironment, host antiviral response, and high tumor heterogeneity. These problems limit the further development and applications of oncolytic virus therapy but also bring new research opportunities to basic and clinical researchers.Therefore, this review summarizes the problems and countermeasures in the research and application of oncolytic virus in anti-glioma therapy from four aspects including crossing the BBB, improving the tumor microenvironment, adjusting the host immune responses mediated by oncolytic viruses, and adapting to tumor heterogeneity.
Glioma are the most common primary tumors in the brain, accounting for 81% of central nervous system malignancies. The current standard of care for patients with glioma is still surgical resection and postoperative radiochemotherapy. However, the prognosis of glioma is very poor with a median survival of only 15 months due to its highly aggressive nature, molecular heterogeneity,reproducibility of resistant cancer stem after therapy, and difficulty in crossing the blood-brain barrier (BBB) for chemotherapeutic agents to reach sufficiently high therapeutic levels. In recent years, the emerging oncolytic viruses (OVs) immunotherapy in the treatment of glioma has received much attention and made some progress. Nevertheless, multiple challenges still exist, such as crossing BBB, immune "cold" microenvironment, host antiviral response, and high tumor heterogeneity. These problems limit the further development and applications of oncolytic virus therapy but also bring new research opportunities to basic and clinical researchers.Therefore, this review summarizes the problems and countermeasures in the research and application of oncolytic virus in anti-glioma therapy from four aspects including crossing the BBB, improving the tumor microenvironment, adjusting the host immune responses mediated by oncolytic viruses, and adapting to tumor heterogeneity.
2023, 30(4):296-301.
DOI: 10.3872/j.issn.1007-385X.2023.04.003
Abstract:
Objective: To prepare bsCAR-T cells and observe its targeted killing effect on epidermal growth factor variant Ⅲ(EGFRvⅢ+,simplified as vⅢ+) and CD133+ glioma stem cells. Methods: Based on the previously generated vⅢ/CD133 minibody and second-generation CAR, bispecific CAR (bsCAR) was constructed. Lentiviral bsCAR were prepared for the transfection of human peripheral blood T cells. Flow cytometry (FCM) and Western blot test were used to detect the transfection efficiency and expression of bsCAR. After bsCAR-T cells were co-cultured with vⅢ+/CD133+ U87 glioma stem cells, their killing effects were detected by LDH release test and cytokine IFN-γ secretion. vⅢ+/CD133+ U87 stem cell transplantation tumor model of nude mouse was established to test the inhibition of bsCAR-T cells on transplanted tumors. Results: vⅢscFv and CD133scFv were joined seamlessly by over-lap PCR with CAR expression cassette (S-vⅢ/CD133scFv-Hinge-TM-CD137-CD3z). The above bsCAR construct was then cloned into EcoRⅠand BamHⅠsites of pCDH-CMV-MCS-EF1-copGFP (pbsCAR). Lentiviral bsCAR were prepared by co-transfection of three plasmid (pVSV-G, pCMV-dR8.9 and pbsCAR) into HEK293T cells and later transfected human peripheral blood T cells. The expression of bsCAR detected by flow cytometry was 71.1%.Western blot analysis showed correct expression of bsCAR. The co-culture assay of bsCAR-T cells and vⅢ+/CD133+ U87 stem cells showed that bsCAR-T cells had specific killing effect on glioma stem cells, which was proportional to the effector-target ratio. IFN-γ secretion was (2 350.6±92) pg?mL-1, which was significantly higher than that of the control group (P<0.01). Nude mice transplantation tumor model demonstrated the transplantation tumor inhibition effect of bsCAR-T cells in vivo (P<0.01). Conclusion: bsCAR-T cells can kill specifically vⅢ+/CD133+ glioma stem cells, which provides experimental basis for cell immunotherapy of solid tumors.
Objective: To prepare bsCAR-T cells and observe its targeted killing effect on epidermal growth factor variant Ⅲ(EGFRvⅢ+,simplified as vⅢ+) and CD133+ glioma stem cells. Methods: Based on the previously generated vⅢ/CD133 minibody and second-generation CAR, bispecific CAR (bsCAR) was constructed. Lentiviral bsCAR were prepared for the transfection of human peripheral blood T cells. Flow cytometry (FCM) and Western blot test were used to detect the transfection efficiency and expression of bsCAR. After bsCAR-T cells were co-cultured with vⅢ+/CD133+ U87 glioma stem cells, their killing effects were detected by LDH release test and cytokine IFN-γ secretion. vⅢ+/CD133+ U87 stem cell transplantation tumor model of nude mouse was established to test the inhibition of bsCAR-T cells on transplanted tumors. Results: vⅢscFv and CD133scFv were joined seamlessly by over-lap PCR with CAR expression cassette (S-vⅢ/CD133scFv-Hinge-TM-CD137-CD3z). The above bsCAR construct was then cloned into EcoRⅠand BamHⅠsites of pCDH-CMV-MCS-EF1-copGFP (pbsCAR). Lentiviral bsCAR were prepared by co-transfection of three plasmid (pVSV-G, pCMV-dR8.9 and pbsCAR) into HEK293T cells and later transfected human peripheral blood T cells. The expression of bsCAR detected by flow cytometry was 71.1%.Western blot analysis showed correct expression of bsCAR. The co-culture assay of bsCAR-T cells and vⅢ+/CD133+ U87 stem cells showed that bsCAR-T cells had specific killing effect on glioma stem cells, which was proportional to the effector-target ratio. IFN-γ secretion was (2 350.6±92) pg?mL-1, which was significantly higher than that of the control group (P<0.01). Nude mice transplantation tumor model demonstrated the transplantation tumor inhibition effect of bsCAR-T cells in vivo (P<0.01). Conclusion: bsCAR-T cells can kill specifically vⅢ+/CD133+ glioma stem cells, which provides experimental basis for cell immunotherapy of solid tumors.
2023, 30(4):302-308.
DOI: 10.3872/j.issn.1007-385X.2023.04.004
Abstract:
Objective: To find functional molecules that regulate tumor immune microenvironment (TIME) and influence therapeutic effect and prognosis by focusing on phenotype changes of tumor-associated macrophages (TAM) before and after chemotherapy.Methods: The data set PRJEB45598 from ENA (European Nucleotide Archive) was used to analyze the single-cell sequencing data of biopsy tumor tissues from patients with advanced gastric cancer before and after chemotherapy. 31 subpopulations of cells were obtained using PCA (principal component analysis) and UMAP (uniform manifold approximation and projection). Further TAM subtype analysis and differential gene screening were performed to find the genes highly expressed in M2-like TAM cells after chemotherapy. The mRNA and protein expression changes of the specific gene before and after chemotherapy were verified by subcutaneous melanoma B16-F10 cell transplanted xenograft model. Whether the protein regulates chemotherapy-induced tumor cell death was analyzed in vitro by Incucyte. Results: Focusing on the characteristic expression genes in M2-like TAM in single-cell sequencing data, we found that the mRNA level of galactose-specific lectin 3 (LGALS3) was significantly increased after chemotherapy (P<0.01), and its high expression in various tumors was negatively related to the survival of patients (P<0.05 or P<0.01). LGALS3 washighly expressed in M2-like TAM in melanoma B16-F10 cell transplanted xenograft model in vivo (P<0.01), and its expression was further increased after oxaliplatin chemotherapy (P<0.05). Recombinant LGALS3 protein inhibited oxaliplatin-induced tumor cell deathin vitro. Conclusion: M2-like TAM promotes chemoresistance of tumor cells through synthesis and secretion of LGALS3 after chemotherapy. Therefore, targeting LGALS3 through immunotherapy may effectively improve the therapeutic effect of tumors.
Objective: To find functional molecules that regulate tumor immune microenvironment (TIME) and influence therapeutic effect and prognosis by focusing on phenotype changes of tumor-associated macrophages (TAM) before and after chemotherapy.Methods: The data set PRJEB45598 from ENA (European Nucleotide Archive) was used to analyze the single-cell sequencing data of biopsy tumor tissues from patients with advanced gastric cancer before and after chemotherapy. 31 subpopulations of cells were obtained using PCA (principal component analysis) and UMAP (uniform manifold approximation and projection). Further TAM subtype analysis and differential gene screening were performed to find the genes highly expressed in M2-like TAM cells after chemotherapy. The mRNA and protein expression changes of the specific gene before and after chemotherapy were verified by subcutaneous melanoma B16-F10 cell transplanted xenograft model. Whether the protein regulates chemotherapy-induced tumor cell death was analyzed in vitro by Incucyte. Results: Focusing on the characteristic expression genes in M2-like TAM in single-cell sequencing data, we found that the mRNA level of galactose-specific lectin 3 (LGALS3) was significantly increased after chemotherapy (P<0.01), and its high expression in various tumors was negatively related to the survival of patients (P<0.05 or P<0.01). LGALS3 washighly expressed in M2-like TAM in melanoma B16-F10 cell transplanted xenograft model in vivo (P<0.01), and its expression was further increased after oxaliplatin chemotherapy (P<0.05). Recombinant LGALS3 protein inhibited oxaliplatin-induced tumor cell deathin vitro. Conclusion: M2-like TAM promotes chemoresistance of tumor cells through synthesis and secretion of LGALS3 after chemotherapy. Therefore, targeting LGALS3 through immunotherapy may effectively improve the therapeutic effect of tumors.
2023, 30(4):309-317.
DOI: 10.3872/j.issn.1007-385X.2023.04.005
Abstract:
Objective: To analyze the expression of stimulator of interferon gene (STING) in lung adenocarcinoma and the correlation between clinical features of lung adenocarcinoma patients and the expression of STING, and to investigate the association of STING with endoplasmic reticulum (ER) stress, and the functions and mechanisms of STING in regulating the progression of lung adenocarcinoma. Methods: The expression of STING at pan-cancer level was analyzed by using TIMER database. The expression of STING in lung adenocarcinoma tissue and the correlation between STING expression and clinical features of lung adenocarcinoma patients were explored by using UALCAN and HPA database. The correlation between STING expression and overall survival (OS) rates of lung adenocarcinoma patients was analyzed by using Kaplan-Meier survival function. Analysis of the co-expressed genes with STING was performed based on the expression profile data of lung adenocarcinoma from LinkedOmics database. GO function and KEGG pathway analyses were conducted to investigate the differential expressed genes (DEGs) of STING, and GSEA was performed to explore the potential pathways through which STING might regulate lung adenocarcinoma. The STING agonist, diABZI, and the ER stress inhibitor, TUDCA, were used to treat lung adenocarcinoma cell lines, A549 and H460, and the expressions of STING and ER stress-associated molecules were examined by qPCR and Western blotting, and the cell vitality was detected by CCK-8 assays. Results: The expressions of STING in lung adenocarcinoma tissues and cells were significantly lower than those in normal lung tissues (all P<0.01). The 5-year OS rates of lung adenocarcinoma patients with high STING expression were notably higher than those of low-expression patients (P<0.01), and the expression of STING were closely correlated with clinical characteristics of the lung adenocarcinoma patients, such as age and gender (all P<0.01). High STING expression was enriched in pathways, such as exogenous antigen processing and presentation in lung adenocarcinoma (all P<0.01). The use of STING agonist significantly induced ER stress in lung adenocarcinoma (P<0.05). STING activation significantly lowered the vitality of lung adenocarcinoma cells (all P<0.01), which could be partly reversed by using the ER stress inhibitor (P<0.05). Conclusion: The expression of STING is downregulated in lung adenocarcinoma, which is closely associated with worse clinical prognosis of the lung adenocarcinoma patients. STING could inhibit lung adenocarcinoma cell vitality by inducing ER stress.
Objective: To analyze the expression of stimulator of interferon gene (STING) in lung adenocarcinoma and the correlation between clinical features of lung adenocarcinoma patients and the expression of STING, and to investigate the association of STING with endoplasmic reticulum (ER) stress, and the functions and mechanisms of STING in regulating the progression of lung adenocarcinoma. Methods: The expression of STING at pan-cancer level was analyzed by using TIMER database. The expression of STING in lung adenocarcinoma tissue and the correlation between STING expression and clinical features of lung adenocarcinoma patients were explored by using UALCAN and HPA database. The correlation between STING expression and overall survival (OS) rates of lung adenocarcinoma patients was analyzed by using Kaplan-Meier survival function. Analysis of the co-expressed genes with STING was performed based on the expression profile data of lung adenocarcinoma from LinkedOmics database. GO function and KEGG pathway analyses were conducted to investigate the differential expressed genes (DEGs) of STING, and GSEA was performed to explore the potential pathways through which STING might regulate lung adenocarcinoma. The STING agonist, diABZI, and the ER stress inhibitor, TUDCA, were used to treat lung adenocarcinoma cell lines, A549 and H460, and the expressions of STING and ER stress-associated molecules were examined by qPCR and Western blotting, and the cell vitality was detected by CCK-8 assays. Results: The expressions of STING in lung adenocarcinoma tissues and cells were significantly lower than those in normal lung tissues (all P<0.01). The 5-year OS rates of lung adenocarcinoma patients with high STING expression were notably higher than those of low-expression patients (P<0.01), and the expression of STING were closely correlated with clinical characteristics of the lung adenocarcinoma patients, such as age and gender (all P<0.01). High STING expression was enriched in pathways, such as exogenous antigen processing and presentation in lung adenocarcinoma (all P<0.01). The use of STING agonist significantly induced ER stress in lung adenocarcinoma (P<0.05). STING activation significantly lowered the vitality of lung adenocarcinoma cells (all P<0.01), which could be partly reversed by using the ER stress inhibitor (P<0.05). Conclusion: The expression of STING is downregulated in lung adenocarcinoma, which is closely associated with worse clinical prognosis of the lung adenocarcinoma patients. STING could inhibit lung adenocarcinoma cell vitality by inducing ER stress.
LI Yaru
,
YANG Xia
,
ZHAO Renshuang
,
XIU Zhiru
,
ZHU Yilong
,
HAN Jicheng
,
LI Shanzhi
,
LI Yiquan
,
JIN Ningyi
2023, 30(4):318-323.
DOI: 10.3872/j.issn.1007-385X.2023.04.006
Abstract:
Objective: To explore the effect of neobavaisoflavone (NBIF) on pyroptosis of hepatocellular carcinoma (HCC) Huh-7 cells and its molecular mechanism. Methods: Huh-7 cells were cultured in vitro, and the effects of different concentrations of NBIF on cell survival rate was detected by CCK-8. Morphological changes of Huh-7 cells treated with NBIF were observed under optical microscope.Lactate dehydrogenase (LDH) release test was used to detect the LDH release of cells. The protein levels of gasdermin E (GSDME) and caspase-3 in the cells were detected by WB assay. After silencing caspase-3 and GSDME in Huh-7 cells, the effect of NBIF treatment on cell survival rate was detected by CCK-8. The expression level of GSDME protein was detected by WB assay. The effect of NBIF treatment on cell morphology was observed, and the release of LDH was detected. Results: NBIF above 60 μmol/L could significantly inhibit the proliferation of Huh-7 cells (all P<0.01). The swelling and bubbling phenomenon of NBIF treated cells were observed under optical microscope, and the release of LDH was increased (all P<0.01). WB results showed that NBIF could activate caspase-3 protein, cleave GSDME protein and increase the expression of GSDME-N (P<0.01). After silencing caspase-3 and GSDME genes, the inhibition of NBIF on cells was weakened (all P<0.01), and the expression of GSDME-N protein was inhibited (P<0.01). Under the microscope, the phenomenon of cell swelling and bubbling almost disappeared, and the release of LDH decreased significantly (P<0.05). Conclusion: NBIF can cause pyroptosis of Huh-7 cells through caspase3-GSDME pathway, thus inhibiting the proliferation of Huh-7 cells, which provides a new idea for the treatment of HCC.
Objective: To explore the effect of neobavaisoflavone (NBIF) on pyroptosis of hepatocellular carcinoma (HCC) Huh-7 cells and its molecular mechanism. Methods: Huh-7 cells were cultured in vitro, and the effects of different concentrations of NBIF on cell survival rate was detected by CCK-8. Morphological changes of Huh-7 cells treated with NBIF were observed under optical microscope.Lactate dehydrogenase (LDH) release test was used to detect the LDH release of cells. The protein levels of gasdermin E (GSDME) and caspase-3 in the cells were detected by WB assay. After silencing caspase-3 and GSDME in Huh-7 cells, the effect of NBIF treatment on cell survival rate was detected by CCK-8. The expression level of GSDME protein was detected by WB assay. The effect of NBIF treatment on cell morphology was observed, and the release of LDH was detected. Results: NBIF above 60 μmol/L could significantly inhibit the proliferation of Huh-7 cells (all P<0.01). The swelling and bubbling phenomenon of NBIF treated cells were observed under optical microscope, and the release of LDH was increased (all P<0.01). WB results showed that NBIF could activate caspase-3 protein, cleave GSDME protein and increase the expression of GSDME-N (P<0.01). After silencing caspase-3 and GSDME genes, the inhibition of NBIF on cells was weakened (all P<0.01), and the expression of GSDME-N protein was inhibited (P<0.01). Under the microscope, the phenomenon of cell swelling and bubbling almost disappeared, and the release of LDH decreased significantly (P<0.05). Conclusion: NBIF can cause pyroptosis of Huh-7 cells through caspase3-GSDME pathway, thus inhibiting the proliferation of Huh-7 cells, which provides a new idea for the treatment of HCC.
2023, 30(4):324-330.
DOI: 10.3872/j.issn.1007-385X.2023.04.007
Abstract:
Objective: To investigate the expressions of miR-203a and its target genes in serum and tumor tissues of patients with hepatocellular carcinoma (HCC) and their relationships with clinicopathological characteristics and prognosis. Methods: The target genes of miR-203a were predicted from TargetScan, miRDB and PicTar websites using bioinformatics methods, which were verified by double luciferase gene report experiment. The samples of cancer tissues and para-cancerous tissues, serum and clinical data of 96 patients with HCC whose tumors were surgically removed at the Second People's Hospital of Jintan District, Changzhou City from January 2018 to June 2019 were collected. The serum of 90 healthy people was collected as controls. The serum miR-203a level and the expressions of miR-203a and its target genes in HCC and para-cancerous tissues were detected by qPCR. The expressions of miR-203a and its target genes in HCC patients with different clinicopathological characteristics were comparatively analyzed. The patients were followed-up for 3 years and overall survival (OS) analysis was performed by Kaplan-Meier method. Results: A total of 10 miR-203a-related target genes were screened from databases, including adenomatous polyposis coli (APC), cyclin dependent kinase 6 (CDK6), transcription factor GATA binding protein 6 (GATA6), homeobox D3 (HOXD3), insulin-like growth factor class 1 receptor (IGF1R), insulin-like growth factor binding protein-5 (IGFBP5), potassium intermediate small conductance calcium activated channel subfamily N, member2 (KCNE2), progestin and adipoQ receptor 3 (PAQR3), Protein arginine methyltransferase 5 (PRMT5) and suppressor of cytokine signaling 3 (SOSC3). The expressions of miR-203a, APC and PAQR3 mRNA in the HCC tissues were significantly lower than those in the para-cancerous tissues (all P<0.01), and the expressions of CDK6, GATA6, HOXD3, IGF1R, IGFBP5, KCNE2、PRMT5 and SOSC3 mRNA were significantly higher than those in the para-cancerous tissues (all P<0.01). The expressions of serum miR-203a and miR-203a and its target genes in HCC tissues were related to the clinical stage, differentiation degree, liver function grade and OS rate of the patients (all P<0.01). Conclusion: miR-203a in HCC tissues is in low expression, and the expressions of miR-203a and target genes are related to clinical stage, differentiation, liver function and long-term OS rate.
Objective: To investigate the expressions of miR-203a and its target genes in serum and tumor tissues of patients with hepatocellular carcinoma (HCC) and their relationships with clinicopathological characteristics and prognosis. Methods: The target genes of miR-203a were predicted from TargetScan, miRDB and PicTar websites using bioinformatics methods, which were verified by double luciferase gene report experiment. The samples of cancer tissues and para-cancerous tissues, serum and clinical data of 96 patients with HCC whose tumors were surgically removed at the Second People's Hospital of Jintan District, Changzhou City from January 2018 to June 2019 were collected. The serum of 90 healthy people was collected as controls. The serum miR-203a level and the expressions of miR-203a and its target genes in HCC and para-cancerous tissues were detected by qPCR. The expressions of miR-203a and its target genes in HCC patients with different clinicopathological characteristics were comparatively analyzed. The patients were followed-up for 3 years and overall survival (OS) analysis was performed by Kaplan-Meier method. Results: A total of 10 miR-203a-related target genes were screened from databases, including adenomatous polyposis coli (APC), cyclin dependent kinase 6 (CDK6), transcription factor GATA binding protein 6 (GATA6), homeobox D3 (HOXD3), insulin-like growth factor class 1 receptor (IGF1R), insulin-like growth factor binding protein-5 (IGFBP5), potassium intermediate small conductance calcium activated channel subfamily N, member2 (KCNE2), progestin and adipoQ receptor 3 (PAQR3), Protein arginine methyltransferase 5 (PRMT5) and suppressor of cytokine signaling 3 (SOSC3). The expressions of miR-203a, APC and PAQR3 mRNA in the HCC tissues were significantly lower than those in the para-cancerous tissues (all P<0.01), and the expressions of CDK6, GATA6, HOXD3, IGF1R, IGFBP5, KCNE2、PRMT5 and SOSC3 mRNA were significantly higher than those in the para-cancerous tissues (all P<0.01). The expressions of serum miR-203a and miR-203a and its target genes in HCC tissues were related to the clinical stage, differentiation degree, liver function grade and OS rate of the patients (all P<0.01). Conclusion: miR-203a in HCC tissues is in low expression, and the expressions of miR-203a and target genes are related to clinical stage, differentiation, liver function and long-term OS rate.
2023, 30(4):331-337.
DOI: 10.3872/j.issn.1007-385X.2023.04.008
Abstract:
Objective: To reevaluate the efficacy and safety of camrelizumab combined with apatinib in the treatment of primary hepatic carcinoma (PHC). Methods: The clinical data of PHC patients diagnosed in the First Affiliated Hospital of Anhui Medical University from January 2019 to May 2021 were retrospectively collected. All patients received camrelizumab 200 mg q3w combined with apatinib 250 mg qd for 21 days. Chi-square test was used to compare the baseline characteristics. Kaplan-Meier method was used to calculate the survival curve, from which the median total survival (OS) was estimated, and then Log-Rank test was used for comparison; Single factor Cox regression analysis was used to predict the factors affecting OS. Results: A total of 43 patients with PHC were included in this study. The objective response rate (ORR) of first-line treatment patients was 23.3% (7/30), and the ORR of second-line and above treatment patients was 15.4% (2/13). The disease control rate (DCR) of the two groups were 83.3% (25/30) and 61.5%(8/13), respectively. The median progression-free survival (PFS) was 5.0 months (95% CI 3.2, 6.8) and 4.0 months (95% CI 1.7, 6.3) (P=0.514), respectively. The median total survival (OS) was 13.0 months (95% CI 11.2, 14.8) and 9.0 months (95% CI 2.8, 15.2) (P=0.179). Among 43 patients, 33 (76.7%) had treatment-related AEs of grade 3 or above. The most common AEs were decreased platelet count (14.0%), hypertension (9.3%) and proteinuria (9.3%). Cox univariate analysis showed that Child-Pugh grade was an independent risk factor affecting the prognosis of PHC patients (HR=0.324, 95% CI [0.146, 0.716], P<0.05). Conclusion: Camrelizumab plus apatinib significantly improved OS, ORR, and DCR in PHC patients , AEs were tolerable and manageable.
Objective: To reevaluate the efficacy and safety of camrelizumab combined with apatinib in the treatment of primary hepatic carcinoma (PHC). Methods: The clinical data of PHC patients diagnosed in the First Affiliated Hospital of Anhui Medical University from January 2019 to May 2021 were retrospectively collected. All patients received camrelizumab 200 mg q3w combined with apatinib 250 mg qd for 21 days. Chi-square test was used to compare the baseline characteristics. Kaplan-Meier method was used to calculate the survival curve, from which the median total survival (OS) was estimated, and then Log-Rank test was used for comparison; Single factor Cox regression analysis was used to predict the factors affecting OS. Results: A total of 43 patients with PHC were included in this study. The objective response rate (ORR) of first-line treatment patients was 23.3% (7/30), and the ORR of second-line and above treatment patients was 15.4% (2/13). The disease control rate (DCR) of the two groups were 83.3% (25/30) and 61.5%(8/13), respectively. The median progression-free survival (PFS) was 5.0 months (95% CI 3.2, 6.8) and 4.0 months (95% CI 1.7, 6.3) (P=0.514), respectively. The median total survival (OS) was 13.0 months (95% CI 11.2, 14.8) and 9.0 months (95% CI 2.8, 15.2) (P=0.179). Among 43 patients, 33 (76.7%) had treatment-related AEs of grade 3 or above. The most common AEs were decreased platelet count (14.0%), hypertension (9.3%) and proteinuria (9.3%). Cox univariate analysis showed that Child-Pugh grade was an independent risk factor affecting the prognosis of PHC patients (HR=0.324, 95% CI [0.146, 0.716], P<0.05). Conclusion: Camrelizumab plus apatinib significantly improved OS, ORR, and DCR in PHC patients , AEs were tolerable and manageable.
2023, 30(4):338-343.
DOI: 10.3872/j.issn.1007-385X.2023.04.009
Abstract:
成纤维细胞生长因子受体（FGFR）是一种受体酪氨酸激酶（RTK），与其配体成纤维细胞生长因子（FGF）相结合，激活下游的信号转导通路，参与调控细胞的正常生理活动。当FGFR基因发生扩增、突变或者融合等异常改变时，就会导致下游细胞信号通路的异常激活，促进细胞的增殖、迁移、侵袭及上皮-间质转化，进而促进肿瘤的发展。同时，FGFR在多种肿瘤中均呈高表达，因此FGF/FGFR 可作为肿瘤治疗的重要靶点。根据药物作用机制，可以将抗FGFR 信号通路药物分为两大类，分别为FGFR-酪氨酸激酶抑制剂（TKI）和阻断FGF/FGFR 的单克隆抗体。目前，已有多种针对FGF/FGFR 的靶向药物进入临床试验阶段，在肿瘤治疗中取得较好的临床效果，有的靶向药物获批用于临床肿瘤的治疗，为肿瘤的精准治疗带来了新的曙光。
成纤维细胞生长因子受体（FGFR）是一种受体酪氨酸激酶（RTK），与其配体成纤维细胞生长因子（FGF）相结合，激活下游的信号转导通路，参与调控细胞的正常生理活动。当FGFR基因发生扩增、突变或者融合等异常改变时，就会导致下游细胞信号通路的异常激活，促进细胞的增殖、迁移、侵袭及上皮-间质转化，进而促进肿瘤的发展。同时，FGFR在多种肿瘤中均呈高表达，因此FGF/FGFR 可作为肿瘤治疗的重要靶点。根据药物作用机制，可以将抗FGFR 信号通路药物分为两大类，分别为FGFR-酪氨酸激酶抑制剂（TKI）和阻断FGF/FGFR 的单克隆抗体。目前，已有多种针对FGF/FGFR 的靶向药物进入临床试验阶段，在肿瘤治疗中取得较好的临床效果，有的靶向药物获批用于临床肿瘤的治疗，为肿瘤的精准治疗带来了新的曙光。
2023, 30(4):344-351.
DOI: 10.3872/j.issn.1007-385X.2023.04.010
Abstract:
以靶向治疗为代表的新兴治疗方法是传统一线放化疗耐药的有效补充，人表皮生长因子受体2（HER2）是胃癌靶向治疗中十分重要的靶点之一，曲妥珠单抗联合化疗已被用于晚期胃癌的一线治疗方案，帕妥珠单抗和马格妥昔单抗治疗胃癌的安全性和有效性已得到了验证。然而，单克隆抗体因其分子量较大、不能穿透血脑屏障，且耐药而导致治疗效果下降，因此需探索其他靶向HER2的疗法在胃癌中的疗效。小分子药物酪氨酸激酶抑制剂（TKI）如拉帕替尼、吡咯替尼等具有分子量小、可穿透血脑屏障和口服生物利用度高等优点，未来经过大型临床试验验证后有望成为胃癌围手术期治疗、新辅助治疗的选择药物。抗体-药物偶联物（ADC）如T-DM1、T-DXd等尽管其发挥肿瘤杀伤作用的机制不同，但能够克服单克隆抗体的耐药，是曲妥珠单抗等单抗治疗失败患者治疗药物的补充。因此，对胃癌患者进行更加细致的分层后，靶向HER2的各类胃癌治疗药物有望发挥更加显著的作用。
以靶向治疗为代表的新兴治疗方法是传统一线放化疗耐药的有效补充，人表皮生长因子受体2（HER2）是胃癌靶向治疗中十分重要的靶点之一，曲妥珠单抗联合化疗已被用于晚期胃癌的一线治疗方案，帕妥珠单抗和马格妥昔单抗治疗胃癌的安全性和有效性已得到了验证。然而，单克隆抗体因其分子量较大、不能穿透血脑屏障，且耐药而导致治疗效果下降，因此需探索其他靶向HER2的疗法在胃癌中的疗效。小分子药物酪氨酸激酶抑制剂（TKI）如拉帕替尼、吡咯替尼等具有分子量小、可穿透血脑屏障和口服生物利用度高等优点，未来经过大型临床试验验证后有望成为胃癌围手术期治疗、新辅助治疗的选择药物。抗体-药物偶联物（ADC）如T-DM1、T-DXd等尽管其发挥肿瘤杀伤作用的机制不同，但能够克服单克隆抗体的耐药，是曲妥珠单抗等单抗治疗失败患者治疗药物的补充。因此，对胃癌患者进行更加细致的分层后，靶向HER2的各类胃癌治疗药物有望发挥更加显著的作用。
2023, 30(4):352-356.
DOI: 10.3872/j.issn.1007-385X.2023.04.011
Abstract:
结直肠癌（CRC）是临床常见的消化道恶性肿瘤之一，具有较高患病率及复发转移风险，其起病隐匿且危害性强，临床须及时诊断并采取对症治疗以提高患者预后质量，降低不良结局风险。目前根治性手术是治疗CRC的最有效方法之一，通过切除病灶达到病情控制目的，但该治疗策略仍存在一定复发转移风险，临床多采用CRC根治性手术联合免疫治疗策略。近年来随着肿瘤免疫技术及理念的发展，免疫疗法的疗效及安全性也持续提高。根据现有研究进展，肿瘤疫苗、过继T细胞疗法（ACT）、免疫检查点抑制剂（ICI）及其他免疫疗法对于杀死CRC细胞，减轻肿瘤负担，降低CRC根治性手术后的复发风险有着重要价值。阐明CRC根治性手术联合免疫治疗的临床应用进展现状，以及治疗作用机制，可为CRC患者病情控制及防止复发转移提供更可靠的依据。
结直肠癌（CRC）是临床常见的消化道恶性肿瘤之一，具有较高患病率及复发转移风险，其起病隐匿且危害性强，临床须及时诊断并采取对症治疗以提高患者预后质量，降低不良结局风险。目前根治性手术是治疗CRC的最有效方法之一，通过切除病灶达到病情控制目的，但该治疗策略仍存在一定复发转移风险，临床多采用CRC根治性手术联合免疫治疗策略。近年来随着肿瘤免疫技术及理念的发展，免疫疗法的疗效及安全性也持续提高。根据现有研究进展，肿瘤疫苗、过继T细胞疗法（ACT）、免疫检查点抑制剂（ICI）及其他免疫疗法对于杀死CRC细胞，减轻肿瘤负担，降低CRC根治性手术后的复发风险有着重要价值。阐明CRC根治性手术联合免疫治疗的临床应用进展现状，以及治疗作用机制，可为CRC患者病情控制及防止复发转移提供更可靠的依据。
2023, 30(4):357-360.
DOI: 10.3872/j.issn.1007-385X.2023.04.012
Abstract:
原位疫苗是近年来备受关注的一种肿瘤免疫治疗策略，可将免疫抑制性肿瘤微环境转变为免疫刺激性微环境。然而，该治疗模式的持续临床效益需要多个层面的长期免疫激活。南京大学医学院附属鼓楼医院肿瘤中心采用原位疫苗模式治疗1例晚期子宫内膜癌（EC）患者，经历5.5个月的PFS后，虽然总体疗效评价为PD，但目标病灶仍为PR，反映了该治疗策略的潜力。通过复习相关文献，对原位疫苗产生效应的机制以及实际应用中存在的问题进行了深入分析，以期为晚期无标准治疗方案的实体瘤患者提供新的有效治疗思路。
原位疫苗是近年来备受关注的一种肿瘤免疫治疗策略，可将免疫抑制性肿瘤微环境转变为免疫刺激性微环境。然而，该治疗模式的持续临床效益需要多个层面的长期免疫激活。南京大学医学院附属鼓楼医院肿瘤中心采用原位疫苗模式治疗1例晚期子宫内膜癌（EC）患者，经历5.5个月的PFS后，虽然总体疗效评价为PD，但目标病灶仍为PR，反映了该治疗策略的潜力。通过复习相关文献，对原位疫苗产生效应的机制以及实际应用中存在的问题进行了深入分析，以期为晚期无标准治疗方案的实体瘤患者提供新的有效治疗思路。
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Supported by:Beijing E-Tiller Technology Development Co., Ltd.