Oncoimmunology最新文献_第9页

A mitochondrial checkpoint to adaptive anticancer immunity. 适应性抗癌免疫的线粒体检查点。

IF 7.2 2区医学

Oncoimmunology Pub Date : 2023-10-16 eCollection Date: 2023-01-01 DOI: 10.1080/2162402X.2023.2271693

Oliver Kepp, Peng Liu, Guido Kroemer, Lorenzo Galluzzi

引用次数: 0

Preclinical characterization of an mRNA-encoded anti-Claudin 18.2 antibody. mRNA编码的抗Claudin 18.2抗体的临床前特征。

IF 7.2 2区医学

Oncoimmunology Pub Date : 2023-10-16 eCollection Date: 2023-01-01 DOI: 10.1080/2162402X.2023.2255041

Hayat Bähr-Mahmud, Ursula Ellinghaus, Christiane R Stadler, Leyla Fischer, Claudia Lindemann, Anuhar Chaturvedi, Jan Diekmann, Stefan Wöll, Imke Biermann, Bernhard Hebich, Caroline Scharf, Manuela Siefke, Alexandra S Roth, Martin Rao, Kerstin Brettschneider, Eva-Maria Ewen, Uğur Şahin, Özlem Türeci

{"title":"Preclinical characterization of an mRNA-encoded anti-Claudin 18.2 antibody.","authors":"Hayat Bähr-Mahmud, Ursula Ellinghaus, Christiane R Stadler, Leyla Fischer, Claudia Lindemann, Anuhar Chaturvedi, Jan Diekmann, Stefan Wöll, Imke Biermann, Bernhard Hebich, Caroline Scharf, Manuela Siefke, Alexandra S Roth, Martin Rao, Kerstin Brettschneider, Eva-Maria Ewen, Uğur Şahin, Özlem Türeci","doi":"10.1080/2162402X.2023.2255041","DOIUrl":"10.1080/2162402X.2023.2255041","url":null,"abstract":"IMAB362/Zolbetuximab, a first-in-class IgG1 antibody directed against the cancer-associated gastric-lineage marker CLDN18.2, has recently been reported to have met its primary endpoint in two phase 3 trials as a first-line treatment in combination with standard of care chemotherapy in CLDN18.2-positive Her2 negative advanced gastric cancer. Here we characterize the preclinical pharmacology of BNT141, a nucleoside-modified RNA therapeutic encoding the sequence of IMAB362/Zolbetuximab, formulated in lipid nanoparticles (LNP) for liver uptake. We show that the mRNA-encoded antibody displays a stable pharmacokinetic profile in preclinical animal models, mediates CLDN18.2-restricted cytotoxicity comparable to IMAB362 recombinant protein and inhibits human tumor xenograft growth in immunocompromised mice. BNT141 administration did not perpetrate mortality, clinical signs of toxicity, or gastric pathology in animal studies. A phase 1/2 clinical trial with BNT141 mRNA-LNP has been initiated in advanced CLDN18.2-expressing solid cancers (NCT04683939).","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"12 1","pages":"2255041"},"PeriodicalIF":7.2,"publicationDate":"2023-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/aa/69/KONI_12_2255041.PMC10583639.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49683863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Dipeptidyl peptidase 4 inhibition sensitizes radiotherapy by promoting T cell infiltration. 二肽基肽酶4抑制通过促进T细胞浸润使放射治疗增敏。

IF 7.2 2区医学

Oncoimmunology Pub Date : 2023-10-12 eCollection Date: 2023-01-01 DOI: 10.1080/2162402X.2023.2268257

Yu Tian, Lingyi Kong, Yan Li, Zhiyun Liao, Xing Cai, Suke Deng, Xiao Yang, Bin Zhang, Yijun Wang, Zhanjie Zhang, Bian Wu, Lu Wen, Fang Huang, Yan Hu, Chao Wan, Yifei Liao, Yajie Sun, Kunyu Yang

{"title":"Dipeptidyl peptidase 4 inhibition sensitizes radiotherapy by promoting T cell infiltration.","authors":"Yu Tian, Lingyi Kong, Yan Li, Zhiyun Liao, Xing Cai, Suke Deng, Xiao Yang, Bin Zhang, Yijun Wang, Zhanjie Zhang, Bian Wu, Lu Wen, Fang Huang, Yan Hu, Chao Wan, Yifei Liao, Yajie Sun, Kunyu Yang","doi":"10.1080/2162402X.2023.2268257","DOIUrl":"10.1080/2162402X.2023.2268257","url":null,"abstract":"Radiotherapy could regulate systemic antitumor immunity, while the immune state in the tumor microenvironment (TME) also affects the efficacy of radiotherapy. We have found that higher CD8+ T cell infiltration is associated with longer overall survival of lung adenocarcinoma and melanoma patients receiving radiotherapy. 8-Gray radiation increased the transcriptional levels of chemokines in tumor cells in vitro. However, it was not sufficient to induce significant lymphocyte infiltration in vivo. Dipeptidyl peptidase 4 (DPP4) has been reported to inactivate chemokines via post-translational truncation. Single-cell sequencing revealed that dendritic cells (DCs) had a higher DPP4 expression among other cells in the TME and upregulated DPP4 expression after radiation. Combining a DPP4 inhibitor with radiotherapy could promote chemokines expression and T cell infiltration in the TME, enhancing the antitumor effect of radiotherapy. Moreover, this therapy further enhanced the therapeutic efficacy of anti-PD-1. In this study, we demonstrated the underlying mechanism of why radiotherapy failed to induce sufficient T cell infiltration and proposed an effective strategy to promote T cell infiltration and sensitize radiotherapy. These findings demonstrate the translational value of DPP4 inhibition as a complementary approach to enhance the efficacy of radiotherapy and the combination of radiotherapy with immunotherapy.","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"12 1","pages":"2268257"},"PeriodicalIF":7.2,"publicationDate":"2023-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/d1/96/KONI_12_2268257.PMC10578189.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41240034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

scRNA-seq reveals ATPIF1 activity in control of T cell antitumor activity. scRNA-seq揭示ATPIF1活性控制T细胞抗肿瘤活性。

IF 7.2 2区医学

Oncoimmunology Pub Date : 2022-08-20 eCollection Date: 2022-01-01 DOI: 10.1080/2162402X.2022.2114740

Genshen Zhong, Qi Wang, Ying Wang, Ying Guo, Meiqi Xu, Yaya Guan, Xiaoying Zhang, Minna Wu, Zhishan Xu, Weidong Zhao, Hongkai Lian, Hui Wang, Jianping Ye

{"title":"scRNA-seq reveals ATPIF1 activity in control of T cell antitumor activity.","authors":"Genshen Zhong, Qi Wang, Ying Wang, Ying Guo, Meiqi Xu, Yaya Guan, Xiaoying Zhang, Minna Wu, Zhishan Xu, Weidong Zhao, Hongkai Lian, Hui Wang, Jianping Ye","doi":"10.1080/2162402X.2022.2114740","DOIUrl":"https://doi.org/10.1080/2162402X.2022.2114740","url":null,"abstract":"ATP synthase inhibitory factor 1 (ATPIF1) is a mitochondrial protein with an activity in inhibition of F1Fo-ATP synthase. ATPIF1 activity remains unknown in the control of immune activity of T cells. In this study, we identified ATPIF1 activity in the induction of CD8+ T cell function in tumor models through genetic approaches. ATPIF1 gene inactivation impaired the immune activities of CD8+ T cells leading to quick tumor growth (B16 melanoma and Lewis lung cancer) in ATPIF1-KO mice. The KO T cells exhibited a reduced activity in proliferation and IFN-γ secretion with metabolic reprogramming of increased glycolysis and decreased oxidative phosphorylation (OXPHOS) after activation. T cell exhaustion was increased in the tumor infiltrating leukocytes (TILs) of KO mice as revealed by the single-cell RNA sequencing (scRNA-seq) and confirmed by flow cytometry. In contrast, ATPIF1 overexpression in T cells increased expression of IFN-γ and Granzyme B, subset of central memory T cells in CAR-T cells, and survival rate of NALM-6 tumor-bearing mice. These data demonstrate that ATPIF1 deficiency led to tumor immune deficiency through induction of T cell exhaustion. ATPIF1 overexpression enhanced the T cell tumor immunity. Therefore, ATPIF1 is a potential molecular target in the modulation of antitumor immunity of CD8+ T cells in cancer immunotherapy. Induction of ATPIF1 activity may promote CAR-T activity in cancer therapy.","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"11 1","pages":"2114740"},"PeriodicalIF":7.2,"publicationDate":"2022-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/01/f3/KONI_11_2114740.PMC9397437.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33437927","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 2

A T-cell engaging bispecific antibody with a tumor-selective bivalent folate receptor alpha binding arm for the treatment of ovarian cancer. 一种具有肿瘤选择性二价叶酸受体α结合臂的T细胞参与性双特异性抗体，用于治疗卵巢癌。

IF 7.2 2区医学

Oncoimmunology Pub Date : 2022-08-20 eCollection Date: 2022-01-01 DOI: 10.1080/2162402X.2022.2113697

Brian C Avanzino, Kirthana Prabhakar, Pranjali Dalvi, Sharon Hartstein, Hannes Kehm, Aarti Balasubramani, Andrew A Boudreau, Ben Buelow, Karen Chang, Laura M Davison, Suhasini Iyer, Vidyut Kalwit, Kristin Lewis Wilson, Harbani K Malik-Chaudhry, Will Pierson, Geovanni Pineda, Udaya S Rangaswamy, Sowmya Saiganesh, Ute Schellenberger, Harshad S Ugamraj, Rodolfovan D Yabut, Roland Buelow, Jocelyn Chapman, Nathan D Trinklein, Katherine E Harris

{"title":"A T-cell engaging bispecific antibody with a tumor-selective bivalent folate receptor alpha binding arm for the treatment of ovarian cancer.","authors":"Brian C Avanzino, Kirthana Prabhakar, Pranjali Dalvi, Sharon Hartstein, Hannes Kehm, Aarti Balasubramani, Andrew A Boudreau, Ben Buelow, Karen Chang, Laura M Davison, Suhasini Iyer, Vidyut Kalwit, Kristin Lewis Wilson, Harbani K Malik-Chaudhry, Will Pierson, Geovanni Pineda, Udaya S Rangaswamy, Sowmya Saiganesh, Ute Schellenberger, Harshad S Ugamraj, Rodolfovan D Yabut, Roland Buelow, Jocelyn Chapman, Nathan D Trinklein, Katherine E Harris","doi":"10.1080/2162402X.2022.2113697","DOIUrl":"10.1080/2162402X.2022.2113697","url":null,"abstract":"The use of T-cell engagers (TCEs) to treat solid tumors is challenging, and several have been limited by narrow therapeutic windows due to substantial on-target, off-tumor toxicities due to the expression of low levels of target antigens on healthy tissues. Here, we describe TNB-928B, a fully human TCE that has a bivalent binding arm for folate receptor alpha (FRα) to selectively target FRα overexpressing tumor cells while avoiding the lysis of cells with low levels of FRα expression. The bivalent design of the FRα binding arm confers tumor selectivity due to low-affinity but high-avidity binding to high FRα antigen density cells. TNB-928B induces preferential effector T-cell activation, proliferation, and selective cytotoxic activity on high FRα expressing cells while sparing low FRα expressing cells. In addition, TNB-928B induces minimal cytokine release compared to a positive control TCE containing OKT3. Moreover, TNB-928B exhibits substantial ex vivo tumor cell lysis using endogenous T-cells and robust tumor clearance in vivo, promoting T-cell infiltration and antitumor activity in mouse models of ovarian cancer. TNB-928B exhibits pharmacokinetics similar to conventional antibodies, which are projected to enable favorable administration in humans. TNB-928B is a novel TCE with enhanced safety and specificity for the treatment of ovarian cancer.","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"11 1","pages":"2113697"},"PeriodicalIF":7.2,"publicationDate":"2022-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/ad/33/KONI_11_2113697.PMC9397469.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33437926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0