Molecular Cancer Therapeutics最新文献

{"title":"Novel Amanitin-based Antibody Drug Conjugates (ATAC®) targeting TROP2 for the treatment of Pancreatic Cancer.","authors":"Eleni Papacharisi, Alexandra Braun, Marija Vranic, Andreas M Pahl, Torsten Hechler","doi":"10.1158/1535-7163.MCT-24-0266","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0266","url":null,"abstract":"<p><p>Trophoblast cell surface antigen 2 (TROP2) exhibits aberrant expression in pancreatic cancer, correlating with metastasis, advanced tumor stage and poor prognosis of pancreatic ductal adenocarcinoma (PDAC) patients. TROP2 has been recognized as a promising therapeutic target for antibody drug conjugates (ADCs), as evidenced by the approval of the anti-TROP2 ADC Trodelvy® for the treatment of triple negative breast cancer. In this study we report the generation of novel second-generation amanitin based ADCs (ATAC®s) targeting TROP2, comprising the humanized RS7 antibody of Trodelvy® (hRS7) and the highly potent payload amanitin. The specific in vitro binding, efficient antigen internalization, and high cytotoxicity of hRS7 ATAC®s with half maximal effective concentration (EC50) values in the picomolar range in TROP2-expressing cells constituted the foundation for preclinical in vivo evaluation. The hRS7 ATAC®s demonstrated a significant reduction in tumor growth in vivo in subcutaneous xenograft mouse models of pancreatic cancer and triple negative breast cancer at well-tolerated doses. The antitumor efficacy correlated with the level of TROP2 expression on the tumors and the in vivo tumor uptake of the ATAC®s. The long half-life of 9.7-10.7 days of hRS7 ATAC®s without premature payload release in serum supported a high therapeutic index. Notably, the efficacy of the hRS7 ATAC®s was superior to that of Trodelvy® with complete tumor eradication in both, refractory pancreatic and triple negative breast cancer xenograft models. In summary, hRS7 ATAC®s represent a highly effective and well-tolerated targeted therapy, and our data support their development for pancreatic cancer and other TROP2-expressing tumors.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142676379","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characteristics of a CCL21-gene modified dendritic cell vaccine utilized for a clinical trial in non-small cell lung cancer.","authors":"Michael S Oh, Camelia Dumitras, Ramin Salehi-Rad, Linh M Tran, Kostyantyn Krysan, Raymond J Lim, Zhe Jing, Shahed Tappuni, Aaron Lisberg, Edward B Garon, Steven M Dubinett, Bin Liu","doi":"10.1158/1535-7163.MCT-24-0435","DOIUrl":"10.1158/1535-7163.MCT-24-0435","url":null,"abstract":"<p><p>The treatment of non-small cell lung cancer has made major strides with the use of immune checkpoint inhibitors, but there remains a significant need for therapies that can overcome immunotherapy resistance. Dendritic cell (DC) vaccines have been proposed as a therapy that can potentially enhance the antitumor immune response. We have embarked on a phase I clinical trial of a vaccine consisting of monocyte-derived DCs (moDCs) modified to express the chemokine CCL21 (CCL21-DC) given in combination with pembrolizumab. Here, we report a comprehensive characterization of this CCL21-DC vaccine and interrogate the effects of multiple factors in the manufacturing process. We show that the cellular makeup of the CCL21-DC vaccine is heterogeneous due to the presence of passenger lymphocytes at a proportion that is highly variable among patients. Single cell RNA sequencing of vaccines revealed further heterogeneity within the moDC compartment, with cells spanning a spectrum of DC phenotypes. Transduction with a CCL21-containing adenoviral vector augmented CCL21 secretion by moDCs but otherwise had a minimal effect on vaccine characteristics. A single freeze-thaw cycle for stored vaccines was associated with minor alterations to the DC phenotype, as was the use of healthy donors rather than patient autologous blood. Our results highlight important considerations for the production of DC vaccines and identify underexplored factors that may affect their efficacy and immunologic impact.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667994","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modeling the acute mucosal toxicity to fractionated radiotherapy combined with the ATM inhibitor WSD0628.","authors":"Darwin A Garcia, Sneha Rathi, Margaret A Connors, Michael Grams, Rachael A Vaubel, Katrina K Bakken, Lauren L Ott, Brett L Carlson, Zeng Hu, Paul A Decker, Jeanette E Eckel-Passow, Danielle M Burgenske, Wei Zhong, Joshua D Trzasko, Michael G Herman, William F Elmquist, Nicholas B Remmes, Jann N Sarkaria","doi":"10.1158/1535-7163.MCT-24-0664","DOIUrl":"10.1158/1535-7163.MCT-24-0664","url":null,"abstract":"<p><p>ATM inhibitors are being developed as radiosensitizers to improve the antitumor effects of radiotherapy, but ATM inhibition can also radiosensitize normal tissues. Therefore, understanding the elevated risk for normal tissue toxicities is critical for radiosensitizer development. This study focused on modeling the relationship between acute mucosal toxicity, radiation dose, fractionation schedule, and radiosensitizer exposure. The ATM inhibitor WSD0628 was combined with single or fractionated doses of radiation delivered to the oral cavity or esophagus of FVB mice. The potentiation by WSD0628 was quantified by a sensitizer enhancement ratio (SER), which describes the changes in radiation tolerance for radiation combined with WSD0628 relative to radiation-only regimens. WSD0628 profoundly enhanced radiation-induced acute oral and esophageal toxicities. For oral mucosal toxicity, the enhancement by WSD0628 with 3 fractions of radiation resulted in an SER ranging from 1.3 (0.25 mg/kg) to 3.1 (7.5 mg/kg). For the 7.5 mg/kg combination, the SER increased with increasing number of fractions from 2.2 (1 fraction) to 4.3 (7 fractions) for oral toxicity and from 2.2 (1 fraction) to 3.6 (3 fractions) for esophageal toxicity, which reflects a loss of the normal tissue sparing benefit of fractionated radiation. These findings were used to develop a modified biologically effective dose model to determine alternative radiation schedules with or without WSD0628 that result in similar levels of toxicity. Successful radiosensitizer dose-escalation to maximally effective therapeutic dose will require careful deliberation of tumor site and reduction of radiation dose-volume limits for organs at risk.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142668022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HPV and p53 status as precision determinants of head and neck cancer response to DNA-PKcs inhibition in combination with irradiation.","authors":"Liana Hayrapetyan, Selina Moara Roth, Aurélie Quintin, Lusine Hovhannisyan, Matúš Medo, Rahel Riedo, Julien G Ott, Joachim Albers, Daniel M Aebersold, Yitzhak Zimmer, Michaela Medová","doi":"10.1158/1535-7163.MCT-23-0794","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-23-0794","url":null,"abstract":"<p><p>Major risk factors of head and neck squamous cell carcinoma (HNSCC) are tobacco use and human papillomavirus (HPV). HPV E6 oncoprotein leads to p53 degradation, whereas HPV-negative cancers are frequently associated with TP53 mutations. Peposertib is a potent and selective, orally administered small-molecule inhibitor of the catalytic subunit of the DNA-dependent kinase (DNA-PKcs), a key regulator of non-homologous end joining (NHEJ). NHEJ inhibition along with irradiation (IR)-induced DNA double-strand breaks has the potential to increase antitumor treatment efficacy. Here, we investigated the responses of a panel of HNSCC models with distinct HPV and p53 status to treatments with IR, DNA-PKcs inhibition, and their combination in-vitro and in-vivo. IR-induced DNA damage combined with peposertib administration shortly before IR results in decreased cell viability and proliferation and causes DNA repair delay in all studied HNSCC cell lines. However, our data confirm that the actual cell fate upon this treatment is determined by cellular p53 and/or HPV status. Cells lacking functional p53 due to its degradation by HPV or due to a loss-of-function mutation are arrested in the G2/M phase of the cell cycle and eliminated by apoptosis whereas p53-proficient HNSCC cell lines preferentially undergo senescence. This is also recapitulated in-vivo, where HPV+ UD-SCC-2 xenografts display stronger and more durable responses to the combined treatment as compared to p53 wild-type UM-SCC-74A tumors. In conclusion, DNA-PKcs inhibitor peposertib should be further studied as a potential radiosensitizer for HNSCCs, taking into consideration the genetic background and the HPV status of a particular tumor.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142605519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Trastuzumab-MMAU Antibody-Auristatin Conjugates: Valine-Glucoserine Linker with Stabilized Maleimide Conjugation Improves In Vivo Efficacy and Tolerability.","authors":"Shalom D Goldberg, Tero Satomaa, Olulanu Aina, Olli Aitio, Krista Burke, Vadim Dudkin, Brian Geist, Onyi Irrechukwu, Anna-Liisa Hänninen, Annamari Heiskanen, Jari Helin, Jukka O Hiltunen, Jacqueline Kinyamu-Akunda, Donna M Klein, Neeraj Kohli, Titta Kotiranta, Tuula Lähteenmäki, Ritva Niemelä, Virve Pitkänen, Henna Pynnönen, William Rittase, Kristen Wiley, Junguo Zhou, Juhani Saarinen","doi":"10.1158/1535-7163.MCT-23-0591","DOIUrl":"10.1158/1535-7163.MCT-23-0591","url":null,"abstract":"<p><p>Antibody-drug conjugates (ADC) have shown impressive clinical activity with approval of many agents in hematologic and solid tumors. However, challenges remain with both efficacy and safety of ADCs. This study describes novel trastuzumab-auristatin conjugates with the hydrophilic monomethylauristatin E (MMAE) prodrug MMAU, and optimization of a glycopeptide linker leading to a wider therapeutic window. Trastuzumab was conjugated with auristatin payloads via a series of linkers using a stabilized maleimide handle. The ADCs were characterized in vitro and their relative in vivo antitumor efficacies were assessed in HER2+ xenograft models. Relative linker stabilities and the mechanism of linker cleavage were studied using in vitro assays. Toxicity and toxicokinetics of the best performing ADC were evaluated in cynomolgus monkey (cyno). The trastuzumab-MMAU ADC with stabilized glycopeptide linker showed maleimide stabilization and higher resistance to cleavage by serum and lysosomal enzymes compared with a valine-citrulline conjugated trastuzumab ADC (trastuzumab-vc-MMAE). A single dose of 1 or 2 mg/kg of trastuzumab-MMAU at drug-to-antibody ratios (DAR) of eight and four respectively resulted in xenograft tumor growth inhibition, with superior efficacy to trastuzumab-vc-MMAE. Trastuzumab-MMAUDAR4 was tolerated at doses up to 12 mg/kg in cyno, which represents 2- to 4-fold higher dose than that observed with vedotin ADCs, and had increased terminal half-life and exposure. The optimized trastuzumab-MMAU ADC showed potent antitumor activity and was well tolerated with excellent pharmacokinetics in nonhuman primates, leading to a superior preclinical therapeutic window. The data support potential utility of trastuzumab-MMAU for treatment of HER2+ tumors.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1530-1543"},"PeriodicalIF":5.3,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139697853","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor Microenvironment Reprogramming Improves Nanomedicine-Based Chemo-Immunotherapy in Sarcomas.","authors":"Antonia Charalambous, Fotios Mpekris, Myrofora Panagi, Chrysovalantis Voutouri, Christina Michael, Alberto A Gabizon, Triantafyllos Stylianopoulos","doi":"10.1158/1535-7163.MCT-23-0772","DOIUrl":"10.1158/1535-7163.MCT-23-0772","url":null,"abstract":"<p><p>Sarcomas are a heterogeneous group of rare cancers that originate in soft tissues or bones. Their complexity and tendency for metastases make treatment challenging, highlighting the need for new therapeutic approaches to improve patient survival. The difficulties in treating these cancers primarily stem from abnormalities within the tumor microenvironment (TME), which leads to reduced blood flow and oxygen levels in tumors. Consequently, this hampers the effective delivery of drugs to tumors and diminishes treatment efficacy despite higher toxic doses of chemotherapy. In this study, we tested the mechanotherapeutic ketotifen combined with either pegylated liposomal doxorubicin (PLD) or pegylated liposomal coencapsulated alendronate-doxorubicin (PLAD) plus anti-programmed cell death protein 1 antibody in mouse models of fibrosarcoma and osteosarcoma. We found that ketotifen successfully reprogrammed the TME by reducing tumor stiffness and increasing perfusion, proven by changes measured by shear-wave elastography and contrast-enhanced ultrasound, respectively, and enhanced the therapeutic efficacy of our nanomedicine-based chemo-immunotherapy protocols. Furthermore, we observed a trend toward improved antitumor responses when nano-chemotherapy is given alongside anti-programmed cell death protein 1 and when the immunomodulator alendronate was present in the treatment. We next investigated the mechanisms of action of this combination. Ketotifen combined with nanomedicine-based chemo-immunotherapy increased T-cell infiltration, specifically cytotoxic CD8+ T cells and CD4+ T helper cells, and decreased the number of regulatory T cells. In addition, the combination also altered the polarization of tumor-associated macrophages, favoring the M1 immune-supportive phenotype over the M2 immunosuppressive phenotype. Collectively, our findings provide evidence that ketotifen-induced TME reprogramming can improve the efficacy of nanomedicine-based chemo-immunotherapy in sarcomas.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1555-1567"},"PeriodicalIF":5.3,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141469558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"YAP1 Suppression by ZDHHC7 Is Associated with Ferroptosis Resistance and Poor Prognosis in Ovarian Clear Cell Carcinoma.","authors":"Yoko Furutake, Ken Yamaguchi, Koji Yamanoi, Sachiko Kitamura, Shiro Takamatsu, Mana Taki, Masayo Ukita, Yuko Hosoe, Ryusuke Murakami, Kaoru Abiko, Akihito Horie, Junzo Hamanishi, Tsukasa Baba, Noriomi Matsumura, Masaki Mandai","doi":"10.1158/1535-7163.MCT-24-0145","DOIUrl":"10.1158/1535-7163.MCT-24-0145","url":null,"abstract":"<p><p>Ovarian clear cell carcinoma (OCCC), which has unique clinical characteristics, arises from benign endometriotic cysts, forming an oxidative stress environment because of excess iron accumulation, and exhibits poor prognosis, particularly in advanced stages owing to resistance to conventional therapeutics. Ferroptosis is an iron-dependent form of programmed cell death induced by lipid peroxidation and controlled by Hippo signaling. We hypothesized that overcoming ferroptosis resistance is an attractive strategy because OCCC acquires oxidative stress resistance during its development and exhibits chemoresistant features indicative of ferroptosis resistance. This study aimed to determine whether OCCC is resistant to ferroptosis and clarify the mechanism underlying resistance. Unlike ovarian high-grade serous carcinoma cells, OCCC cells were exposed to oxidative stress. However, OCCC cells remained unaffected by lipid peroxidation. Cell viability assays revealed that OCCC cells exhibited resistance to the ferroptosis inducer erastin. Moreover, Samroc analysis showed that the Hippo signaling pathway was enriched in OCCC cell lines and clinical samples. Furthermore, patients with low expression of nuclear yes-associated protein 1 (YAP1) exhibited a significantly poor prognosis of OCCC. Moreover, YAP1 activation enhanced ferroptosis in OCCC cell lines. Furthermore, suppression of zinc finger DHHC-type palmitoyltransferase 7 (ZDHHC7) enhanced ferroptosis by activating YAP1 in OCCC cell lines. Mouse xenograft models demonstrated that ZDHHC7 inhibition suppressed tumor growth via YAP1 activation by erastin treatment. In conclusion, YAP1 activation regulated by ZDHHC7 enhanced ferroptosis in OCCC. Thus, overcoming ferroptosis resistance is a potential therapeutic strategy for OCCC.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1652-1665"},"PeriodicalIF":5.3,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141492666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dual A2A/A2B Adenosine Receptor Antagonist M1069 Counteracts Immunosuppressive Mechanisms of Adenosine and Reduces Tumor Growth In Vivo.","authors":"Kai Schiemann, Natalya Belousova, Armine Matevossian, Kalyan C Nallaparaju, Giorgio Kradjian, Meghana Pandya, Zhouxiang Chen, Esengul Aral, Eva-Maria Krauel, Elissaveta Petrova, Carsten Boesler, Thomas Kitzing, Marc Lecomte, Christian Wagner, Anne Laure Blayo, Stephan Schann, Bayard Huck, Jacques Moisan, Rinat Zaynagetdinov","doi":"10.1158/1535-7163.MCT-23-0843","DOIUrl":"10.1158/1535-7163.MCT-23-0843","url":null,"abstract":"<p><p>While A2A adenosine receptor (AR) was considered as a major contributor to adenosine-mediated immunosuppression, A2B, having the lowest affinity to adenosine, has also emerged as a potential contributor to tumor promotion. Therefore, in adenosine-rich tumor microenvironment (TME), where A2B could be complementary and/or compensatory to A2A, simultaneous targeting of A2A and A2B ARs can provide higher potential for cancer immunotherapy. We developed M1069-a highly selective dual antagonist of the A2A and A2B AR. In assays with primary human and murine immune cells, M1069 rescued IL2 production from T cells (A2A dependent) and inhibited VEGF production by myeloid cells (A2B dependent) in adenosine-high settings. M1069 also demonstrated superior suppression of the secretion of protumorigenic cytokines CXCL1, CXCL5, and rescue of IL12 secretion from adenosine-differentiated dendritic cells compared to an A2A-selective antagonist (A2Ai). In a one-way mixed lymphocyte reaction (MLR) assay, adenosine-differentiated human and murine dendritic cells treated with M1069 demonstrated superior T-cell stimulatory activity compared to dendritic cells differentiated in presence of A2Ai. In vivo, M1069 decreased tumor growth as a monotherapy and enhanced antitumor activity of bintrafusp alfa (BA) or cisplatin in syngeneic adenosinehi/CD73hi 4T1 breast tumor model, but not in the CD73 knockout 4T1 tumor model or in adenosinelow/CD73low MC38 murine colon carcinoma model. In summary, our dual A2A/A2B AR antagonist M1069 may counteract immune-suppressive mechanisms of high concentrations of adenosine in vitro and in vivo and enhance the antitumor activity of other agents, including BA and cisplatin.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1517-1529"},"PeriodicalIF":5.3,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142004819","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SC134-TCB Targeting Fucosyl-GM1, a T Cell-Engaging Antibody with Potent Antitumor Activity in Preclinical Small Cell Lung Cancer Models.","authors":"Foram Dave, Poonam Vaghela, Bryony Heath, Zuzana Dunster, Elena Dubinina, Dhruma Thakker, Katie Mann, Joe Chadwick, Gaëlle Cane, Bubacarr G Kaira, Omar J Mohammed, Ruhul Choudhury, Samantha Paston, Tina Parsons, Mireille Vankemmelbeke, Lindy Durrant","doi":"10.1158/1535-7163.MCT-24-0187","DOIUrl":"10.1158/1535-7163.MCT-24-0187","url":null,"abstract":"<p><p>Small cell lung cancer (SCLC) is an aggressive disease with limited treatment options. Fucosyl-GM1 (FucGM1) is a glycolipid overexpressed in the majority of SCLC tumors but virtually absent from normal healthy tissues. In this study, we validate a FucGM1-targeting T cell-redirecting bispecific (TCB) antibody for the treatment of SCLC. More than 80% of patient-derived xenograft tissues of SCLC expressed FucGM1, whereas only three normal human tissues: pituitary, thymus, and skin expressed low and focal FucGM1. A FucGM1-targeting TCB (SC134-TCB), based on the Fc-silenced humanized SC134 antibody, exhibited nanomolar efficiency in FucGM1 glycolipid and SCLC cell surface binding. SC134-TCB showed potent ex vivo killing of SCLC cell lines with donor-dependent EC50 ranging from 7.2 pmol/L up to 211.0 pmol/L, effectively activating T cells, with picomolar efficiency, coinciding with target-dependent cytokine production such as IFNγ, IL2, and TNFα and robust proliferation of both CD4 and CD8 T cells. The ex vivo SC134-TCB tumor controlling activity translated into an effective in vivo anti-DMS79 tumor therapy, resulting in 100% tumor-free survival in a human peripheral blood mononuclear cell admixed setting and 40% overall survival (55% tumor growth inhibition) with systemically administered human peripheral blood mononuclear cells. Combination treatment with atezolizumab further enhanced survival and tumor growth inhibition (up to 73%). A 10-fold SC134-TCB dose reduction maintained the strong in vivo antitumor impact, translating into 70% overall survival (P < 0.0001). Whole-blood incubation with SC134-TCB, as well as healthy human primary cells analysis, revealed no target-independent cytokine production. SC134-TCB presents an attractive candidate to deliver an effective immunotherapy treatment option for patients with SCLC.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1626-1638"},"PeriodicalIF":5.3,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11532774/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142056057","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}

{"title":"NAD+ Metabolic Enzyme Inhibitor as Radiosensitizer for Malignant Meningioma and its Modulation of P53 Expression.","authors":"Yifan Lv, Yuxuan Deng, Jie Feng, Jinqiu Liu, Mingxu Yang, Zhuonan Pu, Shaodong Zhang, Zhen Wu, Nan Ji, Deric M Park, Shuyu Hao","doi":"10.1158/1535-7163.MCT-23-0632","DOIUrl":"10.1158/1535-7163.MCT-23-0632","url":null,"abstract":"<p><p>Surgical resection followed by radiotherapy (RT) is recommended for malignant meningioma, but poor outcome is unavoidable. To improve the efficacy of RT in malignant meningioma, a targeted radiosensitizer can be added. Nicotinamide phosphoribosyltransferase (NAMPT), highly expressed in high-grade meningiomas, may play a role in determining the radioresponse. Herein, we evaluated the impact of NAMPT inhibition on radiosensitivity in malignant meningioma in vivo and in vitro. IOMM-Lee and TTMM705 cells were treated with NAMPT inhibition (FK866 or shRNA NAMPT) before irradiation. The subsequent clonogenic assay demonstrated significantly increased radiosensitivity. Combination treatment with FK866 and irradiation significantly increased the number of G2/M-phase cells, percentage of apoptotic cells, and γ-H2A.X level compared with FK866 or RT alone. We examined the effect of NAMPT inhibition on NMI and p53 expression in IOMM-Lee and TTMM705 cells. NAMPT inhibition by FK866 and shRNA treatment increased NMI, p53, CDKN1A and BAX expression. Additionally, we assessed the efficacy of FK866/RT combination treatment in vivo. The combination treatment exhibited increased antitumor efficacy compared with either treatment alone. The Ki67 level was significantly lower, and the p53 and γ-H2A.X levels were significantly higher in the combination treatment group than in the other three groups. In conclusion, these results indicate that FK866 improves radiosensitivity in malignant meningioma, an effect that may be attributed to the increase in p53 expression.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1586-1596"},"PeriodicalIF":5.3,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141748632","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}