Journal for Immunotherapy of Cancer最新文献

{"title":"Intratumoral and peritumoral radiomics of MRI predicts pathologic complete response to neoadjuvant chemoimmunotherapy in patients with head and neck squamous cell carcinoma.","authors":"Jie Sun, Xuewei Wu, Ruhang Ma, Shuixing Zhang, Bin Zhang","doi":"10.1136/jitc-2024-011189","DOIUrl":"https://doi.org/10.1136/jitc-2024-011189","url":null,"abstract":"","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11749613/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143023459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New developments in immunotherapy for SCLC.","authors":"Tsering Dolkar, Christopher Gates, Zhonglin Hao, Reinhold Munker","doi":"10.1136/jitc-2024-009667","DOIUrl":"10.1136/jitc-2024-009667","url":null,"abstract":"<p><p>Small cell lung cancer (SCLC) is an aggressive form of neuroendocrine neoplasm known for its striking initial response to treatment, followed by fast relapse and refractoriness in response to additional lines of therapy. New advances in immunotherapy are paving the way for more effective treatment strategies and have promising results with early clinical trial data. While SCLC rarely harbors actionable mutations, the receptor DLL3 is extensively present in SCLC, making it a potential target for immunotherapy. Three emerging therapeutic options include bispecific T cell engagers targeting DLL3, chimeric antigen receptor T cells (CAR-T cells), and antibody-drug conjugates. Several phase II and phase III clinical trials for bispecific T cell engagers show promise. Additionally, the first CAR-T cell trials in humans for SCLC are currently underway.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11748767/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142949207","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel and potent MICA/B antibody is therapeutically effective in <i>KRAS LKB1</i> mutant lung cancer models.","authors":"Ryan R Kowash, Manoj Sabnani, Laura T Gray, Qing Deng, Nusrat U A Saleh, Luc Girard, Yujiro Naito, Kentaro Masahiro, John D Minna, David E Gerber, Shohei Koyama, Zhiqian Lucy Liu, Hemanta Baruah, Esra A Akbay","doi":"10.1136/jitc-2024-009867","DOIUrl":"10.1136/jitc-2024-009867","url":null,"abstract":"<p><strong>Background: </strong>Concurrent <i>KRAS LKB1</i> (STK11, KL) mutant non-small cell lung cancers (NSCLC) do not respond well to current immune checkpoint blockade therapies, however targeting major histocompatibility complex class I-related chain A or B (MICA/B), could pose an alternative therapeutic strategy through activation of natural killer (NK) cells.</p><p><strong>Methods: </strong>Expression of NK cell activating ligands in NSCLC cell line and patient data were analyzed. Cell surface expression of MICA/B in NSCLC cell lines was determined through flow cytometry while ligand shedding in both patient blood and cell lines was determined through ELISA. We engineered an antibody-dependent cellular cytotoxicity (ADCC) enhanced MICA/B monoclonal antibody, AHA-1031, which prevents ligand shedding without interfering with binding to natural killer group 2D while targeting cancer cells via superior ADCC. We performed in vitro assays using ELISA and flow cytometry-based assays to confirm that our antibody potently binds to and stabilizes MICA/B expression across lung cancer and other solid tumor cell lines. Additionally, we used two KL mutant NSCLC cell lines and a KL mutant patient-derived xenograft (PDX) model to demonstrate in vivo antitumor efficacy and flow cytometry analysis for immune cell activation profiling.</p><p><strong>Results: </strong>NSCLC cell lines exhibit high MICA/B expression and secrete soluble MICA/B in vitro. Soluble MICA/B is also detected in patient blood samples. AHA-1031 binds to the α3 domain of MICA/B, preventing shedding and targeting tumor cells to ADCC. AHA-1031 exhibits high affinity and specificity to MICA/B, preventing MICA/B shedding in tumor lines and inducing ADCC in vitro. Our antibody also effectively binds and stabilizes MICA/B expression in additional tumor types and demonstrates broad specificity. We show that in two KL mutant NSCLC xenograft models and a KL mutant PDX model, treatment with AHA-1031 monotherapy significantly inhibits tumor growth compared with vehicle-treated animals with no observable toxicity. Tumor tissues from treated mice exhibit significantly increased immune cell infiltrates and activated NK cell populations.</p><p><strong>Conclusions: </strong>Activating NK cells through MICA/B stabilization and inducing ADCC offers an alternative and potent therapy option in KL tumors. MICA/B are shed across different tumors making this therapeutic strategy universally applicable.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11749492/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142949211","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anti-PD-1 amplifies costimulation in melanoma-infiltrating T_h1-like Foxp3⁺ regulatory T cells to alleviate local immunosuppression.","authors":"Mikhaël Attias, Fernando Alvarez, Tho-Alfakar Al-Aubodah, Roman Istomine, Paige McCallum, Fan Huang, Abrahim Sleiman, Tamiko Nishimura, Sonia V Del Rincón, Yasser Riazalhosseini, Ciriaco A Piccirillo","doi":"10.1136/jitc-2024-009435","DOIUrl":"10.1136/jitc-2024-009435","url":null,"abstract":"<p><strong>Background: </strong>Immune checkpoint inhibitors targeting programmed cell death protein-1 (PD-1) are the first line of treatment for many solid tumors including melanoma. PD-1 blockade enhances the effector functions of melanoma-infiltrating CD8⁺ T cells, leading to durable tumor remissions. However, 55% of patients with melanoma do not respond to treatment. As Foxp3⁺ regulatory T (T_reg) cells play an important role in tumor-induced immunosuppression and express PD-1, we hypothesized that anti-PD-1 also increases the functions of melanoma-infiltrating T_reg cells, which could be detrimental to treatment efficacy.</p><p><strong>Methods: </strong>The cellular and functional dynamics of T_reg cells were evaluated in C57Bl/6 Foxp3-reporter mice bearing highly immunogenic and PD-1 blockade-sensitive Yale University Mouse Melanoma Exposed to Radiation 1.7 (YUMMER1.7) tumors. T_reg cell responses in tumors and lymphoid compartments were examined throughout tumor growth or therapy and were assessed ex vivo by multiparametric flow cytometry analysis, with in vitro suppression assays using tumor-infiltrating lymphocytes isolated by fluorescence-activated cell sorting (FACS) and <i>in situ</i> through spatial proteomic and transcriptomic profiling.</p><p><strong>Results: </strong>In this highly immunogenic melanoma model, anti-PD-1 monotherapy yielded high responders (HRs) and low responders (LRs). We show that the potent CD8⁺ T cell responses characteristic of HR tumors paradoxically coincide with the expansion of highly-activated, Helios-expressing T_reg cells. In both HRs and LRs, T_reg cells co-localize with CD8⁺ T cells in immunogenic regions of the tumor and display potent suppressive capacity in vitro. Further characterization revealed that melanoma-infiltrating T_reg cells progressively acquire T-bet and interferon gamma expression, exclusively in HRs, and induction of this T helper cell 1 (T_h1)-like phenotype in vitro led to CD8⁺ T cell evasion from T_reg cell-mediated suppression. Using spatial proteomic and transcriptomic profiling, we demonstrate that T_reg cells display an increased activity of PI3K/Akt signaling in regions of HR tumors with an elevated CD8:T_reg cell ratio.</p><p><strong>Conclusions: </strong>PD-1 blockade promotes the expansion of a subset of highly-activated T_reg cells coexpressing PD-1 and Helios. While these cells are potently suppressive outside tumor environments, costimulatory and inflammatory signals present in the tumor microenvironment lead to their local acquisition of T_h1-like characteristics and loss of suppression of effector T cells.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11748786/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143005620","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GP73 reinforces cytotoxic T-cell function by regulating HIF-1α and increasing antitumor efficacy.","authors":"Jialong Liu, Chao Feng, Ruzhou Zhao, Hongbin Song, Linfei Huang, Nan Jiang, Xiaopan Yang, Lanlan Liu, Cuijuan Duan, Luming Wan, Qi Gao, Lijuan Sun, Xufeng Hou, Muyi Liu, Yanhong Zhang, Xuemiao Zhang, Dandan Zhang, Yufei Wang, Yong Li, Xueping Ma, Hui Zhong, Min Min, Congwen Wei, Yuan Cao, Xiaoli Yang","doi":"10.1136/jitc-2024-009265","DOIUrl":"10.1136/jitc-2024-009265","url":null,"abstract":"<p><strong>Background: </strong>Immunotherapy that targets immune checkpoints has achieved revolutionary success, but its application in solid tumors remains limited, highlighting the need for reliable enhancement of the efficacy of immunotherapy. Golgi protein 73 (GP73), a Golgi membrane protein, has been implicated in various cellular processes, including immune regulation. Recent studies suggested that GP73 may play a role in modulating the immune response in patients with cancer. In this study, we investigated the mechanism by which GP73 regulates T-cell-mediated antitumor immunity within the tumor microenvironment.</p><p><strong>Methods: </strong>We used T-cell specific GP73 knockout mice to establish MC38 and B16 tumor models to investigate the impact of GP73-deficient T cells on tumor growth. Single-cell sequencing was subsequently employed to classify tumor-infiltrating immune cells and assess changes in cytokines and metabolic genes. Through RNA sequencing, real-time quantitative PCR, western blotting, flow cytometry, seahorse analysis, glucose uptake, and L-lactic acid secretion assays, we explored how GP73 regulates hypoxia-inducible factor 1α (HIF-1α) to influence T-cell antitumor functionality. Furthermore, we established adoptive transfer experiments to study the ability of GP73-overexpressing T cells to combat tumors. Blood samples of patient with clinical tumor were collected to assess the relationship between immunotherapy efficacy and T-cell GP73 levels.</p><p><strong>Results: </strong>In this study, the absence of GP73 in mouse T cells promoted tumor growth and metastasis, accompanied by a decrease in the proportion of cytotoxic CD8+T cell subsets infiltrating the tumor and an increase in exhausted CD8+ T-cell subsets. Further analysis revealed that the effector function of CD8+T cells in tumors relies on glycolysis regulated by HIF-1α rather than immune checkpoints. GP73-deficient T cells exhibit severely impaired glycolysis in hypoxic environments, whereas ectopic GP73 expression restores HIF-1α levels. In adoptive immunotherapy, overexpression of GP73 in T cells inhibits tumor growth. In cytotoxicity assays, knockdown of GP73 affected the ability of CD8+T cells to kill target cells. Clinically, tumor immunotherapy partial response patients present significantly elevated levels of GP73 expression in T cells.</p><p><strong>Conclusions: </strong>These findings reveal the role of GP73 in regulating T-cell glycolysis and may lead to new therapeutic strategies for the prognosis and treatment of clinical tumor immunotherapy.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11749480/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143005670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lethal clinical outcome and chemotherapy and immunotherapy resistance in patients with urothelial carcinoma with MDM2 amplification or overexpression.","authors":"Kaifeng Jin, Yawei Ding, Jingtong Xu, Zhaopei Liu, Han Zeng, Xiaohe Su, Lingkai Zhang, Jiaxing Sun, Yuzhen Wu, Hailong Liu, Yuan Chang, Yu Zhu, Zewei Wang, Le Xu, Weijuan Zhang, Jiejie Xu","doi":"10.1136/jitc-2024-010964","DOIUrl":"10.1136/jitc-2024-010964","url":null,"abstract":"<p><strong>Background: </strong>The E3 ubiquitin ligase murine double minute 2 (MDM2) binds the p53 transcriptional activation domain and acts as a potent inhibitor of <i>TP53</i> pathway, one of the three most crucial oncogenic pathways in urothelial carcinoma (UC). However, the clinical significance and impact on tumor immune contexture of <i>MDM2</i> amplification in UC remain unclear.</p><p><strong>Methods: </strong>This study analyzed 240 patients with UC with matched clinical annotations from two local cohorts (ZSHS cohort and FUSCC cohort). We assessed the correlation between <i>MDM2</i> status and clinical outcomes, therapeutic efficacy, and immunological characteristics by immunohistochemical analysis and targeted sequencing. Additionally, 2264 UC samples from five independent external cohorts, with genomic, transcriptomic, and clinical data, were used for validation.</p><p><strong>Results: </strong><i>MDM2</i> amplification (<i>MDM2</i> ^Amp) or protein overexpression (MDM2^OE) was associated with inferior overall survival (ZSHS cohort, Log-rank p<0.001; FUSCC cohort, Log-rank p=0.030) and reduced response to platinum-based chemotherapy (ZSHS cohort, Log-rank p<0.001) as well as anti-PD-1/PD-L1 immunotherapy (FUSCC cohort, Log-rank p=0.016) in patients with UC, irrespective of <i>TP53</i>/p53 status. <i>MDM2</i> amplification or overexpression was further linked to high-grade UC tumors with dedifferentiated morphology. In addition, UC with <i>MDM2</i> amplification or overexpression was associated with an immuno-evasive contexture characterized by lower proportion of tertiary lymphoid structure infiltration, lower abundance of CD8⁺ T cells, IFN-γ⁺ cells, GZMB⁺ cells, and decreased expression of immune checkpoint molecules including programmed death-ligand 1 (PD-L1), programmed death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4).</p><p><strong>Conclusions: </strong><i>MDM2</i> amplification or overexpression defines a lethal subset of patients with UC with inferior prognosis and resistance to both platinum-based chemotherapy and immunotherapy irrespective of <i>TP53</i>/p53 status. These tumors are characterized by dedifferentiated morphology and an immunosuppressive microenvironment. Accurate assessment of <i>MDM2</i> status can improve risk stratification and enable personalized genomics-guided treatment for patients with UC.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11749520/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143005693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CREB3L1 facilitates pancreatic tumor progression and reprograms intratumoral tumor-associated macrophages to shape an immunotherapy-resistance microenvironment.","authors":"Haiyan Xu, Shengbai Xue, Yang Sun, Jingyu Ma, Shumin Li, Yanling Wang, Tiebo Mao, Weiyu Ge, Ming Yue, Daiyuan Shentu, Wenxin Lu, Yongchao Wang, Jiong Hu, Jiujie Cui, Xiaofei Zhang, Li Cai, Yu Wang, Liwei Wang","doi":"10.1136/jitc-2024-010029","DOIUrl":"10.1136/jitc-2024-010029","url":null,"abstract":"<p><strong>Background: </strong>To date, a growing body of evidence suggests that unfolded protein response (UPR) sensors play a vital role in carcinogenesis. However, it remains unclear whether they are involved in pancreatic ductal adenocarcinoma (PDAC) and how they relate to clinical outcomes. This study aims to investigate the biological function and mechanism of how a novel UPR sensor, CREB3L1 works in PDAC and further evaluate its clinical application prospect.</p><p><strong>Methods: </strong>We tested UPR signaling including CREB3L1 in Thapsigargin-treated PDAC cells. Subsequently, we defined CREB3L1 expression and further analyzed its expression with clinical characteristics in PDAC. Then, we established gene-modified cells to determine whether CREB3L1 functions in cell proliferation and migration capacity. Besides, we constructed subcutaneously and orthotopically transplanted mice models to verify their progrowing function and pulmonary metastasis models to prove their proinvasion role. What's more, RNAseq, qPCR, Western blotting, immunohistochemistry and multicolor flow cytometry experiments were used to explore the mechanism of how CREB3L1 worked in PDAC. Lastly, CREB3L1 expression correlation with PDAC immunotherapy outcome and immune cell signatures were explored in the patients with advanced PDAC who received PD-1 antibody therapy.</p><p><strong>Results: </strong>We first confirmed CREB3L1 could be induced by endoplasmic reticulum stressor and found its aberrant activation was associated with poorer overall survival in PDAC patients indicating the protumor function of the new UPR sensor. Functionally, we confirmed CREB3L1 contributing to PDAC malignant progression including growth and metastasis by multiple in in vitro and in vivo models. Mechanistically, CREB3L1 upregulated COL3A1 and promoted dense stroma formation for facilitating PDAC and knocking down COL3A1 disrupted CREB3L1 protumor function. Furthermore, CREB3L1-induced TAM polarization toward an M2 phenotype and reduced the infiltration of CD8⁺ T cells. Clinically, CREB3L1 correlated with immune cell signatures as well as immune checkpoint blockade (ICB) treatment response and outcome that CREB3L1aberrant activation indicated poorer efficacy and worse prognosis than the low in PDAC which might empower clinical decision.</p><p><strong>Conclusions: </strong>Collectively, this study revealed CREB3L1 facilitated PDAC progression, shaped an immune exclude tumor microenvironment and distinguished therapy response and outcome of ICB therapy indicating CREB3L1 could be a promising novel molecular target and biomarker for PDAC treatment.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11749327/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143005594","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"XCL1-secreting CEA CAR-T cells enhance endogenous CD8⁺ T cell responses to tumor neoantigens to confer a long-term antitumor immunity.","authors":"Xing-Ning Li, Feifei Wang, Kun Chen, Zhiyuan Wu, Ruochan Zhang, Chentong Xiao, Fei Zhao, Dongmei Wang, Hong Zhao, Yuliang Ran, Chunfeng Qu","doi":"10.1136/jitc-2024-010581","DOIUrl":"10.1136/jitc-2024-010581","url":null,"abstract":"<p><strong>Background: </strong>Therapeutic efficacy of carcinoembryonic antigen (CEA)-specific chimeric antigen receptor (CAR) T cells against colorectal cancer (CRC) remains limited due to the unique characteristics and distinct microenvironments of tumor tissues. We modified CEA-specific CAR-T cells, aiming to stimulate endogenous CD8⁺ T cell responses against neoantigens that were derived from CEA-positive tumors destroyed by the CAR T cells.</p><p><strong>Methods: </strong>In a conventional CEA CAR (reg-CAR), we modified it to express lymphotactin XCL1 and interleukin (IL)-7 genes, constructing a modified 7XCL1-CAR. By generating the CEA-specific 7XCL1-CAR T cells, we assessed their antitumor efficacy against CRC cells with varying levels of CEA expression, both in cell-cultures and in two strains of tumor-bearing syngeneic mice.</p><p><strong>Results: </strong>Following retroviral transduction, 7XCL1-CAR T cells and reg-CAR T cells exhibited similar positive proportions of CEA-CAR and CD4:CD8 ratios. In co-culture system with CEA-negative CT26 cells, no differences in cytotoxicity were observed between 7XCL1-CAR and reg-CAR T cells. However, in co-culture with CT26.CEA^high and CT26.CEA^int cells, 7XCL1-CAR T cells displayed higher cytotoxicity than that reg-CAR T cells after 60 hours. On interaction with CT26.CEA-positive cells, 7XCL1-CAR T cells secreted higher levels of XCL1 and IL-7, effectively recruited the most potent cross-presenting cDC1s (type-I conventional dendritic cells), and sustained the antitumor activity of CAR-T cells. In treating mice that carried tumors derived from universally CEA-positive cells, 7XCL1-CAR T cells exhibited no difference compared with reg-CAR T cells. However, in treating mice with tumors containing both CEA-positive and CEA-negative cells, 7XCL1-CAR T cells displayed greater inhibition than that of reg-CAR-T cells. After treatment of 7XCL1-CAR T cells, tumor-bearing mice exhibited enhanced infiltration of cDC1s, maintained CAR-T activity, and generation of endogenous neoantigen-specific T cells. Consequently, 7XCL1-CAR T cell-treated mice demonstrated resistance to challenge with CEA-negative CT26 cells.</p><p><strong>Conclusion: </strong>Treatment with CEA-specific, XCL1-secreting CAR-T cells for CEA-positive tumors promoted the generation of CD8⁺ T cells against tumor neoantigens, mediating a long-term antitumor immunity against heterogeneous CRCs.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11749649/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143005727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lipid metabolic remodeling delays senescence of T cells to potentiate their immunity against solid tumors.","authors":"Yemin Xu, Li Ding, Mengyue Wu, Xiya Wang, Lu Wang, Zhou Xu, Yinhe Xia, Zhennan Cao, Yanqing Zhang, Ruilong Song, Bin Deng, Gang Chen","doi":"10.1136/jitc-2024-010403","DOIUrl":"10.1136/jitc-2024-010403","url":null,"abstract":"<p><strong>Background: </strong>Tumor cells can drive the senescence of effector T cells by unbalancing their lipid metabolism, thereby limiting adoptive T cell therapy and contributing to tumor immune evasion. Our objective is to provide a feasible strategy for enhancing T cell treatment efficacy against solid tumors.</p><p><strong>Methods: </strong>In this study, liposomal arachidonyl trifluoromethyl ketone (ATK) was anchored onto the adoptive T cell surface via bioorthogonal reactions, aiming to specifically inhibit the group IVA cytosolic phospholipase A₂α (cPLA₂α), a key enzyme facilitating phospholipid metabolism and senescent state of T cells.</p><p><strong>Results: </strong>The surface engineering exerted rare side effects on the activation and migration of T cells, but local and sustained extravasation of ATK downregulated cPLA2α expression, reprogrammed lipid metabolism, and inhibited lipid droplet accumulation. This endows T cells with delayed senescence and declined apoptosis to maintain their tumor-killing potency. Systemic administration of surface-engineered T cells resulted in superior infiltration in solid tumors and improved antitumor efficacy by enhancing the secretion of cytotoxic molecules, thereby prolonging the survival of mice bearing colorectal carcinoma and melanoma xenografts.</p><p><strong>Conclusions: </strong>Lipid-metabolically remodeled T cells with delayed senescence increase efficacy in tumor microenvironment, highlighting a novel strategy for solid tumor immunotherapy.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11749770/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143005701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nivolumab plasma concentration and clearance associated with overall survival in patients with renal cell carcinoma.","authors":"Christophe Maritaz, David Combarel, Cécile Dalban, Louis Blondel, Sophie Broutin, Aurelien Marabelle, Laurence Albiges, Angelo Paci","doi":"10.1136/jitc-2024-010059","DOIUrl":"10.1136/jitc-2024-010059","url":null,"abstract":"<p><strong>Background: </strong>Nivolumab is an immune checkpoint inhibitor (ICI) that selectively inhibits programmed cell death protein 1 activation, restoring antitumor immunity. ICIs are indicated for various types of advanced solid tumors; however, not all patients benefit from them, and tools that could be used in the clinic to predict response to treatment represent an unmet need. Here we describe the development of a new population pharmacokinetic (PPK) model in patients treated with nivolumab in clinical trials. Applying the model to a patient population with renal cell carcinoma identified nivolumab clearance and plasma concentration as predictors of overall survival (OS).</p><p><strong>Methods: </strong>A custom liquid chromatography with tandem mass spectrometry method for quantifying nivolumab plasma concentration was developed and validated following the European Medicines Agency guidelines for bioanalytical method validation. The PPK model was developed using data from patients treated in the NIVIPIT (n=38) and NIVOREN (n=137) trials of nivolumab in metastatic melanoma and renal cell carcinoma, respectively. The PPK model was used to determine pharmacokinetic (PK) parameters such as baseline clearance and simulate individual clearance changes over time. The relationship between PK characteristics (including clearance at Cycle 1 (CLC1), plasma concentration at Cycle 3 and clinical outcomes was assessed in 137 patients treated in NIVOREN. Kaplan-Meier methodology was used in time-to-event analyses.</p><p><strong>Results: </strong>In 137 patients, the median nivolumab CLC1 was 6 mL/hour and the median plasma concentration at Cycle 3 was 48 µg/mL. Median follow-up was 21.0 months (95% CI 20.2 to 22.5 months) with a survival rate at 6 months of 91.2% and 77.9% at 12 months. In univariate analysis, OS was significantly higher in patients with CLC1<6 mL/hour versus ≥6 mL/hour (HR 2.2 (95% CI 1.2 to 4.1), p=0.0146). Shorter OS was observed in patients with plasma concentration at Cycle 3 below the median (48 µg/mL) versus those above the median (HR 0.4 (95% CI 0.2 to 0.8), p=0.0069). Multivariate analysis showed a trend towards lower clearance, but this did not reach statistical significance (p=0.0694).</p><p><strong>Conclusions: </strong>Results of the study may potentially be used to predict outcomes of nivolumab therapy in patients with renal cell carcinoma. Additional applications may include guiding dose adjustments of nivolumab in those who are less likely to respond to the initial dose.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11749330/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143005705","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}