Journal for Immunotherapy of Cancer最新文献

{"title":"Safety and tolerability of immune checkpoint inhibitors in people with HIV infection and cancer: insights from the national prospective real-world OncoVIHAC ANRS CO24 cohort study.","authors":"Lambert Assoumou, Raghiatou Baldé, Christine Katlama, Baptiste Abbar, Pierre Delobel, Thierry Allegre, Armelle Lavole, Alain Makinson, Olivia Zaegel-Faucher, Laurent Greillier, Cathia Soulie, Marianne Veyri, Mathilde Bertheau, Michèle Algarte Genin, Séverine Gibowski, Anne-Geneviève Marcelin, Kevin Bihan, Marine Baron, Dominique Costagliola, Olivier Lambotte, Jean-Philippe Spano","doi":"10.1136/jitc-2024-009728","DOIUrl":"10.1136/jitc-2024-009728","url":null,"abstract":"<p><strong>Background: </strong>Immune checkpoint inhibitors (ICIs) have been a major advance in cancer management. However, we still lack prospective real-world data regarding their usage in people with HIV infection (PWH).</p><p><strong>Methods: </strong>The ANRS CO24 OncoVIHAC study (NCT03354936) is an ongoing prospective observational cohort study in France of PWH with cancer treated with ICI. We assessed the incidence of grade ≥3 immune-related adverse events (irAEs). All grade ≥3 irAEs were reviewed by an event review.</p><p><strong>Results: </strong>Between January 17, 2018, and December 05, 2023, 150 participants were recruited from 33 sites and 140 were included in this analysis. At the data cut-off date of December 05, 2023, the median follow-up was 9.2 months (IQR: 3.9-18.3), with a total of 126.2 person-years.Median age was 59 years (IQR: 54-64) and 111 (79.3%) were men. Median time since HIV diagnosis was 25 years (12-31), the median duration on antiretroviral (ARV) was 19.5 years (7.7-25.4), and the CD4 nadir was 117/µL (51-240). ICI regimens comprised anti-programmed cell death protein-1 (PD-1) for 111 (79.3%) participants, anti-programmed death-ligand 1 for 25 (17.9%), a combination of anti-PD-1 and anti-cytotoxic T-lymphocyte associated protein 4 for 3 (2.1%), and anti-PD-1 along with anti-vascular endothelial growth factor receptor for 1 (0.7%). The most frequent cancers were lung (n=65), head/neck (n=15), melanoma (n=12), liver (n=11) and Hodgkin's lymphoma (n=9).During follow-up, a total of 34 grade ≥3 irAEs occurred in 20 participants, leading to an incidence rate of 26.9 per 100 person-years. The Kaplan-Meier estimates of the proportion of participants with at least one episode of grade ≥3 irAEs were 13.8% at 6 months, 15.0% at 12 months and 18.7% at 18 months. One treatment-related death due to myocarditis was reported (0.7%). Multivariable analysis of cumulative incidence showed that participants with time since HIV diagnosis >17 years (incidence rate ratio (IRR)=4.66, p=0.002), with CD4<200 cells/µL (IRR=4.39, p<0.0001), with positive cytomegalovirus (CMV) serology (IRR=2.76, p=0.034), with history of cancer surgery (IRR=3.44, p=0.001) had a higher risk of incidence of grade ≥3 irAEs.</p><p><strong>Conclusion: </strong>This study showed that the incidence of a first episode of grade ≥3 irAE was 15.0% (95% CI: 9.6% to 22.9%) at 1 year and the cumulative incidence of all severe irAE episodes was 26.9 per 100 person-years. Low CD4 count, positive CMV serology, history of cancer surgery and a longer time since HIV diagnosis were associated with the occurrence of severe irAEs.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":null,"pages":null},"PeriodicalIF":10.3,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11344510/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142046699","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":"Targeting <i>Gsk3a</i> reverses immune evasion to enhance immunotherapy in hepatocellular carcinoma.","authors":"Xin Zheng, Luyu Yang, Xiaotian Shen, Junjie Pan, Yiran Chen, Jixuan Chen, Hao Wang, Jiaqi Meng, Zhenchao Chen, Sunzhe Xie, Yitong Li, Bolun Zhu, Wenwei Zhu, Lunxiu Qin, Lu Lu","doi":"10.1136/jitc-2024-009642","DOIUrl":"10.1136/jitc-2024-009642","url":null,"abstract":"<p><strong>Background: </strong>Immune escape is an important feature of hepatocellular carcinoma (HCC). The overall response rate of immune checkpoint inhibitors (ICIs) in HCC is still limited. Revealing the immune regulation mechanisms and finding new immune targets are expected to further improve the efficacy of immunotherapy. Our study aims to use CRISPR screening mice models to identify potential targets that play a critical role in HCC immune evasion and further explore their value in improving immunotherapy.</p><p><strong>Methods: </strong>We performed CRISPR screening in two mice models with different immune backgrounds (C57BL/6 and NPG mice) and identified the immunosuppressive gene <i>Gsk3a</i> as a candidate for further investigation. Flow cytometry was used to analyze the impact of <i>Gsk3a</i> on immune cell infiltration and T-cell function. RNA sequencing was used to identify the changes in neutrophil gene expression induced by <i>Gsk3a</i> and alterations in downstream molecules. The therapeutic value of the combination of <i>Gsk3a</i> inhibitors and anti-programmed cell death protein-1 (PD-1) antibody was also explored.</p><p><strong>Results: </strong><i>Gsk3a</i>, as an immune inhibitory target, significantly promoted tumor growth in immunocompetent mice rather than immune-deficient mice. <i>Gsk3a</i> inhibited cytotoxic T lymphocytes (CTLs) function by inducing neutrophil chemotaxis. <i>Gsk3a</i> promoted self-chemotaxis of neutrophil expression profiles and neutrophil extracellular traps (NETs) formation to block T-cell activity through leucine-rich α-2-glycoprotein 1 (LRG1). A significant synergistic effect was observed when <i>Gsk3a</i> inhibitor was in combination with anti-PD-1 antibody.</p><p><strong>Conclusions: </strong>We identified a potential HCC immune evasion target, <i>Gsk3a</i>, through CRISPR screening. <i>Gsk3a</i> induces neutrophil recruitment and NETs formation through the intermediate molecule LRG1, leading to the inhibition of CTLs function. Targeting <i>Gsk3a</i> can enhance CTLs function and improve the efficacy of ICIs.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":null,"pages":null},"PeriodicalIF":10.3,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11340705/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142035922","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":"Treatment with oncolytic vaccinia virus infects tumor-infiltrating regulatory and exhausted T cells.","authors":"Kristin DePeaux, William G Gunn, Dayana B Rivadeneira, Greg M Delgoffe","doi":"10.1136/jitc-2024-009062","DOIUrl":"10.1136/jitc-2024-009062","url":null,"abstract":"<p><strong>Background: </strong>Oncolytic viruses (OVs) are an attractive way to increase immune infiltration into an otherwise cold tumor. While OVs are engineered to selectively infect tumor cells, there is evidence that they can infect other non-malignant cells in the tumor. We sought to determine if oncolytic vaccinia virus (VV) can infect lymphocytes in the tumor and, if so, how this was linked to therapeutic efficacy.</p><p><strong>Methods: </strong>To investigate infection of lymphocytes by VV, we used a GFP reporting VV in a murine head and neck squamous cell carcinoma tumor model. We also performed in vitro infection studies to determine the mechanism and consequences of VV lymphocyte infection by VV.</p><p><strong>Results: </strong>Our findings show that VV carries the capacity to infect proportions of immune cells, most notably T cells, after intratumoral treatment. Notably, this infection is preferential to terminally differentiated T cells that tend to reside in hypoxia. Infection of T cells leads to both virus production by the T cells as well as the eventual death of these cells. Using a mouse model which overexpressed the antiapoptotic protein Bcl2 in all T cells, we found that reducing T cell death following VV infection in MEER tumors reduced the number of complete regressions and reduced survival time compared with littermate control mice.</p><p><strong>Conclusions: </strong>These findings suggest that OVs are capable of infecting more than just malignant cells after treatment, and that this infection may be an important part of the OV mechanism. We found that exhausted CD8+ T cells and regulatory CD4+ T cells were preferentially infected at early timepoints after treatment and subsequently died. When cell death in T cells was mitigated, mice responded poorly to VV treatment, suggesting that the deletion of these populations is critical to the therapeutic response to VV.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":null,"pages":null},"PeriodicalIF":10.3,"publicationDate":"2024-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11331848/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141995763","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":"NR4A ablation improves mitochondrial fitness for long persistence in human CAR-T cells against solid tumors.","authors":"Kensuke Nakagawara, Makoto Ando, Tanakorn Srirat, Setsuko Mise-Omata, Taeko Hayakawa, Minako Ito, Koichi Fukunaga, Akihiko Yoshimura","doi":"10.1136/jitc-2023-008665","DOIUrl":"10.1136/jitc-2023-008665","url":null,"abstract":"<p><strong>Background: </strong>Antitumor effect of chimeric antigen receptor (CAR)-T cells against solid tumors is limited due to various factors, such as low infiltration rate, poor expansion capacity, and exhaustion of T cells within the tumor. NR4A transcription factors have been shown to play important roles in T-cell exhaustion in mice. However, the precise contribution of each NR4a factor to human T-cell differentiation remains to be clarified.</p><p><strong>Methods: </strong>In this study, we deleted NR4A family factors, <i>NR4A1</i>, <i>NR4A2, and NR4A3,</i> in human CAR-T cells recognizing human epidermal growth factor receptor type 2 (HER2) by using the CRISPR/Cas9 system. We induced T-cell exhaustion in these cells in vitro through repeated co-culturing of CAR-T cells with Her2⁺A549 lung adenocarcinoma cells and evaluated cell surface markers such as memory and exhaustion phenotypes, proliferative capacity, cytokine production and metabolic activity. We validated the antitumor toxicity of NR4A1/2/3 triple knockout (TKO) CAR-T cells in vivo by transferring CAR-T cells into A549 tumor-bearing immunodeficient mice.</p><p><strong>Results: </strong>Human NR4A-TKO CAR-T cells were resistant against exhaustion induced by repeated antigen stimulation in vitro, and maintained higher tumor-killing activity both in vitro and in vivo compared with control CAR-T cells. A comparison of the effectiveness of NR4A single, double, and TKOs demonstrated that triple KO was the most effective in avoiding exhaustion. Furthermore, a strong enhancement of antitumor effects by NR4A TKO was also observed in T cells from various donors including aged persons. Mechanistically, NR4A TKO CAR-T cells showed enhanced mitochondrial oxidative phosphorylation, therefore could persist for longer periods within the tumors.</p><p><strong>Conclusions: </strong>NR4A factors regulate CAR-T cell persistence and stemness through mitochondrial gene expression, therefore NR4A is a highly promising target for the generation of superior CAR-T cells against solid tumors.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":null,"pages":null},"PeriodicalIF":10.3,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11331892/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141995762","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":"ALOX5 contributes to glioma progression by promoting 5-HETE-mediated immunosuppressive M2 polarization and PD-L1 expression of glioma-associated microglia/macrophages.","authors":"Tao Chen, Jiangang Liu, Chenci Wang, Zhengwei Wang, Jiayi Zhou, Jiani Lin, Jie Mao, Tingzheng Pan, Jianwei Wang, Hongchao Xu, Xiaosheng He, Dinglan Wu, Zhuohao Liu","doi":"10.1136/jitc-2024-009492","DOIUrl":"10.1136/jitc-2024-009492","url":null,"abstract":"<p><strong>Background: </strong>Oxylipin metabolism plays an essential role in glioma progression and immune modulation in the tumor microenvironment. Lipid metabolic reprogramming has been linked to macrophage remodeling, while the understanding of oxylipins and their catalyzed enzymes lipoxygenases in the regulation of glioma-associated microglia/macrophages (GAMs) remains largely unexplored.</p><p><strong>Methods: </strong>To explore the pathophysiological relevance of oxylipin in human glioma, we performed Ultra-high performance liquid chromatography-MS/MS (UHPLC-MS/MS) analysis in human glioma and non-tumor brain tissues. To comprehensively investigate the role of arachidonate lipoxygenase 5 (ALOX5) in glioma, we performed <i>in vivo</i> bioluminescent imaging, immunofluorescence staining and flow cytometry analysis on tumors from orthotopic glioma-bearing mice. We developed an ALOX5-targeted nanobody, and tested its anti-glioma efficacy of combination therapy with α-programmed cell death protein-1 (PD-1).</p><p><strong>Results: </strong>In this study, we found that ALOX5 and its oxylipin 5-hydroxyeicosatetraenoic acid (5-HETE) are upregulated in glioma, accumulating programmed death-ligand 1 (PD-L1)⁺ M2-GAMs and orchestrating an immunosuppressive tumor microenvironment. Mechanistically, 5-HETE derived from ALOX5-overexpressing glioma cells, promotes GAMs migration, PD-L1 expression, and M2 polarization by facilitating nuclear translocation of nuclear factor erythroid 2-related factor 2. Additionally, a nanobody targeting ALOX5 is developed that markedly suppresses 5-HETE efflux from glioma cells, attenuates M2 polarization of GAMs, and consequently ameliorates glioma progression. Furthermore, the combination therapy of the ALOX5-targeted nanobody plus α-PD-1 exhibits superior anti-glioma efficacy.</p><p><strong>Conclusions: </strong>Our findings reveal a pivotal role of the ALOX5/5-HETE axis in regulating GAMs and highlight the ALOX5-targeted nanobody as a potential therapeutic agent, which could potentiate immune checkpoint therapy for glioma.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":null,"pages":null},"PeriodicalIF":10.3,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11332009/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141982365","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":"Case report of fatal immune-mediated myocarditis following treatment with davoceticept (ALPN-202), a PD-L1-dependent CD28 costimulator and dual PD-L1/CTLA-4 checkpoint inhibitor, in combination with pembrolizumab.","authors":"Ludimila Cavalcante, Sreenivasa Chandana, Nehal Lakhani, Amanda Enstrom, Heidi LeBlanc, Joseph Schmalz, Krisztina Lengyel, Frank Schneider, Heather Thomas, Michael J Chisamore, Stanford L Peng, Allison Naumovski, Diwakar Davar","doi":"10.1136/jitc-2024-009475","DOIUrl":"10.1136/jitc-2024-009475","url":null,"abstract":"<p><p>Engagement of programmed death-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) can interfere with the CD28 signaling requisite for T-cell activation. While immune checkpoint inhibitors (ICIs) can relieve this suppression, they are unable to drive CD28 costimulation that may mechanistically contribute to ICI resistance. Thus, CD28 costimulation in the context of checkpoint inhibition may activate immunosuppressed T-cells in the tumor microenvironment. Davoceticept (ALPN-202) is an Fc fusion of a CD80 variant immunoglobulin domain (vIgD) designed to mediate PD-L1-dependent CD28 costimulation while inhibiting the PD-L1 and CTLA-4 checkpoints. PD-L1-restriction of davoceticept's CD28 costimulatory activity may minimize systemic T-cell activation and avoid untoward systemic toxicities. At the same time, preclinical studies have suggested that treatment with davoceticept during PD-1 inhibition may enhance antitumor activity by upregulating PD-L1, potentially synergizing with davoceticept's PD-L1-dependent costimulatory mechanism. This report details two cases of fatal cardiac events following treatment with davoceticept in combination with pembrolizumab (anti-PD-1) in the phase 1 study, NEON-2. Both events occurred in females in their 60s; one with choroidal melanoma and prior immunotherapy, the other with ICI-naïve microsatellite stable colorectal cancer. The clinical courses were fulminant with symptom onset at 2 weeks, followed by rapid decline. Cardiac autopsy from one patient confirmed immune-related myocarditis, and immunosequencing revealed expansion of a single T-cell clone that was not present in the pretreatment tumor. These cases highlight the importance of understanding risk factors that may contribute to immune-related myocarditis and other severe immune-related adverse events when CD28 agonism is targeted in the context of checkpoint inhibition.NEON-2 (NCT04920383).</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":null,"pages":null},"PeriodicalIF":10.3,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11337706/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141982367","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":"An IL-7 fusion protein targeting EDA fibronectin upregulates TCF1 on CD8+ T-cells, preferentially accumulates to neoplastic lesions, and boosts PD-1 blockade.","authors":"Cesare Di Nitto, Domenico Ravazza, Ettore Gilardoni, Thomas Look, Miaomiao Sun, Eleonora Prodi, Vlad Moisoiu, Christian Pellegrino, Markus G Manz, Emanuele Puca, Michael Weller, Tobias Weiss, Dario Neri, Roberto De Luca","doi":"10.1136/jitc-2023-008504","DOIUrl":"10.1136/jitc-2023-008504","url":null,"abstract":"<p><strong>Background: </strong>Anti-PD-1 antibodies have revolutionized cancer immunotherapy due to their ability to induce long-lasting complete remissions in a proportion of patients. Current research efforts are attempting to identify biomarkers and suitable combination partners to predict or further improve the activity of immune checkpoint inhibitors. Antibody-cytokine fusions are a class of pharmaceuticals that showed the potential to boost the anticancer properties of other immunotherapies. Extradomain A-fibronectin (EDA-FN), which is expressed in most solid and hematological tumors but is virtually undetectable in healthy adult tissues, is an attractive target for the delivery of cytokine at the site of the disease.</p><p><strong>Methods: </strong>In this work, we describe the generation and characterization of a novel interleukin-7-based fusion protein targeting EDA-FN termed F8(scDb)-IL7. The product consists of the F8 antibody specific to the alternatively spliced EDA of FN in the single-chain diabody (scDb) format fused to human IL-7.</p><p><strong>Results: </strong>F8(scDb)-IL7 efficiently stimulates human peripheral blood mononuclear cells in vitro. Moreover, the product significantly increases the expression of T Cell Factor 1 (TCF-1) on CD8+T cells compared with an IL2-fusion protein. TCF-1 has emerged as a pivotal transcription factor that influences the durability and potency of immune responses against tumors. In preclinical cancer models, F8(scDb)-IL7 demonstrates potent single-agent activity and eradicates sarcoma lesions when combined with anti-PD-1.</p><p><strong>Conclusions: </strong>Our results provide the rationale to explore the combination of F8(scDb)-IL7 with anti-PD-1 antibodies for the treatment of patients with cancer.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":null,"pages":null},"PeriodicalIF":10.3,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11332014/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141982366","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":"Targeting TNFRSF25 by agonistic antibodies and multimeric TL1A proteins co-stimulated CD8⁺ T cells and inhibited tumor growth.","authors":"Xueyuan Lyu, Linlin Zhao, Sijia Chen, Yulu Li, Yajing Yang, Huisi Liu, Fang Yang, Wenhui Li, Jianhua Sui","doi":"10.1136/jitc-2024-008810","DOIUrl":"10.1136/jitc-2024-008810","url":null,"abstract":"<p><strong>Background: </strong>Tumor necrosis factor receptor superfamily 25 (TNFRSF25) is a T-cell co-stimulatory receptor. Expression of its ligand, TNF-like cytokine 1A (TL1A), on mouse tumor cells has been shown to promote tumor regression. This study aimed to develop TNFRSF25 agonists (both antibodies (Abs) and TL1A proteins) and to investigate their potential antitumor effects.</p><p><strong>Methods: </strong>Anti-mouse TNFRSF25 (mTNFRSF25) Abs and multimeric TL1A proteins were generated as TNFRSF25 agonists. Their agonism was assessed in luciferase reporter and T-cell co-stimulation assays, and their antitumor effects were evaluated in syngeneic mouse tumor models. TNFRSF25 expression within the tumor microenvironment and the effects of an anti-mTNFRSF25 agonistic Ab on tumor-infiltrating T cells were evaluated by flow cytometry. Cell depletion assays were used to identify the immune cell types that contribute to the antitumor effect of the anti-mTNFRSF25 Ab. The Fc gamma receptor (FcγR) dependence of TNFRSF25 agonists was assessed in an <i>in vivo</i> T-cell expansion model and a mouse tumor model using Fc variants and FcγR-deficient mice.</p><p><strong>Results: </strong>TNFRSF25 agonists exhibited antitumor effects in syngeneic mouse tumor models without causing observed side effects. We identified an anti-mTNFRSF25 agonistic Ab, 1A6-m1, which exhibited greater antitumor activity than a higher affinity anti-TNFRSF25 Ab which engages an overlapping epitope with 1A6-m1. 1A6-m1 activated CD8⁺ T cells and antigen-specific T cells, leading to tumor regression; it also induced long-term antitumor immune memory. Although activating TNFRSF25 by 1A6-m1 expanded splenic regulatory T (Treg) cells, it did not influence intratumoral Treg cells. Moreover, 1A6-m1's antitumor effects required the engagement of both inhibitory FcγRIIB and activating FcγRIII. Replacing 1A6-m1's CH1-hinge region with that of human IgG2 (h2) conferred enhanced antitumor effects. Finally, we also generated multimeric human and mouse TL1A fusion proteins as TNFRSF25 agonists, and they co-stimulated CD8⁺ T cells and reduced tumor growth, even in the absence of Fc-FcγR interactions.</p><p><strong>Conclusion: </strong>Our data demonstrates the potential of activating TNFRSF25 by Abs and multimeric TL1A proteins for cancer immunotherapy and provides insights into their development astherapeutics.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":null,"pages":null},"PeriodicalIF":10.3,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11331879/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141982368","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":"Five-year follow-up of neoadjuvant PD-1 inhibitor (sintilimab) in non-small cell lung cancer.","authors":"Bolun Zhou, Fan Zhang, Wei Guo, Shuhang Wang, Ning Li, Bin Qiu, Liang Zhao, Jian Li, Kang Shao, Qi Xue, Fang Lv, Shugeng Gao","doi":"10.1136/jitc-2024-009355","DOIUrl":"10.1136/jitc-2024-009355","url":null,"abstract":"<p><strong>Background: </strong>Neoadjuvant anti-programmed cell death protein-1 (PD-1) therapy exhibits potential in treating resectable non-small cell lung cancer (NSCLC). Previously, we have reported the 3-year clinical outcomes of this trial, implying the effectiveness and feasibility of neoadjuvant sintilimab monotherapy. However, the long-term prognosis of patients receiving neoadjuvant mono-immunotherapy has yet to be elucidated.</p><p><strong>Methods: </strong>For patients with stage IA-IIIB NSCLC, two doses of sintilimab (200 mg) were administered intravenously in the neoadjuvant setting. The 5-year event-free survival (EFS), disease-free survival (DFS), and overall survival (OS) were assessed in these updated results. The predictive role of specific biomarkers in neoadjuvant immunotherapy was also explored.</p><p><strong>Results: </strong>With a median follow-up of 61.0 months, 5-year DFS and OS rates of patients who underwent R0 resection were 65.7% and 80.4%, respectively. The 5-year DFS and OS rates of patients with positive programmed death-ligand 1 (PD-L1) expression were 71.9% and 90.9%, respectively. The presence of PD-L1 positivity (tumor proportion score ≥1%) showed a tendency toward the promising prognosis (OS, HR, 0.143; 95% CI: 0.027 to 0.743), especially for those who did not achieve pathological complete response (pCR). In addition, tumor mutation burden was positively correlated with a favorable prognosis. A total of 10 recurrences and 5 subsequent deaths were identified within the 5-year follow-up, with lung metastasis being the predominant.</p><p><strong>Conclusions: </strong>These updated analyses were the first to unveil the 5-year survival benefits of neoadjuvant sintilimab monotherapy, implying the potential value of PD-1 inhibitors in neoadjuvant therapy.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":null,"pages":null},"PeriodicalIF":10.3,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11331958/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141971150","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":"Epithelium/imcDC2 axis facilitates the resistance of neoadjuvant anti-PD-1 in human NSCLC.","authors":"Yongyuan Chen, Zheyu Shao, Zhixing Hao, Zhongwei Xin, Xiaoke Chen, Lijian Huang, Di Chen, Mingjie Lin, Qinyuan Liu, Xia Xu, Jinfan Li, Dang Wu, Jun Yan, Ying Chai, Pin Wu","doi":"10.1136/jitc-2023-007854","DOIUrl":"10.1136/jitc-2023-007854","url":null,"abstract":"<p><strong>Background: </strong>Therapeutic resistance is a main obstacle to achieve long-term benefits from immune checkpoint inhibitors. The underlying mechanism of neoadjuvant anti-PD-1 resistance remains unclear.</p><p><strong>Methods: </strong>Multi-omics analysis, including mass cytometry, single-cell RNA-seq, bulk RNA-seq, and polychromatic flow cytometry, was conducted using the resected tumor samples in a cohort of non-small cell lung cancer (NSCLC) patients received neoadjuvant anti-PD-1 therapy. Tumor and paired lung samples acquired from treatment-naïve patients were used as a control. In vitro experiments were conducted using primary cells isolated from fresh tissues and lung cancer cell lines. A Lewis-bearing mouse model was used in the in vivo experiment.</p><p><strong>Results: </strong>The quantity, differentiation status, and clonal expansion of tissue-resident memory CD8+ T cells (CD8+ TRMs) are positively correlated with therapeutic efficacy of neoadjuvant anti-PD-1 therapy in human NSCLC. In contrast, the quantity of immature CD1c+ classical type 2 dendritic cells (imcDC2) and galectin-9+ cancer cells is negatively correlated with therapeutic efficacy. An epithelium/imDC2 suppressive axis that restrains the antitumor response of CD8+ TRMs via galectin-9/TIM-3 was uncovered. The expression level of CD8+ TRMs and galectin-9+ cancer cell-related genes predict the clinical outcome of anti-PD-1 neoadjuvant therapy in human NSCLC patients. Finally, blockade of TIM-3 and PD-1 could improve the survival of tumor-bearing mouse by promoting the antigen presentation of imcDC2 and CD8+ TRMs-mediated tumor-killing.</p><p><strong>Conclusion: </strong>Galectin-9 expressing tumor cells sustained the primary resistance of neoadjuvant anti-PD-1 therapy in NSCLC through galectin-9/TIM-3-mediated suppression of imcDC2 and CD8+ TRMs. Supplement of anti-TIM-3 could break the epithelium/imcDC2/CD8+ TRMs suppressive loop to overcome anti-PD-1 resistance.</p><p><strong>Trial registration number: </strong>NCT03732664.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":null,"pages":null},"PeriodicalIF":10.3,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11332012/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141971149","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}