Journal for Immunotherapy of Cancer最新文献

{"title":"Topical TLR7 agonist and radiotherapy in patients with metastatic breast cancer.","authors":"Sylvia Adams, Sandra Demaria, Darawan Rinchai, Ena Wang, Yelena Novik, Ruth Oratz, Maria Fenton-Kerimian, Pascale G Levine, Xiaochun Li, Francesco Marincola, Ping Jin, David Stroncek, Judith Goldberg, Davide Bedognetti, Silvia Chiara Formenti","doi":"10.1136/jitc-2024-011173","DOIUrl":"10.1136/jitc-2024-011173","url":null,"abstract":"<p><strong>Background: </strong>Toll-like receptor (TLR) agonists and radiation therapy hold promise for cancer immunotherapy. We conducted a phase I/II trial combining topical imiquimod (IMQ, a TLR-7 agonist) and local radiotherapy (RT) in patients with metastatic breast cancer accompanied by longitudinal transcriptional analysis of tumor biopsies.</p><p><strong>Methods: </strong>The primary objective of the trial (NCT01421017) was to assess systemic responses by immune-related response criteria (irRC) after an 8-week cycle of topical IMQ and concurrent local RT (cohort 1). An amendment to the trial added two cohorts, both received one dose of cyclophosphamide (CTX) administered 1 week before study treatment initiation, IMQ/RT/CTX (cohort 2) and RT/CTX control (cohort 3). Cutaneous metastases were prospectively assigned to treatment with IMQ and RT (area A) or IMQ alone (area B). Secondary objectives were safety (Common Terminology Criteria for Adverse Events criteria) and local response in skin metastases. In all IMQ cohorts, tumors were biopsied before treatment and at 2 and 3 weeks.</p><p><strong>Results: </strong>31 patients were enrolled (n=12, n=12, and n=7, in cohort 1, 2, and 3, respectively), with 4 out of 24 patients in the IMQ cohorts showing systemic tumor responses (two complete responses (CR) and two partial responses (PR)). No objective responses were observed in the seven patients enrolled in the control arm (RT alone). The treatment was well-tolerated, no grade 4-5 treatment-related adverse events occurred and grade 3 AEs were manageable (anemia, local pain, and local ulceration, n=1 each). Local objective responses were observed in 19/24 (9 CR and 10 PR) and 5/24 (5 PR) in areas treated with combined IMQ-RT and IMQ alone, respectively (p<0.001). All 24 patients treated with IMQ underwent serial biopsies, and 84 samples yielded sufficient material for transcriptional analyses. These revealed that the presence of a T-helper 1 functional orientation of the tumor microenvironment paralleled by the downregulation of DNA-repair genes was associated with CR after IMQ+RT, but not after IMQ alone. No post-treatment activation of immune-effector functions was observed in stable and progressing lesions.</p><p><strong>Conclusions: </strong>Our findings support the safety and clinical efficacy of combining topical IMQ with local RT for recurrent breast cancer, with evidence of local and occasional systemic antitumor activity.</p><p><strong>Trial registration number: </strong>NCT01421017.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 4","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11973781/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788371","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":"Characteristics of second primary malignancies following bispecific antibodies therapy.","authors":"Xiaojie Liang, Baiwei Luo, Bingyu Lin, Dan Liu, Jia Guo, Weixiang Lu, Shengyu Tian, Zihong Cai, Xinyu Zhou, Zhihao Jin, Tong Li, Keren Chen, Hongsheng Zhou, Liang Wang","doi":"10.1136/jitc-2024-011200","DOIUrl":"10.1136/jitc-2024-011200","url":null,"abstract":"<p><strong>Background: </strong>The risk of secondary primary malignancies (SPMs) associated with bispecific antibody (BsAb)-a promising alternative to chimeric antigen receptor (CAR)-T therapy-remains insufficiently explored.</p><p><strong>Methods: </strong>Using large-scale, real-world data from the US Food and Drug Administration's Adverse Event Reporting System, we identified the relative frequency and characteristics of SPMs following BsAbs therapy and conducted a comprehensive comparison of treatment-related SPM profiles between BsAbs and CAR-T therapies.</p><p><strong>Results: </strong>We identified 108 cases among 10,280 BsAb-treated patients. The incidence risk of SPMs was stable over the past 8 years, accounting for 1-2% of all adverse events, with a case fatality rate of 29.63% among the SPM cases. Myeloid leukemias and non-Hodgkin's lymphoma were more frequent in blinatumomab recipients, while solid malignancies predominated in those treated with teclistamab. Time-to-onset (TTO) was significantly shorter in BsAb recipients compared with non-recipients, with weight and treatment duration influencing TTO, while no significant differences in TTO were observed across different BsAb products, ages, and genders. Our findings highlight the first year of BsAbs as a critical window for early detection and intervention. Although the overall risk of SPMs was lower with BsAbs than with CAR-T, the outcomes of SPMs were comparable in both groups. TTO and SPM patterns were statistically similar between the two therapies.</p><p><strong>Conclusion: </strong>Our study provides the first detailed characterization of SPMs post-BsAb, underscoring the need for continued pharmacovigilance and individualized risk management to mitigate SPM risks in patients undergoing BsAb therapy.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 4","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11973794/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788345","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":"Conformation-sensitive targeting of CD18 depletes M2-like tumor-associated macrophages resulting in inhibition of solid tumor progression.","authors":"Ik-Hwan Han, Ilseob Choi, Hongseo Choi, Soyoung Kim, Chanmi Jeong, Juwon Yang, Yingying Cao, Jeongyoon Choi, Heekyung Lee, Jin Sun Shin, Hye Duck Yeom, Eun-Ji Lee, Nari Cha, Hyemin Go, Se Eun Lim, Songah Chae, Won-Jun Lee, Minjin Kwon, Hongsung Kim, Hyojung Choi, Sehyun Pak, Namgyeong Park, Eunbin Ko, Deok-Sang Hwang, Junho H Lee, Hwan-Suck Chung, Seong Ho Kang, Hyunsu Bae","doi":"10.1136/jitc-2024-011422","DOIUrl":"10.1136/jitc-2024-011422","url":null,"abstract":"<p><strong>Background: </strong>Tumor-associated macrophages (TAMs) primarily exist in the M2-like phenotype in the tumor microenvironment (TME). M2-TAMs contribute to tumor progression by establishing an immunosuppressive environment. However, TAM targeting is hindered, mainly owing to a lack of specific biomarkers for M2-TAMs. Previously, we demonstrated that a novel peptide drug conjugate (TB511) consisting of a TAM-binding peptide and the apoptosis-promoting peptide targets M2-TAMs. This was achieved through M2-TAM targeting, although the target mechanism of action remained elusive. Herein, we elucidate the anticancer efficacy of TB511 by identifying new target proteins that preferentially bind to M2-TAMs and clarifying the apoptosis-inducing mechanism in these cells.</p><p><strong>Methods: </strong>We investigated the target proteins and binding site of TB511 using LC-MS/MS analyses, surface plasmon resonance and peptide-protein interaction 3D modeling. Activated CD18 expression in M2 TAMs was assessed using Quantibrite PE beads in PBMCs. The anticancer efficacy of TB511 was tested using colorectal cancer (CRC) and non-small cell lung cancer (NSCLC) mouse model. The immunotherapeutic effect of TB511 was investigated through spatial transcriptomics in human pancreatic ductal adenocarcinoma (PDAC) model.</p><p><strong>Results: </strong>Activated CD18 was highly expressed in human tumor tissues and was significantly higher in M2 TAMs than in other immune cells. TB511 showed high binding affinity to CD18 among the cell membrane proteins of M2 macrophages and appeared to bind to the cysteine-rich domain in the activated form. Moreover, TB511 specifically induced apoptosis in M2 TAMs, but its targeting ability to M2 macrophages was inhibited in CD18 blockade or knockout model. In mouse or humanized mouse models of solid tumors such as CRC, NSCLC, and PDAC, TB511 suppressed tumor growth by targeting M2-TAMs via CD18 and enhancing the presence of CD8⁺ T cells in the TME.</p><p><strong>Conclusions: </strong>Collectively, our findings suggest that activated CD18 holds promise as a novel target protein for cancer therapy, and TB511 shows potential as a therapeutic agent for tumor treatment.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 4","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11973759/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788360","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":"Impact of tumor localization on antitumor immunity with conditionally activated CTLA-4 blockade.","authors":"Marcel Arias-Badia, Chien-Chun Steven Pai, Yee May Lwin, PeiXi Chen, Aahir Srinath, Miho Tanaka, Emily Musser, Andrew Goodearl, Jacob V Gorman, Wendy Ritacco, Lawrence Fong","doi":"10.1136/jitc-2024-010566","DOIUrl":"10.1136/jitc-2024-010566","url":null,"abstract":"<p><strong>Background: </strong>Immune checkpoint blockade (ICB) can induce antitumor efficacy but also induces immune-related adverse events. Systemically administered ICB can activate immune cells throughout the host. Conditionally active ICB with proteolytically cleaved masking domains can potentially reduce the adverse events seen with anti-cytotoxic T-lymphocyte associated protein 4 (CTLA-4) antibody.</p><p><strong>Methods: </strong>We examined how different formats of a conditionally activated dual variable domain IgG (DVD) that binds CTLA-4 and the tumor-associated antigen prostate stem cell antigen (PSCA) can lead to efficacy in syngeneic subcutaneous and metastatic murine tumor models. We also defined the capacity of these DVDs to modulate immune responses by multiparameter flow cytometry.</p><p><strong>Results: </strong>Conditionally active DVDs can uncouple antitumor efficacy from toxicity. A fully cleavable construct (symmetric DVD, sDVD), which can be released from the target tumor cells, showed superior antitumor efficacy compared with asymmetric DVD, which retains its tumor antigen binding. The sDVD elicited the highest tumor-antigen-specific T-cell responses detected in tumors and tumor-draining lymph nodes, as well as presenting the highest rate of intratumoral and splenic \"non-exhausted\" antigen-specific CD8 T cells. SDVD also induced the highest degrees of T-cell memory and self-renewal potential. These effects were dependent on PSCA expression by the tumors.</p><p><strong>Conclusions: </strong>These findings support the notion that ICB modulation of antitumor immunity away from the tumor cells is critically important for optimal antitumor immunity. The bispecific sDVD antibody design may enable improved systemic antitumor responses than traditional ICB in both primary tumors and metastases.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 4","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11966968/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143780085","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":"Phase I study on neoadjuvant combination immunotherapy with mogamulizumab and nivolumab for solid tumors.","authors":"Koichi Jinushi, Takuro Saito, Koji Kurose, Susumu Suzuki, Takashi Kojima, Taishi Takahara, Tomoki Makino, Tetsuya Ogawa, Hiroyoshi Nishikawa, Kazuhiro Kakimi, Shinsuke Iida, Jun Nakajima, Yuichiro Doki, Mikio Oka, Ryuzo Ueda, Hisashi Wada","doi":"10.1136/jitc-2024-010634","DOIUrl":"10.1136/jitc-2024-010634","url":null,"abstract":"<p><strong>Background: </strong>Effector regulatory T cells expressing C-C chemokine receptor 4 (CCR4) suppress antitumor immune responses. We conducted a phase I clinical trial to evaluate the safety and efficacy of preoperative combination therapy with mogamulizumab (an anti-CCR4 antibody) and nivolumab (an anti-programmed death-1 antibody) in patients with solid tumors.</p><p><strong>Methods: </strong>Patients with operable solid tumors were enrolled in a 3+3 design, with preoperative nivolumab (3.0 mg/kg) administered intravenously every 2 weeks three times and mogamulizumab at 0.1 mg/kg (cohort 1), 0.3 mg/kg (cohort 2), or 1.0 mg/kg (cohort 3) every week four times. The primary endpoints were safety and the effects of depleting Forkhead box P3⁺ (FoxP3⁺) T cells in the tumor.</p><p><strong>Results: </strong>16 patients were enrolled between June 2016 and April 2020, including those with renal (n=7), lung (n=5), esophageal (n=3), and oral (n=1) cancers. Grade 3-4 treatment-related adverse events were observed in 6 of 16 patients, with lymphopenia (25%) and maculopapular rash (13%) being the most frequent. Grade 5 interstitial pneumonia was observed in one patient; however, the cause of death was disease progression. There were three partial responses (PRs) (one lung and two esophageal cancers) among clinical responses and one complete response (one lung cancer) and nine PRs (five kidney, two lung, and two esophageal cancers) among pathological responses. CCR4⁺FoxP3⁺ T cells were depleted in the tumors of all patients and increases in lymphocytes in tumor tissue according to the tumor immune microenvironment classification were observed in 50% of the patients, which correlated with a better prognosis.</p><p><strong>Conclusions: </strong>The preoperative combination of mogamulizumab and nivolumab was safely managed, exerted antitumor effects, and may be an effective option in the preoperative setting.</p><p><strong>Trial registration number: </strong>The present study was registered with ClinicalTrials.gov as NCT02946671 (registration date 2016-10-05).</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 4","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11966984/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143780018","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":"Unlocking the power of the microbiome for successful cancer immunotherapy.","authors":"Maria A Clavijo-Salomon, Giorgio Trinchieri","doi":"10.1136/jitc-2024-011281","DOIUrl":"10.1136/jitc-2024-011281","url":null,"abstract":"<p><p>In recent years, evidence has shown that the gut microbiome significantly influences responses to immunotherapy. This has sparked interest in targeting it to improve therapy outcomes and predictions of response and toxicity. Research has demonstrated that dysbiosis, often resulting from antibiotic use, can diminish the effectiveness of immune checkpoint inhibitors, and this lack of efficacy could be linked to systemic inflammation. Certain bacterial species have been identified as having beneficial and harmful effects on immunotherapy in the clinic. While a clear consensus has yet to emerge on the optimal species for therapeutic use, introducing a new microbiome into immunotherapy-refractory patients may boost their chances of responding to further treatment attempts. State-of-the-art interventions targeting the microbiome-such as fecal microbiota transplantation-are being assessed clinically for their safety and potential to enhance treatment outcomes, with promising results. Additionally, the microbiome has been leveraged for its power to predict clinical outcomes using machine learning, and surprisingly, its predictive capability is comparable to that of other described multi-biomarker clinical scores. Here, we discuss developing knowledge concerning the microbiome's significance in cancer immunotherapy and outline future strategies for maximizing its potential in immuno-oncology.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 4","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11966956/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143780027","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":"Comment on \"Nivolumab adjuvant to chemo-radiation in localized muscle-invasive urothelial cancer: primary analysis of a multicenter, single-arm, phase II, investigator-initiated trial (NEXT)\".","authors":"Xin Rui, Tingting Gu, Jiaquan Zhou","doi":"10.1136/jitc-2025-012084","DOIUrl":"10.1136/jitc-2025-012084","url":null,"abstract":"","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 4","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11962765/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143763634","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 PD-1 and CD85j can restore intratumoral CD4⁺ GzmB⁺ T-cell functions to combat MHC-II-expressing tumors.","authors":"Boyu Wang, Xu Wang, Tianlai Wang, Kelin Meng, Taiyan Yu, Yu Xi, Shaojie Hu, Hui Xiong, Rirong Qu, Zhiwei Yuan, Xue Wang, Chenxi Zeng, Wenbin Zou, Yitao Tian, Yixin Cai, Shengling Fu, Xiangning Fu, Lequn Li","doi":"10.1136/jitc-2024-010890","DOIUrl":"10.1136/jitc-2024-010890","url":null,"abstract":"<p><strong>Background: </strong>A subset of CD4⁺ T cells with cytotoxic activity has been identified, and these cells exert their effects by expressing perforin and granzymes. Despite the progress made in characterizing cytotoxic CD4⁺ T cells in various diseases, the status of cytotoxic CD4⁺ T cells in non-small cell lung cancer (NSCLC) and the underlying mechanisms involved in promoting intratumoral cytotoxic CD4⁺ T-cell activation remain unclear.</p><p><strong>Methods: </strong>We used flow cytometry to examine the phenotypic and functional properties of CD4⁺GzmB⁺ T cells in the peripheral blood and tumor tissues of patients with NSCLC. Loss-of-function analyses and RNA sequencing were used to identify the underlying mechanisms involved in the effects of interleukin (IL)-15 on the restoration of CD4⁺GzmB⁺ T-cell function in vitro. A patient-derived lung cancer explant model and an animal model were used to verify the effects of immune checkpoint inhibitors on CD4⁺GzmB⁺ T-cell activation.</p><p><strong>Results: </strong>In patients with NSCLC, impaired cytolytic function of tumor-infiltrated granzyme B (GzmB)-expressing CD4⁺ T cells was restored by IL-15 through activation of the AKT-FOXO1-T-bet axis. Moreover, IL-15 stimulation increased solute carrier family 7 member 5 (SLC7A5) expression in CD4⁺GzmB⁺ T cells in an Protein Kinase B (AKT)-dependent manner, and inhibition of SLC7A5 abrogated the effect of IL-15 on CD4⁺GzmB⁺ T cells. Additionally, we showed that the immune checkpoint molecules programmed cell death-1 (PD-1) and CD85j were mutually exclusively expressed in CD4⁺GzmB⁺ T cells and that dual targeting of PD-1 and CD85j enhanced the effector function of CD4⁺GzmB⁺ T cells by activating the AKT pathway. Notably, tumor cells expressing major histocompatibility complex (MHC)-II and IL-15 determine the effectiveness of CD4⁺GzmB⁺ T-cell-mediated antitumor immunity in response to immunotherapy.</p><p><strong>Conclusions: </strong>Our study demonstrated that tumor-infiltrating CD4⁺GzmB⁺ T cells fail to eliminate tumors. Dual blockade of PD-1 and CD85j alongside IL-15 restores the effector function of CD4⁺GzmB⁺ T cells and drives CD4⁺GzmB⁺ T-cell transformation in the tumor microenvironment to combat MHC-II-expressing tumors.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 4","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11962805/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143763754","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":"Targeted release of a bispecific fusion protein SIRPα/Siglec-10 by oncolytic adenovirus reinvigorates tumor-associated macrophages to improve therapeutic outcomes in solid tumors.","authors":"Yenan Zhang, Bohao He, Peng Zou, Mengdi Wu, Min Wei, Chuning Xu, Jie Dong, Jiwu Wei","doi":"10.1136/jitc-2024-010767","DOIUrl":"10.1136/jitc-2024-010767","url":null,"abstract":"<p><strong>Background: </strong>The pleiotropic roles of tumor-associated macrophages (TAMs) render them attractive targets in antitumor drug development. CD47/SIRPα (signal regulatory protein alpha) and CD24/Siglec-10 (sialic acid-binding immunoglobulin-like lectin 10) signaling pathways have been found to suppress macrophage phagocytosis of malignant cells. Systemic blockade of CD47/SIRPα has shown severe side effects. Intratumoral delivery of a CD47 inhibitor by oncolytic viruses (OVs) may circumvent this hurdle.</p><p><strong>Methods: </strong>To identify the characteristics of recombinant adenovirus (AdV)-SIRPα/Siglec-10, we conducted CCK8 assay, quantitative PCR, western blot, competitive binding assay, in vitro cytotoxicity assay, ELISA and phagocytosis assay. We investigated the antitumor immune responses of AdV-SIRPα/Siglec-10 using flow cytometry, various tumor-bearing mouse models, humanized tumor-bearing mouse models, immune cell depletion, RNA sequencing, and in vitro T cell activation assay.</p><p><strong>Results: </strong>Here, we developed a novel AdV encoding a fusion protein composed of the extracellular domains of murine or human SIRPα and Siglec-10 (SIRPα/Siglec-10), termed AdV-mSS or AdV-huSS. The SIRPα/Siglec-10 was effectively secreted by cells infected with AdV-mSS and functioned as a dual blocker of CD47 and CD24, thereby significantly enhancing macrophage phagocytosis. In a series of tumor models, including subcutaneous and ascitic H22 hepatocellular carcinoma (HCC), subcutaneous Hepa1-6 HCC, MC38 colorectal carcinoma, and Lewis lung carcinoma, AdV-mSS treatment markedly enhanced antitumor efficacy. Mechanistically, AdV-mSS reprogrammed TAMs toward an antitumor phenotype and enhanced the expression of major histocompatibility complex (MHC)-I/II, promoting CD8+T cell proliferation and activation. Depletion of either macrophages or CD8+T cells abrogated the antitumor efficacy of AdV-mSS. Similarly, in a humanized LM3 HCC mouse model, AdV-huSS significantly inhibited tumor growth and prolonged survival.</p><p><strong>Conclusions: </strong>Dual SIRPα/Siglec-10 inhibitor delivered intratumorally by AdV not only reinvigorated the TAM-CD8+T cell axis but also potentially reduced the risk of off-target effects. Further investigation of AdV-huSS in patients with cancer is warranted in the near future.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 4","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11962785/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143763751","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":"First reported case of a spontaneous and healthy pregnancy in a woman with persistent CAR T-cells 5 years after treatment for diffuse large B-cell lymphoma.","authors":"Ethan Abraham Canty, Lori Broderick, Daniel Flaherty, Marin Xavier, Sunita D Nasta, Lina Dajani, Andrew A White","doi":"10.1136/jitc-2024-011092","DOIUrl":"10.1136/jitc-2024-011092","url":null,"abstract":"<p><p>Chimeric antigen receptor T-cell (CAR T-cell) therapy has significantly advanced cancer treatments and remission rates; however, questions exist regarding the impacts on both fertility and immune effects on infants born to mothers who have undergone CAR T-cell therapy. There are no known reported cases of persistence of CAR T-cells after cancer therapy in pregnancy. Here, we present a case of a woman with relapsed refractory diffuse large B-cell lymphoma who undertook an experimental CAR T-cell therapy, had persistence of CAR T-cells 5 years after achieving remission, spontaneously became pregnant and delivered a healthy male infant. Our case provides an example of a healthy pregnancy despite the persistence of CAR T-cells and the resultant healthy newborn without evidence of immunologic or other health effects from the CAR T-cells.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 4","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11962766/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143763605","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}