Journal for Immunotherapy of Cancer最新文献

{"title":"Basic rules to respond to PD-1 blockade cancer immunotherapy.","authors":"Antoni Ribas","doi":"10.1136/jitc-2025-012096","DOIUrl":"https://doi.org/10.1136/jitc-2025-012096","url":null,"abstract":"<p><p>After 15 years of clinical testing and analyses of biopsies from patients with cancers treated with antibodies blocking the programmed death receptor 1 (PD-1) pathway, several requirements for inducing durable clinical responses have become evident. These basic rules for a response to anti-PD-1 include: (1) the cancer must be immunogenic and differentially recognizable by antitumor T cells, (2) there must be pre-existing antitumor T cells that have the ability to recognize the cancer, which had been activated and had received costimulation, but then are kept in a dysfunctional state due to the reactive cancer expression of the PD-1 ligand 1, (3) on PD-1 blockade, T cells are reinvigorated and produce increased amounts of interferon gamma, which forces the cancer cells into becoming enablers of the antitumor immune response, directly increasing the cancer cell immunogenicity and changing the tumor microenvironment from an unfriendly environment to a friendly environment for the antitumor T cells, and (4) reactivating antitumor T cells before surgery using neoadjuvant anti-PD-1 therapy improves patient outcomes, as the surgery would otherwise take away the majority of antitumor T cells. Collectively, these features are the basis of clinical responses and durable benefit of anti-PD-1 therapy in patients with cancer.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 5","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144159124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Response to: 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":"Gliceida M Galarza Fortuna, Umang Swami, Sumati Gupta","doi":"10.1136/jitc-2025-012378","DOIUrl":"https://doi.org/10.1136/jitc-2025-012378","url":null,"abstract":"","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 5","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144159130","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"B7-H3 and CSPG4 co-targeting as Pan-CAR-T cell treatment of triple-negative breast cancer.","authors":"Simone Stucchi, Roberto Borea, Susana Garcia-Recio, Manuela Zingarelli, Patrick D Rädler, Elena Camerini, Caroline Marnata Pellegry, Siobhan O'Connor, H Shelton Earp, Lisa A Carey, Charles M Perou, Barbara Savoldo, Gianpietro Dotti","doi":"10.1136/jitc-2025-011533","DOIUrl":"https://doi.org/10.1136/jitc-2025-011533","url":null,"abstract":"<p><strong>Purpose: </strong>Chimeric antigen receptor T (CAR-T) cell therapy is under clinical investigation in patients with metastatic triple-negative breast cancer (TNBC). However, the identification of targetable antigens remains a high priority to avoid toxicity and prevent tumor escape.</p><p><strong>Experimental design: </strong>Here we analyzed the gene expression of B7-H3 (<i>CD276</i>) and chondroitin sulfate proteoglycan 4 (<i>CSPG4</i>) in 98 TNBC samples identified in the AURORA US Network and Rapid Autopsy RNA sequencing data set at University of North Carolina (UNC). We then performed immunohistochemistry analysis for B7-H3 and CSPG4 protein expression in 151 TNBC samples collected at UNC. Finally, the validity of the proposed B7-H3 and CSGP4 co-targeting was tested in clinically relevant TNBC patient derived xenograft (PDX) models.</p><p><strong>Results: </strong>We observed that <i>CD276</i> and <i>CSPG4</i> genes are broadly and comparably expressed in TNBC samples, and gene expression is generally conserved in tumor metastases. None of the TNBC analyzed met the criteria for simultaneous low expression of <i>CSPG4</i> and <i>CD276</i> genes. Immunohistochemistry analysis showed a median H-score of 138 (105-168, lower and upper quartile, respectively) for B7-H3 expression and a median H-score of 33 (14-78 lower and upper quartile, respectively) for CSPG4 expression. Notably, 49% of the TNBC cores with B7-H3 H-score ≤105 exhibited a CSPG4 H-score exceeding its median value, and 37% and 18% of the TNBC cores with low B7-H3 expression scored CSPG4 expression above its median H-score or exceeded its upper quartile, respectively, confirming that at least one of these two proteins is expressed in 94% of the analyzed tumors. Finally, optimized dual-specific B7-H3 and CSPG4 CAR-T cells eradicated tumors with mixed antigen expression in TNBC PDX models.</p><p><strong>Conclusions: </strong>These data highlight the clinical potential of the proposed approach that could be applicable to the great majority of patients with TNBC as well as most of patients with breast cancer in general.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 5","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144159119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical factors influencing retreatment with anti-PD-(L)1 therapies after treatment in early-stage cancers: a modified Delphi consensus study.","authors":"Lajos Pusztai, Vernon K Sondak, Raquel Aguiar-Ibáñez, Federico Cappuzzo, Christos Chouaid, Chris Elder, Yosuke Hirasawa, Masaru Ishida, Robert Jones, Seung Hyeun Lee, Ryuichi Mizuno, Masayoshi Nagata, David Okonji, Phillip Parente, Bhavesh Shah, Alexander Sun, Dominihemberg Ferreira, Carmel Spiteri, Andrea Lauer, Amrit Kaliasethi, Carol Kao, Smita Kothari, Jan McKendrick","doi":"10.1136/jitc-2024-011184","DOIUrl":"https://doi.org/10.1136/jitc-2024-011184","url":null,"abstract":"<p><p>Anti-programmed death (ligand) 1 (anti-PD-(L)1) therapies were first introduced in the metastatic setting and have since been approved and reimbursed for treating early-stage cancers in the adjuvant, perioperative, and neoadjuvant settings in many cancer types. Current evidence supporting anti-PD(L)-1 retreatment after relapse with prior neoadjuvant and/or adjuvant anti-PD(L)1 therapy is limited and inconclusive. There is no guidance for clinicians on how and when to retreat with anti-PD-(L)1 therapies when anti-PD-(L)1 therapy was administered in the neoadjuvant and/or adjuvant setting. This study aimed to reach consensus on factors to guide decision-making regarding retreatment with anti-PD-(L)1 therapies after prior therapy with an anti-PD-(L)1 agent. This modified Delphi study consisted of a clinician survey across 10 countries followed by three real-time virtual Delphi panels involving clinical experts who had completed the survey. Clinical experts were experienced in using anti-PD-(L)1 treatments in early-stage cancers and/or as retreatment of patients with recurrences following early-stage treatment with anti-PD-(L)1 therapies. Of 28 clinicians providing survey responses, 20 participated in one of three Delphi panels. There was consensus that retreatment can be defined as 'repeated treatment with the same therapeutic class following relapse after or during neoadjuvant and/or adjuvant treatment.' All three panels agreed that decisions around retreatment should consider 'prior immune-related adverse events/toxicity,' 'time-related factors' (eg, time since completion of full treatment course and since discontinuation) and 'previous patient response' (often referred to by clinicians as tumor response, which may have reflected their experience with metastatic disease). Other factors identified as important included country-specific practices, treatment availability, and reimbursement. Generally, the clinical experts considered that retreatment could be considered from ≥3 to 6 months after stopping initial anti-PD-(L)1 treatment, or from ≥6 months after relapse/recurrence. In conclusion, clinicians across different regions recognized a role for retreating patients with anti-PD-(L)1 therapies after initial anti-PD-(L)1 treatment for early-stage cancers. Consensus was reached on some factors to consider regarding whether and when to retreat, although differences in clinical practice between countries/geographical regions made it difficult to achieve consensus for some more nuanced elements of retreatment. Further evidence could help better inform retreatment decisions.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 5","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144159180","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dual roles of IRE1α inhibition in reversing mitochondrial ROS-induced CD8⁺ T-cell senescence and exerting direct antitumor effects in multiple myeloma.","authors":"Yike Wan, Jingjing Wang, Mengping Chen, Junying Wang, Fajun Nan, Honghui Huang, Zhiqiang Liu, Jian Hou","doi":"10.1136/jitc-2024-011044","DOIUrl":"https://doi.org/10.1136/jitc-2024-011044","url":null,"abstract":"<p><strong>Background: </strong>Multiple myeloma (MM) is characterized by the proliferation of malignant plasma cells within the bone marrow (BM) microenvironment, which significantly contributes to immune suppression of CD8⁺ T cells. Our previous research identified that dysregulation of the IRE1α-XBP1s-SLC38A2 axis leads to decreased glutamine uptake and senescence of CD8⁺ T cells in MM. However, the underlying mechanisms of T-cell senescence remain unclear.</p><p><strong>Methods: </strong>Single-cell RNA sequencing was used to analyze mitochondrial function in CD8⁺ T cells in MM. The effects of XBP1s and SLC38A2 on mitochondrial reactive oxygen species (mtROS) were evaluated by flow cytometry under loss-of-function experiments. An IRE1α inhibitor (17#) was administered to explore its effects on T-cell senescence and MM cell growth. RNA sequencing was employed to disclose pathway alterations in T cells treated with 17#. The Vk*MYC mouse model was used to assess the impact of 17# on CD8⁺ T cell senescence and anti-myeloma effects.</p><p><strong>Results: </strong>BM-derived CD8⁺ T cells from patients with MM exhibited downregulated expressions of genes critical for glutamine transport (SLC38A2), mitochondrial respiratory chain, and ATP synthesis, while genes associated with ROS were upregulated. Suppression of XBP1s in CD8⁺ T cells resulted in decreased mtROS levels, whereas inhibition of SLC38A2 increased mtROS levels. Compound 17# significantly reduced senescence marker KLRG1 expression and increased perforin expression in nutrient-deprived BM CD8⁺ T cells from healthy donors and in BM CD8⁺ T cells from patients with MM, while promoting T-cell proliferation. Importantly, 17# did not impair the viability of peripheral blood mononuclear cells from healthy donors or alter the immune phenotypes of healthy CD8⁺ T cells. The NPR2-cGMP-PKG pathway was activated by IRE1α inhibition in restoring T-cell function. Furthermore, 17# exhibited direct inhibitory effects on MM cells. In Vk*MYC mouse model, 17# decreased mtROS levels in BM CD8⁺ T cells, reduced the proportion of senescent (KLRG1⁺CD57⁺CD28^-) T cells, and resulted in a lower tumor burden.</p><p><strong>Conclusion: </strong>Inhibiting IRE1α represents a promising strategy to reverse the senescence of CD8⁺ T cells by mitigating mtROS production. This dual mechanism not only rejuvenates T cells but also directly targets myeloma cells, offering a novel therapeutic approach for MM treatment.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 5","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144159185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Avelumab-based neoadjuvant therapy in patients with muscle-invasive bladder cancer (AURA Oncodistinct-004): a phase 2 multicenter clinical trial.","authors":"Jérémy Blanc, Aurélien Carnot, Philippe Barthélémy, Vinciane Casert, Brieuc Sautois, Jan Van den Brande, Vincent Vanhaudenarde, Lionel Staudacher, Emmanuel Seront, Veronique Debien, Lieveke Ameye, Nuria Kotecki, Françoise Rothé, Sandrine Rorive, Jean-Christophe Fantoni, Thibault Tricard, Thierry Roumeguère, Ahmad Awada, Nieves Martinez Chanza","doi":"10.1136/jitc-2025-012045","DOIUrl":"10.1136/jitc-2025-012045","url":null,"abstract":"<p><strong>Background: </strong>Immunotherapy is becoming a standard of care for non-metastatic muscle-invasive bladder cancer (MIBC). The optimal chemotherapy partner for chemo-immunotherapy combinations remains unknown. We evaluated the efficacy and safety of neoadjuvant avelumab-based regimens in patients with MIBC.</p><p><strong>Methods: </strong>The multicenter phase 2 AURA trial (NCT03674424) enrolled patients with non-metastatic MIBC undergoing radical cystectomy. Cisplatin-eligible patients were randomized to receive avelumab with either dose-dense methotrexate-vinblastine-doxorubicin-cisplatin (ddMVAC-A) or gemcitabine-cisplatin (GC-A). Cisplatin-ineligible patients received either avelumab alone (A) or combined with paclitaxel-gemcitabine (PG-A). The primary endpoint was pathological complete response (pCR). Secondary endpoints included safety, event-free survival, and overall survival (OS).</p><p><strong>Results: </strong>Between July 2018 and September 2021, 137 eligible patients were enrolled in the trial. In the cisplatin-eligible cohort (n=79), pCR rates were 58% (95% CI: 42% to 72%) in the ddMVAC-A arm and 53% (95% CI: 37% to 68%) in the GC-A arm. The 36-month OS rates were 87% (95% CI: 76% to 98%) for ddMVAC-A and 67% (95% CI: 53% to 84%) for GC-A. In the cisplatin-ineligible cohort (n=58), pCR rates were 14% (95% CI: 6% to 31%) in the PG-A arm and 32% (95% CI: 18% to 51%) in the A arm. The 36-month OS rates were 48% (95% CI: 33% to 71%) for PG-A and 42% (95% CI: 27% to 65%) for A. Overall, 51 (38%) patients experienced grade 3-4 treatment-related adverse events.</p><p><strong>Conclusions: </strong>Avelumab combined with cisplatin-based neoadjuvant chemotherapy showed promising efficacy in MIBC with a favorable safety profile, also with the ddMVAC regimen. Among cisplatin-ineligible patients, avelumab monotherapy showed encouraging activity, with no additional benefit observed from the PG-A regimen. These results support the use of the ddMVAC regimen as a potential chemotherapy partner for neoadjuvant chemo-immunotherapy combinations in future phase 3 trials, providing an alternative to the GC regimen currently under investigation.</p><p><strong>Trial registration number: </strong>NCT03674424.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 5","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144142635","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adoptively transferred macrophages for cancer immunotherapy.","authors":"Kyung Soo Park, Alexander P Gottlieb, Morgan E Janes, Supriya Prakash, Neha Kapate, Vineeth Chandran Suja, Lily Li-Wen Wang, Jennifer L Guerriero, Samir Mitragotri","doi":"10.1136/jitc-2024-010437","DOIUrl":"10.1136/jitc-2024-010437","url":null,"abstract":"<p><strong>Background: </strong>Macrophages have been classically associated with their innate immune functions of responding to acute injury or pathogenic insult, but they have been largely overlooked as primary initiators of adaptive immune responses. Here, we demonstrate that adoptively transferred macrophages, with optimal activation prior to administration, act as a potent cellular cancer therapeutic platform against a murine melanoma model.</p><p><strong>Method: </strong>The macrophage therapy was prepared from bone marrow-derived macrophages, pretreated ex vivo with an activation cocktail containing interferon-γ, tumor necrosis factor-α, polyinosinic:polycytidylic acid, and anti-CD40 antibody. The therapy was administered to tumor-bearing mice via the tail vein. Tumor growth and survival of the treated mice were monitored to evaluate therapeutic efficacy. Tumors and spleens were processed to examine immune responses and underlying mechanisms.</p><p><strong>Results: </strong>This immunotherapy platform elicits systemic immune responses while infiltrating the tumor to exert direct antitumor effects in support of the systemic adaptive response. The macrophage-based immunotherapy produced a strong CD8+T cell response along with robust natural killer and CD4+T cell activation, inducing a \"hot\" tumor transition and achieving effective tumor suppression.</p><p><strong>Conclusions: </strong>Owing to their inherent ability to home to and infiltrate inflamed tissues, macrophage-based cancer immunotherapies exhibited a unique in vivo trafficking behavior, efficiently reaching and persisting within tumors. Macrophages orchestrated a multiarmed immune attack led by CD8+T cells, with the potential for local, intratumoral activation of effector cells, demonstrating a novel cancer immunotherapy platform with meaningfully different characteristics than clinically evaluated alternatives.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 5","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144142631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IL-1β blockade prevents cardiotoxicity and improves the efficacy of immune checkpoint blockers and chemotherapy against pancreatic cancer in mice with obesity.","authors":"Nilesh P Talele, Heena Kumra, Igor L Gomes-Santos, William W Ho, Patrik Andersson, Marie Siwicki, Peigen Huang, Dan G Duda, Mikael J Pittet, Dai Fukumura, Rakesh K Jain","doi":"10.1136/jitc-2024-011404","DOIUrl":"10.1136/jitc-2024-011404","url":null,"abstract":"<p><strong>Background: </strong>Immune checkpoint blockers (ICBs) have revolutionized cancer therapy, yet they remain largely ineffective in treating pancreatic ductal adenocarcinoma (PDAC). Moreover, ICBs can cause severe immune-related adverse events (irAEs), including fatal cardiac toxicity. Finally, obesity is a risk factor in PDAC that may differentially modulate ICB efficacy in a malignancy-dependent manner.</p><p><strong>Methods: </strong>We investigated the mechanisms underlying irAEs induced by dual ICB therapy and sought to identify strategies to mitigate them while improving ICB efficacy in the obese setting. To this end, we used a clinically relevant mouse model that integrated key features of human PDAC: (1) high-fat diet-induced obesity, (2) an orthotopic PDAC, and (3) a therapeutic regimen combining chemotherapy (FOLFIRINOX) with ICBs (α-programmed cell death protein-1 + α-cytotoxic T-lymphocyte associated protein-4 antibodies).</p><p><strong>Results: </strong>Obese mice developed cardiac irAEs and had elevated serum interleukin (IL)-1β levels after chemoimmunotherapy. IL-1β blockade not only prevented myocarditis and reduced cardiac fibrosis but also enhanced the antitumor efficacy of the combination of chemotherapy plus dual ICB therapy and significantly improved the overall survival of PDAC-bearing obese mice.</p><p><strong>Conclusions: </strong>Our findings provide the rationale and compelling data to test a Food and Drug Administration-approved anti-IL-1β antibody in combination with chemotherapy and dual ICB therapy in patients with pancreatic cancer with obesity.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 5","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144142606","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tislelizumab as adjuvant therapy following endoscopic surgery for resectable recurrent nasopharyngeal carcinoma: a randomized clinical trial.","authors":"Wanpeng Li, Tian Wang, Haoyuan Xu, Quan Liu, Huankang Zhang, Yufei Yang, Xicai Sun, Huapeng Yu, Yurong Gu, Houyong Li, Hao Ding, Dehui Wang","doi":"10.1136/jitc-2025-011998","DOIUrl":"10.1136/jitc-2025-011998","url":null,"abstract":"<p><strong>Background: </strong>Endoscopic surgery has become the first-line treatment for surgically resectable recurrent nasopharyngeal carcinoma (rNPC), but it is associated with a high risk of postoperative tumor progression. Currently, there is a lack of effective and well-tolerated adjuvant treatment regimens. Thus, the primary objective was to investigate the efficacy and safety of tislelizumab as adjuvant therapy with endoscopic surgery for the treatment of patients with rNPC.</p><p><strong>Methods: </strong>This was a single-center, open-label, randomized, controlled, phase 2 trial between November 23, 2021, and May 8, 2024. Eligible patients included those with complete tumor disappearance as indicated by postoperative imaging, histopathologically diagnosed with undifferentiated or differentiated non-keratinizing rNPC. Patients with rNPC were randomized to receive endoscopic surgery alone or adjuvant tislelizumab treatment 2-6 weeks after endoscopic surgery. Tislelizumab was administered as a 200 mg intravenous infusion every 3 weeks until disease progression, death, unacceptable toxicity, withdrawal of consent, investigator's decision, or 1 year. The primary endpoint was progression-free survival (PFS) at 1 year, and secondary endpoints included 1-year progression-free interval (PFI), 1-year overall survival (OS), and safety.</p><p><strong>Results: </strong>The trial is ongoing. 42 patients were enrolled at a median follow-up of 18 months (IQR 10-27), the 1-year PFS was significantly higher in the tislelizumab group (94%, 95% CI: 83% to 100%) than in the endoscopic surgery alone group (57%, 95% CI: 38% to 85%). The 1-year PFI was also higher in the tislelizumab group (100%, 95% CI: 100% to 100%) than in the endoscopic surgery alone group (60%, 95% CI: 40% to 89%). No significant difference in the 1-year OS was observed at the data cut-off. Grade ≥3 immune-related adverse events (irAEs) occurred in 9% of tislelizumab recipients, and all of these events were elevated blood creatine phosphokinase levels. Additionally, the most common irAEs in this group were hypothyroidism, affecting 27%, and pruritus, observed in 9%.</p><p><strong>Conclusions: </strong>Tislelizumab as adjuvant therapy significantly enhanced PFS and PFI, with a favorable safety profile. Longer follow-up is necessary to determine whether this regimen can be considered as the standard of care for patients with resectable rNPC following endoscopic surgery.</p><p><strong>Trial registration number: </strong>NCT05092217.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 5","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144142614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Decoding resistance to immune checkpoint inhibitors in non-small cell lung cancer: a comprehensive analysis of plasma proteomics and therapeutic implications.","authors":"Michal Harel, Nili Dahan, Coren Lahav, Eyal Jacob, Yehonatan Elon, Igor Puzanov, Ronan J Kelly, Yuval Shaked, Raya Leibowitz, David P Carbone, David R Gandara, Adam P Dicker","doi":"10.1136/jitc-2024-011427","DOIUrl":"10.1136/jitc-2024-011427","url":null,"abstract":"<p><strong>Background: </strong>Immune checkpoint inhibitors (ICIs) have shown substantial benefit for patients with advanced non-small cell lung cancer (NSCLC). However, resistance to ICIs remains a major clinical challenge. Here, we perform a comprehensive bioinformatic analysis of plasma proteomic profiles to explore the underlying biology of treatment resistance in NSCLC.</p><p><strong>Methods: </strong>The analysis was performed on 388 \"resistance-associated proteins\" (RAPs) that were previously described as pretreatment plasma proteomic predictors within the PROphet computational model designed to predict ICI clinical benefit in NSCLC. Putative tissue origins of the RAPs were explored using publicly available datasets. Enrichment analyses were performed to investigate RAP-related biological processes. Plasma proteomic data from 50 healthy subjects and 272 patients with NSCLC were compared, where patients were classified as displaying clinical benefit (CB; n=76) or no CB (NCB; n=196). Therapeutic agents targeting RAPs were identified in drug and clinical trial databases.</p><p><strong>Results: </strong>The RAP set was significantly enriched with proteins associated with lung cancer, liver tissue, cell proliferation, extracellular matrix, invasion, and metastasis. Comparison of RAP expression in healthy subjects and patients with NSCLC revealed five distinct RAP subsets that provide mechanistic insights. The RAP subset displaying a pattern of high expression in the healthy population relative to the NSCLC population included multiple proteins associated with antitumor activities, while the subset displaying a pattern of highest expression in the NCB population included proteins associated with various hallmarks of treatment resistance. Analysis of patient-specific RAP profiles revealed inter-patient diversity of potential resistance mechanisms, suggesting that RAPs may aid in developing personalized therapeutic strategies. Furthermore, examination of drug and clinical trial databases revealed that 17.5% of the RAPs are drug targets, highlighting the RAP set as a valuable resource for drug development.</p><p><strong>Conclusions: </strong>The study provides insight into the underlying biology of ICI resistance in NSCLC and highlights the potential clinical value of RAP profiles for developing personalized therapies.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 5","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12097049/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144127644","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}