Pub Date : 2026-03-05DOI: 10.1158/1078-0432.ccr-25-3749
Huaibin Ge,Housaiyin Li,Aditi Kulkarni,Zhangguo Chen,Pragati Upadhyay,Robert L Ferris,Jing H Wang
PURPOSEImmune checkpoint inhibitors (ICI) elicit variable responses in head and neck squamous cell carcinoma (HNSCC), yet mechanisms driving major pathological responses (MPR) remain poorly defined. We sought to evaluate longitudinal CD8 T-cell repertoire evolution to identify determinants of MPR.EXPERIMENTAL DESIGNWe analyzed high-resolution single-cell TCR sequencing data from paired pre- and post-treatment CD8 tumor-infiltrating lymphocytes (TILs) obtained from HNSCC patients treated with neoadjuvant anti-PD-1 combined with either anti-CTLA-4 or anti-LAG-3.RESULTSContrary to "clonal replacement" hypothesis, post-treatment CD8 T-cell pools were dominated by pre-existing TCR clones regardless of clinical outcome. MPR was uniquely characterized by higher abundance and greater expansion magnitude of "super-expanded" clones. We developed the TCR Adaptivity Index (TAI) to quantify coordinate flux (expansion and contraction) of all TCR clones detected across pre- and post-treatment timepoints; this index emerged as the most significant parameter associated with MPR. Importantly, clonal expansion in non-MPR was "uncoupled" from the productive, therapy-induced transcriptional reprogramming-characterized by markers of effector vigor and cellular fitness-that was observed in MPR. Furthermore, expansion dynamics positively correlated with predicted tumor reactivity as calculated by the Tumor Reactive Signature (TRS) score. Finally, a TRS-integrated TAI remained significantly correlated with MPR.CONCLUSIONSDual ICI drives MPR predominantly through the adaptivity and functional reprogramming of pre-existing immunity. Successful therapy relies on a coordinate repertoire response that promotes transition of putative tumor-reactive super-expanders into productive functional states. TRS-integrated TAI provides a high-throughput framework incorporating clonal dynamics and functional reprogramming to predict therapeutic efficacy.
{"title":"Pre-existing TCR clones drive major pathological responses in HNSCC patients treated with dual immune checkpoint inhibitors.","authors":"Huaibin Ge,Housaiyin Li,Aditi Kulkarni,Zhangguo Chen,Pragati Upadhyay,Robert L Ferris,Jing H Wang","doi":"10.1158/1078-0432.ccr-25-3749","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-3749","url":null,"abstract":"PURPOSEImmune checkpoint inhibitors (ICI) elicit variable responses in head and neck squamous cell carcinoma (HNSCC), yet mechanisms driving major pathological responses (MPR) remain poorly defined. We sought to evaluate longitudinal CD8 T-cell repertoire evolution to identify determinants of MPR.EXPERIMENTAL DESIGNWe analyzed high-resolution single-cell TCR sequencing data from paired pre- and post-treatment CD8 tumor-infiltrating lymphocytes (TILs) obtained from HNSCC patients treated with neoadjuvant anti-PD-1 combined with either anti-CTLA-4 or anti-LAG-3.RESULTSContrary to \"clonal replacement\" hypothesis, post-treatment CD8 T-cell pools were dominated by pre-existing TCR clones regardless of clinical outcome. MPR was uniquely characterized by higher abundance and greater expansion magnitude of \"super-expanded\" clones. We developed the TCR Adaptivity Index (TAI) to quantify coordinate flux (expansion and contraction) of all TCR clones detected across pre- and post-treatment timepoints; this index emerged as the most significant parameter associated with MPR. Importantly, clonal expansion in non-MPR was \"uncoupled\" from the productive, therapy-induced transcriptional reprogramming-characterized by markers of effector vigor and cellular fitness-that was observed in MPR. Furthermore, expansion dynamics positively correlated with predicted tumor reactivity as calculated by the Tumor Reactive Signature (TRS) score. Finally, a TRS-integrated TAI remained significantly correlated with MPR.CONCLUSIONSDual ICI drives MPR predominantly through the adaptivity and functional reprogramming of pre-existing immunity. Successful therapy relies on a coordinate repertoire response that promotes transition of putative tumor-reactive super-expanders into productive functional states. TRS-integrated TAI provides a high-throughput framework incorporating clonal dynamics and functional reprogramming to predict therapeutic efficacy.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"32 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147350345","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}
PURPOSEDespite the clinical adoption of immunotherapy in small cell lung cancer (SCLC), reliable biomarkers predicting clinical benefit are limited. Although HERV-K (HML-2) subfamily has been reported to modulate tumor immune response in multiple malignancies, its functional role in SCLC remains poorly defined, particularly the association with an inflamed microenvironment and favorable immunotherapy outcomes.EXPERIMENTAL DESIGNThe expression profile of locus-specific HERV-K was identified by TELESCOPE in the IMpower133 (n =271) and PKUPH cohort (n = 40). Immunohistochemistry and RNA-fluorescence in situ hybridization were performed on a tissue microarray (n = 48) to validate the expression of HERV-K transcripts. Single-cell RNA sequencing and multiplex immunohistochemistry, including PhenoCycler-Fusion, were used to characterize tumor immune microenvironment.RESULTSAlthough the HERV-K subfamily as a whole lacked prognostic value for immunotherapy in SCLC, a locus-specific HERV-K transcript, ERVK18, was associated with improved outcomes and exhibited the strongest positive correlation with immune-related signatures, representing multiple immune-activated pathways and increased immune cell infiltration. Single-cell and spatial analysis further revealed that high ERVK18 expression indicated elevated cytotoxicity signatures in T cells, along with enhanced spatial proximity between tumor and T cells. In the IMpower133 cohort, high ERVK18 expression was not only associated with better prognosis within atezolizumab+chemotherapy group, but also predicted improved overall survival in patients treated with atezolizumab+chemotherapy versus chemotherapy alone, confirming ERVK18 as a dual prognostic and predictive biomarker for first-line PD-L1 inhibitor response in SCLC.CONCLUSIONSElevated expression of ERVK18 represents inflamed microenvironment and indicates favorable immunochemotherapy prognosis of patients in SCLC.
{"title":"Locus-specific human endogenous retrovirus ERVK18 expression indicates an inflamed microenvironment and favorable immunotherapy outcome in small cell lung cancer.","authors":"Xingyuan Wu,Kunkun Sun,Jingwei Zhang,Songyan Hou,Zihang Yuan,Yan Ju,Jiaming Deng,Jiaming Zhao,Yueqi Jin,Jianqi She,Minghao Du,Mantang Qiu,Fan Yang,Hao Li,Xiao Li,Ence Yang","doi":"10.1158/1078-0432.ccr-25-3302","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-3302","url":null,"abstract":"PURPOSEDespite the clinical adoption of immunotherapy in small cell lung cancer (SCLC), reliable biomarkers predicting clinical benefit are limited. Although HERV-K (HML-2) subfamily has been reported to modulate tumor immune response in multiple malignancies, its functional role in SCLC remains poorly defined, particularly the association with an inflamed microenvironment and favorable immunotherapy outcomes.EXPERIMENTAL DESIGNThe expression profile of locus-specific HERV-K was identified by TELESCOPE in the IMpower133 (n =271) and PKUPH cohort (n = 40). Immunohistochemistry and RNA-fluorescence in situ hybridization were performed on a tissue microarray (n = 48) to validate the expression of HERV-K transcripts. Single-cell RNA sequencing and multiplex immunohistochemistry, including PhenoCycler-Fusion, were used to characterize tumor immune microenvironment.RESULTSAlthough the HERV-K subfamily as a whole lacked prognostic value for immunotherapy in SCLC, a locus-specific HERV-K transcript, ERVK18, was associated with improved outcomes and exhibited the strongest positive correlation with immune-related signatures, representing multiple immune-activated pathways and increased immune cell infiltration. Single-cell and spatial analysis further revealed that high ERVK18 expression indicated elevated cytotoxicity signatures in T cells, along with enhanced spatial proximity between tumor and T cells. In the IMpower133 cohort, high ERVK18 expression was not only associated with better prognosis within atezolizumab+chemotherapy group, but also predicted improved overall survival in patients treated with atezolizumab+chemotherapy versus chemotherapy alone, confirming ERVK18 as a dual prognostic and predictive biomarker for first-line PD-L1 inhibitor response in SCLC.CONCLUSIONSElevated expression of ERVK18 represents inflamed microenvironment and indicates favorable immunochemotherapy prognosis of patients in SCLC.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"130 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147350354","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}
Purpose: Treatment of Locally Advanced Cervical Cancer (LACC) is guided notably by the European Society of Gynaecological Oncology (ESGO) guidelines; unfortunately, relapse remains frequent despite standard chemoradiotherapy and brachytherapy. We evaluated whether histological assessment of non-metastatic para-aortic lymph node (PAoLN) provides prognostic value in LACC. Experimental design: Primary tumor and PAoLNs from 137 non-metastatic LACC patients were stratified by pre-therapeutic 18F-FDG PET/CT into pelvic PET-positive (pPET+, N= 72) and negative (pPET-, N= 65) groups. Immunohistochemistry on whole sections assessed germinal centers, CD4+, CD8+, FOXP3+ cells, neutrophils (CD66b+, neutrophil extracellular traps: NETs) and high-endothelial venules (HEVs). Associations with progression-free survival (PFS) were examined via univariate and multivariate analyses after a median follow-up of 55.4 months. Results: Primary tumor profile was not associated with outcome, whereas PAoLN features were strongly predictive. In pPET- patients, higher NETs were associated with shorter PFS (p=0.015; HR=2.768), while elevated CD4/CD8 ratio improved outcomes (p=0.047, HR=0.497). In pPET+ patients, shorter PFS was linked to FOXP3+ (p=0.04, HR=1.918) and proliferating FOXP3+ cells (p=0.018, HR=1.668) density. Across the full cohort, abundant germinal centers (p=0.0355, HR=0.273) and elevated CD4/CD8 ratio (p=0.001, HR=0.490) independently correlated with lower recurrence risk. Internal validation was conducted through a bootstrap resampling method. Combinatorial analyses revealed distinct predictive signatures according to pPET status: higher NETs, fewer germinal centers and FIGO-IIA1-IIIB status predicted relapse in pPET- patients. Conclusions: Integrating pPET status with PAoLN histological analyses improves recurrence risk stratification in LACC. PAoLN evaluation may serve as a complementary tool to guide treatment intensification and surveillance strategies.
{"title":"Non-metastatic para-aortic lymph node remodeling as a predictor of outcome in locally advanced cervical cancer","authors":"Louis Baudin, Léa Zanella, Alizée Lebeau, Clémence Pleyers, Noémie Gubbels, Silvia Blacher, Laurence Seidel, Athanasios Kakkos, Frédéric Goffin, Pierre Lovinfosse, Christine Gennigens, Sébastien Pirson, Frédéric Kridelka, Agnès Noël","doi":"10.1158/1078-0432.ccr-25-3894","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-3894","url":null,"abstract":"Purpose: Treatment of Locally Advanced Cervical Cancer (LACC) is guided notably by the European Society of Gynaecological Oncology (ESGO) guidelines; unfortunately, relapse remains frequent despite standard chemoradiotherapy and brachytherapy. We evaluated whether histological assessment of non-metastatic para-aortic lymph node (PAoLN) provides prognostic value in LACC. Experimental design: Primary tumor and PAoLNs from 137 non-metastatic LACC patients were stratified by pre-therapeutic 18F-FDG PET/CT into pelvic PET-positive (pPET+, N= 72) and negative (pPET-, N= 65) groups. Immunohistochemistry on whole sections assessed germinal centers, CD4+, CD8+, FOXP3+ cells, neutrophils (CD66b+, neutrophil extracellular traps: NETs) and high-endothelial venules (HEVs). Associations with progression-free survival (PFS) were examined via univariate and multivariate analyses after a median follow-up of 55.4 months. Results: Primary tumor profile was not associated with outcome, whereas PAoLN features were strongly predictive. In pPET- patients, higher NETs were associated with shorter PFS (p=0.015; HR=2.768), while elevated CD4/CD8 ratio improved outcomes (p=0.047, HR=0.497). In pPET+ patients, shorter PFS was linked to FOXP3+ (p=0.04, HR=1.918) and proliferating FOXP3+ cells (p=0.018, HR=1.668) density. Across the full cohort, abundant germinal centers (p=0.0355, HR=0.273) and elevated CD4/CD8 ratio (p=0.001, HR=0.490) independently correlated with lower recurrence risk. Internal validation was conducted through a bootstrap resampling method. Combinatorial analyses revealed distinct predictive signatures according to pPET status: higher NETs, fewer germinal centers and FIGO-IIA1-IIIB status predicted relapse in pPET- patients. Conclusions: Integrating pPET status with PAoLN histological analyses improves recurrence risk stratification in LACC. PAoLN evaluation may serve as a complementary tool to guide treatment intensification and surveillance strategies.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"1 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147350571","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}
Pub Date : 2026-03-04DOI: 10.1158/1078-0432.ccr-25-3535
David A. Gewirtz, Beverly Teicher, Edward Greenberg
It is well established that the majority of anti-cancer agents identified and developed through preclinical studies in cell culture and animal models do not prove to be sufficiently effective in the clinic to move into later stage clinical trials. The simple explanations are that tumor cells in culture or implanted in mice cannot predict what will occur in patients, due in large part to the lack of pharmacokinetics in cell culture and because a mouse is not a miniature human being. Factors such as drug absorption, distribution, metabolism, and excretion (ADME) are likely to be markedly different in mice and humans, and cross-species ADME good laboratory practice (GLP) toxicology findings are often not fully incorporated into later investigational rodent studies. Furthermore, the frequent use of immune-deficient mice to host human tumors eliminates the critical involvement of the immune system. A colleague once remarked that we can cure virtually all cancers in mice. While this is certainly hyperbole, it is true that drug efficacy often appears significantly greater in rodent experiments than in humans. This article attempts to highlight and place in perspective many of the issues that limit the utility of preclinical models in common use for the development of antitumor drugs. We further identify factors that could and should be modified to improve their ultimate translation to the clinic, particularly given current efforts to replace the use of animal models with human cell-based and computer-based assays for drug development.
{"title":"Why preclinical models for cancer drug development fail","authors":"David A. Gewirtz, Beverly Teicher, Edward Greenberg","doi":"10.1158/1078-0432.ccr-25-3535","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-3535","url":null,"abstract":"It is well established that the majority of anti-cancer agents identified and developed through preclinical studies in cell culture and animal models do not prove to be sufficiently effective in the clinic to move into later stage clinical trials. The simple explanations are that tumor cells in culture or implanted in mice cannot predict what will occur in patients, due in large part to the lack of pharmacokinetics in cell culture and because a mouse is not a miniature human being. Factors such as drug absorption, distribution, metabolism, and excretion (ADME) are likely to be markedly different in mice and humans, and cross-species ADME good laboratory practice (GLP) toxicology findings are often not fully incorporated into later investigational rodent studies. Furthermore, the frequent use of immune-deficient mice to host human tumors eliminates the critical involvement of the immune system. A colleague once remarked that we can cure virtually all cancers in mice. While this is certainly hyperbole, it is true that drug efficacy often appears significantly greater in rodent experiments than in humans. This article attempts to highlight and place in perspective many of the issues that limit the utility of preclinical models in common use for the development of antitumor drugs. We further identify factors that could and should be modified to improve their ultimate translation to the clinic, particularly given current efforts to replace the use of animal models with human cell-based and computer-based assays for drug development.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"42 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147350352","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}
Pub Date : 2026-03-04DOI: 10.1158/1078-0432.ccr-25-3052
Susan Slovin, Xin Gao, Xiao X. Wei, David Y. Oh, Rana R. McKay, Gerald Falchook, Arif Hussain, Meredith McKean, Andreas Wibmer, Alan Ho, Jeff D. Eskew, Rajesh Belani, Julia Coronella, Sabrina Haag, Christopher E. Martin, Joanne McCaigue, June Mendoza, Ann Murphy, Hamid Namini, Matthew A. Spear, Devon J. Shedlock, Tanya B. Dorff
Purpose: Chimeric antigen receptor (CAR)-T cell therapies have potential in solid tumors. A higher proportion of stem cell-like memory T cells (TSCM) in CAR-T products could enhance engraftment, persistence, and prolong immune activity. This phase 1 trial (NCT04249947) evaluated the safety and efficacy of P-PSMA-101, an autologous TSCM-rich bone tropic CAR-T therapy targeting prostate-specific membrane antigen (PSMA), in metastatic castrate-resistant prostate carcinoma (mCRPC) patients. Secondary endpoints included objective response rate, PSA response, radiographic progression-free survival (PFS). Patients and Methods: P-PSMA-101 was produced from leukapheresis using the piggyBac® DNA transposon-based platform, which integrates a multi-cistronic transgene encoding an iCasp9 safety switch in addition to the CAR, generating TSCM-rich CAR-T cells. Results: Among 33 treated patients, 18% (n=6) had dose-limiting toxicities (DLTs). Cytokine release syndrome (CRS) occurred in 61% (n=20), with Grade ≥ 3 CRS in 9% (n=3). Activation of the iCasp9-based safety switch was required in 24% (n=8) of cases including one fatal toxicity, and successful resolution in the other seven. P-PSMA-101 yielded ≥50% PSA decline in 21% (n=7) of patients. Among 13 RECIST evaluable patients, one partial response was observed. Stable disease occurred in 61% (n=20), with 21% (n=7) maintaining stability for ≥3 months. Two patients' remissions exceeded 12 months characterized by PSA declines > 90%, corroborated by pharmacokinetic, biomarker, and PSMA-PET imaging data. Conclusions: Robust expansion of P-PSMA-101 CAR T cells resulted in toxicity but also durable responses in patients with mCRPC. Future trials of CAR T may be informed by the results with this nonviral engineering, TSCM cell-enriched approach.
目的：嵌合抗原受体(CAR)-T细胞治疗实体瘤有潜力。CAR-T产品中较高比例的干细胞样记忆T细胞（stem cell-like memory T cells， TSCM）可以增强植入性、持久性和延长免疫活性。这项i期试验（NCT04249947）评估了P-PSMA-101治疗转移性去势抵抗性前列腺癌（mCRPC）患者的安全性和有效性。P-PSMA-101是一种针对前列腺特异性膜抗原（PSMA）的自体富含tscm的骨致性CAR-T疗法。次要终点包括客观缓解率、PSA反应、放射学无进展生存期（PFS）。患者和方法：P-PSMA-101是利用基于piggyBac®DNA转座子的平台从白细胞分离中产生的，该平台除了CAR外，还集成了编码iCasp9安全开关的多顺反子转基因，产生富含tscm的CAR- t细胞。结果：在33名接受治疗的患者中，18% （n=6）出现剂量限制性毒性（dlt）。细胞因子释放综合征（CRS）发生率为61% (n=20)， CRS≥3级发生率为9% （n=3）。24% （n=8）的病例需要激活基于icasp9的安全开关，其中包括1例致命毒性，其他7例成功解决。P-PSMA-101使21% （n=7）患者的PSA下降≥50%。在13例可评估的RECIST患者中，观察到1例部分缓解。61% （n=20）患者病情稳定，21% （n=7）患者病情稳定≥3个月。2例患者缓解超过12个月，以PSA下降为特征；90%，经药代动力学、生物标志物和PSMA-PET成像数据证实。结论：P-PSMA-101 CAR - T细胞的强大扩增在mCRPC患者中产生毒性，但也产生持久的反应。这种非病毒工程、TSCM细胞富集方法的结果可能会为CAR - T的未来试验提供信息。
{"title":"Phase 1 Trial of P-PSMA-101 CAR-T Cells in Patients with Metastatic Castration Resistant Prostate Cancer (mCRPC)","authors":"Susan Slovin, Xin Gao, Xiao X. Wei, David Y. Oh, Rana R. McKay, Gerald Falchook, Arif Hussain, Meredith McKean, Andreas Wibmer, Alan Ho, Jeff D. Eskew, Rajesh Belani, Julia Coronella, Sabrina Haag, Christopher E. Martin, Joanne McCaigue, June Mendoza, Ann Murphy, Hamid Namini, Matthew A. Spear, Devon J. Shedlock, Tanya B. Dorff","doi":"10.1158/1078-0432.ccr-25-3052","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-3052","url":null,"abstract":"Purpose: Chimeric antigen receptor (CAR)-T cell therapies have potential in solid tumors. A higher proportion of stem cell-like memory T cells (TSCM) in CAR-T products could enhance engraftment, persistence, and prolong immune activity. This phase 1 trial (NCT04249947) evaluated the safety and efficacy of P-PSMA-101, an autologous TSCM-rich bone tropic CAR-T therapy targeting prostate-specific membrane antigen (PSMA), in metastatic castrate-resistant prostate carcinoma (mCRPC) patients. Secondary endpoints included objective response rate, PSA response, radiographic progression-free survival (PFS). Patients and Methods: P-PSMA-101 was produced from leukapheresis using the piggyBac® DNA transposon-based platform, which integrates a multi-cistronic transgene encoding an iCasp9 safety switch in addition to the CAR, generating TSCM-rich CAR-T cells. Results: Among 33 treated patients, 18% (n=6) had dose-limiting toxicities (DLTs). Cytokine release syndrome (CRS) occurred in 61% (n=20), with Grade ≥ 3 CRS in 9% (n=3). Activation of the iCasp9-based safety switch was required in 24% (n=8) of cases including one fatal toxicity, and successful resolution in the other seven. P-PSMA-101 yielded ≥50% PSA decline in 21% (n=7) of patients. Among 13 RECIST evaluable patients, one partial response was observed. Stable disease occurred in 61% (n=20), with 21% (n=7) maintaining stability for ≥3 months. Two patients' remissions exceeded 12 months characterized by PSA declines > 90%, corroborated by pharmacokinetic, biomarker, and PSMA-PET imaging data. Conclusions: Robust expansion of P-PSMA-101 CAR T cells resulted in toxicity but also durable responses in patients with mCRPC. Future trials of CAR T may be informed by the results with this nonviral engineering, TSCM cell-enriched approach.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"53 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147350487","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}
Pub Date : 2026-03-04DOI: 10.1158/1078-0432.ccr-25-4600
Chang Liu, Jiarui Li, Dan Liu, Panpan Zhang, Miao Zhang, Ran Xue, Jifang Gong, Lian Liu, Min Tao, Siyuan Cheng, Ting Xu, Jiajia Yuan, Yanshuo Cao, Zhenghang Wang, Yakun Wang, Jun Zhou, Ming Lu, Zhi Peng, Zhihao Lu, Jian Li, Xiaotian Zhang, Tian Wang, Min Wang, Licui Jiang, Huimin Meng, Lin Yang, Changsong Qi, Lin Shen
Purpose: To evaluate the safety, pharmacokinetics, and preliminary clinical activity of UTAA06, an "off-the-shelf" allogeneic B7-H3-targeted chimeric antigen receptor (CAR)-Vδ1T cell therapy, in patients with pretreated, advanced B7-H3-positive solid tumors. Patients and Methods: In this first-in-human, phase I, dose-escalation study (NCT06372236), ten patients with advanced solid tumors (including gastric, colorectal, hepatocellular, ovarian, and neuroendocrine cancers) were enrolled. Following lymphodepletion chemotherapy (cyclophosphamide and fludarabine), patients received UTAA06 infusion across three dose levels (5×10⁸, 8×10⁸, or 1×10⁹ cells). The primary endpoint was safety. Secondary endpoints included pharmacokinetics and anti-tumor efficacy. Results: UTAA06 demonstrated a manageable safety profile; no graft-versus-host disease (GvHD) was observed, and cytokine release syndrome (CRS) was limited to two transient Grade 1 events. A single dose-limiting toxicity (Grade 3 pneumonitis) was reported in one patient at the 5×10⁸ cells dose level. While UTAA06 demonstrated signals of biological activity, including transient reductions in serum tumor markers in 50% of patients, no objective response by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria was observed. Further analysis identified that the limited CAR-T cell persistence was likely driven by subclinical host-versus-graft rejection (HvGR). Conclusions: This study provides clinical proof-of-concept for allogeneic B7-H3-targeted CAR-Vδ1T cells as a safe platform with low risk of GvHD and demonstrable biological activity in solid tumors. However, clinical efficacy was constrained by limited cellular persistence caused by host immune rejection. Future strategies are required to enhance the durability and therapeutic potential of this allogeneic approach.
{"title":"Allogeneic B7-H3-targeted CAR-Vδ1T cell therapy in advanced solid tumors: A phase I study","authors":"Chang Liu, Jiarui Li, Dan Liu, Panpan Zhang, Miao Zhang, Ran Xue, Jifang Gong, Lian Liu, Min Tao, Siyuan Cheng, Ting Xu, Jiajia Yuan, Yanshuo Cao, Zhenghang Wang, Yakun Wang, Jun Zhou, Ming Lu, Zhi Peng, Zhihao Lu, Jian Li, Xiaotian Zhang, Tian Wang, Min Wang, Licui Jiang, Huimin Meng, Lin Yang, Changsong Qi, Lin Shen","doi":"10.1158/1078-0432.ccr-25-4600","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-4600","url":null,"abstract":"Purpose: To evaluate the safety, pharmacokinetics, and preliminary clinical activity of UTAA06, an \"off-the-shelf\" allogeneic B7-H3-targeted chimeric antigen receptor (CAR)-Vδ1T cell therapy, in patients with pretreated, advanced B7-H3-positive solid tumors. Patients and Methods: In this first-in-human, phase I, dose-escalation study (NCT06372236), ten patients with advanced solid tumors (including gastric, colorectal, hepatocellular, ovarian, and neuroendocrine cancers) were enrolled. Following lymphodepletion chemotherapy (cyclophosphamide and fludarabine), patients received UTAA06 infusion across three dose levels (5×10⁸, 8×10⁸, or 1×10⁹ cells). The primary endpoint was safety. Secondary endpoints included pharmacokinetics and anti-tumor efficacy. Results: UTAA06 demonstrated a manageable safety profile; no graft-versus-host disease (GvHD) was observed, and cytokine release syndrome (CRS) was limited to two transient Grade 1 events. A single dose-limiting toxicity (Grade 3 pneumonitis) was reported in one patient at the 5×10⁸ cells dose level. While UTAA06 demonstrated signals of biological activity, including transient reductions in serum tumor markers in 50% of patients, no objective response by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria was observed. Further analysis identified that the limited CAR-T cell persistence was likely driven by subclinical host-versus-graft rejection (HvGR). Conclusions: This study provides clinical proof-of-concept for allogeneic B7-H3-targeted CAR-Vδ1T cells as a safe platform with low risk of GvHD and demonstrable biological activity in solid tumors. However, clinical efficacy was constrained by limited cellular persistence caused by host immune rejection. Future strategies are required to enhance the durability and therapeutic potential of this allogeneic approach.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"42 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147350489","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}
Pub Date : 2026-03-04DOI: 10.1158/1078-0432.ccr-25-3953
Zhi Lin, Cheng Tang, Tong Liu, Xingyi Wang, Zaijie Wu, Fan Hu, Yongkang Gai, Weiwei Ruan, Xiao Zhang, Xiaoli Lan
Purpose: The study aims to compare the diagnostic performance of the novel melanin-targeted [18F]PFPN PET and [18F]FDG PET in mucosal melanoma, evaluate their impact on clinical staging, and assess correlations between imaging metrics and molecular markers. Experimental Design: This prospective study enrolled 65 participants with histologically confirmed mucosal melanoma from February 2021 to January 2025. All participants underwent both [18F]FDG PET and [18F]PFPN PET within one week. Lesion-based and participant-based analyses compared detection sensitivity, false-positive rate, and staging concordance. Quantitative PET parameters were analyzed, and correlations with HMB45, SOX10, MelanA, S100, and mutation status (BRAF, CKIT, NRAS) were evaluated using nonparametric tests, correlation analysis with Bonferroni correction. Decision curve analysis was used to evaluate clinical benefit. Results: Sixty-five participants were included. [18F]PFPN PET showed higher lesion-based sensitivity than [18F]FDG PET (363/399 [91.0%] vs 332/399 [83.2%]) and no false positives (0/363 [0%] vs 4/336 [1.2%]). Normalized SUVmax was significantly higher for [18F]PFPN across all lesion types (P < 0.05). PFPN-based staging was more consistent with clinical staging (6.2% vs 18.5% discordant cases). [18F]PFPN uptake showed significant positive correlations with HMB45 and SOX10 expression, while [18F]FDG parameters showed no such associations. Conclusion: [18F]PFPN PET outperforms [18F]FDG PET in lesion detection and clinical staging in mucosal melanoma, especially for liver and bone metastases. Its association with melanin differentiation markers may support its use in personalized imaging strategies.
目的：本研究旨在比较新型黑色素靶向[18F]PFPN PET和[18F]FDG PET在粘膜黑色素瘤中的诊断性能，评估其对临床分期的影响，并评估影像学指标与分子标志物之间的相关性。实验设计：本前瞻性研究于2021年2月至2025年1月招募了65名组织学证实的粘膜黑色素瘤患者。所有参与者在一周内都接受了[18F]FDG PET和[18F]PFPN PET检查。基于病变和基于参与者的分析比较了检测灵敏度、假阳性率和分期一致性。定量分析PET参数，并使用非参数检验、Bonferroni校正相关分析评估与HMB45、SOX10、MelanA、S100和突变状态（BRAF、CKIT、NRAS）的相关性。采用决策曲线分析法评价临床获益。结果：共纳入65名受试者。[18F]PFPN PET的病变敏感性高于[18F]FDG PET (363/399 [91.0%] vs 332/399[83.2%])，无假阳性（0/363 [0%]vs 4/336[1.2%]）。归一化SUVmax在所有病变类型中均显著高于[18F]PFPN （P < 0.05）。基于pfpn的分期与临床分期更为一致（6.2% vs 18.5%不一致的病例）。[18F]PFPN摄取与HMB45和SOX10表达呈显著正相关，而[18F]FDG参数未显示出这种相关性。结论：[18F]PFPN PET在粘膜黑色素瘤的病变检测和临床分期方面优于[18F]FDG PET，尤其是在肝脏和骨转移方面。它与黑色素分化标志物的关联可能支持其在个性化成像策略中的应用。
{"title":"Comparison of [18F]PFPN and [18F]FDG PET in mucosal melanoma: diagnostic performance, staging impact, and correlation with molecular markers","authors":"Zhi Lin, Cheng Tang, Tong Liu, Xingyi Wang, Zaijie Wu, Fan Hu, Yongkang Gai, Weiwei Ruan, Xiao Zhang, Xiaoli Lan","doi":"10.1158/1078-0432.ccr-25-3953","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-3953","url":null,"abstract":"Purpose: The study aims to compare the diagnostic performance of the novel melanin-targeted [18F]PFPN PET and [18F]FDG PET in mucosal melanoma, evaluate their impact on clinical staging, and assess correlations between imaging metrics and molecular markers. Experimental Design: This prospective study enrolled 65 participants with histologically confirmed mucosal melanoma from February 2021 to January 2025. All participants underwent both [18F]FDG PET and [18F]PFPN PET within one week. Lesion-based and participant-based analyses compared detection sensitivity, false-positive rate, and staging concordance. Quantitative PET parameters were analyzed, and correlations with HMB45, SOX10, MelanA, S100, and mutation status (BRAF, CKIT, NRAS) were evaluated using nonparametric tests, correlation analysis with Bonferroni correction. Decision curve analysis was used to evaluate clinical benefit. Results: Sixty-five participants were included. [18F]PFPN PET showed higher lesion-based sensitivity than [18F]FDG PET (363/399 [91.0%] vs 332/399 [83.2%]) and no false positives (0/363 [0%] vs 4/336 [1.2%]). Normalized SUVmax was significantly higher for [18F]PFPN across all lesion types (P &lt; 0.05). PFPN-based staging was more consistent with clinical staging (6.2% vs 18.5% discordant cases). [18F]PFPN uptake showed significant positive correlations with HMB45 and SOX10 expression, while [18F]FDG parameters showed no such associations. Conclusion: [18F]PFPN PET outperforms [18F]FDG PET in lesion detection and clinical staging in mucosal melanoma, especially for liver and bone metastases. Its association with melanin differentiation markers may support its use in personalized imaging strategies.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"227 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147350578","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}
Pub Date : 2026-03-04DOI: 10.1158/1078-0432.ccr-25-3846
Ehsan Irajizad, Johannes F. Fahrmann, Ranran Wu, Hamid Rudsari, Jennifer B. Dennison, Edwin Ostrin, Jaffer Ajani, Samir Hanash
Purpose: Recent evidence suggests a significant association between microplastic (MPs), forever chemicals, and plasticizers and various diseases including cancer. Here, we evaluated the circulating levels of plastic-associated chemicals for lung cancer incidence and mortality among smokers in the Prostate Lung Colorectal and Ovarian (PLCO) study. Experimental Design: Using mass spectrometry, we screened for 29 known MPs, forever plastics (per- and polyfluoroalkyl substances [PFAS]), and plasticizers chemicals in 245 sera collected preceding a lung cancer diagnosis and 1,200 non-case sera from participants in the PLCO study who had a history of smoking. Five PFAS and 3 plasticizers were detected and quantified in sera. A PFAP model, consisting of PFOS + PFHA + mono-iso-nonyl-phthalate, was developed for predicting lung cancer mortality and risk strata based on quantiles established. Results: Higher circulating levels of PFOS, PFHA, and mono-iso-nonyl-phthalate were associated (p<0.05) with increased risk of lung cancer death but not incidence. Compared to the lowest quantile (reference), individuals with PFAP scores in the highest quantile were at markedly higher risk of death from lung cancer (p<0.0001), with respective cause-specific and sub-distributional HRs of 1.86 (95% CI: 1.18-2.93) and 1.82 (95% CI: 1.15 - 2.88). Sub-stratified analyses confirmed that the PFAP model remained an independent predictor of lung cancer–specific mortality (p < 0.05) across strata defined by age, sex, smoking history, histologic subtype, and stage at diagnosis. Conclusions: In the PLCO cohort elevated levels of PFOS, PFHA, and mono-iso-nonyl-phthalate were associated with increased lung cancer mortality among ever smokers across disease subgroups.
{"title":"Association of blood levels of forever plastics with lung cancer mortality among ever smokers in the Prostate Lung Colorectal and Ovarian (PLCO) cohort study.","authors":"Ehsan Irajizad, Johannes F. Fahrmann, Ranran Wu, Hamid Rudsari, Jennifer B. Dennison, Edwin Ostrin, Jaffer Ajani, Samir Hanash","doi":"10.1158/1078-0432.ccr-25-3846","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-3846","url":null,"abstract":"Purpose: Recent evidence suggests a significant association between microplastic (MPs), forever chemicals, and plasticizers and various diseases including cancer. Here, we evaluated the circulating levels of plastic-associated chemicals for lung cancer incidence and mortality among smokers in the Prostate Lung Colorectal and Ovarian (PLCO) study. Experimental Design: Using mass spectrometry, we screened for 29 known MPs, forever plastics (per- and polyfluoroalkyl substances [PFAS]), and plasticizers chemicals in 245 sera collected preceding a lung cancer diagnosis and 1,200 non-case sera from participants in the PLCO study who had a history of smoking. Five PFAS and 3 plasticizers were detected and quantified in sera. A PFAP model, consisting of PFOS + PFHA + mono-iso-nonyl-phthalate, was developed for predicting lung cancer mortality and risk strata based on quantiles established. Results: Higher circulating levels of PFOS, PFHA, and mono-iso-nonyl-phthalate were associated (p&lt;0.05) with increased risk of lung cancer death but not incidence. Compared to the lowest quantile (reference), individuals with PFAP scores in the highest quantile were at markedly higher risk of death from lung cancer (p&lt;0.0001), with respective cause-specific and sub-distributional HRs of 1.86 (95% CI: 1.18-2.93) and 1.82 (95% CI: 1.15 - 2.88). Sub-stratified analyses confirmed that the PFAP model remained an independent predictor of lung cancer–specific mortality (p &lt; 0.05) across strata defined by age, sex, smoking history, histologic subtype, and stage at diagnosis. Conclusions: In the PLCO cohort elevated levels of PFOS, PFHA, and mono-iso-nonyl-phthalate were associated with increased lung cancer mortality among ever smokers across disease subgroups.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"32 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147350774","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}
Pub Date : 2026-03-04DOI: 10.1158/1078-0432.ccr-25-2854
Akitada Yogo, Naoki Akanuma, Grace E. Kim, Netta Mäkinen, Chrissie Thirlwell, Eric K. Nakakura
Purpose: Small intestinal neuroendocrine tumors (SI-NETs) frequently present as multifocal lesions, but the molecular mechanisms underlying their development and heterogeneity remain unclear. This study aimed to characterize the phenotypes of tumor cell populations across anatomical sites in multifocal SI-NET patients and identify local microenvironmental factors influencing tumor development. Experimental Design: Spatial transcriptomics was performed on 72 tissue microarray cores derived from four patients with multifocal SI-NETs that included tumoral and non-tumoral tissues from various anatomical layers of the small intestine and regional metastatic sites. Unsupervised clustering, over-representation analysis (ORA), and ligand-receptor (L-R) pair analysis were used to define the tumor cell subtypes and associated signaling networks. External datasets were used for validation. Protein expression of selected genes was evaluated by immunohistochemistry and immunofluorescence. Results: Unsupervised clustering revealed four major tumor cell subtypes, ‘mucosal’, ‘mesenteric’, ‘lymphatic’, and ‘deep’, based on their anatomical location and transcriptomic profiles. Each subtype exhibited distinct gene expression patterns and L-R interactions. The ‘mesenteric’ and ‘lymphatic’ subtypes exhibited distinct L-R pairs, such as NRG1 - ERBB3 (HER3) and CXCL12 - CXCR4, respectively. 5HT - HTR1D was found in all subtypes except ‘mucosal’. Across the four subtypes, SST - SSTR1/2,PTN - NCL, MDK - NCL and GJD2 - GJD2 were consistently detected, suggesting fundamental roles in SI-NET biology. Conclusions: While further validation is needed, our findings indicate that multifocal SI-NETs consist of spatially distinct tumor cell subtypes affected by local cellular interactions, providing insight into SI-NET intra-tumoral heterogeneity, possible microenvironmental-triggered tumorigenesis, and potential subtype-targeted therapeutic strategies.
{"title":"Spatial Transcriptomics Reveals Location-Specific Tumor Cell Subtypes and Signaling within Multifocal Small Intestinal Neuroendocrine Tumors","authors":"Akitada Yogo, Naoki Akanuma, Grace E. Kim, Netta Mäkinen, Chrissie Thirlwell, Eric K. Nakakura","doi":"10.1158/1078-0432.ccr-25-2854","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-2854","url":null,"abstract":"Purpose: Small intestinal neuroendocrine tumors (SI-NETs) frequently present as multifocal lesions, but the molecular mechanisms underlying their development and heterogeneity remain unclear. This study aimed to characterize the phenotypes of tumor cell populations across anatomical sites in multifocal SI-NET patients and identify local microenvironmental factors influencing tumor development. Experimental Design: Spatial transcriptomics was performed on 72 tissue microarray cores derived from four patients with multifocal SI-NETs that included tumoral and non-tumoral tissues from various anatomical layers of the small intestine and regional metastatic sites. Unsupervised clustering, over-representation analysis (ORA), and ligand-receptor (L-R) pair analysis were used to define the tumor cell subtypes and associated signaling networks. External datasets were used for validation. Protein expression of selected genes was evaluated by immunohistochemistry and immunofluorescence. Results: Unsupervised clustering revealed four major tumor cell subtypes, ‘mucosal’, ‘mesenteric’, ‘lymphatic’, and ‘deep’, based on their anatomical location and transcriptomic profiles. Each subtype exhibited distinct gene expression patterns and L-R interactions. The ‘mesenteric’ and ‘lymphatic’ subtypes exhibited distinct L-R pairs, such as NRG1 - ERBB3 (HER3) and CXCL12 - CXCR4, respectively. 5HT - HTR1D was found in all subtypes except ‘mucosal’. Across the four subtypes, SST - SSTR1/2,PTN - NCL, MDK - NCL and GJD2 - GJD2 were consistently detected, suggesting fundamental roles in SI-NET biology. Conclusions: While further validation is needed, our findings indicate that multifocal SI-NETs consist of spatially distinct tumor cell subtypes affected by local cellular interactions, providing insight into SI-NET intra-tumoral heterogeneity, possible microenvironmental-triggered tumorigenesis, and potential subtype-targeted therapeutic strategies.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"1 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147350777","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}
Pub Date : 2026-03-04DOI: 10.1158/1078-0432.ccr-25-4948
Evan Y. Yu, Vivek Narayan, Giuseppe Esposito, Russell Szmulewitz, Yang Lu, Michael B. Lilly, Jeremie Calais, Gennady Bratslavsky, Yusuf Menda, Minal Vasanawala, Frédéric Pouliot, David Laidley, Neil Fleshner, Fred Saad, Jean-Claude Provost, Iryna Teslenko, Nand Kishore. Rawat, Gary Ulaner
Purpose: The phase 2 ARROW study was designed to evaluate radioligand therapy with 131I-LNTH-1095, an iodine-131–labeled small molecule targeting PSMA, in combination with enzalutamide in subjects with metastatic castration-resistant prostate cancer after progression on prior abiraterone therapy. Patients and Methods: Men ≥18 years with PSMA-positive prostate cancer (PSMA PET tracer uptake >1× liver SUVmean in all CT-measurable lesions) were randomized 2:1 to 131I-LNTH-1095 (4 cycles of 3.7 GBq/dose every 8 weeks)+enzalutamide (160 mg po qd) vs. enzalutamide alone. The primary endpoint was PSA50 response. Secondary endpoints included rPFS, ORR, OS, and safety. Results: Of 177 screened subjects, 120 were randomized (80: 131I-LNTH-1095+enzalutamide; 40: enzalutamide-monotherapy). PSA50 response was 62.9% (95% CI, 50.5-74.1) for 131I-LNTH-1095+enzalutamide vs. 31.3% (16.1-50.0) for enzalutamide alone (P=.003). Median rPFS was 14.0 months (95% CI: 8.64-18.20) for 131I-LNTH-1095+enzalutamide vs. 11.5 months (2.79–18.43) for enzalutamide alone (P=.10). Incidence of grade ≥3 treatment-emergent adverse events (TEAEs) was 65.8% for 131I-095+enzalutamide vs. 41.0% for enzalutamide-monotherapy; the most frequent TEAEs were fatigue (75.0 vs. 53.8%), nausea (59.2 vs. 33.3%), thrombocytopenia (51.3 vs. 0%), and decreased appetite (48.7 vs. 17.9%), respectively. Two deaths in the 131I-LNTH-1095+enzalutamide group were considered treatment-related. The study was not powered to detect rPFS and OS differences. Conclusions: 131I-LNTH-1095+enzalutamide was associated with a statistically significant improvement in PSA50 response compared to enzalutamide alone despite a lower dosing schedule (4 cycles of 3.7 GBq/dose every 8 weeks) than the other approved PSMA RLT agents. Grade ≥3 adverse events were more frequent with combination therapy, particularly hematologic toxicity. NCT03939689
目的：2期ARROW研究旨在评估131I-LNTH-1095（一种碘-131标记的靶向PSMA的小分子）联合恩杂鲁胺在既往阿比特龙治疗进展后转移性去势抵抗性前列腺癌患者中的放射配体治疗。患者和方法：年龄≥18岁的男性PSMA阳性前列腺癌（PSMA PET示踪剂摄取率为所有ct可测量病变的1倍肝脏SUVmean）随机分为2:1至131I-LNTH-1095（4个周期，每8周3.7 GBq/剂）+恩杂鲁胺（160 mg /次）vs单独恩杂鲁胺。主要终点为PSA50反应。次要终点包括rPFS、ORR、OS和安全性。结果：在177名筛选的受试者中，120名被随机分配（80名：131I-LNTH-1095+enzalutamide； 40名：enzalutamide单药治疗）。131I-LNTH-1095+enzalutamide的PSA50应答率为62.9% (95% CI, 50.5-74.1)，而单独enzalutamide的PSA50应答率为31.3% (16.1-50.0)（P= 0.003）。131I-LNTH-1095+enzalutamide的中位rPFS为14.0个月（95% CI: 8.64-18.20），而单独enzalutamide的中位rPFS为11.5个月（2.79-18.43）（P= 0.10）。131I-095+enzalutamide治疗后出现的≥3级不良事件（teae）的发生率为65.8%，而enzalutamide单药治疗为41.0%；最常见的teae分别是疲劳（75.0 vs. 53.8%）、恶心（59.2 vs. 33.3%）、血小板减少（51.3 vs. 0%）和食欲下降（48.7 vs. 17.9%）。131I-LNTH-1095+enzalutamide组中有2例死亡被认为与治疗有关。该研究没有检测rPFS和OS的差异。结论：与单独使用enzalutamide相比，131I-LNTH-1095+enzalutamide与PSA50反应的统计学显著改善相关，尽管其给药计划较低（每8周4个周期3.7 GBq/剂），但与其他批准的PSMA RLT药物相比。≥3级不良事件在联合治疗中更为常见，尤其是血液毒性。NCT03939689
{"title":"131I-LNTH-1095 Radioligand Therapy Plus Enzalutamide vs. Enzalutamide Alone in Men With PSMA-Avid Metastatic Castration-Resistant Prostate Cancer: A Phase 2 Study","authors":"Evan Y. Yu, Vivek Narayan, Giuseppe Esposito, Russell Szmulewitz, Yang Lu, Michael B. Lilly, Jeremie Calais, Gennady Bratslavsky, Yusuf Menda, Minal Vasanawala, Frédéric Pouliot, David Laidley, Neil Fleshner, Fred Saad, Jean-Claude Provost, Iryna Teslenko, Nand Kishore. Rawat, Gary Ulaner","doi":"10.1158/1078-0432.ccr-25-4948","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-4948","url":null,"abstract":"Purpose: The phase 2 ARROW study was designed to evaluate radioligand therapy with 131I-LNTH-1095, an iodine-131–labeled small molecule targeting PSMA, in combination with enzalutamide in subjects with metastatic castration-resistant prostate cancer after progression on prior abiraterone therapy. Patients and Methods: Men ≥18 years with PSMA-positive prostate cancer (PSMA PET tracer uptake &gt;1× liver SUVmean in all CT-measurable lesions) were randomized 2:1 to 131I-LNTH-1095 (4 cycles of 3.7 GBq/dose every 8 weeks)+enzalutamide (160 mg po qd) vs. enzalutamide alone. The primary endpoint was PSA50 response. Secondary endpoints included rPFS, ORR, OS, and safety. Results: Of 177 screened subjects, 120 were randomized (80: 131I-LNTH-1095+enzalutamide; 40: enzalutamide-monotherapy). PSA50 response was 62.9% (95% CI, 50.5-74.1) for 131I-LNTH-1095+enzalutamide vs. 31.3% (16.1-50.0) for enzalutamide alone (P=.003). Median rPFS was 14.0 months (95% CI: 8.64-18.20) for 131I-LNTH-1095+enzalutamide vs. 11.5 months (2.79–18.43) for enzalutamide alone (P=.10). Incidence of grade ≥3 treatment-emergent adverse events (TEAEs) was 65.8% for 131I-095+enzalutamide vs. 41.0% for enzalutamide-monotherapy; the most frequent TEAEs were fatigue (75.0 vs. 53.8%), nausea (59.2 vs. 33.3%), thrombocytopenia (51.3 vs. 0%), and decreased appetite (48.7 vs. 17.9%), respectively. Two deaths in the 131I-LNTH-1095+enzalutamide group were considered treatment-related. The study was not powered to detect rPFS and OS differences. Conclusions: 131I-LNTH-1095+enzalutamide was associated with a statistically significant improvement in PSA50 response compared to enzalutamide alone despite a lower dosing schedule (4 cycles of 3.7 GBq/dose every 8 weeks) than the other approved PSMA RLT agents. Grade ≥3 adverse events were more frequent with combination therapy, particularly hematologic toxicity. NCT03939689","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"27 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147350353","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}
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