Clinical Cancer Research最新文献

{"title":"Phase 2 Study of Palbociclib in Patients with Tumors with CDK4 or CDK6 Amplification: Results from the NCI-MATCH ECOG-ACRIN Trial (EAY131) Sub-protocol Z1C","authors":"Mark H. O'Hara, Opeyemi Jegede, Mark A. Dickson, Angela M. DeMichele, Richard Piekarz, Robert J. Gray, Victoria Wang, Lisa M. McShane, Lawrence V. Rubinstein, David R. Patton, P. Mickey Williams, Stanley R. Hamilton, Adedayo Onitilo, James V. Tricoli, Barbara A. Conley, Carlos L. Arteaga, Lyndsay N. Harris, Peter J. O'Dwyer, Alice P. Chen, Keith T. Flaherty","doi":"10.1158/1078-0432.ccr-24-0036","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-0036","url":null,"abstract":"Purpose: Amplification of CDK4 and CDK6 is a feature of a variety of malignancies, and preclinical evidence suggests inhibition of CDK4/6 is a plausible treatment strategy in these tumors. Subprotocol Z1C of the NCI-MATCH trial was designed to evaluate the CDK4/6 inhibitor palbociclib in CDK4- or CDK6-amplified tumors. Patients and Methods: Patients had a solid malignancy with progression on at least one systemic therapy for advanced disease. Tumors with ≥ 7 copies of CDK4 or CDK6 were considered amplified and molecularly eligible. Enrolled patients were treated with palbociclib 125 mg daily on days 1-21 of a 28-day cycle. The primary endpoint was ORR. Results: Forty-three patients were enrolled on subprotocol Z1C, and 38 patients were deemed eligible, treated, and included in analyses; 25 patients were eligible, treated, and centrally confirmed to have CDK4 or CDK6 amplification and comprised the primary analysis cohort for ORR endpoint. Among the 25 patients in the primary cohort, one patient had a PR, 4 patients had SD, and 16 patients had PD as best response. Four patients were not evaluable due to lack of follow-up scans. Among the 38 evaluable patients, one patient had a PR, 10 patients had SD, and 21 patients had PD as best response. Partial response and stable disease were only seen in patients with CDK4 amplification. Median progression-free survival was 2.0 months, and median overall survival was 8.8 months. Conclusions: Palbociclib showed limited activity in histology-agnostic CDK4- or CDK6-amplified tumors, though CNS tumors may be worthy of future investigation.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.5,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142487505","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":"Metabolic tumor volume assessed by 18F FDG - PET CT scan as a predictive biomarker for immune checkpoint blockers in advanced NSCLC and its biological correlates","authors":"Filippo G. Dall'Olio, Wael Zrafi, Veronique Roelants, Valentina Ambrosini, Aloyse Fourquet, Cristina Mitea, Francesco Passiglia, Matteo Bauckneht, Gerald Bonardel, Nicole Conci, Jose Carlos Benitez, Vincenzo Arena, Céline Namour, Marie Naigeon, Isabelle Monnet, Kristi Beshiri, Delphine Hoton, Safiye Dursun, Francois Xavier. Danlos, Giulia Argalia, Mihaela Aldea, Guido Rovera, Lisa Derosa, Valerio Iebba, Hester A. Gietema, Valerie Gounant, Valérie Lacroix, Jordi Remon, Daniel Gautheret, Nathalie Chaput, Bastien Job, Patricia L. Kannouche, Monica Velasco-Nuño, Laurence Zitvogel, Eugenia Cella, José Reinaldo Chícharo de Freitas, Damien Vasseur, Mohamed Aymen Bettaieb, Marco Tagliamento, Lizza Hendriks, Antoine Italiano, David Planchard, Aurelien Marabelle, Fabrice Barlesi, Silvia Novello, Desiree De Andreis, Frank Aboubakar Nan, Andrea Ardizzoni, Gerard Zalcman, Camilo Garcia, Benjamin Besse","doi":"10.1158/1078-0432.ccr-24-1993","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1993","url":null,"abstract":"Purpose: This study aimed to explore metabolic tumor volume (tMTV) as assessed 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG-PET/CT), and understand its biological meaning in patients with NSCLC exposed to immune checkpoint blockers(ICBs). Experimental Design: In this study, patients with advanced NSCLC and a positive PET scan within 42 days of first line treatment were enrolled in 11 institutions across 4 countries. Total MTV (tMTV) was analyzed, with a 42% SUVmax threshold. Survival was analyzed according to high tMTV (≥ median). Plasma proteomic profile, whole exome, transcriptome and other analysis were performed on monocentric cohorts to explore its biological correlates. Results: Of the 518 patients included, 167 received ICBs, 257 had chemotherapy plus ICBs, and 94 had chemotherapy. Median tMTV was 99 cm3. Median overall survival (OS) for patients with high tMTV treated with ICBs was 11.4 months vs 29.6 months (P<0.0012) for those with low tMTV. In patients receiving chemotherapy-ICB tMTV did not correlate with OS (P=0.099). In patients with PD-L1≥1% and high tMTV, chemotherapy-ICB combination was associated with longer OS compared with ICBs alone (20 vs 11.4 months,p=0.026), while no survival differences observed in low tMTV group. High tMTV correlated (and its detrimental effect seems to be driven by) a specific proteomic profile and increase in genomic instability. Conclusion: Our analysis indicates high tTMV is linked to an increase in systemic inflammation, specific cytokines production and chromosomal instability. tTMV may serve as one of the biomarker to select the best upfront strategy in patients with PD-L1 positive advanced NSCLC.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.5,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142487556","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":"Phase 1b Study of the Immunocytokine Simlukafusp alfa (FAP-IL2v), in Combination with Cetuximab in Patients with Head and Neck Squamous Cell Carcinoma.","authors":"Aaron R Hansen,Carlos A Gomez-Roca,Debbie G J Robbrecht,Loic Verlingue,Antoine Italiano,Julie E Bauman,Neeltje Steeghs,Hans Prenen,Jérôme Fayette,James Spicer,Jiaxin Niu,Christin Habigt,Meike Schneider,Stefan Evers,Nassim Sleiman,David Dejardin,Caroline Ardeshir,Daniela Schmid,Christophe Boetsch,Jehad Charo,Anton Kraxner,Volker Teichgräber,Nino Keshelava,Marcelo R Bonomi","doi":"10.1158/1078-0432.ccr-24-1562","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1562","url":null,"abstract":"PURPOSEThis phase 1b trial evaluated FAP-IL2v, a novel immune-cytokine engineered to minimize CD25-mediated toxicities, in combination with cetuximab, in patients with recurrent, unresectable, or metastatic head and neck squamous cell carcinoma (HNSCC).PATIENTS AND METHODSPatients received FAP-IL2v either on a continuous weekly (QW) schedule, or QW for 4 weeks and then every 2 weeks (Q2W). Cetuximab was dosed at QW or Q2W schedules. The primary objectives were to evaluate the safety and tolerability, maximum tolerated dose (MTD), pharmacokinetics, and clinical activity for the combination of FAP-IL2v with cetuximab. Exploratory objectives included pharmacodynamic analyses.RESULTSA total of 58 patients were enrolled, 19 patients into the dose-escalation, and 39 patients into the expansion part. The MTD of FAP-IL2v was defined as 10 mg (QW/Q2W) in combination with cetuximab (500 mg/m2, Q2W), which was further tested in the expansion part. The most common FAP-IL2v-related adverse events with a grade 3 or 4 severity were hypophosphatemia (19%), lymphopenia (16%), and infusion-related reaction (14%). The pharmacokinetics of FAP-IL2v in combination with cetuximab was similar to that after administration as monotherapy. Consistent with the proposed mode-of-action, FAP-IL2v preferentially expanded intratumoral NK and CD8 T cells. Four patients achieved a partial response, the objective response rate was 7% (95% CI: 3.2, 14.7).CONCLUSIONSThe safety profile of FAP-IL2v in combination with cetuximab was acceptable and pharmacodynamic markers support the proposed mode-of-action of this combination, but the overall low antitumor activity does not warrant further clinical exploration in HNSCC. [Part C of Study BP29842 (NCT02627274).].","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.5,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142449273","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":"Chemotherapy Sparks Tertiary Lymphoid Structures in Metastatic Ovarian Cancer.","authors":"Jesús Bravo Melgar,Damya Laoui","doi":"10.1158/1078-0432.ccr-24-2738","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-2738","url":null,"abstract":"Ovarian cancer remains resistant to immunotherapy in most patients, highlighting the need to make these tumors more immunogenic. A recent study unveils how chemotherapy is able to induce cancer cell stress in metastatic ovarian carcinomas, inducing the formation of tertiary lymphoid structures that create a \"hotter\" tumor microenvironment.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.5,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142449264","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":"First-In-Human Dose-Escalation Study of Fianlimab, an Anti-Lymphocyte Activation Gene-3 Antibody, with Cemiplimab in patients with advanced malignancies.","authors":"Nehal J Lakhani,Kyriakos P Papadopoulos,Melissa Lynne Johnson,Haeseong Park,Ding Wang,Timothy A Yap,Afshin Dowlati,Robert G Maki,Susanna Ulahannan,Filipa Lynce,Karen Kelly,Stephen Williamson,Jyoti Malhotra,Shuquan Chen,Ana Gonzalez Ortiz,Vladimir Jankovic,Anne Paccaly,Sheila Masinde,Jayakumar Mani,Israel Lowy,Giuseppe Gullo,Tasha Sims,Glenn Kroog","doi":"10.1158/1078-0432.ccr-23-3883","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-23-3883","url":null,"abstract":"PURPOSEPreclinical data indicate that fianlimab (anti-lymphocyte activation gene-3) plus cemiplimab (anti-programmed cell death-1) enhances antitumor activity. Here, we report prespecified final analyses of the dose-escalation part of a first-in-human, phase 1 study (NCT03005782) of fianlimab as monotherapy and in combination with cemiplimab in patients with advanced malignancies.EXPERIMENTAL DESIGNAdult patients received fianlimab 1-40 mg/kg ± cemiplimab 350 mg every 3 weeks (Q3W) across various dose-escalation schedules. Primary objectives were rate of dose-limiting toxicities, adverse events (including immune-mediated), deaths, laboratory abnormalities, and pharmacokinetics. Secondary outcomes were objective response rate, best overall response, duration of response, and antidrug antibody variables.RESULTSSeventy-eight patients were enrolled (fianlimab + cemiplimab, n = 47; fianlimab monotherapy, n = 31). One patient treated with 3 mg/kg fianlimab + cemiplimab experienced dose-limiting toxicities, including increased blood creatine phosphokinase and myasthenic syndrome. No maximum tolerated dose was reached. Any-grade treatment-emergent adverse events occurred in 90% of patients with fianlimab monotherapy, 87% with fianlimab + cemiplimab, and 87% who transitioned from monotherapy to combination therapy. Fianlimab pharmacokinetics were dose-proportional, and similar in monotherapy and combination therapy. Across patients who received fianlimab + cemiplimab, five achieved a partial response; three of whom experienced a response after transitioning from monotherapy to combination therapy. Fianlimab 1600 mg Q3W (20 mg/kg in an 80 kg individual) is the selected dose for phase 2 and 3 studies.CONCLUSIONSFianlimab as monotherapy and in combination with cemiplimab demonstrated acceptable safety and preliminary antitumor activity, which is generally consistent with previous reports of cemiplimab.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.5,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142449295","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":"Reverse Selection Designs for Accommodating Multiple Control Arms.","authors":"Sarah Samorodnitsky,Megan Othus,Michael LeBlanc,Michael C Wu","doi":"10.1158/1078-0432.ccr-24-1282","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1282","url":null,"abstract":"Evaluating a novel treatment in a randomized controlled trial requires comparison against existing therapies. If several existing therapies of similar benefit exist, the identification of a single control regimen may be difficult. For this situation, we propose a reverse selection design which, in its simplest form, includes a single experimental treatment arm and two control arms. Rather than carrying both control arms through the entire trial, the control arms are compared at an early interim analysis, ideally while accrual is ongoing. At this time, the worst-performing control arm is dropped and randomization continues to the remaining arms. At the end of the study, we compare the treatment to the remaining control arm. When no head-to-head comparison of the extant therapies is available or feasible, this design requires a smaller sample size than a traditional three-arm design or two sequential trials in which the extant therapies are compared and the better treatment is used in a subsequent trial as the control arm. This is because the final comparison is only between two arms and because the early interim analysis occurs prior to the end of accrual - yet with enough information such that any substantially better control arm will be selected. We evaluate the operating characteristics of a reverse selection design via simulation and show that it reduces the required sample size needed to compare the treatment against the best control, controls type I error, and likely selects the right control arm to use in the final analysis.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.5,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142449274","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":"Genomic biomarkers predict response to combined ATR inhibition and radiotherapy.","authors":"Benjamin R Schrank,Lauren E Colbert","doi":"10.1158/1078-0432.ccr-24-2306","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-2306","url":null,"abstract":"For decades, chemoradiosensitization with checkpoint kinase inhibitors has been proposed but largely unexplored. A recent study reports the novel ATR kinase inhibitor, RP-3500, synergizes with radiation to control Atm-/- tumors in vivo. RP-3500 did not radiosensitize wild-type or Brca-1 deficient tumors, highlighting the need for a genotype-tailored approach.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.5,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142449272","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":"SWOG/NCI Phase II Dual Anti-CTLA-4/PD-1 Blockade in Rare Tumors (DART): Non-Epithelial Ovarian Cancer.","authors":"Young Kwang Chae,Megan Othus,Sandip Pravin Patel,Kelly J Wilkinson,Emily M Whitman-Purves,Jayanthi Lea,John M Schallenkamp,Nabil Adra,Leonard J Appleman,Mitchell Alden,Jessica Thomes Pepin,John A Ellerton,Andrew Poklepovic,Adam Walter,Murtuza M Rampurwala,William R Robinson,Hye Sung Kim,Liam Il-Young Chung,Christine M McLeod,Gabby Lopez,Helen X Chen,Elad Sharon,Howard Streicher,Christopher W Ryan,Charles D Blanke,Razelle Kurzrock","doi":"10.1158/1078-0432.ccr-24-0606","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-0606","url":null,"abstract":"BACKGROUNDThe role of dual checkpoint inhibition in advanced rare/ultra-rare non-epithelial ovarian cancers (NEOCs) is yet to be explored.METHODSDART is a prospective, multicenter (1,016 US sites), multi-cohort, single-arm phase II trial conducted through the Early Therapeutics and Rare Cancer SWOG/NCI Committee, assessing ipilimumab (anti-CTLA-4) (1mg/kg every 6 weeks) and nivolumab (anti-PD-1) (240mg every 2 weeks) in adults with advanced NEOCs who lack beneficial standard therapy. Primary outcome was overall response rate [ORR; complete response (CR)/partial response (PR)]; secondary outcomes were progression-free survival (PFS), overall survival (OS), clinical benefit rate [CBR; stable disease (SD) ≥6 months plus ORR], and toxicity.RESULTSSeventeen patients (median age: 64; number of prior therapies ranged from 0-8 with no immunotherapy exposure; 8 granulosa, 6 carcinosarcomas, 1 Sertoli-Leydig, 1 yolk sac, 1 Wolffian) were evaluated. In granulosa cell tumors, ORR was 25% (n=2/8; 1 CR, 1 PR) and CBR, 50% (n=4/8); PFS of 58.3 (CR), 50.7+ (PR), 30.4 (SD), and 8.7 (SD) months. Median PFS was 3.5 months (95% confidence intervals (CI) 1.7-11.2 months); median OS, 42.5 months (95% CI 10.1 months-not reached). One Sertoli-Leydig cell tumor showed a 22% regression (PFS 11.2 months). Carcinosarcomas had no response. Three participants (18%) discontinued treatment due to grade 3-4 adverse events.CONCLUSIONSIpilimumab-nivolumab shows activity in treatment-refractory granulosa cell tumors, with 25% (n=2/8) of patients experiencing either CR or PR lasting over 4 years..","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.5,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142448017","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":"Neoadjuvant intratumoral plasmid interleukin-12 electro-gene-transfer and nivolumab in patients with operable locoregionally advanced melanoma.","authors":"Ahmad A Tarhini,Zeynep Eroglu,Islam Eljilany,Jonathan S Zager,Ricardo J Gonzalez,Amod A Sarnaik,C Wayne Cruse,Nikhil I Khushalani,Deanryan B De Aquino,Edith Abraham,Diana M Acevedo,Allison Richards,Michael J Schell,Denise Kalos,Pei-Ling Chen,Jane L Messina,David A Canton,Vernon K Sondak","doi":"10.1158/1078-0432.ccr-24-2768","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-2768","url":null,"abstract":"PURPOSEIntratumoral (IT) TAVO-EP (tavokinogene telseplasmid delivered by electroporation) results in localized expression of interleukin-12 (IL-12) within the tumor microenvironment (TME). This study evaluated neoadjuvant TAVO-EP combined with intravenous (IV) nivolumab followed by surgery and adjuvant nivolumab in patients with operable locoregionally advanced melanoma.PATIENTS AND METHODSThe neoadjuvant phase comprised up to 3 Χ 4-week cycles where TAVO-EP was given IT on days 1, 8, and 15 (optional) concurrently with 480 mg nivolumab IV on day 8 of each 4-week cycle. Surgery followed, and adjuvant nivolumab was initiated after surgery. The primary endpoint was pathologic complete response (pCR). Secondary endpoints included major pathological response (MPR; pCR or near pCR).RESULTSSixteen patients were enrolled and the preoperative radiological response rate was 63%. One patient declined surgery after experiencing a significant clinical response. Among the remaining 15 patients, pCR rate was 60% and MPR was 80%. No patient with MPR has had disease recurrence with a median follow-up from the date of surgery of 15.4 months. At baseline, most patients exhibited low CD8+ TIL, PD-L1 and IFN-γ gene expression signature. There was enhanced immune activation following treatment in the TME and blood including increased immune-related gene expression, CD8+ TIL and proliferating immune cell subsets.CONCLUSIONSThe clinical efficacy of neoadjuvant IT TAVO-EP + nivolumab is promising with 80% of patients achieving an MPR. Evidence of potent immune activation both systemically and within the TME along with a favorable safety profile supports the activity of local IL-12 and anti-PD1 based regimens.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.5,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142448030","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":"Spatial Dynamics of T and B Cell Response Predicts Clinical Outcome of Resectable and Unresectable Hepatocellular Carcinoma.","authors":"Yutaka Kurebayashi,Katsutoshi Sugimoto,Hanako Tsujikawa,Kosuke Matsuda,Rui Nomura,Akihisa Ueno,Yohei Masugi,Ken Yamazaki,Kathryn Effendi,Hirohito Takeuchi,Takao Itoi,Yasushi Hasegawa,Yuta Abe,Minoru Kitago,Hidenori Ojima,Michiie Sakamoto","doi":"10.1158/1078-0432.ccr-24-0479","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-0479","url":null,"abstract":"PURPOSEImmunotherapies have led to a paradigm shift in the treatment of hepatocellular carcinoma (HCC). Studies have revealed the single-cell catalogues of tumor-infiltrating immune cells and the trajectories of their differentiation. Nevertheless, the spatial distribution of these immune cells with distinct phenotypes in tumor microenvironment and their clinicopathological significance in resectable and unresectable HCCs are still largely unclear.EXPERIMENTAL DESIGNWe analyzed the spatial dynamics of intratumoral CD4 and CD8 T cells and their association with B and plasma cells using 283 surgically resected HCCs, 58 unresectable HCC samples before combined immunotherapy (atezolizumab plus bevacizumab [Atezo+Bev]), and autopsy specimens from 50 cases of advanced-stage HCCs through multiplex immunohistochemistry combined with transcriptomic and driver gene mutation analysis. Classification based on the spatial dynamics of T and B cell responses (refined immunosubtype) was developed and its clinicopathological significance was analyzed.RESULTSWe found that stem-like CD4 and CD8 T cells were mainly observed in T cell aggregates. Differentiation of T follicular helper cells were associated with the development of tertiary lymphoid structures, whereas differentiation of CD4 TCXCL13 cells with phenotype resembling T peripheral helper cells were associated with the development of lymphoplasmacytic microenvironment. The refined immunosubtype could predict clinical outcomes of resectable HCC after surgery and unresectable HCC after Atezo+Bev therapy. The immune microenvironment of metastatic lesions tended to reflect those of primary lesions.CONCLUSIONSWe revealed the spatial dynamics of T and B cell response in HCC, which is closely associated with the clinical outcome after surgical resection or Atezo+Bev therapy.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.5,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142448015","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}