Journal for Immunotherapy of Cancer最新文献

{"title":"Early assessment of IL8 and PD1+ Treg predicts response and guides treatment monitoring in cemiplimab-treated cutaneous squamous cell carcinoma.","authors":"Daniela Esposito, Fabiana Napolitano, Daniela Claudia Maresca, Marcella Scala, Annarita Amato, Stefania Belli, Claudia Maria Ascione, Angela Vallefuoco, Giovanna Attanasio, Fabio Somma, Angela Ianaro, Daniela Russo, Silvia Varricchio, Massimo Mascolo, Claudia Costa, Alessia Villani, Massimiliano Scalvenzi, Gianfranco Orlandino, Teresa Troiani, Alberto Servetto, Roberto Bianco, Giuseppe Ercolano, Luigi Formisano","doi":"10.1136/jitc-2024-010421","DOIUrl":"10.1136/jitc-2024-010421","url":null,"abstract":"<p><strong>Purpose: </strong>Anti-programmed cell death 1 (PD1) is the first-choice treatment in patients with advanced cutaneous squamous cell carcinoma (cSCC), when curative options are unavailable. However, reliable biomarkers for patient selection are still lacking.</p><p><strong>Experimental design: </strong>In this translational study, clinical annotations, tissue and liquid biopsies were acquired to investigate the association between sustained objective responses and transcriptional profiles, immune cell dynamics in tumor tissue and peripheral blood samples, as well as circulating cytokine levels.</p><p><strong>Results: </strong>First, we investigated the baseline characteristics of the immune landscape of cSCC biopsies. Gene Set Enrichment Analysis showed upregulation of interleukin (IL)2/STAT5 pathways and downregulation of Interferon signatures in non-responder patients compared with responders. Next, we studied the early changes induced by cemiplimab in tissue biopsies. Notably, after only three weeks, cemiplimab treatment induced an increase in B cells and CD8+ T cells in responders, whereas their abundance decreased in non-responder patients. Moreover, analyzing differentially expressed genes modulated early during treatment, compared with baseline biopsies, we found that IL1β and IL8 exhibited early downregulation in responder patients' tumor specimens. We assessed whether changes in the local tumor microenvironment were mirrored in peripheral blood. Similar to tissue findings, no changes were observed in the whole T regulatory (Treg) population, although PD1+ Tregs, which were downregulated in responder patients (vs T0), showed a rebound enrichment in non-responders after three cycles of cemiplimab. Finally, IL8 mirrored the tissue results, unlike IL1β, with early (T1) and then sustained (T3) downregulation of its levels in responder patients, while increased in non-responders.</p><p><strong>Conclusions: </strong>Taken together, these findings shed light on the significance of early transcriptomic and immune cell modulation in predicting responses to cemiplimab therapy. Additionally, our data suggest that IL8 levels in peripheral blood offer promising avenues for personalized treatment selection and response assessment in patients with cSCC receiving cemiplimab, while PD1+Tregs can be followed longitudinally to monitor response to therapy.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11749811/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970836","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Radiomics signature for dynamic monitoring of tumor inflamed microenvironment and immunotherapy response prediction.","authors":"Kinga Bernatowicz, Ramon Amat, Olivia Prior, Joan Frigola, Marta Ligero, Francesco Grussu, Christina Zatse, Garazi Serna, Paolo Nuciforo, Rodrigo Toledo, Manel Escobar, Elena Garralda, Enriqueta Felip, Raquel Perez-Lopez","doi":"10.1136/jitc-2024-009140","DOIUrl":"10.1136/jitc-2024-009140","url":null,"abstract":"<p><strong>Background: </strong>The efficacy of immune checkpoint inhibitors (ICIs) depends on the tumor immune microenvironment (TIME), with a preference for a T cell-inflamed TIME. However, challenges in tissue-based assessments via biopsies have triggered the exploration of non-invasive alternatives, such as radiomics, to comprehensively evaluate TIME across diverse cancers. To address these challenges, we develop an ICI response signature by integrating radiomics with T cell-inflamed gene-expression profiles.</p><p><strong>Methods: </strong>We conducted a pan-cancer investigation into the utility of radiomics for TIME assessment, including 1360 tumors from 428 patients. Leveraging contrast-enhanced CT images, we characterized TIME through RNA gene expression analysis, using the T cell-inflamed gene expression signature. Subsequently, a pan-cancer CT-radiomic signature predicting inflamed TIME (CT-TIME) was developed and externally validated. Machine learning was employed to select robust radiomic features and predict inflamed TIME. The study also integrated independent cohorts with longitudinal CT images, baseline biopsies, and comprehensive immunohistochemistry panel evaluation to assess the pan-cancer biological associations, spatiotemporal landscape and clinical utility of the CT-TIME.</p><p><strong>Results: </strong>The CT-TIME signature, comprising four radiomic features linked to a T-cell inflamed microenvironment, demonstrated robust performance with AUCs (95% CI) of 0.85 (0.73 to 0.96) (training) and 0.78 (0.65 to 0.92) (external validation). CT-TIME scores exhibited positive correlations with CD3, CD8, and CD163 expression. Intrapatient analysis revealed considerable heterogeneity in TIME between tumors, which could not be assessed using biopsies. Evaluation of aggregated per-patient CT-TIME scores highlighted its promising clinical utility for dynamically assessing the immune microenvironment and predicting immunotherapy response across diverse scenarios in advanced cancer. Despite demonstrating progression disease at the first follow-up, patients within the inflamed status group, identified by CT-TIME, exhibited significantly prolonged progression-free survival (PFS), with some surpassing 5 months, suggesting a potential phenomenon of pseudoprogression. Cox models using aggregated CT-TIME scores from baseline images revealed a statistically significant reduction in the risk of PFS in the pan-cancer cohort (HR 0.62, 95% CI 0.44 to 0.88, p=0.007), and Kaplan-Meier analysis further confirmed substantial differences in PFS between patients with inflamed and uninflamed status (log-rank test p=0.009).</p><p><strong>Conclusions: </strong>The signature holds promise for impacting clinical decision-making, pan-cancer patient stratification, and treatment outcomes in immune checkpoint therapies.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11749429/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970871","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predictive value of ENLIGHT-DP in patients with metastatic lung adenocarcinoma treated with immune checkpoint inhibitors and platinum chemotherapy directly from histopathology slides using inferred transcriptomics.","authors":"Johnathan Arnon, Gal Dinstag, Omer Tirosh, Leon Gugel, Yaron Kinar, Tzivia Gottlieb, Anna Elia, Yakir Rottenberg, Hovav Nechushtan, Michael Tabi, Philip Blumenfeld, Eli Pikarsky, Tuvik Beker, Ranit Aharonov, Aron Popovtzer","doi":"10.1136/jitc-2024-010132","DOIUrl":"10.1136/jitc-2024-010132","url":null,"abstract":"<p><strong>Introduction: </strong>Immune checkpoint inhibitors (ICI) have improved outcomes in non-small cell lung cancer (NSCLC). Nevertheless, the clinical benefit of ICI as monotherapy or in combination with chemotherapy remains widely varied and existing biomarkers have limited predictive value. We present an analysis of ENLIGHT-DP, a novel transcriptome-based biomarker directly from histopathology slides, in patients with lung adenocarcinoma (LUAD) treated with ICI and platinum-based chemotherapy.</p><p><strong>Methods: </strong>We retrospectively scanned high-resolution H&E slides from pretreatment tumor-tissue samples of 50 patients with metastatic LUAD treated with first-line ICI with (46) or without (4) platinum-based chemotherapy and applied our ENLIGHT-DP pipeline to generate, in a blinded manner, an individual prediction score. ENLIGHT-DP predicts response to ICI and targeted therapies given H&E slide scans in two steps: (1) predict individual messenger RNA expression directly from high-resolution H&E scanned slides using DeepPT, a digital-pathology-based algorithm. (2) Use these values as input to ENLIGHT, a transcriptome-based platform that predicts response to ICI and targeted therapies derived from drug-specific networks of gene expressions. We then unblinded the clinical outcomes and evaluated the predictive value of ENLIGHT-DP in comparison to programmed death ligand (PD-L)-1 and tumor mutational burden (TMB).</p><p><strong>Results: </strong>ENLIGHT-DP is predictive of response to treatment with receiver operating characteristic (ROC) area under the curve (AUC) of 0.69 (p=0.01) and outperforms both TMB and PD-L1 expression with ROC AUC of 0.52 and 0.46, respectively. Using a predetermined binary cut-off (established on independent cohorts) for patients predicted to respond to ICI, ENLIGHT-DP achieves 100% positive predictive value (PPV) and 44% sensitivity, superior to both PD-L1>50% (65% PPV and 38% sensitivity) and TMB-high (82% PPV and 26% sensitivity). ENLIGHT-DP was highly predictive in PD-L1<1% and TMB-low outlier groups with ROC AUC of 0.88 and 0.80, respectively (p value<0.05). ENLIGHT-DP is the only biomarker in this cohort significantly correlated with progression-free survival (HR: 0.45, 95% CI: 0.2 to 0.99, p=0.048).</p><p><strong>Conclusion: </strong>We demonstrate the application of ENLIGHT-DP, a transcriptome-based biomarker for accurate prediction of treatment of LUAD with ICI and platinum-based chemotherapy, outperforming PD-L1 and TMB, and relying solely on accessible H&E scanned slides. Further studies on different tumor types, ICI monotherapy and bigger NSCLC cohorts are warranted.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11749536/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970791","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cancer vaccines compensate for the insufficient induction of protective tumor-specific immunity of CD3 bispecific antibody therapy.","authors":"Jim Middelburg, Gaby Schaap, Marjolein Sluijter, Katy Lloyd, Vitalijs Ovcinnikovs, Janine Schuurman, Sjoerd H van der Burg, Kristel Kemper, Thorbald van Hall","doi":"10.1136/jitc-2024-010331","DOIUrl":"10.1136/jitc-2024-010331","url":null,"abstract":"<p><strong>Background: </strong>CD3 bispecific antibody (CD3 bsAb) therapy has become an established treatment modality for some cancer types and exploits endogenous T cells irrespective of their specificity. However, durable clinical responses are hampered by immune escape through loss of tumor target antigen expression. Induction of long-lasting tumor-specific immunity might therefore improve therapeutic efficacy, but has not been studied in detail yet for CD3 bsAbs. Here, we examined multiple combination strategies aiming to improve survival rates in solid tumors and, simultaneously, install endogenous immunity capable of protection to tumor rechallenge.</p><p><strong>Methods: </strong>Two syngeneic mouse tumor models were employed: The immunologically \"cold\" B16F10 melanoma and the immunologically \"hot\" MC38.TRP1 colon carcinoma model. Mice were treated with CD3xTRP1 bsAb (murine Fc-inert immunoglobulin G2a) as monotherapy, or in combination with agonistic costimulatory antibodies, Fc-active tumor-opsonizing antibodies, or tumor-(non)specific vaccines. Treatment efficacy of primary tumors and protection from rechallenge was monitored, as well as induction of tumor-specific T-cell responses.</p><p><strong>Results: </strong>In the immunologically \"cold\" B16F10 model, all combination therapies improved antitumor activity compared with CD3 bsAb monotherapy and induced systemic tumor-specific T-cell responses. However, this endogenous T-cell immunity swiftly waned and failed to protect mice from subsequent tumor rechallenge, except for combination therapy with tumor-specific vaccination. These vaccines strongly improved the therapeutic efficacy of CD3 bsAb against primary tumors and led to long-term immunological protection. In the immunologically \"hot\" MC38.TRP1 model, CD3 bsAb combined with only the vaccine adjuvant was sufficient to generate protective T-cell immunity and, moreover, prevented tumor escape via antigen loss.</p><p><strong>Conclusions: </strong>These results demonstrate the impact of tumor antigenicity on the induction of protective endogenous antitumor immunity during CD3 bsAb treatment and, importantly, show that the combination with tumor-specific vaccines improves therapeutic efficacy and installs long-term immunological memory in both \"hot\" and \"cold\" tumors.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11749218/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970834","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"First-in-human phase I trial of the bispecific CD47 inhibitor and CD40 agonist Fc-fusion protein, SL-172154 in patients with platinum-resistant ovarian cancer.","authors":"Nehal J Lakhani, Daphne Stewart, Debra L Richardson, Lauren E Dockery, Linda Van Le, Justin Call, Fatima Rangwala, Guanfang Wang, Bo Ma, Simon Metenou, Jade Huguet, Elliot Offman, Lini Pandite, Erika Hamilton","doi":"10.1136/jitc-2024-010565","DOIUrl":"10.1136/jitc-2024-010565","url":null,"abstract":"<p><strong>Background: </strong>SL-172154 is a hexameric fusion protein adjoining the extracellular domain of SIRPα to the extracellular domain of CD40L via an inert IgG₄-derived Fc domain. In preclinical studies, a murine equivalent SIRPα-Fc-CD40L fusion protein provided superior antitumor immunity in comparison to CD47- and CD40-targeted antibodies. A first-in-human phase I trial of SL-172154 was conducted in patients with platinum-resistant ovarian cancer.</p><p><strong>Methods: </strong>SL-172154 was administered intravenously at 0.1, 0.3, 1.0, 3.0, and 10.0 mg/kg. Dose escalation followed a modified toxicity probability interval-2 design. Objectives included evaluation of safety, dose-limiting toxicity, recommended phase II dose, pharmacokinetic (PK) and pharmacodynamic (PD) parameters, and antitumor activity.</p><p><strong>Results: </strong>27 patients (median age 66 years (range, 33-85); median of 4 prior systemic therapies (range, 2-9)) with ovarian (70%), fallopian tube (15%), or primary peritoneal (15%) cancer received SL-172154. Treatment-emergent adverse events (TEAEs) were reported for 27 patients (100%), with 24 (88.9%) having a drug-related TEAE and infusion-related reactions being the most common. 12 patients (44.4%) had grade 3/4 TEAEs, and half of these patients (22.2%) had a drug-related grade 3/4 TEAE. There were no fatal adverse events, and no TEAEs led to drug discontinuation. SL-172154 C_max and area under the curve increased with dose with greater than proportional exposure noted at 3.0 and 10.0 mg/kg. CD47 and CD40 target engagement on CD4⁺ T cells and B cells, respectively, approached 100% by 3.0 mg/kg. Dose-dependent responses in multiple cytokines (eg, interleukin 12 (IL-12), IP-10) approached a plateau at ≥3.0 mg/kg. Paired tumor biopsies demonstrated a shift in macrophages from an M2- to an M1-dominant phenotype and increased infiltration of CD8 T cells. PK/PD modeling showed near maximal margination of B cells and a dose-dependent production of IL-12 nearing a plateau at >3.0 mg/kg. The best response was stable disease in 6/27 (22%) patients.</p><p><strong>Conclusions: </strong>SL-172154 was tolerable as monotherapy and induced, dose-dependent, and cyclical immune cell activation, increases in multiple serum cytokines, and trafficking of CD40-positive B cells and monocytes following each infusion. The safety, PK, and PD activity support 3.0 mg/kg as a safe and pharmacologically active dose.</p><p><strong>Trial registration number: </strong>NCT04406623.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11749819/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antibodies against the multifaceted cathepsin D protein open new avenues for TNBC immunotherapy.","authors":"Pénélope Desroys du Roure, Timothée David, Aude Mallavialle, Valérie Laurent-Matha, Pascal Roger, Séverine Guiu, Thierry Chardès, Emmanuelle Liaudet-Coopman","doi":"10.1136/jitc-2024-009548","DOIUrl":"10.1136/jitc-2024-009548","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) is a heterogeneous breast cancer subtype characterized by aggressive clinical behavior and poor prognosis. The immune landscape associated with TNBC often reveals high immunogenicity. Therefore, immunotherapy, which has demonstrated its efficacy in different cancer types, could be a promising strategy for TNBC, given the limited therapeutic options currently available besides conventional chemotherapy. The aspartic protease cathepsin D (cath-D) is a tumor cell-associated extracellular protein with protumor activity, a marker of poor prognosis, and a target for antibody-based therapy in TNBC. This commentary provides a synopsis/narrative summary of the development of anti-cath-D antibodies in different formats, their key roles in restoring the antitumor immunity, particularly via activation of tumor-infiltrating natural killer cells, and their dual antitumor effects on cancer cells and stromal cancer-associated fibroblasts, suggesting their interest for clinical use in the light of the current clinical knowledge on TNBC.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11748927/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970832","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MAF1 inhibits hepatocarcinogenesis by fostering an immunostimulatory tumor microenvironment.","authors":"Di Cao, Yue-Ning Wang, Chao-Yue Sun, Haojiang Li, Ge Ren, Yu-Feng Zhou, Mei-Yin Zhang, Shuo-Cheng Wang, Shi-Juan Mai, Hui-Yun Wang","doi":"10.1136/jitc-2024-009656","DOIUrl":"10.1136/jitc-2024-009656","url":null,"abstract":"<p><strong>Background: </strong>The biological significance of MAF1, a tumor suppressor, in carcinogenesis and immune response of hepatocellular carcinoma (HCC) remains unreported. Understanding the underlying mechanisms by which MAF1 enhances anti-tumor immunity in HCC is crucial for developing novel immunotherapy strategies and enhancing clinical responses to treatment for patients with HCC.</p><p><strong>Methods: </strong>Mice were subjected to hydrodynamic tail vein injections of transposon vectors to overexpress AKT/NRas, or c-Myc, with or without wild-type (WT) or mutant-activated (-4A) MAF1, or short-hairpin MAF1 (shMAF1). Liver tissues and tumors were harvested and analyzed using histology, immunohistochemistry, immunoblotting, quantitative reverse-transcription PCR, and flow cytometry. MAF1 was overexpressed or knocked down in HCC cells via lentiviral transfection. Cell lines were analyzed using RNA sequencing, immunoblotting, dual luciferase reporter, and chromatin precipitation assays.</p><p><strong>Results: </strong>Both MAF1-WT and MAF1-4A proteins significantly inhibit hepatocarcinogenesis in mice, with the mutant form exhibiting a stronger suppressive effect. Although MAF1 knockdown alone does not induce abnormalities in the mouse liver, it accelerates c-Myc-induced carcinogenesis. Our results provide the first in vivo evidence that MAF1 plays a tumor suppressor role by activating PTEN to suppress the AKT-mammalian target of rapamycin signaling pathway during hepatocarcinogenesis in physiologically relevant tumor models. More importantly, we found that MAF1 not only enhances the intratumoral infiltration of CD8⁺ T cells by increasing CXCL10 secretion but also enhances their functional activity by inhibiting PDL1 transcription in mouse liver cancer, which were confirmed in human HCC or in vitro experiments. Furthermore, PDL1 overexpression accelerates mouse hepatocarcinogenesis by antagonizing the tumor-suppressive role of MAF1.</p><p><strong>Conclusions: </strong>Our study uncovers a novel anti-tumor immunity of MAF1 in hepatocarcinogenesis and human HCC. These findings suggest that the stimulated MAF1 could potentially improve immunotherapy in combination with immune checkpoint inhibitors in HCC patients, especially in those with an absence of T cells in HCC tissues.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11749189/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Utilization of primary tumor samples for cancer neoantigen discovery.","authors":"Vid Leko, Eric Groh, Shoshana T Levi, Amy R Copeland, Bradley Sinclair White, Billel Gasmi, Yong Li, Victoria Hill, Devikala Gurusamy, Noam Levin, Sanghyun Peter Kim, Sivasish Sindiri, Jared J Gartner, Todd D Prickett, Maria Parkhust, Frank J Lowery, Stephanie L Goff, Steven A Rosenberg, Paul Robbins","doi":"10.1136/jitc-2024-010993","DOIUrl":"10.1136/jitc-2024-010993","url":null,"abstract":"<p><strong>Background: </strong>The use of tumor-infiltrating T lymphocytes (TIL) that recognize cancer neoantigens has led to lasting remissions in metastatic melanoma and certain cases of metastatic epithelial cancer. For the treatment of the latter, selecting cells for therapy typically involves laborious screening of TIL for recognition of autologous tumor-specific mutations, detected through next-generation sequencing of freshly resected metastatic tumors. Our study explored the feasibility of using archived formalin-fixed, paraffin-embedded (FFPE) primary tumor samples for cancer neoantigen discovery, to potentially expedite this process and reduce the need for resections normally required for tumor sequencing.</p><p><strong>Method: </strong>Whole-exome sequencing was conducted on matched primary and metastatic colorectal cancer samples from 22 patients. The distribution of metastatic tumor mutations that were confirmed as neoantigens through cognate TIL screening was evaluated in the corresponding primary tumors. Mutations unique to primary tumors were screened for recognition by metastasis-derived TIL and circulating T lymphocytes.</p><p><strong>Results: </strong>We found that 25 (65.8%) of the 38 validated neoantigens identified in metastatic tumors from 18 patients with colorectal cancer were also present in matched primary tumor samples. This included all 12 neoantigens encoded by putative cancer driver genes, which are generally regarded as superior targets for adoptive cell therapy. The detection rate for other neoantigens, representing mutations without an established role in cancer biology, was 50% (13/26). Gene products encoding neoantigens detected in the primary tumors were not more likely to be clonal or broadly distributed among the analyzed metastatic lesions compared with those undetected in the primary tumors. Additionally, we found that mutations detected only in primary tumor samples did not elicit recognition by metastatic tumor-derived TIL but could elicit specific recognition by the autologous circulating memory T cells.</p><p><strong>Conclusions: </strong>Our findings indicate that primary FFPE tumor-derived screening libraries could be used to discover most neoantigens present in metastatic tumors requiring treatment. Furthermore, this approach can reveal additional neoantigens not present in resected metastatic tumors, prompting further research to understand their clinical relevance as potential therapeutic targets.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11748769/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hyperleukocytosis in a neuroblastoma patient after treatment with natural killer T cells expressing a GD2-specific chimeric antigen receptor and IL-15.","authors":"Gengwen Tian, Amy N Courtney, Hangjin Yu, Saleh Bhar, Xin Xu, Gabriel A Barragán, Claudia Martinez Amador, Nisha Ghatwai, Michael S Wood, Deborah Schady, Antonino Montalbano, Shantan Reddy, Aoife M Roche, David de la Cerda, Donald Williams Parsons, Erica J Di Pierro, Frederic D Bushman, Andras Heczey, Leonid S Metelitsa","doi":"10.1136/jitc-2024-010156","DOIUrl":"https://doi.org/10.1136/jitc-2024-010156","url":null,"abstract":"<p><p>The ability of immune cells to expand numerically after infusion distinguishes adoptive immunotherapies from traditional drugs, providing unique therapeutic advantages as well as the potential for unmanageable toxicities. Here, we describe a case of lethal hyperleukocytosis in a patient with neuroblastoma treated on phase 1 clinical trial (NCT03294954) with autologous natural killer T cells (NKTs) expressing a GD2-specific chimeric antigen receptor and cytokine interleukin 15 (GD2-CAR.15). This patient was the first to be treated on dose level (DL) 5 and the first patient whose product was restimulated with K562-derived artificial antigen-presenting cells (aAPCs) instead of autologous peripheral blood mononuclear cells (PBMCs). 12 previously treated patients on DLs 1 through 4 did not experience significant toxicity. Our root-cause analysis revealed no genetic alterations of known clinical significance and excluded the possibility of clonal expansion due to insertional retroviral mutagenesis. We report that the use of aAPCs instead of PBMCs for CAR-NKT restimulation contributed to a hyperproliferative state associated with distinct gene expression that possibly led to explosive lymphocyte expansion and uncontrolled toxicity in the patient. These findings warrant the implementation of measures to control immune cell activation during manufacture of cell therapy products, especially those armed with transgenic cytokines.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970845","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":"HDAC and MEK inhibition synergistically suppresses HOXC6 and enhances PD-1 blockade efficacy in BRAF^V600E-mutant microsatellite stable colorectal cancer.","authors":"Zhuang Sun, Mengyuan Shi, Jinhong Xia, Xin Li, Nan Chen, Hanyang Wang, Zhaoya Gao, Jinying Jia, Peng Yang, Dengbo Ji, Jin Gu","doi":"10.1136/jitc-2024-010460","DOIUrl":"10.1136/jitc-2024-010460","url":null,"abstract":"<p><strong>Background: </strong>B-Raf proto-oncogene, serine/threonine kinase (BRAF)^V600E-mutant microsatellite stable (MSS) colorectal cancer (CRC) constitutes a distinct CRC subgroup, traditionally perceived as minimally responsive to standard therapies. Recent clinical attempts, such as BRAF inhibitors (BRAFi) monotherapy and combining BRAFi with other inhibitors, have yielded unsatisfactory efficacy. This study aims to identify a novel therapeutic strategy for this challenging subgroup.</p><p><strong>Methods: </strong>We first performed a large-scale drug screening using patient-derived organoid models and cell lines to pinpoint potential therapies. Subsequently, we investigated the synergistic effects of identified effective inhibitors and probed their cooperative mechanisms. Concurrently, we explored the immune characteristics of BRAF^V600E MSS CRC using RNA sequencing and multiplex immunohistochemistry. Finally, we established a CT26 BRAF^V637E mouse cell line and validated the efficacy of combining these inhibitors and programmed death 1 (PD-1) blockades in immunocompetent mice.</p><p><strong>Results: </strong>Drug screening identified histone deacetylase (HDAC) inhibitor and mitogen-activated protein kinase kinase (MEK) inhibitor as significantly effective against BRAF^V600E MSS CRC. Further research revealed that these two inhibitors have superior synergistic effects by comprehensively inhibiting the activation of the epidermal growth factor receptor, mitogen-activated protein kinase, and phosphoinositide 3-kinase-protein kinase B pathways and suppressing the key target homeobox C6 (HOXC6). HOXC6, overexpressed in BRAF^V600E MSS CRC, regulates the MYC gene and contributes to treatment resistance, tumor growth, and metastasis. Moreover, the combination therapy demonstrated the ability to enhance antitumor immunity by synergistically upregulating the expression of immune activation-related genes, activating the cyclic guanosine monophosphate-adenosine monophosphate synthase/stimulator of interferon genes (cGAS/STING) pathway, and diminishing the tumor cells' DNA mismatch repair capacity. Notably, BRAF^V600E MSS CRC was identified to exhibit a distinct immune microenvironment with increased PD-1⁺ cell infiltration and potential responsiveness to immunotherapy. Echoing the above findings, in vivo, HDAC and MEK inhibitors significantly improved PD-1 blockade efficacy, accompanied by increased CD8⁺ T-cell infiltration.</p><p><strong>Conclusions: </strong>Our findings indicate that combining HDAC inhibitor, MEK inhibitor, and PD-1 blockade is a potential strategy for treating BRAF^V600E-mutant MSS CRC, warranting further investigation in clinical settings.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11749543/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970839","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}