Journal for Immunotherapy of Cancer最新文献

{"title":"Discovery and validation of frameshift-derived neopeptides in Lynch syndrome: paving the way for novel cancer prevention strategies.","authors":"Cristina Bayó, Giancarlo Castellano, Fátima Marín, Joaquín Castillo-Iturra, Teresa Ocaña, Hardeep Kumari, Maria Pellisé, Leticia Moreira, Liseth Rivero, Maria Daca-Alvarez, Oswaldo Ortiz, Sabela Carballal, Rebeca Moreira, Julia Canet-Hermida, Marta Pineda, Capella Gabriel, Georgina Flórez-Grau, Manel Juan, Daniel Benitez-Ribas, Francesc Balaguer","doi":"10.1136/jitc-2024-011177","DOIUrl":"https://doi.org/10.1136/jitc-2024-011177","url":null,"abstract":"<p><strong>Background: </strong>Lynch syndrome (LS), caused by germline pathogenic variants in the mismatch repair genes, leads to high rates of frameshift-derived neopeptide (FSDN) expression due to microsatellite instability (MSI). While colorectal cancer (CRC) prevention is effective, most LS-related tumors lack such strategies. Cancer vaccines targeting FSDNs offer a promising approach for immune interception in LS. This study aimed to identify and validate LS-related FSDNs to develop vaccines for cancer prevention.</p><p><strong>Methods: </strong>We identified LS-related coding MS mutations and predicted FSDN with high coverage on common Human Leukocyte Antigen (HLA)-I and II alleles. We validated FSDN-associated mutations in colorectal adenomas (CrAD), endometrial cancers (EC), and CRC samples from patients with LS, non-LS tumors, and cell lines. Immunogenicity was assessed through interferon (IFN)-γ enzyme-linked immunospot and flow cytometry analysis of tissue-infiltrating lymphocytes (TILs) from LS carriers.</p><p><strong>Results: </strong>We prioritized 53 HLA-I and 45 HLA-II FSDNs in MSI tumors using in silico predictions. Validation revealed 86.7% of FSDN-associated mutations present in LS-CRC samples, with a median of 7.67 (6.5-9) mutations in CrADs and 6.02 (2-10) in CRCs. Sequencing of CrAD and EC samples showed 95% and 77.5% of predicted FSDN-associated mutations, respectively. MSI cancer cell lines transcribed 69.8% of FSDNs. Immunogenicity assays showed that 71% of potential FSDNs elicited IFN-γ responses, with a median of 7.37 (1-10.75) HLA-I and 6 (2-5.75) HLA-II FSDNs per patient. After prioritizing 24 FSDN, in a cohort of 19 LS-derived samples (4 CrAD and 15 normal mucosa), 52% (10/19) demonstrated T-cell reactivity to an HLA-I neoantigen pool. CD8+CD137+ activation markers increased significantly (p=0.037) over time and peptide-specific cells were detected by pentamer staining.</p><p><strong>Conclusions: </strong>Our predicted FSDN set has optimal coverage among LS carriers and can induce IFN-γ inflammatory responses in LS-derived TILs, offering an opportunity for vaccine development.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 4","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12010338/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143990673","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":"MARC, a novel modular chimeric antigen receptor, improves T cell-based cancer immunotherapies by preventing early T cell exhaustion and enhancing persistence.","authors":"Margaux Tual, Angélique Bellemare-Pelletier, Susan Moore, Delphine Guipouy, Negar Farzam-Kia, Leila Jafarzadeh, Jordan Quenneville, Benoit Barrette, Marc K Saba-El-Leil, Jean-Sebastien Delisle, Etienne Gagnon","doi":"10.1136/jitc-2025-011829","DOIUrl":"https://doi.org/10.1136/jitc-2025-011829","url":null,"abstract":"<p><strong>Background: </strong>Chimeric antigen receptor T cell (CAR-T)-based immunotherapies have reshaped the therapeutic landscape of cancer treatment, in particular for patients afflicted with leukemia. However, defects in CAR behaviors and clinical complications have hindered their widespread application across diverse cancer types. Chief among these defects is high tonic signaling, absent in native activating immune receptors, which accelerates T cell exhaustion and undermines treatment efficacy. We hypothesized that these limitations arise because current CAR architectures fail to replicate the modular design of native activating immune receptors, which integrate distinct receptor and signaling modules. This modular assembly is crucial for maintaining proper receptor regulation and function.</p><p><strong>Methods: </strong>Therefore, we set forth to develop a modular chimeric antigen receptor leveraging the same assembly principles found in native activating immune receptors to reestablish the intrinsic safeguards in receptor expression and signaling.</p><p><strong>Results: </strong>The resulting Modular Actuation Receptor Complex (MARC) displayed surface expression levels akin to its native immune receptor counterpart, the NK cell receptor KIR2DS3, while eliminating tonic signaling. In a clinically relevant mouse leukemia model, MARC-T cells exhibited remarkable long-term persistence and a less exhausted phenotype compared with conventional CAR-T cells.</p><p><strong>Conclusions: </strong>With its modular architecture, the MARC offers unparalleled opportunities for optimization and broad applicability across different cell types, paving the way for transformative advancements in cell-based therapies. This innovation holds immense promise as a next-generation therapeutic tool in clinical settings.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 4","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12010287/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144018826","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":"CD22-targeted chimeric antigen receptor-modified T cells for children and adults with relapse of B-cell acute lymphoblastic leukemia after CD19-directed immunotherapy.","authors":"Regina M Myers, Amanda M DiNofia, Yimei Li, Caroline Diorio, Hongyan Liu, Gerald Wertheim, Joseph A Fraietta, Vanessa Gonzalez, Gabriela Plesa, Donald L Siegel, Emma Iannone, Laura Shinehouse, Jennifer L Brogdon, Clare Taylor, Julie K Jadlowsky, Elizabeth O Hexner, Boris Engels, Diane Baniewicz, Colleen Callahan, Marco Ruella, Richard Aplenc, Allison Barz Leahy, Susan E McClory, Susan R Rheingold, Lisa Wray, Carl H June, Shannon L Maude, Noelle V Frey, Stephan A Grupp","doi":"10.1136/jitc-2025-011549","DOIUrl":"https://doi.org/10.1136/jitc-2025-011549","url":null,"abstract":"<p><strong>Background: </strong>Relapse of B-cell acute lymphoblastic leukemia (B-ALL) with CD19-antigen loss after CD19-targeted chimeric antigen receptor (CAR) T-cell therapy has a dismal prognosis. Novel immunotherapeutic strategies for this patient population are urgently needed.</p><p><strong>Methods: </strong>We tested a novel, fully human anti-CD22/4-1BB CAR T-cell construct, CART22-65s, in parallel phase I studies for pediatric and adult B-ALL. After lymphodepletion, CART22-65s was infused using a 3-day fractionated dosing scheme, allowing for omission of the second and third doses in cases of early cytokine release syndrome (CRS).</p><p><strong>Results: </strong>Twenty-two patients, all with relapse after prior CD19-directed immunotherapy, were enrolled. Of 19 infused patients (pediatric, n=17; adult, n=2), 14 (74%) achieved a complete remission (CR), including 4 of 6 (67%) patients refractory to prior inotuzumab. Five of 14 patients in a CR proceeded to consolidative hematopoietic cell transplantation (HCT). With a median follow-up of 38 months, the 12-month relapse-free survival rate was 38.4% (95% CI 19.3% to 76.5%) and overall survival rate was 52.6% (95% CI 34.3% to 80.6%). Two patients received additional CART22-65s treatments for subsequent CD22-positive relapses; one achieved another CR. All CRS (n=17, 89%) and neurotoxicity (n=4, 21%) events after initial infusion were grades 1-2. The only grade 3 CRS/neurotoxicity and the only high-grade immune effector cell-associated hemophagocytic lymphohistocytosis-like syndrome occurred in the retreatment setting. In vivo cellular kinetic data revealed robust CART22-65s proliferation by quantitative PCR peaking at a median of 20 days postinfusion, with the cells persisting out to month 42 in one patient who achieved a long-term remission with CART22-65s alone.</p><p><strong>Conclusions: </strong>The favorable safety profile and high remission rates in exceedingly refractory B-ALL support the continued development of CART22-65s but also highlight the need to use the product in combination with HCT or other novel strategies.</p><p><strong>Trial registration numbers: </strong>NCT02650414 and NCT03620058.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 4","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12007026/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144004479","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":"Past failures and new horizons: the nuances of tertiary lymphoid structures in high-grade serous ovarian cancer may contribute to immunotherapy effectiveness.","authors":"Rufiaat Rashid, Lan Coffman, Tullia C Bruno, Ian MacFawn","doi":"10.1136/jitc-2025-011670","DOIUrl":"https://doi.org/10.1136/jitc-2025-011670","url":null,"abstract":"<p><p>Tertiary lymphoid structures (TLS) are ectopic lymphoid aggregates that allow for optimal B-T cell crosstalk in solid tumors. Further, TLS are found in many solid tumors and are associated with improved patient survival and superior immunotherapeutic response, ultimately reflecting their potential as new therapeutic targets. Despite the prognostic benefit of TLS, women with high-grade serous ovarian cancer (HGSOC) are insensitive to immunotherapies. We have summarized recent work on TLS in patients with HGSOC, ultimately demonstrating how tumor microenvironment factors and therapeutics shape the organization and maturation of TLS. Specifically, TLS function varies across anatomical sites, with more germinal center (GC)+TLS with active B cells found in tumors within the omentum and fallopian tube compared with ovary. Further, cancer-associated stromal cells within patients negate the prognostic benefit of TLS and reduce B cell recruitment and function with blunted differentiation of follicular dendritic cells, which lay the foundation for functional GCs. Neoadjuvant chemotherapy (NACT) also impacts the HGSOC microenvironment, with metastatic tumors showing increased infiltration of effector immune cells (primarily TCF1+PD1+ CD8+ T cells) and \"mature\" TLS formation compared with NACT-naïve patients. These findings provide a rationale for designing therapeutics targeting the HGSOC TLS landscape and restoring immunotherapeutic responses in these patients.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 4","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12007046/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144012537","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":"Single-cell RNA sequencing of human double-negative T cells reveals a favorable cellular signature for cancer therapy.","authors":"Enoch Tin, Ismat Khatri, Karen Fang, Yoosu Na, Michele Nawata, Juan Arteaga, Mark D Minden, Sergio Rutella, Jongbok Lee, Li Zhang","doi":"10.1136/jitc-2024-010684","DOIUrl":"https://doi.org/10.1136/jitc-2024-010684","url":null,"abstract":"<p><strong>Background: </strong>Allogeneic double-negative T-cell (DNT) therapy has emerged as a novel, off-the-shelf cellular treatment with clinical feasibility, safety, and promising efficacy against leukemia. However, the biology of DNTs is less well characterized, and how DNT therapy distinguishes from conventional γδ T-cell therapy remains unclear. Collectively, this hinders our ability to bolster DNT functionalities in cancer therapy. Here, we performed single-cell RNA sequencing with in vitro and in vivo functional analysis on DNTs. As a significant proportion of DNTs express Vγ9Vδ2 (Vδ2) TCR chain, we compared DNTs with donor-matched conventional Vδ2 T cells expanded with zoledronic acid.</p><p><strong>Methods: </strong>Healthy donor-derived allogeneic DNTs and Vδ2 T cells were expanded ex vivo. Single-cell RNA sequencing analysis was performed on both cellular products to identify the transcriptional landscape and inferred cellular interactions within DNTs, followed by comparisons with donor-matched Vδ2 T cells. Unique cellular subsets found only in DNTs were depleted to identify their contributions to the overall efficacy of DNTs against acute myeloid leukemia. The anti-leukemic activity and in vivo persistence of DNTs and Vδ2 T-cells were explored using flow cytometry-based cytotoxicity assays, memory phenotyping, and xenograft models.</p><p><strong>Results: </strong>Despite a shared Vδ2 expression between cellular products, we identified unique cellular compositions in DNTs that contribute to distinct transcriptional and cellular communication patterns relative to the donor-matched Vδ2 T cells, including higher expression of genes identified in chimeric antigen receptor T cells that persist in patients with durable cancer-remission. Vδ2^- DNTs exhibited strong persistence characteristics, and their presence promoted the cytotoxic capabilities of Vδ2⁺ DNTs in repeated stimulation assays. This unique genetic signature and diverse cellular composition of DNTs resulted in better overall ex vivo expansion, prolonged persistence, and superior anti-leukemic activity compared with Vδ2 T cells in vitro and in vivo.</p><p><strong>Conclusions: </strong>These results highlight the unique transcriptional, cellular, and functional profile of human DNTs and support the continued clinical investigation of allogeneic DNT therapy. The data also provide a reference gene signature that may help improve the efficacy of other types of allogeneic adoptive cellular therapies.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 4","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12007110/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144026132","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":"Shp-1 regulates the activity of low-affinity T cells specific to endogenous self-antigen during melanoma tumor growth and drives resistance to immune checkpoint inhibition.","authors":"Joseph G Matous, Jeremy P Snook, Nico A Contreras, Andrew G Ramstead, Krystal R Charley, Elizabeth M Kolawole, Jacob N Kisiolek, Kaitlyn A Flint, Ashleigh J Soedel, Breyana Robinson, Anaiya B Mendoza, Yohichi Kumaki, Brian D Evavold, Matthew A Williams","doi":"10.1136/jitc-2024-010879","DOIUrl":"https://doi.org/10.1136/jitc-2024-010879","url":null,"abstract":"<p><strong>Background: </strong>The presence of activated CD8 T cells in the tumor microenvironment is correlated with an effective immune response to immune checkpoint inhibitor (ICI) therapy. However, ICI predominantly targets high-affinity T cells, which may be less abundant in tumors with few neoantigens. Targeting the intracellular phosphatase Src homology region 2 domain-containing phosphatase-1 (Shp-1) in combination with ICI lowers the T cell activation threshold and enhances the ability of low-affinity T cells to mount a productive antitumor response.</p><p><strong>Methods: </strong>In this study, we sought to determine whether temporal inhibition of Shp-1 during active tumor growth could rescue the activity of low-affinity T cells specific for endogenous self-antigens. To address this question, we implanted Yale University Mouse Melanoma (YUMM) tumor cell lines into WT mice and, on tumor establishment, administered an inhibitor of Shp-1 (TPI-1) with or without ICI treatment. We analyzed treatment-dependent changes in the immune infiltrate in the tumor via flow cytometry, major histocompatibility complex (MHC) tetramer-mediated detection of tyrosinase-related protein 2 (TRP-2)_180-188-specific T cells and a micropipette-based two-dimensional affinity assay to measure the T cell receptor (TCR) affinity.</p><p><strong>Results: </strong>Administration of ICI and a Shp-1 inhibitor to mice with established YUMM tumors, but neither agent alone, resulted in a significant delay in tumor growth and an increased frequency of CD8 tumor-infiltrating T cells with enhanced effector and reduced exhaustion characteristics. In particular, combined treatment increased the frequency of CD8 T cells specific for the MHC Class I-restricted tumor self-antigen TRP-2_180-188. We found that the increase in effector T cells was almost entirely due to an increase in T cells with very low TCR affinity.</p><p><strong>Conclusions: </strong>We conclude that approaches for altering TCR signaling threshold are effective in enhancing the antitumor response of low-affinity T cells specific for endogenous self-antigens in settings of ICI resistance and/or where neoantigens are not available to drive antitumor responses.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 4","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12007028/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143965238","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":"LILRB2 blockade facilitates macrophage repolarization and enhances T cell-mediated antitumor immunity.","authors":"Des C Jones, Lorraine Irving, Rebecca Dudley, Seraina Blümli, Marcin Wolny, Elisavet I Chatzopoulou, Stacy Pryts, Shreya Ahuja, D Gareth Rees, Alan M Sandercock, Saravanan Rajan, Reena Varkey, Michael Kierny, Andrew Kayserian, Kathy Mulgrew, Georgina Bowyer, Saly Songvilay, Kamila Bienkowska, Matthew S Glover, Sonja Hess, Simon J Dovedi, Robert W Wilkinson, Fernanda Arnaldez, Mark Cobbold","doi":"10.1136/jitc-2024-010012","DOIUrl":"https://doi.org/10.1136/jitc-2024-010012","url":null,"abstract":"<p><strong>Background: </strong>Immune checkpoint inhibitors have revolutionized the treatment of solid tumors, enhancing clinical outcomes by releasing T cells from inhibitory effects of receptors like programmed cell death protein 1 (PD-1). Despite these advancements, achieving durable antitumor responses remains challenging, often due to additional immunosuppressive mechanisms within the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) contribute significantly to the immunosuppressive TME and play a pivotal role in shaping T cell-mediated antitumor responses. Leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2), expressed on myeloid cells, including TAMs, is an inhibitory receptor, which contributes to macrophage-mediated immunosuppression. In this study, we present AZD2796, a high-affinity anti-LILRB2 antibody designed to repolarize TAMs from an immunosuppressive to a proinflammatory phenotype.</p><p><strong>Methods: </strong>Anti-LILRB2 antibodies were identified using single-B-cell encapsulation Immune Replica technology. The ability of AZD2796 to enhance proinflammatory responses from macrophages treated with CD40 ligand or lipopolysaccharide was assessed using a macrophage stimulation assay. A tumor cell/macrophage/T cell co-culture assay was developed to evaluate the effect of AZD2796, as a single agent and in combination with an anti-PD-1 antibody, on the cytolytic activity of antigen-specific T cells. In vivo assessments were then carried out to determine the ability of AZD2796 to alter tumor growth rate in mice humanized with CD34 hematopoietic stem cells.</p><p><strong>Results: </strong>In preclinical assessments, AZD2796 skewed macrophage differentiation away from an immunosuppressive phenotype and enhanced the proinflammatory function of macrophages. AZD2796 significantly increased the anti-tumor response of T cells following PD-1 checkpoint blockade, while AZD2796 monotherapy reduced tumor growth in humanized mouse models.</p><p><strong>Conclusions: </strong>These findings support the potential of AZD2796 as an anti-cancer therapy, with the ability to synergize with T-cell-based therapeutics.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 4","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12007065/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144012460","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":"T-bet overexpression enhances CAR T cell effector functions and antigen sensitivity.","authors":"Jennifer M Cimons, Kole R DeGolier, Samuel D Burciaga, Michael C Yarnell, Amanda J Novak, Amalia M Rivera-Reyes, M Eric Kohler, Terry J Fry","doi":"10.1136/jitc-2024-010962","DOIUrl":"https://doi.org/10.1136/jitc-2024-010962","url":null,"abstract":"<p><strong>Background: </strong>T cells modified to express a chimeric antigen receptor (CAR) are successful against B-lineage malignancies but fail to induce durable remissions in up to half of patients and have shown limited efficacy against other types of cancer. Strategies to improve CAR T cell potency and responses to low antigen densities without inducing CAR T cell dysfunction or limiting persistence are necessary to expand durability of remissions.</p><p><strong>Methods: </strong>We overexpressed T-bet in human and mouse CAR T cells to mimic exposure to signal 3 cytokines during T cell priming to promote T helper cell 1 (Th1) polarization of CD4+CAR T cells with the goal of enhancing antitumor activity. Using human CAR T cells and xenograft models we interrogated the impact of T-bet overexpression on CAR T cell antitumor activity in vitro and in vivo. We also used a syngeneic murine CAR T cell model to study the impact of T-bet overexpression on long-term persistence and secondary responses to tumor rechallenge.</p><p><strong>Results: </strong>T-bet overexpression reduced expression of the Th2 cytokine interleukin 4 and promoted polyfunctional production of Th1-associated cytokines in response to CAR stimulation. T-bet overexpression enhanced some effector functions in vitro but did not improve CAR T cell-mediated control of leukemia expressing high levels of antigen in vivo. T-bet overexpression also improved effector function of murine CD19 CAR T cells with no impairment to the persistence or ability of persistent CAR T cells to re-expand and clear a secondary leukemia challenge. Finally, T-bet overexpression promoted enhanced in vitro function against leukemia expressing low levels of CD19, which translated to improved control of CD19lo leukemia in vivo by human C19 CAR T cells containing a 4-1BB costimulatory domain.</p><p><strong>Conclusions: </strong>Together, our data demonstrate that T-bet overexpression induces a reduction in Th2 cytokine production, an increase in polyfunctional Th1 cytokine production and enhances 4-1BB CAR T cell activity against cancers expressing low levels of target antigen without promoting a loss in functional CAR T cell persistence.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 4","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12007057/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144017925","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":"Novel PD-1-targeted, activity-optimized IL-15 mutein SOT201 acting in cis provides antitumor activity superior to PD1-IL2v.","authors":"Hana Matuskova, Pavel Marasek, Vladyslav Mazhara, Ekaterina Simonova, Lucie Kosinova, Petr Danek, Klara Danova, Katerina Sajnerova, Iva Malatova, Klara Hrabankova, Denise Greco, Ondrej Martinec, Matej Fabisik, Nada Podzimkova, Kamila Hladikova, Katerina Behalova, Zuzana Antosova, Milada Sirova, Romana Mikyskova, Milan Reinis, Marek Kovar, David Béchard, Ulrich Moebius, Lenka Palova Jelinkova, Radek Spisek, Martin Steegmaier, Irena Adkins","doi":"10.1136/jitc-2024-010736","DOIUrl":"https://doi.org/10.1136/jitc-2024-010736","url":null,"abstract":"<p><strong>Background: </strong>SOT201 and its murine surrogate mSOT201 are novel cis-acting immunocytokines consisting of a humanized/murinized/, Fc-silenced anti-programmed cell death protein 1 (PD-1) monoclonal antibody (mAb) fused to an attenuated human interleukin (IL)-15 and the IL-15Rα sushi+ domain. Murine mPD1-IL2v is a conjugate of a murinized, Fc silenced anti-PD-1 mAb bearing human IL-2 with abolished IL-2Rα binding. These immunocytokines spatiotemporally reinvigorate PD-1⁺ CD8⁺ tumor-infiltrating lymphocytes (TILs) via cis-activation and concomitantly activate the innate immunity via IL-2/15Rβγ signaling.</p><p><strong>Methods: </strong>Human peripheral blood mononuclear cell and cell lines were used to evaluate cis/trans activity of SOT201. Anti-PD-1 mAb responsive (MC38, CT26) and resistant (B16F10, CT26 STK11 KO) mouse tumor models were used to determine the anticancer efficacy, and the underlying immune cell activity was analyzed via single-cell RNA sequencing and flow cytometry. The expansion of tumor antigen-specific CD8⁺ T cells by mSOT201 or mPD1-IL2v and memory CD8⁺ T-cell generation in vivo was determined by flow cytometry.</p><p><strong>Results: </strong>SOT201 delivers attenuated IL-15 to PD-1⁺ T cells via cis-presentation, reinvigorates exhausted human T cells and induces higher interferon-γ production than pembrolizumab in vitro. mSOT201 administered as a single dose exhibits strong antitumor efficacy with several complete responses in all tested mouse tumor models. While mPD1-IL2v activates CD8⁺ T cells with a 50-fold higher potency than mSOT201 in vitro, mSOT201 more effectively reactivates effector exhausted CD8⁺ T cells (Tex), which demonstrate higher cytotoxicity, lower exhaustion and lower immune checkpoint transcriptional signatures in comparison to mPD1-IL2v in MC38 tumors in vivo. This can be correlated with a higher rate of complete responses in the MC38 tumor model following mSOT201 treatment when compared with mPD1-IL2v. mSOT201 increased the relative number of tumor antigen-specific CD8⁺ T cells, and unlike mPD1-IL2v stimulated greater expansion of adoptively transferred ovalbumin-primed CD8⁺ T cells simultaneously limiting the peripheral CD8⁺ T-cell sink, leading to the development of memory CD8⁺ T cells in vivo.</p><p><strong>Conclusions: </strong>SOT201 represents a promising therapeutic candidate that preferentially targets PD-1⁺ TILs, delivering balanced cytokine activity for reviving CD8⁺ Tex cells in tumors. SOT201 is currently being evaluated in the Phase I clinical study VICTORIA-01 (NCT06163391) in patients with advanced metastatic cancer.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 4","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12007054/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143990506","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":"PCI-DB: a novel primary tissue immunopeptidome database to guide next-generation peptide-based immunotherapy development.","authors":"Steffen Lemke, Marissa L Dubbelaar, Patrick Zimmermann, Jens Bauer, Annika Nelde, Naomi Hoenisch Gravel, Jonas Scheid, Marcel Wacker, Susanne Jung, Anna Dengler, Yacine Maringer, Hans-Georg Rammensee, Cecile Gouttefangeas, Sven Fillinger, Tatjana Bilich, Jonas S Heitmann, Sven Nahnsen, Juliane S Walz","doi":"10.1136/jitc-2024-011366","DOIUrl":"https://doi.org/10.1136/jitc-2024-011366","url":null,"abstract":"<p><strong>Background: </strong>Various cancer immunotherapies rely on the T cell-mediated recognition of peptide antigens presented on human leukocyte antigens (HLA). However, the identification and selection of naturally presented peptide targets for the development of personalized as well as off-the-shelf immunotherapy approaches remain challenging.</p><p><strong>Methods: </strong>Over 10,000 raw mass spectrometry (MS) files from over 3,000 tissue samples were analyzed, summing to approximately seven terabytes of data. The raw MS data were processed using the standardized and open-source nf-core pipelines MHCquant2 and epitopeprediction, providing a uniform procedure for data handling. A global false discovery rate was applied to minimize false-positive identifications.</p><p><strong>Results: </strong>Here, we introduce the open-access Peptides for Cancer Immunotherapy Database (PCI-DB, https://pci-db.org/), a comprehensive resource of immunopeptidome data originating from various malignant and benign primary tissues that provides the research community with a convenient tool to facilitate the identification of peptide targets for immunotherapy development. The PCI-DB includes >6.6 million HLA class I and >3.4 million HLA class II peptides from over 40 tissue types and cancer entities. First application of the database provided insights into the representation of cancer-testis antigens across malignant and benign tissues, enabling the identification and characterization of cross-tumor entity and entity-specific tumor-associated antigens (TAAs) as well as naturally presented neoepitopes from frequent cancer mutations. Further, we used the PCI-DB to design personalized peptide vaccines for two patients suffering from metastatic cancer. In a retrospective analysis, PCI-DB enabled the composition of both a multi-peptide vaccine comprising non-mutated, highly frequent TAAs matching the immunopeptidome of the individual patient's tumor and a neoepitope-based vaccine matching the mutational profile of a patient with cancer. Both vaccine approaches induced potent and long-lasting T-cell responses, accompanied by long-term survival of these patients with advanced cancer.</p><p><strong>Conclusion: </strong>The PCI-DB provides a highly versatile tool to broaden the understanding of cancer-related antigen presentation and, ultimately, supports the development of novel immunotherapies.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 4","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12001369/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143990704","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}