bims-tuinly 2025-09-07 papers

bims-tuinly

Biomed News

on Tumor-infiltrating lymphocytes therapy

Issue of 2025–09–07
ten papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Immune correlates and mechanisms of TIL therapy efficacy: current insights and knowledge gaps.
IL-7-PD-L1 nano-antibody mediated "zipper" effect augments the tumoricidal activity of tumor-infiltrating lymphocytes.
Fast tumor-infiltrating lymphocytes (TILs): rapid manufacture of an adoptive cellular therapeutic from pleural infiltrating T cells for intrapleural administration.
Mechanisms and clinical advancements of cell-based immunotherapies in non-small cell lung cancer: an integrated perspective.
γδ T cells are the prime antitumoral T cells in pediatric neuroblastoma.
Single-cell clonal lineage tracing identifies the transcriptional program controlling the cell fate decisions by neoantigen-specific CD8 + T cells.
CAR T cell therapy for central nervous system solid tumors: current progress and future directions.
Exploration of the Roles and Mechanisms Between Tumor-Infiltrating Lymphocytes and Hepatocellular Carcinoma Based on Single-Cell Transcriptomics.
Multifunctional Hybrid Membrane-Coated Nanomotors for Magnetically Guided, Cascade-Activated Chemoimmunotherapy for Triple-Negative Breast Cancer.
Novel Radiofluorinated Nanobody PET Tracer for Preclinical Studies of TIM3 Expression.

Trends Cancer. 2025 Aug 29. pii: S2405-8033(25)00200-6. [Epub ahead of print]

Immune correlates and mechanisms of TIL therapy efficacy: current insights and knowledge gaps.

Blanca Navarro Rodrigo, Yaquelin Ortiz Miranda, Jesús Corria-Osorio, George Coukos, Alexandre Harari.

  Tumor-infiltrating lymphocyte (TIL) therapy has emerged as a transformative approach in cancer immunotherapy, particularly following the recent US Food and Drug Administration (FDA) approval of lifileucel for advanced melanoma. This review synthesizes current insights into the immune correlates and mechanisms underlying the efficacy of TIL therapy, highlighting the pivotal role of tumor immunogenicity, TIL functional states, and the tumor microenvironment (TME). Recent advances in single-cell profiling and biomarker discovery have enabled more precise patient selection and therapy optimization, while novel expansion protocols and engineered TILs are addressing resistance and broadening applicability to non-melanoma tumors. Collectively, these developments underscore the promise of next-generation TIL therapies to revolutionize treatment paradigms across a wider spectrum of solid cancers.

Keywords:  TIL therapy; adoptive cell transfer; biomarkers; correlates of efficacy; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1016/j.trecan.2025.08.002
Exp Hematol Oncol. 2025 Aug 29. 14(1): 112

IL-7-PD-L1 nano-antibody mediated "zipper" effect augments the tumoricidal activity of tumor-infiltrating lymphocytes.

Zhongjie Yu, Zhen Guo, Bin Jiang, Yueshu Zhu, Lin Shao, Xinhua Zhang, Yi Zhao, Di Wu, Aotian Xu.

  Cancer represents a pressing global health concern, characterized by a substantial number of unmet clinical needs. Cell therapy has emerged as a promising and efficacious approach for cancer treatment, particularly tumor-infiltrating lymphocytes (TILs), which have demonstrated remarkable improvements in patients' overall survival rates across various clinical studies. However, the tumor microenvironment exerts a adverse effect on TILs, leading to their rapid exhaustion and functional disorder. Consequently, this impedes their ability to effectively eradicate tumors and thus hinders the achievement of the anticipated therapeutic efficacy. Here, we employed lentiviral vector-mediated genetic engineering to manipulate TILs for the expression of TIGIT shRNA, IL-7-PD-L1 nano-antibody fusion protein, and the 'molecular switch' HuEGFRt. The engineered TILs exhibited higher viability, reinforced cell expansion, and reduced reliance on IL-2. The stem-like proportion of engineered TILs is significantly augmented, and their activation level is enhanced when co-cultured with tumor cells. Meanwhile, the engineered TILs exert sustained cytotoxicity after repeated stimulation from tumor cells. The use of Cetuximab has been demonstrated in vitro to induce specific apoptosis of engineered TILs through HuEGFRt, thereby ensuring safety throughout the treatment process. In the mouse tumor model, following infusion of engineered TILs, the tumor volume significantly reduced, once again demonstrating the effectiveness of engineered TILs. The findings of our study demonstrate the exceptional performance of engineered TILs, which undoubtedly holds great promise for the clinical application of engineered TILs, ultimately benefiting a larger population of cancer patients.

Keywords:  Cytotoxicity; IL-7; PD-L1 nano-antibody; TIGIT; Tumor microenvironment; Tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1186/s40164-025-00702-y
Cytotherapy. 2025 Aug 13. pii: S1465-3249(25)00762-5. [Epub ahead of print]

Fast tumor-infiltrating lymphocytes (TILs): rapid manufacture of an adoptive cellular therapeutic from pleural infiltrating T cells for intrapleural administration.

Vera S Donnenberg, John Lister, Charlene L Briedenbaugh, Patrick L Wagner, David L Bartlett, Albert D Donnenberg.

   BACKGROUND AIMS: Cancers of many different tissue origins can metastasize to the pleura, a space with a unique immune environment that predisposes to aggressive tumor behavior and the development of effusions, an exudative leakage of serous fluid accompanied by an immune infiltrate. Effusions are drained therapeutically to relieve dyspnea, often several times per week. Characteristically, they contain 50-1000 × 106 viable pleural T cells (PITs), which can be reliably activated and expanded in culture, making them an ideal source for generation of a cellular therapeutic. We sought to determine the feasibility of a Good Manufacturing Practice-compliant, rapidly manufactured adoptive cellular therapeutic from pleural-infiltrating T cells and to determine the cytolytic activity against autologous tumor, cytokine secretion profile, and immune check point molecule (ICM) expression.
METHODS: Six products were generated from consecutively collected malignant pleural effusions (MPEs) drained from patients with breast (4) or non-small cell lung (2) cancer metastatic to the pleura. CD4+ and CD8+ cells were immunomagnetically selected, stimulated with anti-CD3/anti-CD28 and expanded in the presence of interleukin (IL)-7 and IL-15 (12.5 ng/mL each) using the Miltenyi CliniMACS Prodigy device. Cells were cultured for 8- 12 days. Cytokines were assayed in the MPE and in the culture medium before harvest using a multiplexed bead assay. Cytolytic activity of the final cellular product formulation against an autologous tumor was measured in a 4-hour killing assay by lactate dehydrogenase release. T-cell content, ICM expression and intracellular interferon ɣ were assessed by flow cytometry.
RESULTS: All MPEs successfully generated products containing 0.7 to 3.2 × 109 viable T cells. All final products showed no growth in bacterial or fungal cultures. T-cell purity was 98.3 ± 1.7% (mean, standard deviation), viability was 97.6 ± 1.7% and T-cell fold expansion was 14.3 ± 10.6. Twenty cytokines (excluding IL-7 and IL-15) were present in the culture supernatants at ≥10 pmol/L. These include granzyme B, interferon-ɣ, IL-13, perforin, granulocyte-macrophage colony-stimulating factor and tumor necrosis factor-α. In the final cellular product formulation, 69 ± 28% of CD4+ T cells, and 75 ± 27% of CD8+ T-cells produced interferon-ɣ without additional stimulation. ICM expression was well correlated between CD4+ and CD8+ T cells and was relatively low, with TIGIT (44.6 ± 10.9%) and programmed cell death protein 1(21.1 ± 6.7%) being the highest. All products evidenced cytolytic activity against an autologous tumor, with maximal lysis ranging from 19.4% to 100% and cytolytic indices ranging from 4.3 to 21.1.
CONCLUSIONS: We conclude that Fast tumor-infiltrating lymphocytes (Fast TIL), an adoptive cellular therapeutic generated from drained MPEs, can be rapidly and reliably manufactured using the Prodigy system. The products have demonstrable in vitro effector activity against an autologous tumor. Expression of interferon-ɣ in the majority of cells, without accompanying elevated expression of ICM, suggests that the cells have not been exhausted during expansion. Based in part on the results presented here, the US Food and Drug Administration has issued Investigational New Drug status (IND # 30892) for the rapid manufacture of PIT-based cellular therapeutic (Fast TIL), paving the way for a first-in-human clinical trial (supported by CDMRP-TTSA CA230972). We plan to infuse this product intrapleurally, accompanied by low-dose intrapleural IL-2 with the expectation that infused cells will immediately encounter tumor antigens, continue to expand in the pleural space, and migrate to the peripheral circulation.

Keywords:  adoptive cellular therapy; malignant pleural effusion; pleural infiltrating T cells; tumor infiltrating lymphocytes

DOI:  https://doi.org/10.1016/j.jcyt.2025.06.011
Front Immunol. 2025 ;16 1633100

Mechanisms and clinical advancements of cell-based immunotherapies in non-small cell lung cancer: an integrated perspective.

Lixian Yang, Yaoyao Gong.

  Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide, with only modest improvements in survival despite advances in conventional therapies. Cell-based immunotherapy, which utilizes ex vivo expanded or genetically modified immune cells, has emerged as a promising therapeutic alternative. Approaches such as natural killer (NK) cells, tumor-infiltrating lymphocytes (TILs), dendritic cell (DC)-based vaccines, cytokine-induced killer (CIK) cells, and chimeric antigen receptor T (CAR-T) cells have shown encouraging potential in preclinical and early clinical studies. However, their clinical efficacy in NSCLC is significantly constrained by multiple factors, including the immunosuppressive tumor microenvironment (TME), intratumoral antigenic heterogeneity, and limited persistence and expansion of adoptively transferred cells. To address these barriers, advances in cellular engineering, rational combinatorial regimens, and refined patient selection strategies are actively being explored. This review provides a critical overview of the current landscape of cell-based therapies in NSCLC, focusing on recent breakthroughs, persistent limitations, and evolving strategies to enhance therapeutic outcomes. By contextualizing these developments, we aim to clarify the translational potential of cellular immunotherapy and its role in redefining the treatment paradigm for NSCLC.

Keywords:  cell therapy; chimeric antigen receptor T cell therapy; clinical trials; dendritic cellcytokine-induced killer cell therapy; lymphocyteactivated killer cell therapy; non-small cell lung cancer; tumor-infiltrating lymphocyte cell therapy

DOI:  https://doi.org/10.3389/fimmu.2025.1633100
Life Sci Alliance. 2025 Nov;pii: e202503249. [Epub ahead of print]8(11):

γδ T cells are the prime antitumoral T cells in pediatric neuroblastoma.

Suzanne M Castenmiller, Anne L Borst, Leyma Wardak, Jan J Molenaar, Maria Papadopoulou, Ronald R de Krijger, Alida Fw van der Steeg, Max M van Noesel, David Vermijlen, Rosa de Groot, Judith Wienke, Monika C Wolkers.

High-risk pediatric neuroblastoma patients have a dismal survival rate despite intensive treatment regimens. New treatment options are thus required. Even though HLA expression in neuroblastoma is low and immune cell infiltrates are limited, the presence of tumor-infiltrating lymphocytes (TILs) is indicative of better patient survival. Here, we show that most tumor lesions contain viable immune cell infiltrates after induction chemotherapy, with high percentages of CD3+ T cells. We therefore expanded the TILs and tested their antitumoral activity. With sufficient starting material, TIL expansion was as efficient as for adult solid tumors. However, whereas TIL products from adult tumors almost exclusively contained αβ T cells, in neuroblastoma-derived TIL products, γδ T cells expanded with similar efficacy as αβ T cells. Importantly, the antitumor responses in response to autologous tumor digest primarily originated from (Vδ1- and Vδ3-expressing) γδ T cells, and not from αβ T cells. In conclusion, this finding creates a window of opportunity for immunotherapy for neuroblastoma patients, with γδ T cells as potential prime responders.

DOI: https://doi.org/10.26508/lsa.202503249
bioRxiv. 2025 Aug 18. pii: 2025.08.13.670223. [Epub ahead of print]

Single-cell clonal lineage tracing identifies the transcriptional program controlling the cell fate decisions by neoantigen-specific CD8 + T cells.

Ying Luo, Chen Yao, Tuoqi Wu.

Neoantigen-specific T cells specifically recognize tumor cells and are critical for cancer immunotherapies. However, the transcriptional program controlling the cell fate decisions by neoantigen-specific T cells is incompletely understood. Here, using joint single-cell transcriptome and TCR profiling, we mapped the clonal expansion and differentiation of neoantigen-specific CD8 + T cells in the tumor and draining lymph node in mouse prostate cancer. Compared to other antitumor CD8 + T cells and bystanders, neoantigen-specific CD8 + tumor-infiltrating lymphocytes (TILs) upregulated gene signatures of T cell activation and exhaustion. In the tumor draining lymph node, we identified TCF1 + TOX - T SCM , TCF1 + TOX + T PEX , and TCF1 - TOX + effector-like T EX subsets among neoantigen-specific CD8 + T cells. Clonal tracing analysis of neoantigen-specific CD8 + T cells revealed greater clonal expansion in divergent clones and less expansion in clones biased towards T EX, T PEX , or T SCM . The T PEX subset had greater clonal diversity and likely represented the root of neoantigen-specific CD8 + T cell differentiation, whereas highly clonally expanded effector-like T EX cells were positioned at the branch point where neoantigen-specific clones exited the lymph node and differentiated into T EX TILs. Notably, T SCM differentiation of neoantigen-specific CD8 + clones in the lymph node negatively correlated with exhaustion and clonal expansion of the same clones in the tumor. In addition, the gene signature of neoantigen-specific clones biased toward tumor infiltration relative to lymph node residence predicted a poorer response to immune checkpoint inhibitor. Together, we identified the transcriptional program that controls the cell fate choices by neoantigen-specific CD8 + T cells and correlates with clinical outcomes in cancer patients.

DOI: https://doi.org/10.1101/2025.08.13.670223
Front Immunol. 2025 ;16 1600403

CAR T cell therapy for central nervous system solid tumors: current progress and future directions.

Yaroslav Kaminskiy, Vitaly Degtyarev, Alexey Stepanov, Michael Maschan.

  Central nervous system (CNS) tumors are the second most common type of cancer in children and remain the leading cause of mortality in pediatric oncology. For patients with high-risk CNS tumors, standard treatments often prove ineffective, with survival rates being less than 10%. Hence, there is an urgent need to develop alternative treatment strategies for this patient population. Globally, numerous clinical trials are actively investigating a range of novel therapeutic approaches, from pharmacological and immunological therapies to physical modalities targeting the tumor. Among these emerging therapies, CAR T cell therapy has shown great promise, with the first objective clinical responses already reported. This review aims to evaluate the current landscape of CAR T cell therapy for pediatric CNS tumors, focusing on clinical efficacy, toxicity profiles of systemic and locoregional delivery, antigen heterogeneity, and key challenges in clinical implementation. We provide a comprehensive analysis of reported clinical trials, including not only CAR T cell studies but also investigations involving tumor-infiltrating lymphocytes (TILs), NK and lymphokine-activated killer (LAK) cells, offering a broader perspective on immunotherapeutic approaches for CNS malignancies.

Keywords:  CAR T; CAR T solid tumors; CNS tumors; DIPG; DMG; brain cancer; glioblastoma; glioma

DOI:  https://doi.org/10.3389/fimmu.2025.1600403
Int J Genomics. 2025 ;2025 1575734

Exploration of the Roles and Mechanisms Between Tumor-Infiltrating Lymphocytes and Hepatocellular Carcinoma Based on Single-Cell Transcriptomics.

Taiyu Shi, Donghao Cheng, Xinyan Du, Jianning Wang, Siyuan Jiang, Liangyu Yang, Fen Chen, Chenxu Gong, Yan Ou, Bangjie Chen, Yiwen Jia.

  Hepatocellular carcinoma (HCC) remains a major global health challenge, with limited effective treatment options, particularly in advanced-stage patients. The tumor immune microenvironment (TIME) plays a crucial role in HCC progression and treatment response, with tumor-infiltrating lymphocytes (TILs) being key modulators of immune activity. In this study, we investigated the immunosuppressive role of TIL-related genes in NASH-associated HCC (NASH-HCC) and identified their potential as independent prognostic factors. We employed Gene Set Enrichment Analysis (GSEA) and Weighted Gene Coexpression Network Analysis (WGCNA) to explore immune suppression in NASH-HCC and identify TIL-related gene modules. Machine learning approaches were utilized to construct a prognostic model, validated using multiple cohorts from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). The model's predictive power was assessed using Kaplan-Meier survival analysis and receiver operating characteristic (ROC) curves. Furthermore, single-cell RNA sequencing (scRNA-seq) analysis was performed to examine the role of TIL-related genes in different immune cell populations within TIME. We identified 10 distinct cell types in HCC and demonstrated that T cells exhibited the highest TIL pathway activity, playing a critical role in cellular communication via MIF signaling. Our findings highlight the immunosuppressive nature of TILs in NASH-HCC and provide valuable insights into their prognostic significance, potentially guiding future immunotherapeutic strategies.

Keywords:  hepatocellular carcinoma; machine learning; postoperative prediction model; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1155/ijog/1575734
ACS Appl Mater Interfaces. 2025 Sep 04.

Multifunctional Hybrid Membrane-Coated Nanomotors for Magnetically Guided, Cascade-Activated Chemoimmunotherapy for Triple-Negative Breast Cancer.

Man Lung Lee, Li Wang, Jack Chun Hin Chen, Ellen Ngar-Yun Poon, Dinggeng He, Hung-Wing Li.

  Here, we report a multifunctional hybrid membrane-coated nanomotor for cancer chemoimmunotherapy, which consists of mesoporous silica-coated iron oxide nanoparticles (MF) as a drug carrier, loaded with doxorubicin (DOX), l-arginine (l-arg), and glucose oxidase (GOx), and camouflaged with a hybrid of red blood cell membranes (mRBC) and cancer cell membranes (CCM). RM-GDL-MF has a cascade of catalytic reactions, where glucose is catalyzed by GOx to produce H2O2, and l-arg is oxidized by the produced H2O2 to release nitric oxide (NO), leading to self-propelled motion in order to promote the penetration of the extracellular matrix (ECM) in the tumor. The hybrid membrane provides not only stealth properties from mRBC to evade immune clearance but also tumor-orientation ability to target the tumor from the CCM. The generation of reactive oxygen species (ROS) was demonstrated to induce immunogenic cell death (ICD), thereby enhancing antitumor immune responses through the recruitment of CD8+ tumor-infiltrating lymphocytes (TILs), promotion of dendritic cell maturation, and reprogramming of macrophages toward the proinflammatory M1 phenotype. In vitro and in vivo experiments demonstrated that RM/R4-GDL-MF had significant tumor accumulation efficiency and antitumor efficacy. This multimodal nanomotor shows great potential for effectively treating tumors.

Keywords:  cell membrane coating; chemotherapy; immunotherapy; nanomotor; triple-negative breast cancer

DOI:  https://doi.org/10.1021/acsami.5c10644
Mol Pharm. 2025 Sep 05.

Novel Radiofluorinated Nanobody PET Tracer for Preclinical Studies of TIM3 Expression.

Dongye Zheng, Yong Huang, Chengze Li, Yanye Lu, Zhaoheng Xie, Ying Liang, Qiushi Ren, Xiangxi Meng.

  T-cell immunoglobulin and mucin domain-3 (TIM3) is an inhibitory checkpoint glycoprotein expressed on immune cells, particularly tumor-infiltrating lymphocytes (TILs), and plays a critical role in suppressing antitumor immune responses. While dual blockade of TIM3 and programmed cell death protein 1 (PD1) has shown promising results in enhancing immune responses in advanced cancers, the lack of reliable, noninvasive methods for detecting TIM3 expression in tumors remains a major challenge. To address this, we developed and characterized a novel positron emission tomography (PET) tracer, [18F]AlF-RESCA-HVCR2N2, based on a TIM3-specific nanobody labeled via [18F]AlF radiochemistry. The tracer demonstrated high specificity and affinity for TIM3 (KD = 4.644 nM) in vitro, enabling the clear visualization of TIM3-expressing lesions in tumor models through PET imaging. Dynamic imaging and kinetic analyses revealed favorable pharmacokinetics, and a preliminary correlation was observed between PET signal intensity and histologically assessed TIM3 expression in tumor tissues. These results highlight the potential of [18F]AlF-RESCA-HVCR2N2 as a sensitive and noninvasive tool for quantifying TIM3 expression in vivo, with significant implications for patient stratification, treatment monitoring, and the development of TIM3-targeted immunotherapies.

Keywords:  PET imaging; RESCA; TIM3; nanobody; radiofluorination

DOI:  https://doi.org/10.1021/acs.molpharmaceut.5c00839