bims-tuinly 2025-03-23 papers

bims-tuinly

Biomed News

on Tumor-infiltrating lymphocytes therapy

Issue of 2025–03–23
twelve papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

The Clinical TIL Experience in Melanoma: Past, Present, Future.
Surgical Considerations in Tumor-Infiltrating Lymphocyte Therapy: Challenges and Opportunities.
Tumor-Infiltrating Lymphocyte Therapy for Melanoma and Other Solid Tumors: Looking Back, Yet Moving Forward.
Safety and efficacy of combined treatment with tumor-infiltrating lymphocytes and oncolytic adenovirus TILT-123 in metastatic melanoma.
Tumor-Infiltrating Lymphocyte Therapy: A New Frontier.
Optimizing TIL therapy for uveal melanoma: lessons learned and unlearned from cutaneous melanoma.
T lymphocyte-based immune response and therapy in hepatocellular carcinoma: focus on TILs and CAR-T cells.
Prognostic Significance of Immune and Stromal Components in Colorectal Cancer: Practical Tools for Routine Pathologic Assessment.
Frequent PD-L1 expression in oral squamous cell carcinoma of non-smokers and non-drinkers, and association of tumor infiltrating lymphocytes with favorable prognosis.
Defining the Quality Attributes for Tumor-Infiltrating Lymphocyte Medicinal Products.
Prediction and analysis of tumor infiltrating lymphocytes across 28 cancers by TILScout using deep learning.
A new marker for predicting sentinel lymph node metastasis in early (cT1-2N0) breast cancer: Tumor-infiltrating lymphocytes (TILs).

Transplant Cell Ther. 2025 Mar;pii: S2666-6367(24)00784-X. [Epub ahead of print]31(3S): S626-S634

The Clinical TIL Experience in Melanoma: Past, Present, Future.

James W Smithy, Adam J Schoenfeld, Allison Betof Warner.

  The recent approval of lifileucel by the US Food and Drug Administration in February 2024 was the culmination of over 3 decades of research in adoptive cell therapy with tumor-infiltrating lymphocytes (TILs) for unresectable melanoma. In this review, we highlight key historical data for TIL therapy in melanoma as well as ongoing efforts to improve its efficacy and applicability.

Keywords:  Autologous; Immunotherapy; Melanoma; Tumor infiltrating lymphocytes

DOI:  https://doi.org/10.1016/j.jtct.2024.11.013
Transplant Cell Ther. 2025 Mar;pii: S2666-6367(24)00800-5. [Epub ahead of print]31(3S): S591-S598

Surgical Considerations in Tumor-Infiltrating Lymphocyte Therapy: Challenges and Opportunities.

Amanda Kirane, David Lee, Charlotte Ariyan.

  Adoptive T cell therapy (ACT) using tumor-infiltrating lymphocytes (TILs) is a promising personalized immunotherapy approach, spearheaded by Dr. Steven Rosenberg, targeting various cancer types. Despite initial challenges in TIL production, recent advancements have showcased its superiority to immune checkpoint blockade in metastatic melanoma, even after anti-PD-1 therapy failure. The expedited manufacturing process, now around 3 weeks, coupled with the US Food and Drug Administration approval of lifileucel in 2024, is poised to propel TIL therapy into mainstream oncology. This commentary delves into the critical surgical aspects of TIL harvesting, emphasizing the integral role of surgeons in ensuring optimal TIL quality, safety, and therapeutic effectiveness. By shedding light on these considerations, this article aims to guide and enhance collaborative efforts in advancing TIL therapy for patients facing limited treatment options.

Keywords:  Cell therapy; Immunotherapy; Melanoma; Surgery; Tumor infiltrating lymphocytes

DOI:  https://doi.org/10.1016/j.jtct.2024.11.015
Transplant Cell Ther. 2025 Mar;pii: S2666-6367(24)00801-7. [Epub ahead of print]31(3S): S581-S590

Tumor-Infiltrating Lymphocyte Therapy for Melanoma and Other Solid Tumors: Looking Back, Yet Moving Forward.

Alexander N Shoushtari, Daniel J Powell.

  Lifileucel, the first solid tumor adoptive tumor infiltrating lymphocyte (TIL) therapy product to receive regulatory approval in advanced melanoma, represents a critical achievement in the pursuit of improving outcomes using cellular therapies in patients with solid tumors. This review traces the development of adoptive TIL therapy from the initial human studies in melanoma, through recent advances in studies of other solid tumors, and previews ongoing and future areas for preclinical and clinical advances to improve upon this novel therapeutic strategy.

Keywords:  Cellular therapy; Clinical trial; Melanoma; Preclinical; Solid tumor; Tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1016/j.jtct.2024.11.017
Cell Rep Med. 2025 Mar 18. pii: S2666-3791(25)00089-8. [Epub ahead of print]6(3): 102016

Safety and efficacy of combined treatment with tumor-infiltrating lymphocytes and oncolytic adenovirus TILT-123 in metastatic melanoma.

Tine J Monberg, Santeri A Pakola, Benedetta Albieri, Eva Ellebaek, Marco Donia, Rikke L Eefsen, Troels H Borch, Tatiana V Kudling, Torben Lorentzen, Helle W Hendel, Cecilie Vestergaard, Cathrine Lorentzen, Rikke B Holmstroem, Victor Arias, Amir Khammari, Claudia Kistler, João M Santos, James H A Clubb, Lyna Haybout, Marie C W Westergaard, Özcan Met, Dafne C A Quixabeira, Elise Jirovec, Riikka Havunen, Suvi Sorsa, Victor Cervera-Carrascon, Brigitte Dreno, Akseli Hemminki, Inge Marie Svane.

  Tumor-infiltrating lymphocytes (TILs) are effective in the treatment of metastatic melanoma (MM), but toxicity limits its application. TILT-123 (igrelimogene litadenorepvec) is an oncolytic adenovirus producing interleukin-2 (IL-2) and tumor necrosis factor (TNF) upon replication. In this phase 1 trial, 17 patients with metastatic checkpoint inhibitor-resistant melanoma are treated with TILT-123 and TILs without preconditioning chemotherapy or postconditioning IL-2. The treatment is safe and feasible. According to computed tomography (CT), the objective response rate is 11.7% (2/17) and disease control is observed in 35% (6/17), including a partial response lasting >8 months and a durable complete response in a mucosal melanoma patient. According to positron emission tomography (PET), disease control is observed in 7/15 (47%) with minor or partial responses in 4/15 (27%). In the initial TILT-123 monotherapy phase of the trial, disease control is observed in 6/17 (35%) and 10/16 (63%) in CT and PET, respectively. The study demonstrates good tolerability and preliminary efficacy.

Keywords:  TIL therapy; cancer immunotherapy; combination immunotherapy; cutaneous melanoma; mucosal melanoma; oncolytic virus therapy; tumor-infiltrating lymphocytes; uveal melanoma

DOI:  https://doi.org/10.1016/j.xcrm.2025.102016
Transplant Cell Ther. 2025 Mar;pii: S2666-6367(24)00783-8. [Epub ahead of print]31(3S): S599-S609

Tumor-Infiltrating Lymphocyte Therapy: A New Frontier.

Diane Tseng, Sylvia Lee.

  In recent years, the successful use of tumor-infiltrating lymphocyte (TIL) therapy to treat melanoma not only culminated in a landmark Food and Drug Administration approval, but has also fueled the emergence of a new, rapidly growing field in TIL cellular immunotherapy surrounding novel enhancements in TIL design, refined manufacturing strategies to enrich for more potent TIL populations, as well as numerous clinical trials now investigating TIL therapy in additional solid tumor types beyond melanoma. This review provides a summary of the latest advances in TIL therapy and what lies ahead for the field. The first section explores several solid cancers that demonstrate the greatest potential for future indications of TIL therapy. The second section provides insight into the promising innovations for designing the next generation of TIL with greater specificity, persistence, safety, and function.

Keywords:  Breast cancer; Cervical cancer; Melanoma; Non–small cell lung cancer; T cell therapy; Tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1016/j.jtct.2024.11.014
Immunotherapy. 2025 Mar 18. 1-9

Optimizing TIL therapy for uveal melanoma: lessons learned and unlearned from cutaneous melanoma.

Shravan Leonard-Murali, Udai S Kammula.

  Adoptive transfer of tumor infiltrating lymphocytes (TIL-ACT) is a personalized cancer therapy that harnesses the anti-tumor activity of tumor resident T cells through ex vivo activation and expansion. This therapy involves the infusion of a single dose of ex vivo expanded TIL together with high dose IL-2 following a preparative lymphodepleting chemotherapy. The United States Food and Drug Administration approved lifileucel in 2024 as the first autologous TIL product for patients with advanced cutaneous melanoma (CM), adding to the list of approved immunotherapies for this highly immunogenic cancer. However, the role for TIL-ACT in other solid tumors is unclear, especially for poorly immunogenic cancers with low tumor mutational burden. In this review, we describe the historical development of TIL-ACT, summarize the clinical results in advanced CM, and describe the novel application of TIL-ACT to metastatic uveal melanoma (UM), a prototypic immunotherapy-resistant solid tumor. We will highlight key biologic differences between CM and UM, their consequential influence on the manufacturing of UM-specific TIL products, and the development of novel biomarkers for precision TIL-ACT for metastatic UM.

Keywords:  Uveal melanoma; adoptive cell therapy; immune checkpoint inhibition; immune exclusion; immunotherapy; tumor infiltrating lymphocytes

DOI:  https://doi.org/10.1080/1750743X.2025.2478808
Naunyn Schmiedebergs Arch Pharmacol. 2025 Mar 18.

T lymphocyte-based immune response and therapy in hepatocellular carcinoma: focus on TILs and CAR-T cells.

Thikra Majid Muhammed, Saade Abdalkareem Jasim, Ahmed Hussein Zwamel, Safia Obaidur Rab, Suhas Ballal, Abhayveer Singh, Anima Nanda, Subhashree Ray, Ahmed Hjazi, Hatif Abdulrazaq Yasin.

  Hepatocellular carcinoma (HCC) is among the leading causes of cancer-related death worldwide. The primary therapies for HCC are liver transplantation, hepatic tumor excision, radiofrequency ablation, and molecular-targeted medicines. An unfavorable prognosis marks HCC and has limited pharmacological response in therapeutic studies. The tumor immune microenvironment (TME) imposes significant selection pressure on HCC, resulting in its evolution and recurrence after various treatments. As the principal cellular constituents of tumor-infiltrating lymphocytes (TILs), T cells have shown both anti-tumor and protumor actions in HCC. T cell-mediated immune responses are pivotal in cancer monitoring and elimination. TILs are recognized for their critical involvement in the progression, prognosis, and immunotherapeutic management of HCC. Foxp3 + , CD8 + , CD3 + , and CD4 + T cells are the extensively researched subtypes of TILs. This article examines the functions and processes of several subtypes of TILs in HCC. Emerging T cell-based therapies, including TILs and chimeric antigen receptor (CAR)-T cell therapy, have shown tumor regression in several clinical and preclinical studies. Herein, it also delves into the existing T cell-based immunotherapies in HCC, with emphasis on TILs and CAR-T cells.

Keywords:  Chimeric antigen receptor cells; Hepatocellular carcinoma; T lymphocyte; Tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1007/s00210-025-04035-9
Arch Pathol Lab Med. 2025 Mar 21.

Prognostic Significance of Immune and Stromal Components in Colorectal Cancer: Practical Tools for Routine Pathologic Assessment.

Mi Jang, Yongki Hong, Soojung Hong, Eun Kyung Kim.

CONTEXT.—: In colorectal cancer (CRC), the tumor microenvironment includes cancer-associated fibroblasts and a variety of immune cells, which are increasingly recognized for their prognostic significance.
OBJECTIVE.—: To evaluate the tumor microenvironment in CRC using methodologies applicable in routine pathologic practice.
DESIGN.—: A comprehensive evaluation of the local immune response and tumor to stroma ratio (TSR) was performed in 930 CRC cases by thoroughly reviewing the whole hematoxylin-eosin (H&E) slides. Local immune responses were assessed using peritumoral inflammatory infiltration (Klintrup-Mäkinen and modified Klintrup-Mäkinen methods), intratumoral stromal tumor-infiltrating lymphocytes (TILs; International TILs Working Group system and deep stromal TIL system), and Crohn-like lymphoid reaction (CLR).
RESULTS.—: In the multivariate analysis, age (>68 years), stage III-IV, microsatellite stability, signet ring cell/undifferentiated carcinoma, extramural venous invasion, high TSR (>50%), and CLR were independent prognostic factors for disease-specific survival. Excluding microsatellite stability, these factors also served as significant prognostic indicators for progression-free survival. Among the 4 methods for measuring local immune response, evaluating the proportion of TILs within the deepest intratumoral stroma was an independent predictor of progression-free survival.
CONCLUSIONS.—: We suggest that evaluating CLR, TSR, and stromal TILs on hematoxylin-eosin-stained slides represent a practical and straightforward approach with significant prognostic value.

DOI: https://doi.org/10.5858/arpa.2024-0350-OA
Transl Oncol. 2025 Mar 15. pii: S1936-5233(25)00088-9. [Epub ahead of print]55 102357

Frequent PD-L1 expression in oral squamous cell carcinoma of non-smokers and non-drinkers, and association of tumor infiltrating lymphocytes with favorable prognosis.

F J Mulder, E J de Ruiter, Tfb Gielgens, F Farshadpour, R de Bree, Mfcm van den Hout, B Kremer, S M Willems, Ejm Speel.

   OBJECTIVES: To determine the presence and prognostic value of PD-L1 and PD-L2 expression, and tumor-infiltrating lymphocytes (TILs) in oral squamous cell carcinoma (OSCC) of non-smokers and non-drinkers (NSND).
MATERIALS AND METHODS: Clinical characteristics and tumor tissue of 86 NSND with OSCC were retrospectively collected and analyzed for protein expression on tissue microarrays. Immunohistochemistry was performed for expression of PD-L1 CPS, PD-L2 TPS, and PD-1, CD45, CD8, CD4, CD3, and FoxP3-positive TILs/mm2. Slides were digitally evaluated using QuPath. Differences in 5-year DFS and OS were determined by log rank analysis. Predictors for survival were determined by multivariable cox regression analysis.
RESULTS: Eighty-eight percent (76/86) of OSCC showed PD-L1 expression (CPS ≥1). Patients with high numbers of CD4-positive TILs showed a better DFS and OS than patients with low numbers of CD4-positive TILs. In the best multivariable model, CD4-positive TILs were an independent predictor for DFS (p = 0.010) and OS (p = 0.002) too. Additionally, patients with high numbers of CD45-positive TILs and a high CD8/FoxP3 ratio showed a better OS, of which the CD8/FoxP3 ratio was a near significant independent predictor (p = 0.050). Over 40 % of OSCC were PD-L1+/TIL+.
CONCLUSION: A large number of OSCC in NSND show PD-L1 expression (CPS ≥1). CD4 was a significant predictor for DFS and OS, in addition to the CD8/FoxP3 ratio being a near significant predictor for OS. The combination of frequent high CD8-positive TIL infiltrates in PD-L1-positive tumors makes NSND with OSCC in theory interesting candidates for treatment with immune checkpoint inhibitors.

Keywords:  Head and neck cancer; Non-drinkers; Non-smokers; Programmed death ligand 1; Tumor infiltrating lymphocytes

DOI:  https://doi.org/10.1016/j.tranon.2025.102357
Transplant Cell Ther. 2025 Mar;pii: S2666-6367(24)00368-3. [Epub ahead of print]31(3S): S610-S625

Defining the Quality Attributes for Tumor-Infiltrating Lymphocyte Medicinal Products.

Justin J Lievense, Cynthia Nijenhuis, Inge Jedema, Arendien Jonker-Hoogerkamp, Justin T Moyers, Omid Hamid, Jos H Beijnen, John B A G Haanen, Bastiaan Nuijen.

  Tumor-infiltrating lymphocyte (TIL) medicinal products (MPs) show promise for treating solid tumors, especially metastatic melanoma, in the clinical trial setting. Through these studies, TIL developers have gained an immunological perspective into the mechanism of action (MoA) and infusion product characteristics that influence clinical response. However, to reach marketing authorization for any of the TIL MPs, it will be beneficial to gain a pharmaceutical (process) development perspective as well, from which control of the TIL MPs manufacturing process can be demonstrated and a suitable control strategy can be developed. To do this, a well-defined TIL MP must be established. Defining and optimizing MPs from a pharmaceutical perspective is done by identifying and improving product characteristics or quality attributes (QAs) thought to impact safety and efficacy. Through awareness of the QAs relevant to TIL MPs and considering them throughout pharmaceutical development, improvements and changes can be validated. This approach to pharmaceutical development is part of the quality-by-design workflow, of which this review tackles the first steps. Here, the QAs are structured within a quality target product profile (QTPP), and the corresponding regulatory expectations are considered, spanning quantity, identity, purity, microbiological assays, and biological activity. Based on the regulatory expectations and available literature, the (critical) QAs and points of consideration are proposed when developing TIL MPs. The active pharmaceutical ingredient of the TIL MP is defined as the CD45+CD3+ cells. By analyzing identity attributes correlated to clinical efficacy, four broadly applicable in vivo functionalities associated with TIL MPs MoA and clinical effectiveness are described: tumor recognition, cytotoxic capacity, tumor homing, and persistence. How these in vivo functionalities are quantified in potency assays and the limitations of their methods/readouts are also discussed. The QTPP is a foundation for developing a robust, substantiated control strategy for regulatory approval and increasing patient access. Harmonizing TIL MP development under a unified QTPP applicable in different settings could also facilitate comparisons and, therefore, the development of safer and more efficacious TIL MP variations.

Keywords:  Adoptive cell therapy; Pharmaceutical development; Quality attributes; Quality-by-design; Tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1016/j.jtct.2024.04.015
NPJ Precis Oncol. 2025 Mar 19. 9(1): 76

Prediction and analysis of tumor infiltrating lymphocytes across 28 cancers by TILScout using deep learning.

Huibo Zhang, Lulu Chen, Lan Li, Yang Liu, Barnali Das, Shuang Zhai, Juan Tan, Yan Jiang, Simona Turco, Yi Yao, Dmitrij Frishman.

The density of tumor-infiltrating lymphocytes (TILs) serves as a valuable indicator for predicting anti-tumor responses, but its broad impact across various types of cancers remains underexplored. We introduce TILScout, a pan-cancer deep-learning approach to compute patch-level TIL scores from whole slide images (WSIs). TILScout achieved accuracies of 0.9787 and 0.9628, and AUCs of 0.9988 and 0.9934 in classifying WSI patches into three categories-TIL-positive, TIL-negative, and other/necrotic-on validation and independent test sets, respectively, surpassing previous studies. The biological significance of TILScout-derived TIL scores across 28 cancers was validated through comprehensive functional and correlational analyses. A consistent decrease in TIL scores with an increase in cancer stage provides direct evidence that the lower TIL content may stimulate cancer progression. Additionally, TIL scores correlated with immune checkpoint gene expression and genomic variation in common cancer driver genes. Our comprehensive pan-cancer survey highlights the critical prognostic significance of TILs within the tumor microenvironment.

DOI: https://doi.org/10.1038/s41698-025-00866-0
PLoS One. 2025 ;20(3): e0320487

A new marker for predicting sentinel lymph node metastasis in early (cT1-2N0) breast cancer: Tumor-infiltrating lymphocytes (TILs).

Xihao Ni, Weitao Wang, Huimin Sun, Ran An, Ying Lei, Chang-Liang Wang.

BACKGROUND: Tumor-infiltrating lymphocytes (TILs) are associated with lymph node metastasis and prognosis in breast cancer. Therefore, we explored the value of TILs in predicting sentinel lymph node metastasis (SLNM) in patients with early-stage (cT1-2N0) breast cancer and provided a new method for preoperative assessment of SLNM status.
METHODS: This study included 337 patients with early-stage breast cancer who underwent surgery at our hospital from January 2022 to December 2023. The expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and Ki-67 in the patients was assessed using immunohistochemistry (IHC). TILs in the core needle biopsy samples were evaluated histopathologically, and patients were divided into high and low TILs groups based on the density of TILs. Statistical analysis was conducted, and a predictive model was established.
RESULTS: The study found that patients with high TILs had a significantly lower rate of SLNM compared to those with low TILs (P < 0.001). The cT stage and the level of TILs were identified as independent predictive factors for SLNM. The ROC curve analysis indicated that the density of TILs has good predictive efficacy for SLNM. Based on the results of the multivariate regression analysis, a nomogram predictive model for SLNM was constructed.
CONCLUSIONS: Our study showed that the density of TILs and cT stage are independent predictive factors for SLNM in early-stage (cT1-2N0) breast cancer, and the predictive effect of TILs density on SLNM is significant in Luminal and triple-negative breast cancers.

DOI: https://doi.org/10.1371/journal.pone.0320487