bims-tuinly 2025-02-09 papers

bims-tuinly

Biomed News

on Tumor-infiltrating lymphocytes therapy

Issue of 2025–02–09
seven papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Complete metabolic response as early predictor of long-term efficacy after adoptive T cell therapy using tumor-infiltrating lymphocytes.
Preclinical data and design of a phase I clinical trial of neoantigen-reactive TILs for advanced epithelial or ICB-resistant solid cancers.
Flow Cytometry-Based Isolation and Therapeutic Evaluation of Tumor-Infiltrating Lymphocytes in a Mouse Model of Pancreatic Cancer.
Optical-magnetic Imaging for Optimizing Lymphodepletion-TIL Combination Therapy in Breast Cancer.
The prognostic value of the tumor-stroma ratio compared to tumor-infiltrating lymphocytes in triple-negative breast cancer: a review.
The Impact of Nutritional Status and Tumor-Infiltrating Lymphocytes (CD4+ and CD8+) on Chemotherapy Response in Colorectal Cancer Patients.
A minimal gene set characterizes TIL specific for diverse tumor antigens across different cancer types.

J Immunother Cancer. 2025 Feb 06. pii: e010575. [Epub ahead of print]13(2):

Complete metabolic response as early predictor of long-term efficacy after adoptive T cell therapy using tumor-infiltrating lymphocytes.

Troels Holz Borch, Rikke Andersen, Helle Westergren Hendel, Kasper Madsen, Eva Ellebaek, Inge Marie Svane.

  Introduction: Adoptive cell therapy using tumor-infiltrating lymphocytes (TILs) has proved to be an effective treatment for metastatic melanoma, even in patients failing anti-PD-1 blockade. Nevertheless, progression is observed in a substantial subgroup of patients following an initial objective response to treatment with TILs. These patients might benefit from additional consolidating treatment before clinical progression, but thus far, it is not possible to identify this subgroup of patients prone to progress. In this study the predictive value of early metabolic response after TIL therapy is explored.Materials and methods: 60 patients treated with TIL therapy in 4 different clinical trials and with available [18F]2-fluoro-2-deoxy-d-glucose positron emission tomography-CT (FDG-PET/CT) scans at baseline and at least one follow-up scan 6-8 weeks and/or 12-16 weeks post-TIL infusion were included.Results: Obtaining complete metabolic response (CMR) was associated with significantly superior median overall survival (mOS) compared with not obtaining CMR (p<0.0001). Of particular interest, metabolic response divided RECIST partial responders (22 patients) into two groups with significantly different clinical outcomes. Neither mOS (range 32.2-149.8+) nor median progression-free survival (mPFS; range 20.7-123.4+) were reached for patients with partial response (PR)/CMR (10 patients), whereas patients with PR/non-CMR (12 patients) had a mOS of 28.7 months (p=0.0016) and a mPFS of 7.8 months (p<0.0001).Overall, not achieving a CMR was associated with a short mPFS of 3.2 months, and 97.9% (47/48) of all patients in this group progressed within 12 months.Conclusion: In conclusion, early CMR is a strong predictor of long-term survival after TIL therapy in metastatic melanoma patients. Furthermore, FDG-PET/CT scans appear superior to CT scans for providing early prognostic information after TIL therapy in melanoma and can be used to tailor patient-specific management and follow-up strategies.

Keywords:  Adoptive cell therapy - ACT; Immunotherapy; Nuclear medicine; Tumor infiltrating lymphocyte - TIL

DOI:  https://doi.org/10.1136/jitc-2024-010575
Immunooncol Technol. 2025 Mar;25 101030

Preclinical data and design of a phase I clinical trial of neoantigen-reactive TILs for advanced epithelial or ICB-resistant solid cancers.

J Palomero, V Galvao, I Creus, J Lostes, M Aylagas, A Marín-Bayo, M Rotxés, M Sanz, M Lozano-Rabella, A Garcia-Garijo, A Yuste-Estevanez, D Grases, J Díaz-Gómez, J González, J F Navarro, J J Gartner, I Braña, X Villalobos, N Bayó-Puxan, J Jiménez, A N Palazón, S Muñoz, G Villacampa, A Piris-Giménez, P Barba, M Codinach, L Rodríguez, S Querol, E Muñoz-Couselo, J Tabernero, S Martín-Lluesma, A Gros, E Garralda.

   Background: Adoptive cell therapy (ACT) of ex vivo expanded tumor-infiltrating lymphocytes (TILs) can mediate objective tumor regression in 28%-49% of metastatic melanoma patients. However, the efficacy of TIL therapy in most epithelial cancers remains limited. We present the design of a phase I clinical study that aims to assess the safety and efficacy of NEXTGEN-TIL, a TIL product selected based on ex vivo neoantigen recognition, in patients with advanced epithelial tumors and immune checkpoint blockade (ICB)-resistant solid tumors.
Materials and methods: Pre-rapid expansion protocol (REP) TIL cultures expanded in high-dose interleukin 2 (HD-IL-2) from patients with metastatic solid tumors were screened for recognition of autologous tumor cell lines (TCLs) and/or neoantigens. Six good manufacturing practice (GMP)-grade validations of pre-REP TIL expansion were carried out and TIL cultures from these six intermediate products were selected to carry out the clinical-scale GMP validation of the REP.
Results: TILs expanded in 82% of patient-derived tumor biopsies across different cancer types and these frequently contained tumor- and neoantigen-reactive T cells. During GMP validations, a variable number of TIL cultures expanded, constituting the intermediate products (pre-REP). Three finished products were manufactured using a REP which reached cell doses ranging from 4.3e9 to 1.1e11 and met the established specifications. The NEXTGEN-TIL clinical trial entails a first expansion of TILs from tumor fragments in HD-IL-2 followed by TIL screening for neoantigen recognition and REP of selected neoantigen-reactive TIL cultures. Treatment involves a classical non-myeloablative lymphodepleting chemotherapy followed by NEXTGEN-TIL product administration together with HD-IL-2.
Conclusions: NEXTGEN-TIL exploits ex vivo expanded neoantigen-reactive TIL to potentially improve efficacy in patients with epithelial and ICB-resistant tumors, with a safety profile like traditional TILs.

Keywords:  adoptive cell transfer; neoantigen-reactive T cells; phase I clinical trial; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1016/j.iotech.2024.101030
J Vis Exp. 2025 Jan 17.

Flow Cytometry-Based Isolation and Therapeutic Evaluation of Tumor-Infiltrating Lymphocytes in a Mouse Model of Pancreatic Cancer.

Xiangqin Zhao, Xinbo Gao, Wenwen Yu, Yi Lu, Xuesong Li, Lu Tan, Xiubao Ren, Yifei Wang, Weijie Song, Jihui Hao, Ying Ma.

Pancreatic cancer is an aggressive malignancy with a dismal prognosis and limited therapeutic options. Adoptive cell therapy, which involves isolating and activating a patient's own immune cells, such as tumor-infiltrating lymphocytes (TILs), before re-infusing them, represents a promising experimental approach. However, techniques for adoptive cell transfer in preclinical pancreatic cancer models are not well established. Here, we describe a detailed protocol for adoptive cell therapy using TILs from a syngeneic pancreatic cancer mouse model. The procedure involves implanting live or irradiated mouse pancreatic cancer cells in fluorescence-labeled reporter mice to initiate immune cell influx, then isolating lymphocytes from primary tumors via flow cytometry sorting and/or activating and expanding tumor-reactive T cells ex vivo, and adoptively transferring these activated T cells intraperitoneally into tumor-bearing mice, followed by interleukin-2 administration. Bioluminescent tumor imaging allows for longitudinal monitoring of orthotopic tumor growth and response to therapy, especially evaluating the tumor-specific cytotoxic effects. This approach recapitulates the logistics involved in developing adoptive cell transfer therapies for pancreatic cancer patients. The results demonstrate enhanced antitumor efficacy of adoptively transferred tumor-reactive T cells compared to irrelevant lymphocyte controls. This versatile methodology enables the in vivo study of adoptive immunotherapy in pancreatic cancer as well as the optimization of cell processing parameters and combination treatment regimens.

DOI: https://doi.org/10.3791/67413
Mol Imaging Biol. 2025 Feb 05.

Optical-magnetic Imaging for Optimizing Lymphodepletion-TIL Combination Therapy in Breast Cancer.

Jiaqian Li, Lishuang Guo, Yuan Feng, Guanghui Li, He Sun, Wei Huang, Jie Tian, Yang Du, Yu An.

   PURPOSE: Lymphodepletion before tumor-infiltrating lymphocytes (TIL) infusion can activate the immune system, enhance the release of homeostatic cytokines, and decrease the number of immunosuppressive cells. This process is crucial for improving the therapeutic efficacy of TIL therapy. However, the challenge of in vivo assessing TILs targeting tumors limits the optimization of lymphodepleting conditioning regimen (LDC).
PROCEDURES: This study aims to employ magnetic particle imaging (MPI) and fluorescence molecular imaging (FMI) to monitor TIL biodistribution in vivo and optimize LDC in triple-negative breast cancer TIL therapy. MPI provides quantitative imaging capabilities without depth limitations, effectively complementing the high sensitivity of FMI. The efficacy of different LDCs in enhancing TIL therapy was assessed using FMI, and MPI quantified the number of TILs accumulated in the 4T1 tumor.
RESULTS: TILs preserved viability, phenotypes, and anti-tumor efficacy after being labeled with superparamagnetic iron oxide and fluorescence dye DiR. The dual-modality imaging system effectively discerned variations in LDC treatments that enhanced TIL therapy. Compared to TIL monotherapy, lymphodepletion with TIL therapy improves tumor dual-modality imaging signal intensity, increases the expression of monocyte chemotactic protein-1 in serum and tumor tissue, and enhances the therapeutic effect of TILs.
CONCLUSION: Our results confirm the utility of optical-magnetic dual-modality imaging for tracking the biodistribution of TILs in vivo. With the help of optical-magnetic dual-modality imaging, we successfully optimize TIL combination therapy. Optical-magnetic dual-modality imaging provides a new approach to develop personalized immunotherapy strategies and mine potential therapeutic mechanisms for TIL.

Keywords:  Fluorescence molecular imaging; Lymphodepletion; Magnetic particle imaging; Triple-negative breast cancer; Tumor infiltrating lymphocyte therapy

DOI:  https://doi.org/10.1007/s11307-025-01985-7
Virchows Arch. 2025 Feb 04.

The prognostic value of the tumor-stroma ratio compared to tumor-infiltrating lymphocytes in triple-negative breast cancer: a review.

Layla Andour, Sophie C Hagenaars, Barbara Gregus, Anna Mária Tőkes, Zsófia Karancsi, Rob A E M Tollenaar, Judith R Kroep, Janina Kulka, Wilma E Mesker.

  Previous literature extensively explored biomarkers to personalize treatment for breast cancer patients. The clinical need is especially high in patients with triple-negative breast cancer (TNBC) due to its aggressive nature and limited treatment modalities. This review aims to evaluate the value of tumor-infiltrating lymphocytes (TILs) and tumor-stroma ratio (TSR) as prognostic biomarkers in TNBC patients and assess their clinical potential. A literature search was conducted in PubMed, Embase, Emcare, Web of Science, and Cochrane Library. Papers comparing survival outcomes of TNBC patients with low/high or negative/positive TSR and immune cells were included. The most frequently mentioned subgroups of TILs were selected and reported in this review. Data from 43 articles on TILs and eight articles on TSR were included. Among TNBC patients, high CD8 expression was generally associated with better survival. Notable, the poor survival outcomes were related to high intra-tumoral PD-L1 expression, whereas high stromal PD-L1 expression more often was correlated with favorable outcomes. For the TSR, a high amount of stroma in the primary tumor of TNBC patients was consistently associated with worse survival. This review highlights that a high number of CD8-positive T-cells is a promising prognostic factor for TNBC patients. PD-L1 expression analyzed for intra-tumoral and stromal expression separately reports strong but contrasting information. Finally, the TSR shows potential to be an important prognostic marker, especially for TNBC patients. Utilizing both biomarkers, either on itself or combined, could enhance clinical decision-making and personalization of treatment.

Keywords:  Breast cancer; CD-marker; Prognosis; Tumor-infiltrating lymphocytes; Tumor-stroma ratio

DOI:  https://doi.org/10.1007/s00428-025-04039-z
Cancer Manag Res. 2025 ;17 197-209

The Impact of Nutritional Status and Tumor-Infiltrating Lymphocytes (CD4+ and CD8+) on Chemotherapy Response in Colorectal Cancer Patients.

Kiki Lukman, Rhandy Septianto, Reno Rudiman, Tommy Ruchimat, Yunia Sribudiani, Prapanca Nugraha, Etis Primastari, Deny Budiman.

   Introduction: The World Health Organization reports that colorectal cancer (CRC) is the second leading cause of cancer-related mortality globally, with an estimated 1.9 million new cases annually. Tumor-infiltrating lymphocytes (TILs) are frequently associated with colorectal cancer and are believed to play a significant role in the immune response to cancer cells. Regarding chemotherapy responses in patients with colorectal cancer, this study aims to investigate the association between nutritional status and infiltrating lymphocyte counts, specifically CD4+ and CD8+.
Materials and Methods: This prospective observational study analyzed the impact of nutritional status using body mass index (BMI) and TILs levels (CD4+/CD8+) on chemotherapy outcomes in CRC patients treated at a tertiary hospital in West Java, Indonesia, from July 2023 to June 2024.
Results: Thirty-six research subjects were included. Eighteen participants had high levels of TILs CD4+ and CD8+ expression. Nutritional status, age, histological type, tumor site, stage, and metastasis showed no significant correlation with the expression of either CD4+ or CD8+. Nutritional status, levels of CD4+ and CD8+ were significantly associated with chemotherapy responses in CRC patients (p<0.001).
Conclusion: Nutritional status and elevated TIL levels (CD4+/CD8+) positively correlate with better chemotherapy response in CRC patients.

Keywords:  chemotherapy response; colorectal cancer; prognostic; tumor infiltrating lymphocytes

DOI:  https://doi.org/10.2147/CMAR.S503985
Nat Commun. 2025 Feb 03. 16(1): 1070

A minimal gene set characterizes TIL specific for diverse tumor antigens across different cancer types.

Zhen Zeng, Tianbei Zhang, Jiajia Zhang, Shuai Li, Sydney Connor, Boyang Zhang, Yimin Zhao, Jordan Wilson, Dipika Singh, Rima Kulikauskas, Candice D Church, Thomas H Pulliam, Saumya Jani, Paul Nghiem, Suzanne L Topalian, Patrick M Forde, Drew M Pardoll, Hongkai Ji, Kellie N Smith.

Identifying tumor-specific T cell clones that mediate immunotherapy responses remains challenging. Mutation-associated neoantigen (MANA) -specific CD8+ tumor-infiltrating lymphocytes (TIL) have been shown to express high levels of CXCL13 and CD39 (ENTPD1), and low IL-7 receptor (IL7R) levels in many cancer types, but their collective relevance to T cell functionality has not been established. Here we present an integrative tool to identify MANA-specific TIL using weighted expression levels of these three genes in lung cancer and melanoma single-cell RNAseq datasets. Our three-gene "MANAscore" algorithm outperforms other RNAseq-based algorithms in identifying validated neoantigen-specific CD8+ clones, and accurately identifies TILs that recognize other classes of tumor antigens, including cancer testis antigens, endogenous retroviruses and viral oncogenes. Most of these TIL are characterized by a tissue resident memory gene expression program. Putative tumor-reactive cells (pTRC) identified via MANAscore in anti-PD-1-treated lung tumors had higher expression of checkpoint and cytotoxicity-related genes relative to putative non-tumor-reactive cells. pTRC in pathologically responding tumors showed distinguished gene expression patterns and trajectories. Collectively, we show that MANAscore is a robust tool that can greatly enrich candidate tumor-specific T cells and be used to understand the functional programming of tumor-reactive TIL.

DOI: https://doi.org/10.1038/s41467-024-55059-3