bims-tuinly 2025-01-19 papers

bims-tuinly

Biomed News

on Tumor-infiltrating lymphocytes therapy

Issue of 2025–01–19
ten papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Characteristics of successful expansion of tumor-infiltrating lymphocytes from colorectal cancer liver metastasis.
Durable complete response after combined treatment with tumor-infiltrating lymphocytes and oncolytic adenovirus (TILT-123) in a patient with metastatic mucosal melanoma.
Adoptive cell therapy with tumor-infiltrating lymphocytes in combination with nivolumab in patients with advanced melanoma.
A novel semi-quantitative scoring method for CD8+ tumor-infiltrating lymphocytes based on infiltration sites in gastric cancer.
Engineered Cellular Therapies for the Treatment of Thoracic Cancers.
The differences in the distribution characteristics and prognostic value of tumor-infiltrating T lymphocyte subsets between lung adenocarcinoma and lung squamous cell carcinoma.
Utilization of primary tumor samples for cancer neoantigen discovery.
CD93 blockade promotes effector T-cell infiltration and facilitates adoptive cell therapy in solid tumors.
Clinical utility of tumor-infiltrating lymphocyte evaluation by two different methods in breast cancer patients treated with neoadjuvant chemotherapy.
Myeloid cells meet CD8+ T cell exhaustion in cancer: What, why and how.

Sci Rep. 2025 Jan 10. 15(1): 1639

Characteristics of successful expansion of tumor-infiltrating lymphocytes from colorectal cancer liver metastasis.

Jina Baek, Gyuheon Choi, GunHee Lee, Hyun Lee, Gyungyub Gong, Hye Seon Park, Chae-Lyul Lim, Joo Young Kim, Hee Jin Lee.

  Adoptive cell therapy (ACT) utilizing tumor-infiltrating lymphocytes (TILs) has emerged as a successful treatment modality for various malignancies. However, TILs cultured from colorectal cancer (CRC) liver metastasis remain underexplored. Fifteen CRC liver metastasis tissues underwent initial expansion (IE) of TILs and rapid expansion (REP). Histologic examination including the level of stromal TILs and Klintrup-Mäkinen score, were assessed by pathologists and deep learning-derived spatial analysis. We performed correlation analysis between expanded TILs and histopathologic factors. All cases exhibited successful IE, with a mean IE TIL count per fragment and total IE TIL per case of 2.59 ± 2.79e5 cells and 167.79 ± 126.97e5 cells, respectively. Five cases underwent REP, with a median fold change of 3,610 (range, 1,136-4,925). The median CD4+/CD8 + ratio in IE TILs and REP TILs were 3.66 and 0.68, respectively. A significant correlation was observed between the mean number of expanded TILs per fragment and KM score (p = 0.022). Successful expansion of TILs from CRC liver metastasis was achieved. Assessment of KM score may serve as a predictive tool for the obtainable TILs before IE. These findings lay the groundwork for future studies to establish effective ACT in patients with metastatic CRC.

Keywords:  Adoptive cell therapy; Colorectal cancer; Liver metastasis; Tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1038/s41598-025-85892-5
Immunooncol Technol. 2024 Dec;24 100726

Durable complete response after combined treatment with tumor-infiltrating lymphocytes and oncolytic adenovirus (TILT-123) in a patient with metastatic mucosal melanoma.

T J Monberg, T Kudling, B Albieri, S Pakola, E Ellebaek, M Donia, R L Eefsen, C von Buchwald, C Kistler, J M Santos, J Clubb, L Haybout, M C W Westergaard, D C A Quixabeira, E Jirovec, R Havunen, S Sorsa, V Cervera-Carrascon, A Hemminki, I M Svane.

   Background: Despite significant advancements in the treatment of malignant melanoma, metastatic mucosal melanoma remains a therapeutic challenge due to its complex pathogenesis, distinct pathological characteristics, and limited response to immunotherapy. Combining different immunotherapeutic approaches offers a potential strategy to address these challenges. Tumor-infiltrating lymphocyte (TIL) therapy and oncolytic virus therapy represent promising treatment modalities that may synergize with each other.
Patient and methods: We present a case of a 48-year-old woman with metastatic sinonasal mucosal melanoma who achieved a durable complete pathological response following treatment with multiple injections of the oncolytic virus TILT-123 (igrelimogene litadenorepvec) and a single infusion of TILs, without preconditioning chemotherapy or postconditioning interleukin-2.
Results: Immunohistochemical analysis and single-cell sequencing revealed interesting alterations in injected and noninjected tumors as well as in peripheral blood, during the treatment course, suggesting that TILT-123 facilitated TIL engraftment into the tumor, ultimately leading to a complete response.
Conclusions: This case underscores the potential of combined immunotherapeutic approaches as a promising strategy for patients with metastatic mucosal melanoma.

Keywords:  case report; mucosal melanoma; oncolytic virus therapy; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1016/j.iotech.2024.100726
Immunooncol Technol. 2024 Dec;24 100728

Adoptive cell therapy with tumor-infiltrating lymphocytes in combination with nivolumab in patients with advanced melanoma.

D König, B Kasenda, M Sandholzer, A Chirindel, A Zingg, R Ritschard, H Thut, K Glatz, E A Kappos, D Schaefer, C Kettelhack, J Passweg, K Baur, A Holbro, A Buser, D Lardinois, L T Jeker, N Khanna, F Stenner, M S Matter, N Rodrigues Mantuano, M Binder, A Zippelius, H Läubli.

   Background: Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TIL) is a personalized immunotherapy. The efficacy of TIL-ACT has been demonstrated prospectively in patients with advanced melanoma but is not limited to melanoma patients. Many patients are refractory to TIL-ACT, however, or their cancer becomes resistant. Combining anti-programmed cell death protein 1 (anti-PD-1) with TIL-ACT to antagonize the immunosuppressive tumor microenvironment may synergize to enhance the antitumor potential.
Material and methods: We set up the BaseTIL trial (NCT04165967), a single-center investigator-initiated phase I trial, to test feasibility and safety of TIL-ACT followed by PD-1 blockade in patients with advanced cutaneous melanoma with disease progression after at least one line of anti-PD-1. TIL-ACT included tumor collection, ex vivo TIL expansion, lymphodepletion with cyclophosphamide and fludarabine, TIL transfer, and in vivo TIL stimulation with interleukin 2 (125 000 IU/kg, 10 days). TIL-ACT was followed by nivolumab treatment for a maximum of 2 years. Nine patients were planned for inclusion.
Results: Between 2020 and 2022, we enrolled 11 patients and 9 underwent a TIL transfer (median transfused cell number: 66.25 × 109). Two patients did not start lymphodepletion. Nine patients received at least 1 dose of interleukin 2 (median number: 10; range, 1-10), seven started nivolumab (median number: 5; range, 2-23). All patients had hematologic adverse events (AEs). Most common non-hematologic AEs were fever and cytokine release syndrome. No nivolumab-associated AEs of ≥ grade 2 occurred. The objective response rate to TIL-ACT was 22% (2/9, 2 partial remission).
Conclusions: TIL-ACT with nivolumab is feasible and safe. Larger trials are needed to further determine the efficacy of this combination.

Keywords:  adoptive cell therapy; melanoma; nivolumab; phase I trial; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1016/j.iotech.2024.100728
Am J Cancer Res. 2024 ;14(12): 5965-5986

A novel semi-quantitative scoring method for CD8+ tumor-infiltrating lymphocytes based on infiltration sites in gastric cancer.

Yudai Nakabayashi, Jun Kiuchi, Takeshi Kubota, Takuma Ohashi, Keiji Nishibeppu, Taisuke Imamura, Kenji Nanishi, Hiroki Shimizu, Tomohiro Arita, Yusuke Yamamoto, Hirotaka Konishi, Ryo Morimura, Shuhei Komatsu, Atsushi Shiozaki, Hisashi Ikoma, Yoshiaki Kuriu, Hitoshi Fujiwara, Hitoshi Tsuda, Eigo Otsuji.

  No established method currently exists for evaluating tumor-infiltrating lymphocytes (TILs) in gastric cancer (GC), and their clinical significance based on infiltration site in GC remains unclear. In this study, we developed a method to evaluate TILs according to their infiltration site as a prognostic marker for GC. We retrospectively analyzed 103 patients with advanced GC who underwent curative resection. TILs located at the invasive margin (TILIM) and the center of tumors (TILCT) were scored semi-quantitatively using immunohistochemical staining of CD8+ T cells. The sum of the TILIM and TILCT scores was defined as the TILs score. Based on this score, patients were classified into low and high TILs groups. Quantitative TILs were also assessed to validate the semi-quantitative scoring method. Furthermore, we confirmed a tumor suppressive effect due to CD8+ T cells co-cultured in GC cell lines in vitro. In the univariate analysis, patients with low TILIM were significantly more likely to be female, younger, and have undifferentiated histological types and deeper tumor invasion compared to those with high TILIM. Similarly, patients with low TILCT had significantly more positive lymph node metastases than those with high TILCT. In the multivariate analysis, deeper tumor invasion and positive lymph node metastasis were identified as independent risk factors for patients with low TILIM and low TILCT, respectively. According to our semi-quantitative TILs scoring method, the low TILs group had significantly poorer prognoses compared to the high TILs group. This group had significantly larger tumor diameters, deeper tumor invasion, and more positive lymph node metastases. Additionally, deeper tumor invasion was an independent risk factor for the low TILs group. Quantitative TILs analysis revealed that the low TILs group had significantly lower TIL levels compared to the high TILs group. In vitro, CD8+ T cells induced apoptosis in GC cells in a concentration-dependent manner. Furthermore, these cells significantly suppressed the proliferative, migratory, and invasive capacities of GC cells. Our simple and versatile semi-quantitative scoring method for CD8+ TILs indicates that CD8+ TILs are sensitive prognostic markers. The low TILs group accurately reflects the low quantitative TIL levels and is associated with poor oncological prognosis.

Keywords:  CD8+ T cells; gastric cancer; immunohistochemical staining; semi-quantitative scoring; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.62347/JKCU5881
Cancers (Basel). 2024 Dec 26. pii: 35. [Epub ahead of print]17(1):

Engineered Cellular Therapies for the Treatment of Thoracic Cancers.

Spencer M Erickson, Benjamin M Manning, Akhilesh Kumar, Manish R Patel.

  Thoracic malignancies (lung cancers and malignant pleural mesothelioma) are prevalent worldwide and are associated with high morbidity and mortality. Effective treatments are needed for patients with advanced disease. Cell therapies are a promising approach to the treatment of advanced cancers that make use of immune effector cells that have the ability to mediate antitumor immune responses. In this review, we discuss the prospect of chimeric antigen receptor-T (CAR-T) cells, natural killer (NK) cells, T cell receptor-engineered (TCR-T) cells, and tumor-infiltrating lymphocytes (TILs) as treatments for thoracic malignancies. CAR-T cells and TILs have proven successful in several hematologic cancers and advanced melanoma, respectively, but outside of melanoma, results have thus far been unsuccessful in most other solid tumors. NK cells and TCR-T cells are additional cell therapy platforms with their own unique advantages and challenges. Obstacles that must be overcome to develop effective cell therapy for these malignancies include selecting an appropriate target antigen, combating immunosuppressive cells and signaling molecules present in the tumor microenvironment, persistence, and delivering a sufficient quantity of antitumor immune cells to the tumor. Induced pluripotent stem cells (iPSCs) offer great promise as a source for both NK and T cell-based therapies due to their unlimited expansion potential. Here, we review clinical trial data, as well as recent basic scientific advances that offer insight into how we may overcome these obstacles, and provide an overview of ongoing trials testing novel strategies to overcome these obstacles.

Keywords:  CAR-T cells; NK cells; cell therapy; lung cancer; mesothelioma

DOI:  https://doi.org/10.3390/cancers17010035
Chin Clin Oncol. 2024 Dec;13(6): 83

The differences in the distribution characteristics and prognostic value of tumor-infiltrating T lymphocyte subsets between lung adenocarcinoma and lung squamous cell carcinoma.

Zhen Zhang, Shaoyan Zhang, Yalai Xu, Xiaoning Liu, Wenjie Dong.

   BACKGROUND: The characteristics of tumor immune microenvironment are important factors affecting the efficacy of immunotherapy, and there are differences in the distribution of tumor-infiltrating lymphocyte (TIL) subsets in different types of tumors. This study aims to compare the distributions of cluster of differentiation (CD) 4+ and CD4+ T cell subsets of TILs and their clinical significance between lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC).
METHODS: The tumor tissues of 78 LUAD and 56 LUSC patients who underwent surgery at The Second Affiliated Hospital of Zhengzhou University between October 2020 and October 2022 were collected, TIL level were detected by pathological observation, and the proportions of CD4+, CD4+ T cell subsets and CD4+/CD4+ ratio in TILs were detected by flow cytometry. These indicators were compared between LUAD and LUSC, and their correlations with clinicopathological characteristics and patient survival were analyzed.
RESULTS: There was no significant difference in the TILs level between LUAD and LUSC (P>0.05). The CD4+/CD4+ ratio in LUSC was lower, and proportion of CD4+ T cells was higher than those in LUAD (all P<0.05). In LUAD, the proportions of CD4+, CD4+ T cells and CD4+/CD4+ were correlated with tumor size or tumor-node-metastasis (TNM) stage, while in LUSC, only the proportions of CD4+ and CD4+ T cells were correlated with tumor size, degree of differentiation or TNM stage. In LUAD patients, higher proportions of CD4+, CD4+ T cells and lower CD4+/CD4+ predicted longer survival, and high CD4+/CD4+ (>1.04) was an independent risk factor for PFS and OS (P<0.05); In LUSC patients, there was no correlation between the proportions of CD4+ T cells, CD4+ T cells and CD4+/CD4+ ratio, and patient prognosis (P>0.05).
CONCLUSIONS: There were differences in the distribution and balance of CD4+ and CD4+ TIL subsets between LUAD and LUSC, among which CD4/CD4+ ratio closely affected the prognosis of LUAD patients but had relatively weak prognostic value in LUSC patients due to the restriction of CD4+ T cells.

Keywords:  CD4; CD8; Lung adenocarcinoma (LUAD); lung squamous cell carcinoma (LUSC); tumor-infiltrating lymphocytes (TILs)

DOI:  https://doi.org/10.21037/cco-24-62
J Immunother Cancer. 2025 Jan 11. pii: e010993. [Epub ahead of print]13(1):

Utilization of primary tumor samples for cancer neoantigen discovery.

Vid Leko, Eric Groh, Shoshana T Levi, Amy R Copeland, Bradley Sinclair White, Billel Gasmi, Yong Li, Victoria Hill, Devikala Gurusamy, Noam Levin, Sanghyun Peter Kim, Sivasish Sindiri, Jared J Gartner, Todd D Prickett, Maria Parkhust, Frank J Lowery, Stephanie L Goff, Steven A Rosenberg, Paul Robbins.

   BACKGROUND: The use of tumor-infiltrating T lymphocytes (TIL) that recognize cancer neoantigens has led to lasting remissions in metastatic melanoma and certain cases of metastatic epithelial cancer. For the treatment of the latter, selecting cells for therapy typically involves laborious screening of TIL for recognition of autologous tumor-specific mutations, detected through next-generation sequencing of freshly resected metastatic tumors. Our study explored the feasibility of using archived formalin-fixed, paraffin-embedded (FFPE) primary tumor samples for cancer neoantigen discovery, to potentially expedite this process and reduce the need for resections normally required for tumor sequencing.
METHOD: Whole-exome sequencing was conducted on matched primary and metastatic colorectal cancer samples from 22 patients. The distribution of metastatic tumor mutations that were confirmed as neoantigens through cognate TIL screening was evaluated in the corresponding primary tumors. Mutations unique to primary tumors were screened for recognition by metastasis-derived TIL and circulating T lymphocytes.
RESULTS: We found that 25 (65.8%) of the 38 validated neoantigens identified in metastatic tumors from 18 patients with colorectal cancer were also present in matched primary tumor samples. This included all 12 neoantigens encoded by putative cancer driver genes, which are generally regarded as superior targets for adoptive cell therapy. The detection rate for other neoantigens, representing mutations without an established role in cancer biology, was 50% (13/26). Gene products encoding neoantigens detected in the primary tumors were not more likely to be clonal or broadly distributed among the analyzed metastatic lesions compared with those undetected in the primary tumors. Additionally, we found that mutations detected only in primary tumor samples did not elicit recognition by metastatic tumor-derived TIL but could elicit specific recognition by the autologous circulating memory T cells.
CONCLUSIONS: Our findings indicate that primary FFPE tumor-derived screening libraries could be used to discover most neoantigens present in metastatic tumors requiring treatment. Furthermore, this approach can reveal additional neoantigens not present in resected metastatic tumors, prompting further research to understand their clinical relevance as potential therapeutic targets.

Keywords:  Adoptive cell therapy - ACT; Gastrointestinal Cancer; T cell Receptor - TCR; Tumor infiltrating lymphocyte - TIL; Tumor mutation burden - TMB

DOI:  https://doi.org/10.1136/jitc-2024-010993
J Immunother Cancer. 2025 Jan 13. pii: e010554. [Epub ahead of print]13(1):

CD93 blockade promotes effector T-cell infiltration and facilitates adoptive cell therapy in solid tumors.

Yi Sun, Elliott Yee, Yuki Fujiwara, Kaitlyn Dickinson, Yujie Guo, Zhiwei Sun, Junyi Hu, Eduardo Davila, Richard D Schulick, Yuwen Zhu.

   BACKGROUND: Adaptive cellular therapy (ACT), particularly chimeric antigen receptor (CAR)-T cell therapy, has been successful in the treatment of hemopoietic malignancies. However, poor trafficking of administered effector T cells to the tumor poses a great hurdle for this otherwise powerful therapeutic approach in solid cancers. Our previous study revealed that targeting CD93 normalizes tumor vascular functions to improve immune checkpoint blockade therapy. The objective of this study is to evaluate whether CD93 blockade improves ACT in solid cancers.
METHODS: Monoclonal antibodies (mAbs) against CD93 or IGFBP7 were administered in implanted mouse melanoma models to assess the effect of CD93 blockade on ACT. Different sources of effector T cells were used, including pre-activated CD8+OT-1, pmel-1 transgenic T cells, and CAR-T cells. Rip-OVA and Rip-TAG-OVA transgenic mice were used to evaluate the selective impact of CD93 blockade on effector T-cell infiltration in tumors. For mechanistic studies, vascular maturation was determined by immunofluorescent staining and flow cytometry was performed to examine tumor-infiltrating T lymphocytes. Neutralizing mAbs against adhesion molecules ICAM1 and VCAM1 were infused to assess their involvement.
RESULTS: Blockade of the CD93 pathway increases the expression of adhesion molecules on tumor vasculature to improve effector T-cell infiltration and function. T-cell transfer and CD93 blockade synergistically improve tumor vascular maturation, as well as inhibit tumor progression. Anti-CD93 selectively promotes effector T-cell infiltration in a tumorous setting where the CD93 pathway is upregulated. In a solid mouse tumor model, blockade of the CD93 pathway improves CAR-T therapy.
CONCLUSIONS: CD93 blockade normalizes tumor vasculature leading to improved effector T-cell infiltration and function in solid cancers. Our study advocates the application of CD93 blockade for ACT in solid cancers.

Keywords:  Adoptive cell therapy - ACT; Immunotherapy; Solid tumor; T cell; Tumor infiltrating lymphocyte - TIL

DOI:  https://doi.org/10.1136/jitc-2024-010554
Breast Cancer. 2025 Jan 14.

Clinical utility of tumor-infiltrating lymphocyte evaluation by two different methods in breast cancer patients treated with neoadjuvant chemotherapy.

Masayuki Nagahashi, Eri Ishikawa, Takahiro Nagai, Haruka Kanaoka, Aoi Oshiro, Yusa Togashi, Akira Hattori, Junko Tsuchida, Tomoko Higuchi, Arisa Nishimukai, Keiko Murase, Yuichi Takatsuka, Takako Kihara, Yiwei Ling, Shujiro Okuda, Seiichi Hirota, Yasuo Miyoshi.

   PURPOSE: The aim of this study was to examine the clinical utility of tumor-infiltrating lymphocytes (TILs) evaluated by "average" and "hot-spot" methods in breast cancer patients.
METHODS: We examined 367 breast cancer patients without neoadjuvant chemotherapy (NAC) by average and hot-spot methods to determine the consistency of TIL scores between biopsy and surgical specimens. TIL scores before NAC were also compared with the pathological complete response (pCR) rate and clinical outcomes in 144 breast cancer patients that received NAC. TIL scores evaluated by the two methods were predicted from clinicopathological data using random forest regression.
RESULTS: Surgical specimens showed higher TIL scores than biopsy specimens using the hot-spot method (p < 0.001), while biopsy and surgical specimens showed similar TIL scores using the average method. There was a linear relationship between the pCR rate and TIL scores determined using hot-spot (p < 0.001) and average methods (p = 0.001). Patients without pCR and low TILs by the average method had significantly worse overall survival compared to other patients (p = 0.02). The root mean squared errors of the predicted TIL score for the test set were 19.662 (hot-spot) and 10.955 (average).
CONCLUSION: The average method may have an advantage for breast cancer patients receiving NAC, since the TIL score using this method is more consistent between biopsy and surgical specimens, and it associates better with clinical outcomes. Our exploratory study showed that machine learning from clinicopathological data may better predict TIL scores assessed by the average, rather than hot-spot, method.

Keywords:  Breast neoplasm; Machine learning; Neoadjuvant chemotherapy; Pathological complete response; Tumor-infiltrating lymphocyte

DOI:  https://doi.org/10.1007/s12282-025-01665-y
Chin J Cancer Res. 2024 Dec 30. 36(6): 616-651

Myeloid cells meet CD8+ T cell exhaustion in cancer: What, why and how.

Yijie Zhai, Xiaoting Liang, Mi Deng.

  Exhausted T cell (Tex) is a specific state of T cell dysfunction, in which these T cells gradually lose their effector function and change their phenotype during chronic antigen stimulation. The enrichment of exhausted CD8+ T cell (CD8+ Tex) in the tumor microenvironment is one of the important reasons leading to the poor efficacy of immunotherapy. Recent studies have reported many reasons leading to the CD8+ T cell exhaustion. In addition to cancer cells, myeloid cells can also contribute to T cell exhaustion via many ways. In this review, we discuss the history of the concept of exhaustion, CD8+ T cell dysfunction states, the heterogeneity, origin, and characteristics of CD8+ Tex. We then focus on the effects of myeloid cells on CD8+ Tex, including tumor-associated macrophages (TAMs), dendritic cells (DCs) and neutrophils. Finally, we systematically summarize current strategies and recent advancements in therapies reversing and CD8+ T cell exhaustion.

Keywords:  CD8+ T cell exhaustion; Cancer; immunotherapy; myeloid cells; reinvigorate T cell exhaustion

DOI:  https://doi.org/10.21147/j.issn.1000-9604.2024.06.04