bims-tuinly 2025-03-30 papers

bims-tuinly

Biomed News

on Tumor-infiltrating lymphocytes therapy

Issue of 2025–03–30
ten papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Tumor-Infiltrating Lymphocyte Therapy for Melanoma Has Arrived (at Last).
Entering a new era of tumor-infiltrating lymphocyte cell therapy innovation.
Anti-CD137 agonist antibody-independent and clinically feasible preparation of tumor-infiltrating lymphocytes from soft tissue sarcoma and osteosarcoma.
Tumor-Infiltrating Lymphocyte Scoring Improves Progression Risk Prediction in Stage II Melanoma: A Retrospective Cohort Study.
The Role of the Tumor Microenvironment (TME) in Advancing Cancer Therapies: Immune System Interactions, Tumor-Infiltrating Lymphocytes (TILs), and the Role of Exosomes and Inflammasomes.
Genetically engineered macrophages reverse the immunosuppressive tumor microenvironment and improve immunotherapeutic efficacy in TNBC.
A SITC vision: adapting clinical trials to accelerate drug development in cancer immunotherapy.
Recent developments on checkpoint inhibitors, CAR T cells, and beyond for T cell-based immunotherapeutic strategies against cancer.
Atezolizumab and bevacizumab combination in advanced hepatocellular carcinoma patients: The imperative for safety assessment studies.
Protocol for investigating the impact of transcription regulator deficiency on tumor-specific CD8+ T cell responses via adoptive cell transfer.

J Invest Dermatol. 2025 Mar 27. pii: S0022-202X(24)03033-1. [Epub ahead of print]

Tumor-Infiltrating Lymphocyte Therapy for Melanoma Has Arrived (at Last).

Alexandra M Haugh, David E Fisher, Donald P Lawrence.



Keywords:  Cellular therapy; Immunotherapy; Melanoma; TIL; Tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1016/j.jid.2024.04.039
Cytotherapy. 2024 Dec 28. pii: S1465-3249(24)00970-8. [Epub ahead of print]

Entering a new era of tumor-infiltrating lymphocyte cell therapy innovation.

Rodabe N Amaria, Krishna V Komanduri, Adam J Schoenfeld, Giridharan Ramsingh, Rachel A Burga, Madan H Jagasia.

  The therapeutic potential of adoptive cell therapy using tumor-infiltrating lymphocytes (TIL) has been established in advanced melanoma. In February 2024, lifileucel became the first TIL cell therapy to be approved by the FDA and is indicated for adult patients with advanced melanoma. Although the benefit of TIL cell therapy is best characterized in patients with advanced melanoma, several trials are ongoing investigating its safety and efficacy in other solid tumor indications. Nevertheless, wider applicability and adoption of TIL cell therapy will require continued innovation to provide a safer and more efficacious cell therapy product. Several investigational TIL cell therapy products are in preclinical and early clinical development and are applying novel technologies to overcome key challenges. Herein, we summarize the current state of TIL cell therapy and highlight innovations that may reshape its future.

Keywords:  TIL cell therapy; adoptive cell therapy; immuno-oncology; immunotherapy; tumor-infiltrating lymphocytes (TIL)

DOI:  https://doi.org/10.1016/j.jcyt.2024.12.010
Front Immunol. 2025 ;16 1557006

Anti-CD137 agonist antibody-independent and clinically feasible preparation of tumor-infiltrating lymphocytes from soft tissue sarcoma and osteosarcoma.

Yining Jin, Zhiliang Jia, Xueqing Xia, Nancy B Gordon, Joseph A Ludwig, Neeta Somaiah, Shulin Li.

   Background: Tumor infiltrating lymphocytes (TILs) therapy has been proved for treatment of metastatic melanoma and is under investigation for other types of solid tumors. However, these successes are threatened by discontinued supply of GMP-grade anti-CD137 agonist, a key TIL preparation reagent. Therefore, exploring a GMP-adherent method for expanding endogenous TILs without anti-CD137 agonist is urgent. Toward this end, we aimed to establish an anti-CD137-independent and clinically feasible TIL expansion protocol to prepare TILs from under investigated sarcoma tumors.
Methods: We collected resected tumors from patients and cut tissues into fragments. We used IL-2 and T-cell activator CD3/CD28 without anti-CD137 agonist to expand nonselected TILs in 2-3 weeks, then rapidly expanded them over 2 weeks. Their phenotypes were characterized using flow cytometry. Their antitumor activity was validated in vitro using cytotoxic T lymphocyte assays measuring CD107a on the TILs and the viability of tumor cells and in vivo using an autologous patient-derived xenograft (PDX) tumor model.
Results: We successfully expanded TILs in > 90% of collected samples. TILs generated preferentially increased CD8+ T cells but suppressed CD4+ T cells. A small portion of TILs were resident memory T cells. The expanded TILs reduced autologous tumor cells by 37.5% within 24 hours. Infusion of TILs in mice bearing autologous PDX tumors strongly inhibited liposarcoma growth. FDA has approved use of this GMP-feasible protocol in our clinical trial (IND 30562).
Conclusion: It is feasible to generate antitumor TILs using CD3/CD28 activator to replace the unavailable anti-CD137 agonist. Our study supports the further development of TIL-based therapy.

Keywords:  GMP; adoptive cell therapy; immunotherapy; sarcoma; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.3389/fimmu.2025.1557006
J Am Acad Dermatol. 2025 Mar 21. pii: S0190-9622(25)00509-2. [Epub ahead of print]

Tumor-Infiltrating Lymphocyte Scoring Improves Progression Risk Prediction in Stage II Melanoma: A Retrospective Cohort Study.

George Adigbli, Benedict Reed, Bhavika Khera, Mahaveer Sangha, Simran Thadani, Annika Wilder-Smith, Milosz Wojtowicz, Mary Pissaridou, Ameer Mustafa, Eleni Ieremia, Olivia Espinosa, Jonathan Dunne, Fadi Issa, Oliver Cassell.

   BACKGROUND: AJCC 8th edition substaging might be suboptimal for predicting melanoma progression. Using it to select stage II patients for adjuvant immunotherapy risks overtreating low-risk stage IIB/IIC patients and undertreating high-risk stage IIA patients. Prognostic capability of tumor-infiltrating lymphocytes (TILs) is unclear in stage II melanoma.
OBJECTIVE: To evaluate AJCC substaging and TIL scoring as predictors of progression in stage II melanoma.
METHODS: Retrospective cohort study of 366 SLN(-) stage II melanoma patients from four UK hospitals (2004-2017), with long-term follow-up.
RESULTS: 23% of melanomas progressed (median 9.5-year follow-up). Among those, 41.5% were stage IIA, 41.5% IIB, and 17.1% IIC. TIL scoring independently predicted progression risk (non-brisk vs brisk: OR 0.298,p=0.009; non-brisk vs absent: OR 0.436,p=0.049) and PFS. Non-brisk TILs, present in 80% of progressing tumors, denoted high risk. TIL scoring split patients into high and low risk across substages: stage IIA patients with non-brisk TILs had similar 5-year PFS to stage IIB/IIC patients with absent/brisk TILs.
LIMITATIONS: Retrospective study design and unknown generalizability.
CONCLUSION: Stage II melanoma progression is poorly predicted by AJCC 8 substage. TIL scoring offers improved risk stratification across substages and could serve as a cost-effective method to better identify patients who may benefit from adjuvant immunotherapies.

Keywords:  AJCC staging; Melanoma; adjuvant immunotherapy; biomarker; cancer prognosis; cancer staging; immunology; oncology; pathology; personalized medicine; prognostic factor; progression risk; progression-free survival (PFS); retrospective cohort study; risk stratification; sentinel lymph node (SLN); skin cancer; stage II melanoma; surgical oncology; tumor-infiltrating lymphocyte (TIL)

DOI:  https://doi.org/10.1016/j.jaad.2025.03.046
Int J Mol Sci. 2025 Mar 18. pii: 2716. [Epub ahead of print]26(6):

The Role of the Tumor Microenvironment (TME) in Advancing Cancer Therapies: Immune System Interactions, Tumor-Infiltrating Lymphocytes (TILs), and the Role of Exosomes and Inflammasomes.

Atef M Erasha, Hanem El-Gendy, Ahmed S Aly, Marisol Fernández-Ortiz, Ramy K A Sayed.

  Understanding how different contributors within the tumor microenvironment (TME) function and communicate is essential for effective cancer detection and treatment. The TME encompasses all the surroundings of a tumor such as blood vessels, fibroblasts, immune cells, signaling molecules, exosomes, and the extracellular matrix (ECM). Subsequently, effective cancer therapy relies on addressing TME alterations, known drivers of tumor progression, immune evasion, and metastasis. Immune cells and other cell types act differently under cancerous conditions, either driving or hindering cancer progression. For instance, tumor-infiltrating lymphocytes (TILs) include lymphocytes of B and T cell types that can invade malignancies, bringing in and enhancing the ability of immune system to recognize and destroy cancer cells. Therefore, TILs display a promising approach to tackling the TME alterations and have the capability to significantly hinder cancer progression. Similarly, exosomes and inflammasomes exhibit a dual effect, resulting in either tumor progression or inhibition depending on the origin of exosomes, type of inflammasome and tumor. This review will explore how cells function in the presence of a tumor, the communication between cancer cells and immune cells, and the role of TILs, exosomes and inflammasomes within the TME. The efforts in this review are aimed at garnering interest in safer and durable therapies for cancer, in addition to providing a promising avenue for advancing cancer therapy and consequently improving survival rates.

Keywords:  cancer therapy; exosomes; immune cells; inflammasomes; tumor infiltrating lymphocytes (TILs); tumor microenvironment (TME)

DOI:  https://doi.org/10.3390/ijms26062716
Mol Ther. 2025 Mar 20. pii: S1525-0016(25)00198-4. [Epub ahead of print]

Genetically engineered macrophages reverse the immunosuppressive tumor microenvironment and improve immunotherapeutic efficacy in TNBC.

Ranran Jiang, Liechi Yang, Xin Liu, Yujun Xu, Lulu Han, Yuxin Chen, Ge Gao, Meng Wang, Tong Su, Huizhong Li, Lin Fang, Nan Sun, Hongwei Du, Junnian Zheng, Gang Wang.

The main challenges in current immunotherapy for triple-negative breast cancer (TNBC) lie in the immunosuppressive tumor microenvironment (TME). Considering tumor-associated macrophages (TAMs) are the most abundant immune cells in the TME, resetting TAMs is a promising strategy for ameliorating the immunosuppressive TME. Here, we developed genetically engineered macrophages (GEMs) with gene-carrying adenoviruses, to maintain the M1-like phenotype and directly deliver the immune regulators IL-12 and CXCL9 into local tumors, thereby reversing the immunosuppressive TME. In tumor bearing mice, GEMs demonstrated targeted enrichment in tumors and successfully reprogramed TAMs to M1-like macrophages. Moreover, GEMs significantly enhanced the accumulation, proliferation, and activation of CD8+ T cells, mature dendritic cells (DCs), and natural killer (NK) cells within tumors, while diminishing M2-like macrophages, immunosuppressive myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs). This treatment efficiently suppressed tumor growth. In addition, combination therapy with GEMs and anti-programmed cell death protein 1 (αPD-1) further improved IFN-γ+CD8+ T cell percentages and tumor inhibition efficacy in an orthotopic murine TNBC model. Therefore, this study provides a novel strategy for reversing the immunosuppressive TME and improving immunotherapeutic efficacy through live macrophage-mediated gene delivery.

DOI: https://doi.org/10.1016/j.ymthe.2025.03.024
J Immunother Cancer. 2025 Mar 22. pii: e010760. [Epub ahead of print]13(3):

A SITC vision: adapting clinical trials to accelerate drug development in cancer immunotherapy.

Thomas U Marron, Jason J Luke, Brianna Hoffner, Jane Perlmutter, Connie Szczepanek, Valsamo Anagnostou, Ann W Silk, Pedro J Romero, Elizabeth Garrett-Mayer, Leisha A Emens.

  Clinical trials of cancer immunotherapy (IO) were historically based on a drug development paradigm built for chemotherapies. The remarkable clinical activity of programmed cell death protein 1/programmed death ligand 1 blockade, chimeric antigen receptor-T cells, and T cell engagers yielded new insights into how the mechanistic underpinnings of IO are reflected in the clinic. These insights and the sheer number of novel immunotherapies currently in the pipeline have made it clear that our strategies and tools for IO drug development must adapt. Recent innovations like engineered T cells and tumor-infiltrating lymphocytes demonstrate that immune-based treatments may rely on real-time manufacturing programs rather than off-the-shelf drugs. We now recognize adoptively transferred cells as living drugs. Progression criteria have been redefined due to the unique response patterns of IO. Harnessing the power of both biomarkers and the neoadjuvant setting earlier in drug development is of broad interest. The US Food and Drug Association is increasingly impacting the design of trials with respect to dose optimization and clinical endpoints. The use of novel endpoints such as pathologic complete/major response, treatment-free survival, and minimal residual disease is becoming more common. There is growing acceptance of using patient-reported outcomes as trial endpoints to better measure the true clinical benefit and impact of novel IO agents on quality of life. New opportunities created by modern data science and artificial intelligence to inform and accelerate drug development continue to emerge. The importance of streamlining the clinical research ecosystem and enhancing clinical trial access to facilitate the enrollment of diverse patient populations is broadly recognized. Patient advocacy is critical both to drive the science of IO, and to promote patient satisfaction. To capitalize on these opportunities, the Society for Immunotherapy of Cancer (SITC) has established a goal of at least 100 new, unique IO approvals over the next 10 years. Accordingly, SITC has developed initiatives designed to integrate the viewpoints of diverse stakeholders and galvanize the field in further adapting clinical trials to the unique features of IO, moving us closer to our ultimate goal of using IO to cure and prevent cancer.

Keywords:  Adoptive cell therapy - ACT; Biomarker; Immune Checkpoint Inhibitor; Patient reported outcome - PRO; Tumor microenvironment - TME

DOI:  https://doi.org/10.1136/jitc-2024-010760
J Oncol Pharm Pract. 2025 Mar 28. 10781552251324896

Recent developments on checkpoint inhibitors, CAR T cells, and beyond for T cell-based immunotherapeutic strategies against cancer.

Shaukat Ali, Mahnoor Arshad, Muhammad Summer, Maryam Zulfiqar, Shehzeen Noor, Laiba Nazakat, Muhammad Abdullah Javed.

  ObjectiveThere was a dire need to construct a review of the recent developments on Immune checkpoint inhibitors (ICIs), CAR T Cells, and other approaches for T cell-based immunotherapeutic strategies against cancer as cancer has become one of the most fatal diseases that is responsible for causing several deaths per annum.Data sourcesMultiple published data was acquired from the high-impact factor journal articles.Data summaryMultiple clinical strategies have been in use today such as radiotherapy, chemotherapy and immunotherapy to treat cancer of different types. Among novel cancer management strategies, the role of cancer immunotherapy by T cells has become immensely important. Cancer immunotherapy has revolutionized treatment approaches and it basically utilizes the body's immune system to treat cancer. At the forefront of this revolution, T cells are considered as the fundamental components of immune system.ConclusionsThe current review explores the therapeutic potential of T cells in the fight against cancer by applying strategies such as various ICIs (PD-1/PD-L1, CTLA-4, TIGIT, BTLA, TIM3, LAG3) and adoptive cell therapy. ICIs stimulate the body's existing anti-tumor T-cell response by the way of removing immune system inhibitors. On the other hand, in adoptive cell therapy (ACT) patient's T cells are modified to identify and attack tumor cells. Furthermore, this review also highlights significant successes that are observed with these therapies, notably PD-1 blockade and CAR T-cell therapy for various tumors. Moreover, this review also explores the potential of therapeutic vaccination, bispecific antibodies and cytokine therapy to enhance the antitumor activity. Therapeutic vaccines expose immune system to various tumor-associated antigens and training it to identify and then attack cancer cells, showing promising results in different types of cancers such as prostate cancer and melanoma. While, cytokine therapy is accompanied by the use of cytokines such as interleukin-2 (IL-2) to stimulate immune cell activity and proliferation, thereby boosting the overall anti-tumor immune response. Lastly, the current review explores the promising future of T cell-based immunotherapy, envisioning advancements in CAR design and gene editing techniques that can enhance efficacy across a broader spectrum of cancers.

Keywords:  CAR T cells; T cells; adoptive T cell therapy; cancer; immune checkpoint inhibitors (ICIs)

DOI:  https://doi.org/10.1177/10781552251324896
World J Clin Cases. 2025 Mar 26. 13(9): 99043

Atezolizumab and bevacizumab combination in advanced hepatocellular carcinoma patients: The imperative for safety assessment studies.

Mina Tharwat, Ahmed Tawheed, Mohamed El-Kassas.

  Hepatocellular carcinoma (HCC) is the most prevalent cancer of the hepatobiliary tract and the third leading cause of cancer-related mortality worldwide. Atezolizumab and bevacizumab combination is currently considered among the front-line treatment modalities for advanced unresectable HCC. Most studies examining this combination were focused on evaluating its effectiveness. Despite numerous case reports documenting some side effects, there is a limited number of large-scale studies assessing these side effects. In this article, we comment on the case report by Park et al published recently, reporting a fatal intra-tumoral hemorrhage in a patient with HCC who received systemic therapy in the form of the combination of atezolizumab and bevacizumab.

Keywords:  Atezolizumab; Bevacizumab; Hemorrhage; Hepatocellular carcinoma; Side effects

DOI:  https://doi.org/10.12998/wjcc.v13.i9.99043
STAR Protoc. 2025 Mar 25. pii: S2666-1667(25)00109-1. [Epub ahead of print]6(2): 103703

Protocol for investigating the impact of transcription regulator deficiency on tumor-specific CD8+ T cell responses via adoptive cell transfer.

Luming Xu, Yuzhu Wang, Mengqu Ran, Wen Liu, Lilin Ye, Qizhao Huang.

  Transcription factors play a crucial role in the differentiation of tumor-specific CD8+ T cells and significantly influence their capacity to repress tumors. Here, we present a protocol for creating a transcription regulator inhibitor of DNA 3 (ID3) conditional knockout mouse in tumor-specific CD8+ T cells, induced by tamoxifen. We describe steps for examining the impact of ID3 deficiency on the differentiation of tumor-specific memory CD8+ T cells (Ttsm) and progenitors of exhausted CD8+ T cells (Tpex) in tumor-draining lymph nodes through a co-adoptive transfer assay. For complete details on the use and execution of this protocol, please refer to Ran et al.1.

Keywords:  Cancer; Cell-based Assays; Immunology

DOI:  https://doi.org/10.1016/j.xpro.2025.103703