ACT Up TIL Now: The Evolution of Tumor-Infiltrating Lymphocytes in Adoptive Cell Therapy for the Treatment of Solid Tumors

Hulen, Thomas Morgan; Chamberlain, Christopher Aled; Svane, Inge Marie; Met, Özcan

doi:10.3390/immuno1030012

Cited by 14 publications

(6 citation statements)

References 127 publications

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“…Adoptive cell therapy using autologous tumor-infiltrating lymphocytes (TIL-based ACT) has been clinically explored for the treatment of metastatic melanoma for decades (1)(2)(3)(4). This was the most effective therapeutic strategy until the inception of checkpoint inhibition (CPI) therapy which drastically changed the treatment landscape of melanoma cancers (5).…”

Section: Introductionmentioning

confidence: 99%

Ex vivo modulation of intact tumor fragments with anti-PD-1 and anti-CTLA-4 influences the expansion and specificity of tumor-infiltrating lymphocytes

et al. 2023

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Checkpoint inhibition (CPI) therapy and adoptive cell therapy with autologous tumor-infiltrating lymphocytes (TIL-based ACT) are the two most effective immunotherapies for the treatment of metastatic melanoma. While CPI has been the dominating therapy in the past decade, TIL-based ACT is beneficial for individuals even after progression on previous immunotherapies. Given that notable differences in response have been made when used as a subsequent treatment, we investigated how the qualities of TILs changed when the ex vivo microenvironment of intact tumor fragments were modulated with checkpoint inhibitors targeting programmed death receptor 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Initially, we show that unmodified TILs from CPI-resistant individuals can be produced, are overwhelmingly terminally differentiated, and are capable of responding to tumor. We then investigate these properties in ex vivo checkpoint modulated TILs finding that that they retain these qualities. Lastly, we confirmed the specificity of the TILs to the highest responding tumor antigens, and identified this reactivity resides largely in CD39+CD69+ terminally differentiated populations. Overall, we found that anti-PD-1 will alter the proliferative capacity while anti-CTLA4 will influence breadth of antigen specificity.

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Section: Introductionmentioning

confidence: 99%

Ex vivo modulation of intact tumor fragments with anti-PD-1 and anti-CTLA-4 influences the expansion and specificity of tumor-infiltrating lymphocytes

et al. 2023

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“…Clonal activation and expansion of TILs is performed by coculturing the cells for several weeks with irradiated and peptide loaded feeder cells, in the presence of IL-2 ( 150 ). Feeder cells can be either autologous or allogeneic antigen-presenting cells (APCs) or tumor cells expressing the peptide(s) of interest (e.g., pp65 or H3K27M) on their MHC ( 151 ). The use of these feeder cells dates back to the 1980s and has shown to promote T cell culture ( 152 ).…”

Section: Functional Assaysmentioning

confidence: 99%

A Toolkit for Profiling the Immune Landscape of Pediatric Central Nervous System Malignancies

et al. 2022

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The prognosis of pediatric central nervous system (CNS) malignancies remains dismal due to limited treatment options, resulting in high mortality rates and long-term morbidities. Immunotherapies, including checkpoint inhibition, cancer vaccines, engineered T cell therapies, and oncolytic viruses, have promising results in some hematological and solid malignancies, and are being investigated in clinical trials for various high-grade CNS malignancies. However, the role of the tumor immune microenvironment (TIME) in CNS malignancies is mostly unknown for pediatric cases. In order to successfully implement immunotherapies and to eventually predict which patients would benefit from such treatments, in-depth characterization of the TIME at diagnosis and throughout treatment is essential. In this review, we provide an overview of techniques for immune profiling of CNS malignancies, and detail how they can be utilized for different tissue types and studies. These techniques include immunohistochemistry and flow cytometry for quantifying and phenotyping the infiltrating immune cells, bulk and single-cell transcriptomics for describing the implicated immunological pathways, as well as functional assays. Finally, we aim to describe the potential benefits of evaluating other compartments of the immune system implicated by cancer therapies, such as cerebrospinal fluid and blood, and how such liquid biopsies are informative when designing immune monitoring studies. Understanding and uniformly evaluating the TIME and immune landscape of pediatric CNS malignancies will be essential to eventually integrate immunotherapy into clinical practice.

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“…23 Strategies to improve TIL therapy including combinations with immune checkpoint inhibitors (ICI), selection of neoantigen-targeted TIL, and genetically engineered TIL via clustered regularly interspaced short palindromic repeat (CRISPR) technology comprise an exciting field of preclinical research. 3 However, TIL therapy faces practical obstacles that are hindering its incorporation into clinical practice, including elevated rates of toxicity, requirement of highly specialized facilities and human resources, extended manufacturing periods, and regulatory considerations. 24 The challenges in its large-scale implementation underscore the relevance of identifying pertinent biomarkers for optimal patient selection.…”

Section: Introductionmentioning

confidence: 99%

Biomarkers for response to TIL therapy: a comprehensive review

Albarrán Fernández,

Ballestín Martínez,

Stoltenborg Granhøj

et al. 2024

J Immunother Cancer

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Adoptive cell therapy with tumor-infiltrating lymphocytes (TIL) has demonstrated durable clinical responses in patients with metastatic melanoma, substantiated by recent positive results of the first phase III trial on TIL therapy. Being a demanding and logistically complex treatment, extensive preclinical and clinical effort is required to optimize patient selection by identifying predictive biomarkers of response. This review aims to comprehensively summarize the current evidence regarding the potential impact of tumor-related factors (such as mutational burden, neoantigen load, immune infiltration, status of oncogenic driver genes, and epigenetic modifications), patient characteristics (including disease burden and location, baseline cytokines and lactate dehydrogenase serum levels, human leucocyte antigen haplotype, or prior exposure to immune checkpoint inhibitors and other anticancer therapies), phenotypic features of the transferred T cells (mainly the total cell count, CD8:CD4 ratio, ex vivo culture time, expression of exhaustion markers, costimulatory signals, antitumor reactivity, and scope of target tumor-associated antigens), and other treatment-related factors (such as lymphodepleting chemotherapy and postinfusion administration of interleukin-2).

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ACT Up TIL Now: The Evolution of Tumor-Infiltrating Lymphocytes in Adoptive Cell Therapy for the Treatment of Solid Tumors

Cited by 14 publications

References 127 publications

Ex vivo modulation of intact tumor fragments with anti-PD-1 and anti-CTLA-4 influences the expansion and specificity of tumor-infiltrating lymphocytes

Ex vivo modulation of intact tumor fragments with anti-PD-1 and anti-CTLA-4 influences the expansion and specificity of tumor-infiltrating lymphocytes

A Toolkit for Profiling the Immune Landscape of Pediatric Central Nervous System Malignancies

Biomarkers for response to TIL therapy: a comprehensive review

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