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Adoptive Transfer of Tumor Infiltrating Lymphocytes for Advanced Solid Cancers

ABSTRACT: This is a Phase 2 study to evaluate the efficacy of a non-myeloablative lymphodepleting preparative regimen followed by infusion of autologous TIL and high-dose aldesleukin in patients with locally advanced, recurrent, or metastatic cancer associated with one of the following cancer types: 1.) gastric/esophagogastric, 2.) colorectal, 3.) pancreatic, 4.) sarcoma, 5.) mesothelioma, 6.) neuroendocrine, 7.) squamous cell cancer, 8.) Merkle cell, 9.) mismatch repair deficient and/or microsatellite unstable cancers, and 10.) patients who have exhausted conventional systemic therapy options by using the objective response rate (ORR).

DISEASE(S): Neuroendocrine Tumors,Microsatellite Instability,Sarcoma,Colorectal Cancer,Mesothelioma,Mismatch Repair Deficiency,Pancreatic Cancer,Merkel Cell Carcinoma,Carcinoma, Merkel Cell,Neoplasms, Squamous Cell,Carcinoma, Squamous Cell,Squamous Cell Cancer,Gastric Cancer

PROVIDER: 2304475 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Adoptive Cell Therapy Using Cancer Specific CD8+ Tumor Infiltrating Lymphocytes in Adult Patients With Solid Tumors

Project description:The subject of this study is the adoptive transfer of selected autologous tumor infiltrating lymphocytes (TIL) after in vitro expansion for the treatment of solid tumor malignancies. The TIL selection process is based on evidence showing that CD8+ TIL which co-express both CD39 and CD103 harbor the bulk of tumor-reactivity and that the remaining CD8 TIL is mainly composed of non-tumor reactive bystander cells. All of the expanded TIL that are produced (1-40 billion are expected) will be delivered in the form of a cell suspension to the participants by intravenous infusion. It is proposed that these selected TIL will produce a more potent and efficacious treatment of late-stage cancer.

| 63320 | ecrin-mdr-crc

Adoptive cell therapy using cultured tumor infiltrating lymphocytes for Japanese patients with refractory melanoma

Project description:Three patients who failed immune-checkpoint inhibitors were treated with the adoptive cell therapy using ex vivo cultured tumor infiltrating lymphocytes (TIL-ACT), which was composed of preparation of TIL culture, lympho-depleting non-myeloablative preconditioning, TIL infusion, and following relatively low dose intravenous IL-2 administration. Then we evaluated treatment feasibility, safety and clinical response. To further investigate the relationship between the tumor microenvironment and the patient's clinical course, we performed gene expression analysis of the pre-treatment tumor cells and immunohistochemistry of the tumor tissue focusing on delineating the immune components and immunologic milieu within the tumor. Together with the results of genomic and immunological analysis of ex vivo cultured TILs by flowcytometry and quantitative real-time polymerase chain reaction, we considered the various immunostimulating or immunosupprrsive factors giving influence on the effects of the conducted TIL-ACT.

2021-08-18 | GSE155389 | GEO

CD4 Polarized T cells Reduce the Expansion of Tumor Infiltrating Lymphocytes in Melanoma Patients Treated with Adoptive Cell Therapy [ChIP-seq]

Project description:Background: Adoptive cell therapy (ACT) with tumor infiltrating lymphocytes (TIL) is effective in treating PD-1 refractory melanoma, but requires adequate ex vivo expansion of TIL. Methods: CD4+ and CD8+ TIL from metastatic melanoma patients treated with TIL ACT were analyzed by RNA-seq (n=12) and ChIP-seq of acetylated histone 3 (n=19). Patients were grouped into “TIL high” and “TIL low” based on division at the median number of TIL infused. The number of TIL infused and CD4+ TIL frequency were correlated with overall survival (OS). Results: The number of TIL infused correlated with longer OS (R2=0.57, p=0.00076), and the percent of CD4+ infused was negatively correlated with the total number of TIL infused (R2=0.64, p=0.00047). RNA-seq analysis of CD4+ TIL showed increases in Th2/Th17/Treg transcripts and pathways in the TIL low group. ChIP-seq analysis of CD8+ TIL showed decreased acetylation in the TIL low group in genes upregulated during CD8+ activation. Conclusion: The numbers of TIL infused were associated with increased overall survival, while RNA-seq suggested that polarized CD4+ cells in the transferred TIL were associated with decreased overall expansion. These data suggest that improper CD4+ TIL polarization may reduce expansion and treatment efficacy.

2023-07-17 | GSE218005 | GEO

CD4 Polarized T cells Reduce the Expansion of Tumor Infiltrating Lymphocytes in Melanoma Patients Treated with Adoptive Cell Therapy [RNA-seq]

2023-07-17 | GSE218004 | GEO

Adoptive cell transfer using autologous tumor infiltrating lymphocytes in gynecologic malignancies.

Project description:During the last decade, the field of cancer immunotherapy has been entirely transformed by the development of new and more effective treatment modalities with impressive response rates and the prospect of long survival. One of the major breakthroughs is adoptive cell transfer (ACT) based on autologous T cells derived from tumor-infiltrating lymphocytes (TILs). TIL-based ACT is a highly personalized cancer treatment. T cells are harvested from autologous fresh tumor tissues, and after ex vivo activation and extensive expansion, are reinfused to patients. TIL-based therapies have only been offered in small phase I/II studies in a few centers given the highly specialized care required, the complexity of TIL production and the very intensive nature of the three-step treatment protocol. The treatment includes high-dose lymphodepleting chemotherapy, the infusion of the expanded and activated T cells and interleukin-2 (IL-2) injections to increase survival of the T cells. Despite the limited data on ACT, the small published studies consistently confirm an impressive clinical response rate of up to 50% in metastatic melanoma patients, including a significant proportion of patients with durable complete response. These remarkable results justify the need for larger clinical trials in other solid tumors, including gynecologic malignancies. In this review we provide an overview of the current clinical results, future applications of TIL-based ACT in gynecologic malignancies, and on risks and challenges associated with modern T cell therapy.

| S-EPMC6167746 | biostudies-literature

Adoptive transfer of tumor-infiltrating lymphocytes in melanoma: a viable treatment option.

Project description:The treatment of metastatic melanoma patients with autologous tumor-infiltrating lymphocytes (TIL) shows robust, reproducible, clinical responses in clinical trials executed in several specialized centers over the world. Even in the era of targeted therapy and immune checkpoint inhibition, TIL therapy can be an additional and clinically relevant treatment line. This review provides an overview of the clinical experiences with TIL therapy thus far, including lymphodepleting regimens, the use of interleukin-2 (IL-2) and the associated toxicity. Characteristics of the TIL products and the antigen recognition pattern will be discussed, as well as the current and upcoming production strategies, including the selective expansion of specific fractions from the cell product. In addition, the future potential of TIL therapy in melanoma and other tumor types will be covered.

| S-EPMC6171186 | biostudies-literature

Inhibition of Akt promotes immunologic memory in tumor-infiltrating lymphocytes isolated from patients with melanoma

Project description:Adoptive cell immunotherapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) can result in complete regression of advanced melanoma in some patients, but the efficacy of this potentially curative therapy is limited by poor persistence of TIL after adoptive-transfer. Pharmacologic inhibition of the serine/threonine kinase Akt has recently been shown to promote immunologic memory in viral-specific murine models, but whether this approach may enhance features of memory (e.g. long-term persistence) in TIL which are characteristically exhausted and senescent is not established. Here we show that pharmacologic inhibition of Akt enables expansion of TIL with the transcriptional, metabolic and functional properties characteristic of memory T cells. Consequently, Akt inhibition results in enhanced persistence of TIL after adoptive transfer into an immunodeficient animal model and augments antitumor immunity of CD8 T cells in a mouse model of cell-based immunotherapy for melanoma. Pharmacologic inhibition of Akt represents a novel immunometabolomic approach to enhance the persistence of anti-tumor T cells and improve the efficacy of cellbased immunotherapy for metastatic cancer.

2015-06-03 | GSE60977 | GEO

RNA Profiling in Patients' tumor infiltrating lymphocytes

Project description:Identifying tumor antigen-specific T cells from cancer patients has been a goal of tumor immunologists for several decades. Co-expression of CD103 and CD39 on CD8 TIL highly enriches for tumor-reactive T cells. CD39+CD103+ CD8 TIL have a distinct TCR repertoire compared to other CD8 TIL subsets and are clonally expanded within the tumor. They are highly enriched for tumor antigen recognition and efficiently killed autologous tumor cells. Patients with head and neck cancer whose CD8 TIL contained a higher frequency of CD39+CD103+ cells experienced a greater overall survival. This work describes a simple and effective method for detecting tumor-reactive CD8 TIL.

2018-05-26 | GSE114944 | GEO

SPP1+ macrophages in HR+ breast cancer are associated with tumour-infiltrating lymphocytes.

Project description:Breast cancer, categorised into hormone receptor-positive (HR+), HER2-positive (HER2+), and triple-negative (TNBC) subtypes, exhibits varied outcomes based on the number of tumour-infiltrating lymphocytes (TILs). Increased TIL levels are associated with better outcomes in HER2+ and TNBC, while HR+ individuals with high TIL levels show shorter survival but greater neoadjuvant chemotherapy response. To explore the divergent roles of TIL levels across various subtypes and their effect on immune cell composition, we employed single-cell RNA sequencing on 31 patients with breast cancer. HR+ breast cancer with high TIL levels (TIL-high) revealed increased SPP1+ macrophages, increased SPP1 expression in other monocytes/macrophages (mono/macro) subgroups, and enriched pathways associated with extracellular matrix (ECM) remodelling in mono/macro. Moreover, cell–cell interaction analyses revealed enhanced SPP1, MIF, and FN1 signalling in the interaction between SPP1+ macrophages and T-cells in TIL-high HR+ breast cancer. Spatial transcriptomics data highlighted the close proximity of SPP1+ macrophages, CD8+ T-cells, and CD4+ T-cells in TIL-high HR+ breast cancer. Our findings unveil the novel influence of SPP1+ macrophages on T-cells in TIL-high HR+ breast cancer, potentially explaining the poor prognosis and offering insights for targeted interventions.

2024-10-09 | GSE261774 | GEO

Microbial Peptides Activate Tumor-Infiltrating Lymphocytes in Glioblastoma

Project description:Microbial organisms play key roles in numerous physiological processes in the human body and have recently been shown to modify the response to cancer radiotherapy and immune checkpoint inhibitors. Here, we demonstrate that HLA molecules of both glioblastoma tissues as well as tumor cell lines present bacteria-specific peptides. This finding prompted us to examine whether tumor-infiltrating lymphocytes (TILs) recognize intratumoral microbiota. Indeed, bacterial peptides eluted from HLA-DR II molecules are recognized by both TILs, albeit weakly, and peripheral blood-derived memory CD4+ T cells, which, upon stimulation with bacterial peptides, also recognize several tumor antigens. Furthermore, using an unbiased antigen discovery approach for a TIL CD4+ T cell clone (TCC) we show that it recognizes a broad spectrum of peptides from pathogenic bacteria, commensal gut microbiota and also glioblastoma-related tumor antigens. These peptides were strongly stimulatory for bulk TILs and peripheral blood memory cells. Our data hint at how bacterial pathogens and bacterial gut microbiota can be involved in specific immune recognition of tumor antigens.

2023-02-20 | PXD036811 | Pride

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