Cell type-directed Tim-3 targeting in melanoma

黑色素瘤中细胞类型定向的 Tim-3 靶向

基本信息

批准号：
10626932
负责人：
Steven Russell Barthel
金额：
$ 57.23万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10626932
关键词：
Affinity Antibodies Antibody Affinity Antibody Response Antibody Therapy Antigen-Presenting Cells Binding Biological Markers Biological Models Blocking Antibodies Cancer Patient Cell Lineage Cells Cellular Immunity Charge Clinical Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Collaborations Cytotoxic T-Lymphocytes Data Dendritic Cells Disparity Epitopes Evaluation Glycoproteins Growth Human Immune Immune Targeting Immune checkpoint inhibitor Immunity Immunobiology Immunoglobulins Immunooncology Immunotherapy Impairment Infiltration Investigation Lectin Ligands Link MAP Kinase Gene Macrophage Malignant Neoplasms Mass Spectrum Analysis Mediating Mediator Melanoma Cell Membrane Metastatic Melanoma Modality Modeling Modification Mucins Mus Natural Killer Cells Neoplasm Metastasis Outcome Pathway interactions Patients Phosphorylation Polysaccharides Proteins RNA Interference Regimen Research Sialic Acids Signal Pathway Signal Transduction T-Lymphocyte Therapeutic Therapeutic Trials Therapeutic antibodies Tissues Treatment Efficacy Treatment outcome Tumor Immunity Variant Western Blotting antagonist anti-cancer anticancer activity cancer cell cancer clinical trial cell killing cell type clinical effect clinical predictors efficacy validation glycosylation immune checkpoint immune checkpoint blockade immunogenicity improved outcome inhibitor knock-down melanoma mutant neoplastic cell next generation novel oncology trial potential biomarker pre-clinical predict clinical outcome response tumor tumor growth tumorigenesis

项目摘要

PROJECT SUMMARY Immune checkpoint blockade has elicited unprecedented clinical responses in patients with metastatic melanoma and other cancers. A promising new checkpoint under investigation in cancer therapeutic trials is T- cell immunoglobulin and mucin domain 3 (Tim-3). Tim-3 blockade reverses T-cell impairment, thereby reinvigorating antitumor T-cell immunity. However, we found that Tim-3 inhibitors, including those in clinical trials, not only target T-cell-Tim-3, but also have varying affinity for Tim-3 on dendritic cells (DCs), macrophages (MΦs), NK and melanoma cells. Clinical benefit might thus not exclusively rely on antagonism of T-cell-Tim-3, but also on inhibition of these additional Tim-3-expressing cell types. In support, blockade of T- cell-Tim-3 suppressed, while melanoma-directed Tim-3 inhibition enhanced tumor growth in murine melanoma models, thereby counteracting desired efficacy of Tim-3 therapy. Consistently, enforced expression of Tim-3 on melanoma cells suppressed tumorigenesis, metastasis formation, and proliferative pathway activity. Our preliminary studies thus identify melanoma cell-intrinsic, DC-, MΦ-, and NK-cell-Tim-3 as unexpected variables and/or potential confounders of treatment outcome. They further highlight the need to define therapeutic consequences of Tim-3 antibody (Ab) responses at the level of specific cell types. The Tim-3 protein bears multiple N- and O-glycostructures that differ dramatically in composition, size, and charge between cell lineages and which might explain the marked variations in Tim-3 Ab clone reactivity we found between cell types. For example, the clinical Tim-3 trial candidate, TSR-022, avidly bound T-cell- and melanoma-, but not NK-, DC-, or MΦ-Tim-3, while other Tim-3 Abs showed high affinity for Tim-3 on T-cells, MΦs, DCs, and/or NK, but not melanoma cells. Notably, glycan-modifying regimens shifted inhibitor binding towards desired T-cell- Tim-3 recognition and reduced melanoma-Tim-3 reactivity. Our preliminary data highlights the critical need for dissecting immune- vs. melanoma cell-Tim-3 glyco-epitopes, Ab affinity, signaling, and immunobiology. Results will help optimize Tim-3 therapeutic efficacy by validating regimens that preferentially target immune cell-Tim-3 glycans, while avoiding unwanted blockade of melanoma cell-Tim-3. Our aims are to 1) define cell type- associated Tim-3 glycan moieties, ligands, Ab affinities, and signaling networks, 2) examine immune cell- vs. melanoma-intrinsic effects of existing Tim-3 antagonists and their relevance to interpreting therapeutic benefit, and 3) identify new Tim-3 targeting strategies that accentuate immune cell-Tim-3 inhibition. We will use state- of-the-art gain and loss of Tim-3 function and glycan-modifying strategies, Tim-3 inhibitors with variable tissue- associated affinities, and immune and melanoma model systems to define cell type-specific Tim-3 functions and glycomolecular targets. Our initiative also implements clinical tumor biospecimens from patients receiving immune checkpoint inhibitors. Together, these studies will pave the way for next generation biomarkers and treatment modalities that discriminate immune- from cancer cell-Tim-3 for optimized immunotherapy outcomes.

项目摘要免疫检查点封锁封锁引起了转移性患者的未经预科临床反应黑色素瘤和其他癌症。细胞免疫球蛋白和粘蛋白结构域3（TIM-3）。但是，抗肿瘤的T细胞免疫。但是，我们发现TIM-3抑制剂，包括临床试验，不仅靶向T-Cell-TIM-3，而且对TIM-3对树突状细胞具有不同的亲和力（DCS）巨噬细胞（MφS），NK和黑色素瘤细胞可能不仅在 T-Cell-TIM-3，但也抑制表达Thim-3的细胞类型。细胞-TIM-3抑制，而黑色素瘤定向的TIM-3抑制作用增强了鼠类融合的肿瘤生长模型，可能需要对TIM 3治疗的期望。黑色素瘤细胞抑制了肿瘤发生，转移形成和增殖途径活性。因此，预审前研究将黑色素瘤细胞中性，DC-，Mφ-和NK-Cell-TIM-3视为意外变量和/或潜在的治疗结果。特定细胞类型水平的TIM-3抗体（AB）反应的后果。多个N和糖缩在组成，大小和电荷之间急剧不同谱系，这可能解释了我们在细胞之间发现的TIM-3 AB克隆反应性的明显变化例如。 NK-，DC-或Mφ-TIM-3，而其他TIM-3 ABS在T-Cells，Mφs，DCS和/或NK上显示出对TIM-3的高亲和力，但不是黑色素瘤细胞。 TIM-3识别和降低黑色素瘤-TIM-3反应性。免疫与黑色素瘤细胞-3糖果，AB亲和力，信号传导和免疫生物学结果。将通过验证拜丁人tartential靶向Immmune Cell-TIM-3来降低TIM-3的治疗功效同时，避免了对黑色素瘤细胞-3的不必要的封锁。我们的目标是1）相关的TIM-3聚糖部分，配体，AB亲和力和信号网络，2）检查免疫细胞Vs。黑色素瘤内在现有TIM-3拮抗剂以及与解释治疗益处的相关性， 3）确定强调免疫细胞-TIM-3抑制的新的TIM-3靶向策略。 TIM-3功能的增益和丧失和糖化策略，TIM-3抑制剂具有可变的组织 - 相关亲和力以及免疫和黑色素瘤模型系统以定义细胞的Typific TIM-3功能和Gllycomolecular靶标。免疫检查点抑制剂。将免疫与癌症细胞-TIM-3区分开的治疗方式可通过优化的免疫疗法结局。