Development of pHLIP-phosphoantigen conjugates for lymphoma therapy

开发用于淋巴瘤治疗的 pHLIP-磷酸抗原缀合物

基本信息

批准号：
10646988
负责人：
Raman Bahal
金额：
$ 18.82万
依托单位：
UNIVERSITY OF CONNECTICUT STORRS
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10646988
关键词：
Acetates Address Agonist Alanine Transaminase Alcohols Animal Cancer Model Animal Model Animal Testing Antibodies Antigens Aspartate Transaminase Beta Cell Binding Biological Biological Assay Cancerous Cell Line Cell membrane Cell model Cells Cellular immunotherapy Circular Dichroism Clinical Coculture Techniques Cytoplasm Cytoplasmic Tail D Cells Development Dose Drug Carriers Drug Targeting Effectiveness Environment Enzyme-Linked Immunosorbent Assay Esters Exhibits Failure Fluorescence Follicular Lymphoma Goals High Pressure Liquid Chromatography Histology Human Immune Immune checkpoint inhibitor Immune response Immune system Immunologic Stimulation Immunologics Immunotherapy Infiltration Integral Membrane Protein Ligand Binding Ligands Link Luciferases Lymphoma Lymphoma cell Maleimides Malignant Neoplasms Mass Spectrum Analysis Mediating Membrane Methods Monitor Mus Normal Cell Oxygen Patients Pattern Peptides Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Phosphorus Physiological Plasma Production Proteins Public Health Quality Control Reaction Research Resistance Role Serum Solid Neoplasm Specificity Sulfhydryl Compounds T cell response T-Cell Activation T-Cell Receptor T-Lymphocyte Testing Therapeutic Time Toxic effect Transplantation Tryptophan Tumor Immunity Tumor Tissue alpha-beta T-Cell Receptor analog anti-cancer biophysical analysis butyrophilin cancer cell cancer immunotherapy cancer therapy checkpoint therapy chemical synthesis chemotherapy clinical application clinical development cytokine design experimental study immune checkpoint immunotoxicity improved in vivo in vivo Model large cell Diffuse non-Hodgkin&apos s lymphoma liver function mouse model nanomolar neoplastic cell novel novel anticancer drug phosphonate prevent receptor refractory cancer response sarcoma small molecule success tumor tumor microenvironment γδ T cells

项目摘要

Abstract An attractive strategy for cancer treatment is to strengthen the ability of the patient’s immune system to detect and clear cancerous cells. However, antibody-based immune checkpoint inhibitors have limited effectiveness against some types of tumors such as diffuse large B cell lymphoma and follicular lymphoma, while solid tumors such as sarcomas are often more broadly resistant to both immune checkpoint inhibitors and cell-based immunotherapy. Therefore, further immunotherapy options are necessary for these indications. The objective of our research is to develop a drug conjugate that stimulates the immune response to cancer by targeting BTN3A1. This protein is required for activation of gamma delta T cells and functions as an immune checkpoint in alpha beta T cells. Gamma delta T cells exhibit different patterns of tumor infiltration relative to alpha beta T cells targeted by current immunotherapy approaches, and some recent studies have shown that when gamma delta cells can infiltrate tumors they can even have a stronger impact on overall survival relative to tumor infiltrating alpha beta cells. Therefore, gamma delta T cell activation holds great promise for cancer immunotherapy in cases where alpha beta T cells are ineffective. In contrast to T cells that express the alpha beta T cell receptor and respond to peptide antigens, T cells that express the Vgamma9Vdelta2 T cell receptor respond to small phosphorous-containing compounds known as phosphoantigens (pAgs) and are MHC independent, which can be a benefit to immunotherapy. However, no known direct activators of gamma delta T cells are available for human use. The transmembrane pAg receptor BTN3A1 is critical for TCR mediated Vgamma9Vdelta2 T cell activation. Due to MHC independence and non-traditional antigen response, BTN3A1 ligands offer a potential alternative to boost anti-cancer immunity when immune checkpoint therapy fails. Here, we propose to test the central hypothesis that novel synthetic pHLIP-pAg conjugates can engage BTN3A1 in tumors to trigger an anti- cancer immune response. To develop tumor specific distribution of the pAgs, we will take advantage of the emerging pHLIP (pH (low) insertion peptide) which inserts into tumor cell membranes in the acidic tumor microenvironment. We will synthesize pHLIP-pAg conjugates optimized for in vivo application and characterize their activation of gamma delta T cells. We will examine the activity of these new conjugates in cellular and animal models of lymphoma, assessing both the activity and potential toxicity of these novel agents. Additional studies will evaluate the conjugates against more immunologically cold sarcomas. The ultimate goal is to identify a pHLIP-pAg that will be used for treatment of cancers that are resistant to immune checkpoint inhibitors. These findings will come at a time when the biological understanding of anti-cancer immunity is far from complete, and thus these studies have the potential for dramatic impact on the field of cancer immunotherapy.

抽象的癌症治疗的一个有吸引力的策略是增强患者免疫系统检测的能力并清除癌细胞。然而，基于抗体的免疫检查点抑制剂的效果有限。针对某些类型的肿瘤，如弥漫性大 B 细胞淋巴瘤和滤泡性淋巴瘤，而实体瘤例如肉瘤通常对免疫检查点抑制剂和基于细胞的药物具有更广泛的抵抗力因此，针对这些适应症需要进一步的免疫治疗选择。我们的研究是开发一种药物缀合物，通过靶向 BTN3A1 来刺激对癌症的免疫反应。这种蛋白质是激活 γ δ T 细胞所必需的，并作为 α 中的免疫检查点发挥作用。 β T 细胞相对于 alpha beta T 细胞表现出不同的肿瘤浸润模式。当前免疫治疗方法的目标，最近的一些研究表明，当γδ 细胞可以浸润肿瘤，相对于肿瘤浸润，它们甚至可以对总体生存产生更大的影响因此，γδT 细胞激活对于癌症免疫治疗具有巨大的前景。与表达 alpha beta T 细胞受体的 T 细胞相比，alpha beta T 细胞无效。表达 Vgamma9Vdelta2 T 细胞受体的 T 细胞对小肽抗原做出反应含磷化合物称为磷酸抗原 (pAg)，并且不依赖于 MHC，可以然而，目前尚无已知的 γ δ T 细胞直接激活剂。跨膜 pAg 受体 BTN3A1 对于 TCR 介导的 Vgamma9Vdelta2 T 细胞至关重要。由于 MHC 独立性和非传统抗原反应，BTN3A1 配体提供了潜在的潜力。免疫检查点治疗失败时增强抗癌免疫力的替代方案在这里，我们建议测试一下。中心假设是，新型合成 pHLIP-pAg 缀合物可以与肿瘤中的 BTN3A1 结合，触发抗- 为了开发 pAg 的肿瘤特异性分布，我们将利用新兴的 pHLIP（pH（低）插入肽）可插入酸性肿瘤中的肿瘤细胞膜我们将合成针对体内应用优化的 pHLIP-pAg 缀合物并进行表征。我们将检查这些新缀合物在细胞和细胞中的活性。淋巴瘤动物模型，评估这些新药的活性和潜在毒性。研究将评估缀合物对更多免疫冷肉瘤的作用，最终目标是鉴定。 pHLIP-pAg 将用于治疗对免疫检查点抑制剂有抵抗力的癌症。研究结果将在人们对抗癌免疫的生物学理解还远未完成的时候出现，并且因此，这些研究有可能对癌症免疫治疗领域产生巨大影响。