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种有吸引力的策略是增强患者免疫系统检测的能力并清除取消的单元格。然而，基于抗体的免疫粘点抑制剂的有效性有限针对某些类型的肿瘤，例如弥漫性大B细胞淋巴瘤和卵泡淋巴瘤，而实体瘤例如肉瘤通常更广泛地对免疫粘液抑制剂和基于细胞的抑制作用具有更广泛的抵抗力免疫疗法。因此，对于这些适应症，需要进一步的免疫疗法选择。目的我们的研究是开发一种通过靶向BTN3A1来刺激癌症免疫响应的药物共轭物。该蛋白是激活伽马三角细胞的必需蛋白，并且在α中充当免疫切口 βT细胞。相对于αβT细胞，γ三角T细胞暴露了不同的肿瘤浸润模式以当前的免疫疗法方法针对细胞可以渗入肿瘤，甚至可以对肿瘤浸润的总体存活产生更大的影响 αβ细胞。因此，伽玛三角细胞激活对癌症免疫疗法具有很大的希望 αβT细胞无效的情况。与表达alpha beta T细胞接收器的T细胞相反并响应胡椒抗原，表达vgamma9vdelta2 t细胞接收器的T细胞对小含磷酸化的化合物称为磷脂剂（PAGS），是MHC独立的，可以对免疫疗法有好处。但是，没有已知的伽马三角t细胞的直接激活剂可用于人使用。跨膜PAG受体BTN3A1对于TCR介导的VGAMMA9VDELTA2 T细胞至关重要激活。由于MHC独立性和非传统抗原反应，BTN3A1配体具有潜力当免疫检查点疗法失败时，可以替代促进抗癌免疫学。在这里，我们建议测试中心假设是，新型的合成phlip-pag共轭物可以在肿瘤中吸引BTN3A1以触发抗 - 癌症免疫反应。为了发展PAG的肿瘤特异性分布，我们将利用新兴的phlip（pH（低）插入肽）将插入酸性肿瘤中的肿瘤细胞膜插入微环境。我们将合成为体内应用优化的Phlip-pag结合物，并表征它们激活伽马三角细胞。我们将研究这些新结合物在细胞和淋巴瘤的动物模型，评估了这些新型药物的活性和潜在毒性。额外的研究将评估偶联物针对更具免疫学上的冷肉瘤。最终目标是确定一种phlip-PAG，用于治疗对免疫抑制剂抗性的癌症。这些发现对抗癌免疫的生物学理解远非完整，并且因此，这些研究有可能对癌症免疫疗法领域产生巨大影响。