Project 1

项目1

基本信息

批准号：
10673926
负责人：
Mark M. AWAD
金额：
$ 32.3万
依托单位：
DANA-FARBER CANCER INST
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：
2022-08-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10673926
关键词：
ALK gene Adjuvant Adoptive Cell Transfers Adult Aftercare Alleles Antitumor Response Avidity Biopsy CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cancer Center Cancer Etiology Cancer Patient Cancer Vaccines Cell Line Cell Therapy Cessation of life Chromosomal Rearrangement Chromosomal translocation Clinical Clinical Trials Cytotoxic Chemotherapy Data Disease Disease Progression Down-Regulation Drug resistance Drug usage Engineering Enrollment Epitopes Evolution FDA approved Flow Cytometry Formulation Foundations Funding Future Genes Goals Grant HLA A*0201 antigen HLA-B*0702 Haplotypes Histocompatibility Antigens Class I Immune Immune checkpoint inhibitor Immune response Immune system Immunity Immunotherapeutic agent Immunotherapy Industry Infiltration Length Libraries Longevity Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Mass Spectrum Analysis Microfluidics Modeling Mus Non-Small-Cell Lung Carcinoma Oncogenes PD-1 inhibitors Participant Pathway interactions Patients Peptides Peripheral Blood Mononuclear Cell Phase Phase I Clinical Trials Phosphotransferases Positioning Attribute Progression-Free Survivals Refractory Relapse Research Resistance Resistance development Safety Specificity Stains T cell response T-Cell Receptor Genes T-Lymphocyte Techniques Testing Therapeutic Therapeutic Effect Time Tissues Transgenic Mice Tumor Escape Tumor-Associated Process Tumor-Infiltrating Lymphocytes Tyrosine Kinase Inhibitor Vaccination Vaccine Adjuvant Vaccinee Vaccines Validation anaplastic lymphoma kinase anti-PD-1 cancer cell chemotherapy cohort crizotinib design drug resistance development efficacy testing enzyme linked immunospot assay first-in-human immune resistance immunogenic immunogenicity innovation kinase inhibitor mouse model mutant neoplastic cell next generation novel novel therapeutic intervention objective response rate participant enrollment patient screening pill pre-clinical primary endpoint resistance mutation safety testing screening secondary endpoint success targeted treatment tumor tumor growth vaccine evaluation vaccine formulation

ALK gene Adjuvant Adoptive Cell Transfers Adult Aftercare Alleles Antitumor Response Avidity Biopsy CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cancer Center Cancer Etiology Cancer Patient Cancer Vaccines Cell Line Cell Therapy Cessation of life Chromosomal Rearrangement Chromosomal translocation Clinical Clinical Trials Cytotoxic Chemotherapy Data Disease Disease Progression Down-Regulation Drug resistance Drug usage Engineering Enrollment Epitopes Evolution FDA approved Flow Cytometry Formulation Foundations Funding Future Genes Goals Grant HLA A*0201 antigen HLA-B*0702 Haplotypes Histocompatibility Antigens Class I Immune Immune checkpoint inhibitor Immune response Immune system Immunity Immunotherapeutic agent Immunotherapy Industry Infiltration Length Libraries Longevity Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Mass Spectrum Analysis Microfluidics Modeling Mus Non-Small-Cell Lung Carcinoma Oncogenes PD-1 inhibitors Participant Pathway interactions Patients Peptides Peripheral Blood Mononuclear Cell Phase Phase I Clinical Trials Phosphotransferases Positioning Attribute Progression-Free Survivals Refractory Relapse Research Resistance Resistance development Safety Specificity Stains T cell response T-Cell Receptor Genes T-Lymphocyte Techniques Testing Therapeutic Therapeutic Effect Time Tissues Transgenic Mice Tumor Escape Tumor-Associated Process Tumor-Infiltrating Lymphocytes Tyrosine Kinase Inhibitor Vaccination Vaccine Adjuvant Vaccinee Vaccines Validation anaplastic lymphoma kinase anti-PD-1 cancer cell chemotherapy cohort crizotinib design drug resistance development efficacy testing enzyme linked immunospot assay first-in-human immune resistance immunogenic immunogenicity innovation kinase inhibitor mouse model mutant neoplastic cell next generation novel novel therapeutic intervention objective response rate participant enrollment patient screening pill pre-clinical primary endpoint resistance mutation safety testing screening secondary endpoint success targeted treatment tumor tumor growth vaccine evaluation vaccine formulation

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项目摘要

PROJECT SUMMARY About 5% of non-small cell lung cancers (NSCLCs) are driven by chromosomal translocations of the anaplastic lymphoma kinase (ALK) gene. ALK-positive NSCLC is highly sensitive to ALK tyrosine kinase inhibitors (TKIs), and there are currently five FDA-approved ALK TKIs (crizotinib, alectinib, ceritinib, brigatinib, and lorlatinib) for clinical use. While patients initially benefit from these ALK-targeting therapies, essentially all cancers will develop drug resistance. Upon relapse, standard cytotoxic chemotherapy has modest activity and immune checkpoint inhibitors (ICIs) do not provide any substantial benefit despite evidence that the expression of ALK by tumor cells induces a spontaneous immune response in patients. In preclinical mouse models, we demonstrated that the spontaneous ALK-specific immune response generated by ALK-driven lung cancers is insufficient to build an efficacious anti-tumor response. However, a vaccine that potentiates ALK-specific immune responses in mouse models can achieve a significant therapeutic effect including complete cure. Building on these studies, we propose to develop the first therapeutic ALK vaccine for clinical use in patients with advanced ALK+ NSCLC. To achieve this goal, through immunoproteomic analysis, we have identified the precise ALK peptides that are processed by tumor cells and presented by two major MHC class I molecules in ALK-driven cell lines. We confirmed that these peptides are immunogenic in transgenic mice, patients, and healthy donors. These validated ALK peptides will be included in the formulation of an ALK vaccine for clinical use together with a novel highly potent vaccine adjuvant. The clinical trial will also be supported with additional funding from industry and foundation grants. Leveraging these data and support, we will launch a first-in-human Phase I clinical trial to test the efficacy of the ALK vaccine in NSCLCs that have progressed after treatment with ALK TKIs. In this trial, the safety, tolerability, and efficacy of the ALK vaccine will be tested in two cohorts of patients expressing either HLA-A*0201 or HLA-B*0702 MHC-I molecules. The ALK vaccine will be added to ALK TKIs (cohort 1) or administered together with an ICI (cohort 2) at the time of acquired TKI resistance. Circulating and intratumoral immune responses to the ALK vaccine will be determined in treated patients. Potential mechanisms of escape will be also studied in patients and mouse models. Finally, a discovery effort will allow the identification of ALK peptides presented on additional MHC class I molecules to support a future design of a vaccine with broader application to patients with different MHC-I molecules. Through this project we expect to develop the first cancer vaccine to treat ALK-driven lung cancers that could be eventually use to treat any ALK-driven tumor.

项目摘要大约5％的非小细胞肺癌（NSCLC）是由变性的染色体易位驱动的淋巴瘤激酶（ALK）基因。 ALK阳性NSCLC对ALK酪氨酸激酶抑制剂（TKIS）高度敏感，目前有五个FDA批准的Alk Tkis（Crizotinib，Alectinib，Ceritinib，Brigatinib和Lorlatinib）临床用途。尽管患者最初受益于这些靶向靶向疗法，但本质上所有的癌症都会发展耐药性。复发后，标准的细胞毒性化疗具有适度的活性和免疫检查点抑制剂（ICI）没有提供任何实质性的益处诱导患者自发免疫反应。在临床前鼠标模型中，我们证明了 ALK驱动的肺癌产生的自发ALK特异性免疫反应不足以构建有效的抗肿瘤反应。但是，一种增强小鼠中ALK特异性免疫反应的疫苗模型可以实现重大的治疗效果，包括完整的治疗。在这些研究的基础上，我们建议开发第一种用于晚期ALK+ NSCLC患者临床使用的治疗性ALK疫苗。到通过免疫蛋白质组分析实现此目标，我们已经确定了精确的ALK肽由肿瘤细胞处理，并由ALK驱动的细胞系中的两个主要MHC I类分子呈现。我们证实这些肽在转基因小鼠，患者和健康供体中具有免疫原性。这些经过验证的ALK肽将包括在ALK疫苗的制剂中，以供临床使用以及新型高度有效的疫苗佐剂。临床试验还将获得行业的额外资金以及基金会赠款。利用这些数据和支持，我们将启动第一阶段I期临床试验进行测试 ALK疫苗在用ALK TKIS治疗后进展的NSCLC中的功效。在这次审判中， ALK疫苗的安全性，耐受性和功效将在两名表达的患者中进行测试 HLA-A*0201或HLA-B*0702 MHC-I分子。 ALK疫苗将添加到ALK TKIS（同类1）或在获得TKI电阻时，与ICI（同类2）一起给药。循环和肿瘤内在治疗的患者中将确定对碱疫苗的免疫反应。逃生的潜在机制还将在患者和小鼠模型中进行研究。最后，发现工作将允许识别碱在其他MHC I类分子上呈现的肽，以支持更广泛的疫苗的未来设计应用于不同MHC-I分子的患者。通过这个项目，我们期望发展第一个癌症疫苗以治疗碱驱动的肺癌，最终可以用来治疗任何ALK驱动的肿瘤。