Project 1

项目1

• 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
• 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

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）是由间变性细胞的染色体易位引起的。 淋巴瘤激酶（ALK）基因。ALK阳性NSCLC对ALK酪氨酸激酶抑制剂（TKI）高度敏感， 目前有五种FDA批准的ALK TKI（克唑替尼、阿来替尼、塞瑞替尼、brigatinib和劳拉替尼）用于 临床应用。虽然患者最初受益于这些ALK靶向治疗，但基本上所有癌症都会发展 耐药性复发时，标准细胞毒性化疗具有适度的活性和免疫检查点。 尽管有证据表明肿瘤细胞表达ALK， 在病人体内引发自发免疫反应在临床前小鼠模型中，我们证明了 由ALK驱动的肺癌产生的自发性ALK特异性免疫应答不足以建立一个 有效的抗肿瘤反应。然而，在小鼠中增强ALK特异性免疫应答的疫苗， 模型可以达到显著的治疗效果，包括完全治愈。基于这些研究，我们 建议开发第一种治疗性ALK疫苗，用于晚期ALK+ NSCLC患者的临床应用。到 为了实现这一目标，通过免疫蛋白质组学分析，我们已经确定了精确的ALK肽， 由肿瘤细胞加工，并由ALK驱动的细胞系中的两种主要MHC I类分子呈递。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 经验证的ALK肽将与新型ALK疫苗一起包含在临床使用的ALK疫苗配方中 高效疫苗佐剂。该临床试验还将得到来自行业的额外资助， 基金会赠款。利用这些数据和支持，我们将启动一项首次人体I期临床试验， ALK疫苗在ALK TKI治疗后进展的NSCLC中的疗效。本试验中 ALK疫苗的安全性、耐受性和有效性将在两个表达以下任一种情况的患者队列中进行检测： HLA-A*0201或HLA-B*0702 MHC-I分子。ALK疫苗将添加至ALK TKI（队列1）或 在获得性TKI耐药时与ICI一起给药（队列2）。循环和肿瘤内 将在治疗的患者中确定对ALK疫苗的免疫应答。潜在的逃逸机制 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ALK 在额外的MHC I类分子上呈递的肽，以支持未来设计具有更广泛免疫原性的疫苗。 应用于具有不同MHC-I分子的患者。通过这个项目，我们希望开发出第一种癌症， 治疗ALK驱动的肺癌的疫苗，最终可用于治疗任何ALK驱动的肿瘤。