An off-the-shelf tumor cell vaccine with HLA-matching alleles for the personalized treatment of advanced solid tumors

具有 HLA 匹配等位基因的现成肿瘤细胞疫苗，用于晚期实体瘤的个性化治疗

• 批准号: 10758772
• 负责人: William Williams
• 金额: $ 39.99万
• 依托单位: BRIACELL THERAPEUTICS CORP
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10758772
• 关键词: Address; Alleles; Allogenic; Allogenic Cell Vaccine; Antigen-Presenting Cells; Antigens; Autologous; Biological Assay; Breast; Breast Cancer Patient; Breast Cancer cell line; CD3 Antigens; CD4 Positive T Lymphocytes; CD80 gene; CD86 gene; CRISPR/Cas technology; CSF2 gene; Cancer Patient; Cancer Vaccines; Cancer cell line; Cell Line; Cells; Cellular immunotherapy; Characteristics; Clinic; Clinical; Clinical Data; Clinical Trials; Collection; Complex; Cross Presentation; DNA; Data; Dendritic Cells; Engineering; Excision; Gene Chips; Gene Expression; Gene Expression Profiling; Generations; Genes; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; HLA Antigens; Histocompatibility Antigens Class I; Histocompatibility Antigens Class II; Human; IL17 gene; IL7 gene; Immune; Immune response; Immune system; Immunology; Immunotherapeutic agent; Immunotherapy; In Vitro; Interferon Type II; Interferon alpha; Interleukin-12; Interleukin-2; Interleukin-4; Jurkat Cells; Logistics; Luciferases; MEL Gene; MHC Class I Genes; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Measures; Metastatic breast cancer; Mixed Lymphocyte Culture Test; Molecular Analysis; Oncology; Patients; Peptides; Phase; Phase II Clinical Trials; Population; Prostate; Proteins; RNA; Randomized; Recurrence; Research; Safety; Solid Neoplasm; T-Cell Activation; T-Cell Proliferation; T-Cell Receptor; T-Lymphocyte Subsets; Technology; Testing; Therapeutic; Transfection; Transgenic Organisms; Treatment Protocols; Tumor Antigens; Vaccines; cancer cell; cancer immunotherapy; cancer type; cellular engineering; chemokine; cost; cytokine; cytotoxic CD8 T cells; effective therapy; efficacious treatment; first-in-human; genome sequencing; individual patient; lead candidate; lung cancer cell; malignant breast neoplasm; manufacture; melanoma; neoplastic cell; novel; overexpression; patient population; personalized immunotherapy; personalized medicine; pre-clinical; preclinical efficacy; response; transcriptome sequencing; tumor; vaccine efficacy; whole genome

SUMMARY Cancer vaccines hold promise as immunotherapy due to strong and durable cancer-specific immune responses. Different types of cancer vaccines have been developed, including DNA/RNA-based, protein/peptide-based, dendritic cell-, and whole cell-based vaccines. Allogeneic tumor cell vaccines are limited by the variability in HLA-restricted cellular responses they elicit, typically not matching the HLA alleles of the patient’s tumor, which reduce vaccine efficacy. Autologous cellular vaccines require costly personalized manufacturing. Thus, there remains an urgent and unmet need for new treatment regimens with greater impact on long-term survival. To address the need for new immunotherapeutic approaches to treat advanced solid tumors, BriaCell Therapeutics is developing a novel whole-cell immunotherapeutic approach that acts through two complementary mechanisms of action: 1) cross-presentation of cancer cell antigens and 2) direct T cell activation. This dual mechanism of action is considered unique and represents a significant advance over previous attempts to develop whole-cell cancer vaccines. Enhanced clinical response via direct T cell activation is achieved when a patient’s HLA molecules match those in the therapeutic cell line. Our first-generation Bria- IMT product has demonstrated substantial tumor regression in patients with metastatic breast cancer who match Bria-IMT with at least one HLA allele. Bria-IMT is a breast cancer cell line (SV-BR-1-GM) that secretes granulocyte-macrophage colony-stimulating factor and functions as an antigen-presenting cell (APC) and is able to directly activate CD4+ T cells. We completed a molecular analysis of SV-BR-1-GM cells by microarray gene expression profiling and identified a distinctive 22-gene immune signature consisting of HLA molecules, cytokines, and chemokines. Based on this unique immune signature, BriaCell has selected additional cell lines of different origins in addition to breast cancer: melanoma, prostate, and lung cancers, and will engineer cell lines that express a defined set of cytokines and co-stimulatory molecules as well as a discrete collection of HLA alleles that, collectively, will have the potential to treat almost 100% of the US population at the level of one HLA class I or II allele match with 90% matching at 2 HLA alleles. These cells (termed Bria-OTS, for “off-the-shelf”) will be used as a pre-manufactured and ready-to-use personalized immunotherapy for the treatment of advanced solid tumors. The goal of this Phase I proposal is to generate a collection of melanoma, breast, prostate, and lung cancer Bria-OTS cell lines that will match at least one HLA locus of the US population to cover a large proportion of cancer patients in dire need of an effective therapy. In addition to cell line engineering (Aim 1), this project will validate preclinical activity using cell-based assays to demonstrate the functionality of the Bria-OTS cells (Aim 2). Following a successful Phase I proposal, the novel cell lines will advance to IND enabling studies and subsequent first-in-human clinical trials.

总结 癌症疫苗作为免疫疗法有希望，因为它具有强大和持久的癌症特异性免疫 应答已经开发了不同类型的癌症疫苗，包括基于DNA/RNA的， 基于蛋白质/肽的疫苗、树突细胞疫苗和基于全细胞的疫苗。同种异体肿瘤细胞疫苗有限 它们引起的HLA限制性细胞反应的变异性，通常不匹配的HLA等位基因， 患者的肿瘤，从而降低疫苗的效力。自体细胞疫苗需要昂贵的个性化 制造业因此，对具有更大影响的新治疗方案的需求仍然迫切且未得到满足 关于长期生存。 为了满足对治疗晚期实体瘤的新免疫方法的需求，BriaCell Therapeutics正在开发一种新的全细胞免疫方法， 互补作用机制：1）癌细胞抗原的交叉呈现和2）直接T细胞 activation.这种双重作用机制被认为是独特的，代表了一个重大的进步， 之前开发全细胞癌症疫苗的尝试。通过直接T细胞活化增强临床应答 当患者的HLA分子与治疗细胞系中的分子相匹配时，即可实现这一目标。我们的第一代布里亚 IMT产品已证明在符合以下条件的转移性乳腺癌患者中肿瘤显著消退： 具有至少一个HLA等位基因的Bria-IMT。Bria-IMT是一种乳腺癌细胞系（SV-BR-1-GM）， 粒细胞-巨噬细胞集落刺激因子，作为抗原呈递细胞（APC）发挥功能， 直接激活CD 4 + T细胞。我们利用基因芯片技术对SV-BR-1-GM细胞进行了分子生物学分析 表达谱分析并鉴定了由HLA分子组成的独特的22基因免疫特征， 细胞因子和趋化因子。基于这种独特的免疫特征，BriaCell选择了其他细胞系 除了乳腺癌之外，还可以治疗不同来源的癌症：黑色素瘤、前列腺癌和肺癌， 表达一组确定的细胞因子和共刺激分子以及HLA的离散集合的细胞系 这些等位基因共同具有在一种HLA水平上治疗几乎100%的美国人口的潜力 I类或II类等位基因匹配，其中2个HLA等位基因的匹配率为90%。这些细胞（称为Bria-OTS，即“现成”） 将被用作一种预先制造和随时可用的个性化免疫疗法，用于治疗晚期 实体瘤第一阶段的目标是收集黑色素瘤、乳腺癌、前列腺癌和 肺癌Bria-OTS细胞系，其将匹配美国人群的至少一个HLA基因座，以覆盖大的 急需有效治疗的癌症患者比例。除了细胞系工程（Aim 1）之外， 一个项目将使用基于细胞的试验验证临床前活性，以证明Bria-OTS的功能 细胞（目标2）。在成功的I期提案之后，新的细胞系将进入IND使能研究 以及随后的首次人体临床试验。