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

基本信息

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
项目类别：
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

项目摘要

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.

概括由于强大而持久的癌症特异性免疫系统，癌症疫苗有望成为免疫疗法已经开发出不同类型的癌症疫苗，包括基于 DNA/RNA 的疫苗。基于蛋白质/肽、树突状细胞和全细胞的疫苗是有限的。通过它们引发的 HLA 限制性细胞反应的变异性，通常与 HLA 等位基因不匹配患者的肿瘤，这会降低疫苗功效，需要昂贵的个性化疫苗。因此，对具有更大影响的新治疗方案仍然存在迫切且未得到满足的需求。关于长期生存。为了满足治疗晚期实体瘤的新免疫治疗方法的需求，BriaCell Therapeutics 正在开发一种新型全细胞免疫治疗方法，该方法通过两种方式发挥作用：互补的作用机制：1) 癌细胞抗原的交叉呈递和 2) 直接 T 细胞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。先前尝试通过直接 T 细胞激活来开发全细胞癌症疫苗。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。 IMT 产品已证明，符合条件的转移性乳腺癌患者的肿瘤明显消退 Bria-IMT 具有至少一个 HLA 等位基因 Bria-IMT 是一种分泌乳腺癌细胞系 (SV-BR-1-GM)。粒细胞-巨噬细胞集落刺激因子，具有抗原呈递细胞 (APC) 的功能，并且能够通过微阵列基因直接激活CD4+ T细胞我们完成了SV-BR-1-GM细胞的分子分析。表达谱并鉴定出由 HLA 分子组成的独特 22 基因免疫特征，基于这种独特的免疫特征，BriaCell 选择了其他细胞系。除乳腺癌外，还有不同来源的癌症：黑色素瘤、前列腺癌和肺癌，并将改造细胞表达一组确定的细胞因子和共刺激分子以及 HLA 离散集合的细胞系这些等位基因加在一起将有可能在一个 HLA 水平上治疗几乎 100% 的美国人这些细胞的 2 个 HLA 等位基因的 I 类或 II 类等位基因匹配率为 90%（称为 Bria-OTS，意为“现成的”）。将用作预制且随时可用的个性化免疫疗法，用于治疗晚期该第一阶段提案的目标是产生黑色素瘤、乳腺癌、前列腺癌和实体瘤的集合。肺癌 Bria-OTS 细胞系将与美国人口的至少一个 HLA 基因座相匹配，以覆盖大除了细胞系工程（目标 1）之外，迫切需要有效治疗的癌症患者比例。该项目将使用基于细胞的检测来验证临床前活性，以展示 Bria-OTS 的功能细胞（目标 2）。在 I 期提案成功后，新型细胞系将进入 IND 研究阶段。以及随后的首次人体临床试验。