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

摘要 由于强大而持久的癌症特异性免疫，癌症疫苗有望成为免疫疗法 回应。不同类型的癌症疫苗已经被开发出来，包括基于DNA/RNA的， 基于蛋白质/多肽、树突状细胞和全细胞的疫苗。同种异体肿瘤细胞疫苗有限 通过它们引起的人类白细胞抗原限制性细胞反应的变异性，通常不匹配人类白细胞抗原的等位基因 患者的肿瘤，这降低了疫苗的效力。自体细胞疫苗需要昂贵的个性化 制造业。因此，对产生更大影响的新的治疗方法的迫切需要仍然没有得到满足。 关于长期生存的问题。 为了满足治疗晚期实体肿瘤的新免疫治疗方法的需求，BriaCell Treateutics正在开发一种新的全细胞免疫治疗方法，该方法通过两种 互补的作用机制：1)癌细胞抗原的交叉递呈和2)直接T细胞 激活。这种双重行动机制被认为是独一无二的，是对 之前曾尝试开发全细胞癌症疫苗。通过直接激活T细胞增强临床反应 当患者的人类白细胞抗原分子与治疗细胞系中的分子相匹配时，就可以实现。我们的第一代布里亚- IMT产品在匹配的转移性乳腺癌患者中显示出显著的肿瘤消退 至少有一个HLA等位基因的BRIA-IMT。Bria-IMT是一种乳腺癌细胞系(SV-BR-1-GM)，它能分泌 粒细胞巨噬细胞集落刺激因子和作为抗原提呈细胞(APC)的功能，并能够 直接激活CD4+T细胞。我们利用基因芯片技术完成了对SV-BR-1-GM细胞的分子分析 表达谱并鉴定出由人类白细胞抗原分子组成的独特的22个基因的免疫特征， 细胞因子和趋化因子。基于这种独特的免疫特征，BriaCell选择了更多的细胞系 除了乳腺癌之外，还有不同的起源：黑色素瘤、前列腺癌和肺癌，并将工程细胞 表达一组确定的细胞因子和共刺激分子以及一组离散的人类白细胞抗原的品系 这些等位基因加在一起，有可能在一个人类白细胞抗原的水平上治疗几乎100%的美国人口 I、II类等位基因匹配，其中2个等位基因的匹配率为90%。这些细胞(称为Bria-OTS，意为“现成”) 将作为一种预制和即用的个性化免疫疗法用于治疗晚期 实体瘤。这个第一阶段提案的目标是产生一组黑色素瘤、乳腺癌、前列腺癌和 肺癌Bria-OTS细胞株将匹配至少一个美国人群的HLA基因座以覆盖大量 迫切需要有效治疗的癌症患者比例。除了细胞系工程(目标1)之外，这一点 项目将使用基于细胞的分析来验证临床前活动，以演示Bria-OTS的功能 细胞(目标2)。在第一阶段提案成功后，新的细胞系将进入IND使能研究 以及随后的首个人类临床试验。

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.