Actively engaging NK cells during virotherapy to induce neoantigen-specific antitumor immunity

在病毒治疗过程中积极参与 NK 细胞诱导新抗原特异性抗肿瘤免疫

• 批准号: 10405290
• 负责人: SHAUN XIAOLIU ZHANG
• 金额: $ 38.42万
• 依托单位: UNIVERSITY OF HOUSTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10405290
• 关键词: Activated Natural Killer Cell; CD8 receptor; CD8-Positive T-Lymphocytes; Clinic; Clinical; Colon Carcinoma; Consequentialism; Cross Presentation; Data; Dendritic Cells; Development; Disease; ERBB2 gene; Effectiveness; Ensure; Epidermal Growth Factor Receptor; Event; FCGR3B gene; Future; Herpesvirus 1; Homing; Human Herpesvirus 2; Immune; Immune system; Immunity; In Vitro; Infiltration; Injections; Interleukin-2; Malignant Neoplasms; Malignant neoplasm of lung; Measurable; Mediating; Natural Killer Cells; Nodule; Oncolytic; Oncolytic viruses; Outcome; Patients; Procedures; Receptor Activation; Route; Series; Simplexvirus; Site; Solid Neoplasm; System; Systemic disease; T-Lymphocyte; Testing; Therapeutic; Therapeutic Effect; Time; Translating; Treatment Efficacy; Tumor Antigens; Tumor Immunity; Virotherapy; Virus; XCL1 gene; antitumor effect; arm; base; cancer immunotherapy; cell killing; chemokine; clinical application; clinical practice; combinatorial; design; draining lymph node; effective therapy; experimental study; improved; in vivo; individual patient; joint destruction; macrophage; melanoma; migration; neoantigens; neoplastic cell; neutralizing antibody; novel; novel strategies; oncolysis; oncolytic virotherapy; receptor; tumor; tumor microenvironment

PROJECT SUMMARY Significant progress in recent years on the development of oncolytic virotherapy has led to the FDA approval of a type I herpes simplex virus (HSV-1) based oncolytic virus (Talimogene Laherparepvec or T-VEC) for the treatment of advanced melanoma. However, it has become increasingly clear that there is a need to further improve the current version of OV for a better clinical benefit. Our lab has constructed a HSV-2 based oncolytic virus - FusOn-H2, the first of its kind, by a novel mechanism. Our recent studies showed that arming FusOn- H2 with a chimeric NK engager (C-NK-E) that can engage the infiltrated natural killer (NK) cells with tumor cells could significantly enhance the effectiveness of this virotherapy. Moreover, we observed that tumor destruction by the joint effect of the direct oncolysis and the engaged NK cells led to a measurable elicitation of neoantigen-specific antitumor immunity. Based on these exciting findings, we propose to develop a three- pronged strategy to enhance the antitumor efficacy of FusOn-H2 via combinatorial immuno-oncolytic virotherapy (IOV). The antitumor activities from this strategic three-pronged IOV come in waves in a sequential order. The first wave comes immediately and it derives primarily from the virus-mediated direct oncolysis. The second wave comes from the NK-mediated tumor cell killing enabled jointly by the virotherapy-trigged NK cell infiltration and the released C-NK-E from the armed virus. The third wave is the outcome of a series of chain events that ultimately result in induction and homing of neoantigen-specific T cells. Our major hypothesis is that this three-pronged strategy will act in a consequential and concerted way to significantly enhance the therapeutic efficacy of this IOV. We have designed three specific aims to test our major hypothesis. In Aim 1, we will dissect the mechanism of C-NK-E-armed virus in generating neoantigen-specific immunity and to design additional strategies to further potentiate this effect. Neoantigens are attractive targets for cancer immunotherapy, but there lacks a simple and effective way of delivering them. In principle, OV offers a simple means to release these neoantigens in individual patients, and our proposed strategy will ensure their efficient and timely presentation to the host’s immune system without the need for additional procedures. In Aim 2, we will investigate if combining C-NK-Es that engage two different activation receptors can further potentiate the NK cell killing and neoantigen-specific T cell immunity. In Aim 3, we will demonstrate that the three-pronged IOV can produce an efficient therapeutic effect against metastatic diseases by the systemic delivery route. We have recently developed novel strategies to overcome key obstacles for systemic delivery - the rapid clearance by the macrophage system and the neutralizing antibodies. We hypothesize that the combination of the high potency of the three-pronged IOV with the improved systemic delivery will lead to effective treatment of metastatic diseases. Our studies in this proposal thus overcome the two major hurdles hindering OV - the relatively weak therapeutic activity and lack of means for effective systemic delivery, and the developed strategy can be translated into the clinic in the near future.

项目摘要 近年来，关于溶瘤病毒疗法的发展取得了重大进展，导致了FDA批准 基于I型疱疹病毒（HSV-1）的溶瘤病毒（talimogene laherparepvec或t-vec） 治疗晚期黑色素瘤。但是，越来越清楚的是，有必要进一步 改善当前版本的OV，以获得更好的临床益处。我们的实验室已经构建了基于HSV-2的溶瘤 病毒-Fuson -H2是一种新型机制。我们最近的研究表明，武装fuson- H2具有Chimeric NK Endager（C-NK-E），可以与肿瘤接合浸润的天然杀手（NK）细胞 细胞可以显着提高该病毒疗法的有效性。而且，我们观察到肿瘤 直接癌症和参与NK细胞的关节作用的破坏导致了可测量的启发 新抗原特异性抗肿瘤免疫。基于这些令人兴奋的发现，我们建议开发一个三 通过组合免疫 - 溶解溶剂，提高fuson-H2的抗肿瘤效率的策略 病毒疗法（IOV）。该战略三管齐下的IOV的抗肿瘤活动在顺序的 命令。第一波立即出现，它源自病毒介导的直接闭塞。 第二波来自NK介导的肿瘤细胞杀死，由病毒疗法造成的NK细胞共同启用 从武装病毒浸润和释放的C-NK-E。第三波是一系列链的结果 最终导致新抗原特异性T细胞的诱导和归巢的事件。我们的主要假设是 这项三管齐下的策略将以相应而协调一致的方式行事，以显着增强 该IOV的治疗效率。我们设计了三个特定的目标来检验我们的主要假设。在AIM 1中， 我们将剖析C-NK-E臂病毒在产生新抗原特异性免疫和至 设计其他策略以进一步潜在这种效果。新抗原是癌症的有吸引力的靶标 免疫疗法，但缺乏一种简单有效的交付方式。原则上，OV提供了一个简单的 在个别患者中释放这些新抗原的手段，我们提出的策略将确保其有效 并及时向主机的免疫系统介绍，而无需其他程序。在AIM 2中，我们 将研究是否将接合两个不同激活受体的C-NK-E组合可以进一步潜力 NK细胞杀伤和新抗原特异性T细胞免疫。在AIM 3中，我们将证明三管齐下的 IOV可以通过全身输送路线对转移性疾病产生有效的热效应。 我们最近开发了新的策略来克服全身交付的关键障碍 - 快速 巨噬细胞系统和中和抗体的清除。我们假设组合 三管齐下的IOV具有改进的全身交付的高效力将导致有效 转移性疾病的治疗。因此，我们在该提案中的研究克服了这两个主要障碍 OV-相对较弱的治疗活动和缺乏有效全身性传递的手段，以及 开发的策略可以在不久的将来转化为诊所。