Intravenous VSV virotherapy in lymphoma

淋巴瘤静脉注射 VSV 病毒治疗

• 批准号: 10658290
• 负责人: Nabila Nora Bennani
• 金额: $ 61.98万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-11 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658290
• 关键词: Antibodies; Antigens; Automobile Driving; Biopsy; Blood; Blood Cells; Cells; Clinical; Cytometry; Cytotoxic T-Lymphocytes; Disease remission; Dose; Dose Limiting; Engineering; Epitope spreading; Foundations; Frequencies; Funding; Gene Expression Profile; Genes; Goals; Grant; Human; Image; Immune; Immune response; Immunocompetent; Immunomodulators; Immunotherapy; In complete remission; Interferon Type II; Interferon-beta; Intravenous; Intravenous infusion procedures; Kinetics; Lymphoma; Malignant Neoplasms; Mediating; Mixed Neoplasm; Monitor; Multiple Myeloma; Mus; Mutation; Normal Cell; Oncolytic; Outcome; PET/CT scan; Patients; Pharmaceutical Preparations; Play; Population; Pre-Clinical Model; Refractory; Regimen; Regulatory T-Lymphocyte; Relapse; Reporting; Role; SLC5A5 gene; Safety; Signal Transduction; Specificity; Splenic Diseases; T cell receptor repertoire sequencing; T-Cell Lymphoma; T-Lymphocyte; Testing; Time; Toxic effect; Treatment outcome; Tumor Antigens; Vesicular stomatitis Indiana virus; Viral; Viral Genes; Virotherapy; Virus; Whole Blood; anti-CTLA4; anti-PD-1; biomarker identification; clinical development; exome sequencing; first-in-human; genetic signature; immune activation; immune checkpoint; immune checkpoint blockade; immunotherapeutic virotherapy; improved; lymph nodes; neoplastic cell; next generation; oncolytic Vesicular Stomatitis Virus; partial response; permissiveness; pharmacokinetics and pharmacodynamics; responders and non-responders; response; therapy outcome; transcriptome sequencing; tumor; tumor-immune system interactions

The overarching goal of this grant is to develop an optimal viro-immunotherapy approach for the treatment of relapsed refractory (R/R) T cell lymphoma (TCL). VSV-IFNβ-NIS is an oncolytic Vesicular Stomatitis Virus (VSV) engineered to selectively infect and kill tumor cells, while sparing normal cells. In the recently completed first-in-human dose escalation study utilizing a single intravenous (IV) infusion of VSV-IFNβ-NIS in patients with R/R multiple myeloma (MM) and TCL, we reported that the virus can be safely administered up to the highest dose level tested (1.7e11 TCID50) with no dose limiting toxicities. The most exciting and significant clinical activity was seen in patients with TCL who received one dose of 1.7e11 TCID50 VSV-IFNβ-NIS as a single agent, with 5 clinical responses (2 CR and 3 PR) in 10 heavily pretreated patients with multi-focal TCL. Pharmacokinetics (PK) and pharmacodynamics (PD) correlative analyses suggest that responses are due to a combination of direct oncolytic tumor destruction and immune-mediated tumor control. However, not all patients responded, and several patients had mixed tumor responses only. We recently showed in preclinical models that addition of anti-CTLA-4 (αCTLA4) and anti-PD1 (αPD1) antibodies given prior to VSV- IFNβ-NIS resulted in complete remission of established tumors in 100% of mice. Thus, the goal of this grant is to improve the 50% response rate and durability of response (DOR) in patients with TCL by maximizing the potency of VSV-IFNβ- NIS using immune checkpoint blockade (ICB) to amplify the antitumor activity of virotherapy-boosted tumor-reactive CTL. In parallel, we seek to identify biomarkers and immune correlates differentiating responders from non-responders in TCL through analysis of tumor biopsies and blood. We thus have the following specific aims: Specific Aim 1. Determine the safety, PK/PD and efficacy of one IV of VSV-IFNβ-NIS in combination with immune checkpoint antibodies for patients with R/R TCL. Hypothesis: Immune activation with αCTLA4 and αPD1 antibodies followed by destruction of TCL with VSV virotherapy will maximize the boosting of antitumor cytotoxic T cells to bring about long-term tumor control and remission. Specific Aim 2. Determine the baseline tumor gene expression profile (antiviral and immune) and tumor mutation burden (TMB) and evaluate their impact on clinical response. Hypothesis: A VSV permissive gene signature and high TMB are positive contributing factors to the depth and durability of response. Specific Aim 3. Determine the impact of VSV-IFNβ-NIS treatment with αCTLA4 and αPD1 immune boosting on the kinetics, magnitude and specificity of antitumor CTL and Treg immune responses. Hypothesis: Timely addition of the immune modulators with VSV virotherapy will result in enhanced frequency and duration of antigen reactive T cells. Upon completion of this study, we will achieve a deeper understanding of parameters that drive responses in viro- immunotherapy, and potentially derive a new treatment option worthy of further clinical development in patients with R/R TCL. Results from this study will also provide the foundation for building more effective dosing for other cancer indications.

这笔赠款的总体目标是开发一种最佳的维罗免疫疗法来处理继电器 难治性（R/R）T细胞淋巴瘤（TCL）。 VSV-IFNβ-NIS是一种设计为 选择性感染并杀死肿瘤细胞，同时保留正常细胞。在最近完成的人类剂量中 R/R多发性骨髓瘤（MM）的患者使用单个静脉内（IV）输注VSV-IFNβ-NIS的升级研究 和TCL，我们报告说，该病毒可以安全地施用到经过测试的最高剂量水平（1.7E11 TCID50），并使用 无剂量限制战术。在接受的TCL患者中，观察到最令人兴奋，最重要的临床活动 1.7E11 TCID50 VSV-IFNβ-NIS作为单个药物，有5个临床反应（2 cr和3 pr），在10个重度中 预处理多焦点TCL的患者。药代动力学（PK）和药效学（PD）相关分析 表明反应是由于直接肿瘤肿瘤破坏和免疫介导的肿瘤的组合 控制。但是，并非所有患者都做出反应，几名患者仅患有混合肿瘤反应。我们最近 在临床前模型中显示了在VSV-之前给出的抗CTLA-4（αCTLA4）和抗PD1（αPD1）抗体 IFNβ-NIS导致100％的小鼠完全缓解已建立的肿瘤。那是这笔赠款的目标是改善 通过最大化VSV-IFNβ-的效力 NIS使用免疫切除点（ICB）扩增病毒疗法促进肿瘤反应的抗肿瘤活性 CTL。同时，我们试图识别生物标志物和免疫反相，使响应者与非反应者区分开 在TCL中，通过分析肿瘤活检和血液。 因此，我们有以下具体目标： 具体目标1。确定一个VSV-IFNβ-NIS的安全性，PK/PD和效率与免疫结合 R/R TCL患者的检查点抗体。假设：用αCTLA4和αPD1抗体的免疫激活 然后用VSV病毒疗法破坏TCL将最大化抗肿瘤细胞毒性T细胞的增强 关于长期肿瘤控制和缓解。 具体目标2。确定基线肿瘤基因表达谱（抗病毒和免疫）和肿瘤突变 负担（TMB）并评估其对临床反应的影响。假设：VSV允许基因签名和高 TMB是对响应深度和持久性的积极因素。 具体目标3。确定用αCTLA4和αPD1免疫增强对VSV-IFNβ-NIS治疗的影响 抗肿瘤CTL和Treg免疫反应的动力学，大小和特异性。假设：及时添加 VSV病毒疗法的免疫调节剂将导致抗原反应性T细胞的频率和持续时间增强。 这项研究完成后，我们将对参数进行更深入的了解，这些参数可以推动viro的响应 免疫疗法，并有可能获得一种新的治疗选择，值得在 R/R TCL。这项研究的结果还将为其他癌症建立更有效剂量的基础 适应症。