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Intravenous VSV virotherapy in lymphoma

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:
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-05-11 至 2028-04-30

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中文摘要
翻译
这项资助的首要目标是开发一种治疗复发的最佳病毒免疫治疗方法
英文摘要
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.
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Neo-antigens暴露对肾移植术后体液性排斥反应的影响及其机制研究
  • 批准号:
    2022J011295
  • 项目类别:
    省市级项目
  • 资助金额:
    10.0万元
  • 批准年份:
    2022
  • 负责人:
    王亚伟
  • 依托单位:
结核分枝杆菌持续感染期抗原(latency antigens)的重组BCG疫苗研究