Intravenous VSV virotherapy in lymphoma

该基金的总体目标是开发一种最佳的病毒免疫治疗方法，用于治疗复发性 难治性（R/R）T细胞淋巴瘤（TCL）。VSV-IFNβ-NIS是一种溶瘤性水泡性口炎病毒（VSV）， 选择性地感染和杀死肿瘤细胞，而不伤害正常细胞。在最近完成的首次人体试验中 一项在R/R多发性骨髓瘤（MM）患者中使用VSV-IFNβ-NIS单次静脉（IV）输注的递增研究 和TCL，我们报告说，该病毒可以安全地给予最高剂量水平（1.7e11 TCID 50）， 无剂量限制性毒性。最令人兴奋和显著的临床活动是在TCL患者中观察到的， 1剂1.7e11 TCID 50 VSV-IFNβ-NIS作为单药，在10例重度感染者中有5例临床应答（2例CR和3例PR）， 多灶性TCL的预治疗患者。药代动力学（PK）和药效学（PD）相关性分析 表明反应是由于直接溶瘤肿瘤破坏和免疫介导肿瘤 控制然而，并非所有患者都有反应，一些患者仅具有混合肿瘤反应。我们最近 在临床前模型中显示，在VSV之前添加抗CTLA-4（α CTLA 4）和抗PD 1（α PD 1）抗体， IFNβ-NIS导致100%的小鼠中建立的肿瘤完全缓解。因此，这笔赠款的目标是改善 通过最大限度地提高VSV-IFNβ-的效力，使TCL患者的缓解率和缓解持久性（DOR）达到50% NIS使用免疫检查点阻断（ICB）来增强病毒疗法增强的肿瘤反应性抗体的抗肿瘤活性。 CTL.与此同时，我们寻求识别区分有反应者和无反应者的生物标志物和免疫相关物 在TCL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。确定一次IV VSV-IFNβ-NIS联合免疫治疗的安全性、PK/PD和疗效， R/R TCL患者的检查点抗体。假设：α CTLA 4和α PD 1抗体的免疫激活 随后用VSV病毒疗法破坏TCL将使抗肿瘤细胞毒性T细胞的加强最大化， 长期的肿瘤控制和缓解。 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 负荷（TMB），并评价其对临床应答的影响。假设：VSV允许基因签名和高表达 TMB是积极的促进因素，对反应的深度和持久性。 具体目标3。确定VSV-IFNβ-NIS治疗与α CTLA 4和α PD 1免疫加强对VSV-IFNβ-NIS治疗的影响。 抗肿瘤CTL和Treg免疫应答的动力学、幅度和特异性。假设：及时添加 免疫调节剂与VSV病毒疗法将导致抗原反应性T细胞的频率和持续时间增加。 完成本研究后，我们将更深入地了解驱动病毒反应的参数， 免疫疗法，并可能获得一种新的治疗选择，值得进一步临床开发的患者 R/R TCL。这项研究的结果也将为其他癌症建立更有效的剂量提供基础。 迹象。

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.