Intravenous VSV virotherapy in lymphoma

这笔赠款的首要目标是开发一种治疗复发的最佳病毒免疫疗法。 难治性(R/R)T细胞淋巴瘤(TCL)β是一种溶瘤水泡性口炎病毒 选择性地感染和杀死肿瘤细胞，而不感染正常细胞。在最近完成的第一次人类剂量中 β-NiS单次静脉注射治疗R/R多发性骨髓瘤的疗效观察 和TCL，我们报告说，该病毒可以安全地注射到测试的最高剂量水平(1.7e11 TCID50)。 没有剂量限制毒性。最令人兴奋和显著的临床活动是在TCL患者接受了 单剂1剂1.7E11TCID50VSV-干扰素β-NIS，10例重型患者中5例临床有效(CR2例，PR3例) 治疗前多灶性TCL患者。药代动力学(PK)与药效学(PD)相关性分析 提示这些反应是由于直接溶瘤肿瘤的破坏和免疫介导的肿瘤的共同作用。 控制力。然而，并不是所有的患者都有反应，有几名患者只有混合的肿瘤反应。我们最近 在临床前模型中显示，在α之前给予抗CTLA-4(αCTLA 4)和抗PD1(VSVPD1)抗体- 干扰素β-nis可使已建立的肿瘤100%完全缓解。因此，这笔赠款的目标是改善 通过最大限度地发挥β-干扰素的效力对TCL患者的50%应答率和应答耐受性 NIS使用免疫检查点阻断(ICB)来放大病毒治疗增强的肿瘤反应的抗肿瘤活性 CTL.同时，我们试图确定区分应答和无应答的生物标志物和免疫相关性。 通过对肿瘤活检组织和血液的分析，在TCL中发现。 因此，我们有以下具体目标： 具体目的1.检测β-NIS静脉滴注联合免疫的安全性、PK/PD和疗效 R/R TCL患者的检查点抗体。假设：αCTLA4和αPD1抗体激活免疫 随之而来的是用VSV破坏TCL病毒疗法将最大限度地增强抗肿瘤细胞毒性T细胞 关于长期的肿瘤控制和缓解。 特定目标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允许的基因签名和HIGH TMB是促进反应深度和持久性的积极因素。 β-NIS联合αCTLA_4和α_PD1免疫增强治疗对小鼠免疫功能的影响 抗肿瘤CTL和Treg免疫反应的动力学、大小和特异性。假设：适时添加 免疫调节剂与VSV病毒治疗将导致抗原反应性T细胞频率和持续时间的增加。 这项研究完成后，我们将对驱动病毒反应的参数有更深入的了解。 免疫疗法，并有可能获得一种值得进一步临床开发的新的治疗方案 R/R TCL。这项研究的结果也将为建立更有效的治疗其他癌症的剂量提供基础 有迹象表明。

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.