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, ...