Intrapleural interleukin-2–expressing oncolytic virotherapy enhances acute antitumor effects and T-cell receptor diversity in malignant pleural disease

Abstract

Objective: The mainstay of treatment for patients with malignant pleural disease is fluid drainage and systemic therapy. A tumor-specific oncolytic virus or T-cell-activating interleukin-2 immunotherapy may provide an opportunity for local control. We previously developed a vaccinia virus-expressing interleukin-2, an oncolytic virus that mediated tumor regression in preclinical peritoneal tumor models with expansion of tumor-infiltrating lymphocytes. We evaluated the antitumor efficacy and immune modulatory effects of vaccinia virus-expressing interleukin-2 in malignant pleural disease.Methods: A murine model of malignant pleural disease was established with percutaneous intrapleural deposition of the Lewis lung carcinoma cell line and monitored with bioluminescent imaging. After intrapleural or systemic administration of vaccinia viruses (vaccinia virus yellow fluorescent protein control, vaccinia virus-expressing interleukin-2), systemic anti-programmed cell death-1 antibody, or combination therapy (vaccinia virus-expressing interleukin-2 and anti-programmed cell death-1), tumor mass, immune cell infiltration, T-cell receptor diversity, and survival were assessed.Results: Intrapleural vaccinia virus resulted in significant tumor regression compared with phosphate-buffered saline control (P < .05). Inclusion of the interleukin-2 transgene further increased intratumoral CD8 þ T cells (P < .01) and programmed cell death-1 expression on CD8 þ tumor-infiltrating lymphocytes (P < .001). Intrapleural vaccinia virus-expressing interleukin-2 was superior to systemic vaccinia virus-expressing interleukin-2, with reduced tumor burden (P < .0001) and improved survival (P < .05). Intrapleural vaccinia virus-expressing interleukin-2 alone or combined treatment with systemic TCR Vβ DiversityαPD-1

Oncolytic Viruses for Malignant Glioma: On the Verge of Success?

“…Several OVs have been designed to express immunostimulatory cytokines, such as IL-2 [123][124][125], IL-12 [126,127], IL15Rα-IL15 fusion protein [128], IL-4 [129], GM-CSF [130,131] and chemokines [132,133], which have shown promising results in pre-clinical studies in malignant glioma tumor models; however, this review focuses on OVs that are in clinical studies. At least two OVs, M032-and DNX-2440-expressing immunostimulatory proteins to potentiate anti-tumor immune responses are currently in clinical trials in malignant glioma patients.…”

“…Oncolytic virotherapy uses two main approaches to achieve the higher levels of pro-inflammatory factors in the TME: (1) engineering OVs to express immunostimulatory proteins and (2) the administration of immune stimulators and OVs in combination. Several OVs have been designed to express immunostimulatory cytokines, such as IL-2 [ 123 , 124 , 125 ], IL-12 [ 126 , 127 ], IL15Rα-IL15 fusion protein [ 128 ], IL-4 [ 129 ], GM-CSF [ 130 , 131 ] and chemokines [ 132 , 133 ], which have shown promising results in pre-clinical studies in malignant glioma tumor models; however, this review focuses on OVs that are in clinical studies. At least two OVs, M032- and DNX-2440-expressing immunostimulatory proteins to potentiate anti-tumor immune responses are currently in clinical trials in malignant glioma patients.…”

Fighting Fire With Fire: Oncolytic Virotherapy for Thoracic Malignancies

“…67 We have found that intrapleural injection has greater antitumor efficacy than systemic treatment with enhanced diversity in the recruited T cell repertoire. 68…”

Commentary: Interleukin 2: The gasoline that lit the immunotherapeutic fire

“…Commentary: Interleukin 2: The gasoline that lit the immunotherapeutic fire R. Taylor Ripley, MD Ekeke and colleagues 1 present an interesting report in which they develop a malignant pleural effusion model with Lewis lung cancer cells in mice with direct pleural injections of recombinant interleukin (IL) 2 on a vaccinia backbone. They found that direct administration of IL-2 to the pleural resulted in lower tumor burden and longer survival compared with systemic administration of IL-2.…”