Correlative analysis from a phase I clinical trial of intrapleural administration of oncolytic vaccinia virus (Olvi-vec) in patients with malignant pleural mesothelioma.

Autor:	Chintala NK; Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States., Choe JK; Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States., McGee E; Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States., Bellis R; Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States., Saini JK; Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States., Banerjee S; Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States., Moreira AL; Department of Pathology, New York University (NYU) Grossman School of Medicine, New York, NY, United States., Zauderer MG; Thoracic Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States., Adusumilli PS; Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States.; Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, United States., Rusch VW; Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2023 Feb 16; Vol. 14, pp. 1112960. Date of Electronic Publication: 2023 Feb 16 (Print Publication: 2023).
DOI:	10.3389/fimmu.2023.1112960
Abstrakt:	Background: The attenuated, genetically engineered vaccinia virus has been shown to be a promising oncolytic virus for the treatment of patients with solid tumors, through both direct cytotoxic and immune-activating effects. Whereas systemically administered oncolytic viruses can be neutralized by pre-existing antibodies, locoregionally administered viruses can infect tumor cells and generate immune responses. We conducted a phase I clinical trial to investigate the safety, feasibility and immune activating effects of intrapleural administration of oncolytic vaccinia virus (NCT01766739). Methods: Eighteen patients with malignant pleural effusion due to either malignant pleural mesothelioma or metastatic disease (non-small cell lung cancer or breast cancer) underwent intrapleural administration of the oncolytic vaccinia virus using a dose-escalating method, following drainage of malignant pleural effusion. The primary objective of this trial was to determine a recommended dose of attenuated vaccinia virus. The secondary objectives were to assess feasibility, safety and tolerability; evaluate viral presence in the tumor and serum as well as viral shedding in pleural fluid, sputum, and urine; and evaluate anti-vaccinia virus immune response. Correlative analyses were performed on body fluids, peripheral blood, and tumor specimens obtained from pre- and post-treatment timepoints. Results: Treatment with attenuated vaccinia virus at the dose of 1.00E+07 plaque-forming units (PFU) to 6.00E+09 PFU was feasible and safe, with no treatment-associated mortalities or dose-limiting toxicities. Vaccinia virus was detectable in tumor cells 2-5 days post-treatment, and treatment was associated with a decrease in tumor cell density and an increase in immune cell density as assessed by a pathologist blinded to the clinical observations. An increase in both effector (CD8+, NK, cytotoxic cells) and suppressor (Tregs) immune cell populations was observed following treatment. Dendritic cell and neutrophil populations were also increased, and immune effector and immune checkpoint proteins (granzyme B, perforin, PD-1, PD-L1, and PD-L2) and cytokines (IFN-γ, TNF-α, TGFβ1 and RANTES) were upregulated. Conclusion: The intrapleural administration of oncolytic vaccinia viral therapy is safe and feasible and generates regional immune response without overt systemic symptoms. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT01766739, identifier NCT01766739. Competing Interests: In the last 3 years, MZ has received consulting fees from Curis, Ikena, Takeda, GlaxoSmithKline, Aldeyra Therapeutics, and Novocure and honoraria for CME content from PER, Medscape, Research to Practice, Medical Learning Institute and OncLive. Memorial Sloan Kettering receives research funding from the Department of Defense, the National Institutes of Health, Precog, GlaxoSmithKline, Epizyme, Polaris, Sellas Life Sciences, Bristol Myers Squibb, Millenium/Takeda, Curis, and Atara for research conducted by MZ. MZ serves as Chair of the Board of Directors of the Mesothelioma Applied Research Foundation, uncompensated. PA declares research funding from ATARA Biotherapeutics; Scientific Advisory Board Member and Consultant for Abound Bio, ATARA Biotherapeutics, Bayer, Bio4T2, Carisma Therapeutics, Imugene, ImmPactBio, Johnson&Johnson, Orion Pharma, Outpace Bio, Pleuri-tech, Putnam associates; Patents, royalties and intellectual property on mesothelin-targeted CAR and other T-cell therapies licensed to ATARA Biotherapeutics, issued patent method for detection of cancer cells using virus, and pending patent applications on PD-1 dominant negative receptor, wireless pulse-oximetry device, and on an ex vivo malignant pleural effusion culture system. Memorial Sloan Kettering Cancer Center MSK has licensed intellectual property related to mesothelin-targeted CARs and T-cell therapies to ATARA Biotherapeutics, and has associated financial interests. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2023 Chintala, Choe, McGee, Bellis, Saini, Banerjee, Moreira, Zauderer, Adusumilli and Rusch.)
Databáze:	MEDLINE
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