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

   

Authors:	Chintala, N. K.; Choe, J. K.; McGee, E.; Bellis, R.; Saini, J. K.; Banerjee, S.; Moreira, A. L.; Zauderer, M. G.; Adusumilli, P. S.; Rusch, V. W.
Article Title:	Correlative analysis from a phase I clinical trial of intrapleural administration of oncolytic vaccinia virus (Olvi-vec) in patients with malignant pleural mesothelioma
Abstract:	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. Copyright © 2023 Chintala, Choe, McGee, Bellis, Saini, Banerjee, Moreira, Zauderer, Adusumilli and Rusch.
Keywords:	adult; clinical article; controlled study; human tissue; aged; middle aged; human cell; clinical trial; drug tolerability; fatigue; drug safety; hypophosphatemia; flow cytometry; metastasis; breast cancer; anemia; carcinoma, non-small-cell lung; lung neoplasms; immunofluorescence; cell population; drug dose escalation; fever; hyperglycemia; lymphocytopenia; lung tumor; alanine aminotransferase; aspartate aminotransferase; granzyme b; feasibility study; neutrophil; gamma interferon; immunogenicity; vaccination; oncolytic virus; oncolytic viruses; oncolytic virotherapy; pleura mesothelioma; vaccinia virus; mesothelioma; transforming growth factor beta1; perforin; cell density; maximum tolerated dose; phase 1 clinical trial; pleura fluid; pleural effusion, malignant; drug therapy; video assisted thoracoscopic surgery; immunocompetent cell; body fluid; clinical observation; hypocalcemia; tumor necrosis factor; programmed death 1 receptor; non small cell lung cancer; vaccinia; tumor microenvironment; neutralizing antibody; virus neutralization; rantes; virus shedding; oncolytic viral therapy; regional therapy; malignant pleura effusion; hemagglutinin; oncolytic vaccinia virus; humans; human; male; female; article; programmed death 1 ligand 2; viral plaque assay; intrapleural drug administration; pleural cancers; mesothelioma, malignant; plaque forming unit; malignant pleural effusion (mpe)
Journal Title:	Frontiers in Immunology
Volume:	14
ISSN:	1664-3224
Publisher:	Frontiers Media S.A.
Date Published:	2023-01-01
Start Page:	1112960
Language:	English
DOI:	10.3389/fimmu.2023.1112960
PUBMED:	36875061
PROVIDER:	scopus
PMCID:	PMC9977791
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85149524838&doi=10.3389%2ffimmu.2023.1112960&partnerID=40&md5=6dd38c574eb95180093cd363fb5bfc62
Notes:	The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Corresponding author is MSK author: Prasad S. Adusumilli -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/204338