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

Our plain-English summary of Correlative analysis from a phase I clinical trial of intrapleural administration of oncolytic vaccinia virus (Olvi-vec) in patients with malignant pleural mesothelioma, by N.K. Chintala, J.K. Choe, E. McGee, et al (Frontiers in Immunology, 2023).

The study

• Authors: N.K. Chintala, J.K. Choe, E. McGee, R. Bellis, J.K. Saini, S. Banerjee, A.L. Moreira, M.G. Zauderer, P.S. Adusumilli, V.W. Rusch
• Journal: Frontiers in Immunology
• Published: 2023;14:1112960
• Cited by: 27 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This single-center, open-label phase I trial was run at Memorial Sloan Kettering Cancer Center in New York. From February 2013 to April 2015, 18 patients with cancer-related fluid around the lungs (malignant pleural effusion) took part: 15 had malignant pleural mesothelioma, 2 had non-small cell lung cancer and 1 had triple negative breast cancer. After the fluid was drained, a weakened, genetically engineered vaccinia virus (Olvi-vec) was placed in the chest cavity at rising doses. There were no dose-limiting toxicities and one reversible grade 4 low calcium level. Because the maximum tolerated dose was not reached, no recommended dose was set. Virus was seen in 7 of 14 post-treatment tumor samples. In the 4 patients with matched before-and-after biopsies, tumor cell density scores fell in all 4 and immune cell density scores rose in 3. Median overall survival was 22 months among mesothelioma patients. The authors said this cannot be attributed to the treatment. The authors concluded the therapy was safe and feasible and generated a regional immune response without overt systemic symptoms.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Open-label, dose-escalating, non-randomized, single-center phase I clinical trial with correlative laboratory analyses of fluids, blood and tumor specimens
• Who was studied: 18 patients with malignant pleural effusion treated at Memorial Sloan Kettering Cancer Center, New York, enrolled February 2013 to April 2015. Fifteen had malignant pleural mesothelioma (13 epithelioid, 1 biphasic, 1 sarcomatoid), 2 had non-small cell lung cancer and 1 had triple negative breast cancer. Five were female, and the mean age was 66 years.
• Exposure: The study examined a treatment, not an asbestos exposure. Patients received intrapleural attenuated vaccinia virus (Olvi-vec, formerly GL-ONC1) at doses from 1.00E+07 to 6.00E+09 plaque-forming units, as one dose or as three consecutive daily doses, after the effusion was drained. The article gives no asbestos exposure information.
• Main results:
  • All 18 patients: there were no dose-limiting toxicities and the maximally tolerated dose was not reached. As a result, the primary objective of setting a recommended dose was not met.
  • All 18 patients: there was one reversible grade 4 laboratory abnormality (hypocalcemia). The most frequent grade 3 adverse events were lymphopenia (3 patients, 17%), fatigue (2 patients, 11%) and hypophosphatemia (2 patients, 11%).
  • Post-treatment tumor samples stained for the virus: positive in 7 of 14 specimens.
  • Patients with matched pre- and post-treatment specimens (n=4): the tumor cell density score fell in all 4, and the immune cell density score rose in 3 of 4.
  • Comparing available pre-treatment specimens with all post-treatment specimens (n=13): mean CD8+ cells increased and mean mesothelin-positive tumor cells decreased, but neither change was statistically significant.
  • Virus outside the chest cavity was limited: low positivity in the urine of 2 patients, the blood lysate of 1 patient and the sputum of 1 patient.
  • Of 7 patients with baseline serum available, 4 had low levels and 3 had no anti-vaccinia neutralizing antibodies before treatment. Five had high levels at day 60.
  • Pleural fluid: by 48 hours, levels of IFN-gamma, TNF-alpha, VEGF, IL-1ra, IL-1b and IP-10 rose significantly. Serum: IL-8 rose by day 3 (p=0.0065), and at day 60 only RANTES (CCL5) was significantly elevated compared with baseline (p=0.0276).
  • Median overall survival was 19.5 months for all patients and 22 months for patients with malignant pleural mesothelioma. All patients later received other therapies.
• The authors' conclusion: The authors concluded that intrapleural oncolytic vaccinia viral therapy is safe and feasible and generates a regional immune response without overt systemic symptoms. They said their correlative analyses support its potential use for patients with malignant pleural mesothelioma.
• Limitations the authors state:
  • The trial included a small number of patients from a single institution, with heterogeneous types and stages of disease.
  • Not all specimens were available from all patients.
  • The survival observed cannot be attributed to the treatment, because this was a phase I study and limited clinical anti-tumor efficacy was seen right after treatment.
  • It is uncertain whether the immune changes are limited to tumors with pre-existing immune suppressor responses.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Clinical Trial, Pleural Mesothelioma, Pleural Effusion, Non-Small Cell Lung Cancer, Sputum, PD-L1, Cytokine.

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