Oncolytic herpesvirus therapy for mesothelioma - A phase I/IIa trial of intrapleural administration of HSV1716

Our plain-English summary of Oncolytic herpesvirus therapy for mesothelioma - A phase I/IIa trial of intrapleural administration of HSV1716, by S.J. Danson, J. Conner, J.G. Edwards, et al (Lung Cancer, 2020).

The study

• Authors: S.J. Danson, J. Conner, J.G. Edwards, K.G. Blyth, P.M. Fisher, M. Muthana, A. Salawu, F. Taylor, E. Hodgkinson, P. Joyce, J. Roman, K. Simpson, A. Graham, K. Learmonth, P.J. Woll
• Journal: Lung Cancer
• Published: 2020;150:145-151
• Cited by: 46 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Objectives: Malignant Pleural Mesothelioma (MPM) remains a major oncological challenge with limited therapeutic options. HSV1716 is a replication restricted oncolytic herpes simplex virus with anti-tumor effects in multiple cell lines including MPM. Intrapleural treatment appeals because MPM is typically multifocal but confined to the pleura, and distant metastases are uncommon. We assessed the safety and possible efficacy of intrapleural HSV1716 for inoperable MPM.

Materials And Methods: Patients with MPM received 1 × 107iu HSV1716 injected via an indwelling intrapleural catheter (IPC) on one, two or four occasions a week apart. The primary endpoint was the safety and tolerability of HSV1716. Secondary endpoints were assessment of HSV1716 replication, detection of immune response and evaluation of tumor response.

Results: Of thirteen patients enrolled, five had received previous pemetrexed-cisplatin chemotherapy, and eight were chemotherapy naïve. Three patients were enrolled to receive one dose, three patients to two doses and seven patients to four doses. The treatment was well-tolerated with few virus-related adverse events and no dose limiting toxicities. Twelve patients were evaluable for response, as one patient withdrew early after a catheter fracture. There was evidence of viral replication/persistence in pleural fluid in seven of the twelve patients. Induction of Th1 cytokine responses to HSV1716 treatment occurred in eight patients and four patients developed novel anti-tumor IgG. No objective responses were observed but disease stabilization was reported in 50 % of patients at 8 weeks.

Conclusions: Intrapleural HSV1716 was well-tolerated and demonstrated an anti-tumor immune response in MPM patients. These results provide a rationale for further studies with this agent in MPM and in combination with other therapies.

Copyright © 2020 Elsevier B.V. All rights reserved.

In plain English

This was a small early-phase (phase I/IIa) treatment trial, not a study of asbestos exposure. Thirteen UK patients had malignant pleural mesothelioma that could not be removed by surgery, and each already had a drainage tube (indwelling pleural catheter) in the chest. They received HSV1716, a modified herpes simplex virus designed to multiply in and destroy tumor cells. It was put into the chest cavity through the catheter once, twice or four times, a week apart. No dose-limiting side effects were found. Seven of 13 patients (54%) had side effects judged treatment-related, and there were no treatment-related serious adverse events. Of 12 patients assessed, none had a tumor response meeting the study's criteria. Six had stable disease and six had progressive disease. Viral DNA was found in chest fluid in nine patients, and in seven it lasted at least 14 days after the last dose. Eight of 11 patients tested showed rises in immune signalling proteins in chest fluid. The authors concluded the treatment was well-tolerated and said combination with immune checkpoint drugs should be explored. They also said numbers were too small to link responses to dose.

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: Phase I/IIa open-label, dose-escalation treatment trial (single center at first, a second center added for the multiple-dose phase); no statistical comparison between dose levels
• Who was studied: 13 patients with malignant pleural mesothelioma (MPM) not suitable for surgery, all with an existing indwelling pleural catheter. Centers were Sheffield and Glasgow, UK. Per Table 1: median age 70 (range 59-84), 10 men and 3 women, 11 epithelioid, 1 mixed, 1 unknown subtype. There were 3 patients in the one-dose group, 3 in the two-dose group and 7 in the four-dose group. Study dates are not given.
• Exposure: No asbestos exposure was studied. The exposure was the experimental treatment: the oncolytic herpes simplex virus HSV1716, at 1×10^7 infectious units per dose (printed '1×107iu'). It was injected into the pleural cavity through the catheter as one, two or four weekly doses.
• Main results:
  • No dose-limiting toxicities were identified at any dose level.
  • Of all 13 patients, 7 (54%) reported 16 treatment-related adverse events. This included 6 patients (86%) in the four-dose group and 1 patient (33%) in the one-dose group. None were reported in the two-dose group.
  • Frequent adverse events across all patients, as given in the text, were pyrexia (31%), influenza-like symptoms (23%), fatigue/lethargy (31%), cough (23%) and constipation (23%). Table 2 instead lists fatigue/lethargy as 5 (38%).
  • There were no treatment-related serious adverse events. There was one grade 3 serious adverse event of pleural infection, judged unrelated.
  • Of 12 patients evaluable for response (scans at days 29 and 57), none had an objective response. Stable disease was seen in 2 patients in each dose group. Progressive disease was seen in 1, 1 and 4 patients in the one-, two- and four-dose groups.
  • HSV DNA was found in pleural fluid in 9 patients, including all 6 evaluable patients in the four-dose group. In 7 of these 9, it was detectable for at least 14 days after the last dose.
  • Virus shedding in blood, buccal (mouth) swabs and urine was negative in 11 of 12 patients.
  • All patients given two or four doses had increased circulating anti-HSV-1 IgG antibodies. The three patients given one dose had no such response.
  • In 8 of 11 patients tested, pleural fluid levels of the cytokines IL-2, TNF alpha and interferon gamma rose 5-10 fold after HSV1716.
  • Novel IgG antibody targets were found after treatment in the sera of four patients.
• The authors' conclusion: The authors concluded that intrapleural HSV1716 was well-tolerated and replicates in the pleural cavity, and that it provoked novel anti-tumor IgG responses. They suggested that combination with an immune checkpoint inhibitor should be explored.
• Limitations the authors state:
  • Patients were required to have a pleural catheter in place. Reduced fluid volumes during the study may have been due to the catheter rather than the virus treatment.
  • Numbers were too small to relate clinical responses to dose level or assay results.
  • A genotyping test designed to identify the HSV1716 mutation could not be used, because pleural fluid interfered with it.
  • One positive mouth swab could not be checked further, so ordinary (wild-type) herpes virus was not ruled out.
  • Strong neutralization of the virus by pleural fluid made it unlikely that live virus could be measured in the fluid.

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: Mesothelioma, Pleural Mesothelioma, Appeal, Pleura, Pemetrexed (Alimta), Cisplatin, Chemotherapy, Cytokine.

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