This phase I study evaluated HVJ-E, an inactivated Sendai virus particle, for safety and preliminary efficacy in chemotherapy-resistant MPM. High doses led to stable disease, while low doses saw progression, indicating a dose-dependent antitumor effect with no serious adverse events. Findings support a phase II trial with higher doses. Trial registration: UMIN000019345.
Abstract
A phase I clinical study was conducted to evaluate the safety and preliminary efficacy of HVJ-E, an inactivated Sendai virus particle with antitumor properties, in patients with chemotherapy-resistant malignant pleural mesothelioma (MPM). HVJ-E was administered intratumorally and subcutaneously. No serious adverse events were observed, but expected side effects occurred. Low-dose patients showed disease progression, while high-dose patients achieved stable disease, indicating a dose-dependent effect. The study suggests that HVJ-E is safe and shows potential antitumor activity, with stronger effects at higher doses, leading to a phase II trial for MPM. Trial registration: UMIN000019345.
Introduction
Malignant pleural mesothelioma (MPM) is a rare, aggressive tumor typically associated with poor prognosis and limited treatment options. Standard treatments include chemotherapy, immunotherapy, radiation, and surgery, with immune checkpoint inhibitors (ICIs) offering some benefit but often limited by advanced-stage diagnosis. HVJ-E, a modified non-replicative Sendai virus, has shown antitumor potential by inducing immune responses and tumor cell death. Unlike oncolytic virus therapies, HVJ-E is safe for general clinical use and can be administered intratumorally with minimal systemic effects. Encouraged by preclinical success, a phase I clinical trial was initiated to assess HVJ-E's tolerability and preliminary efficacy in chemotherapy-resistant MPM.
Clinical research overview
This phase I/II clinical trial at Osaka University Hospital (2015-2017) examined the effects of intratumoral and subcutaneous HVJ-E in patients with chemotherapy-resistant MPM. Following the Declaration of Helsinki and IRB approval (#157908), safety was the primary endpoint, using a 3+3 dose-escalation design. Dose-limiting toxicity (DLT) criteria were based on CTCAE guidelines, with dose levels set at 30,000 mNAU and 60,000 mNAU, informed by prior trials and non-clinical safety data. The trial was registered under UMIN #UMIN000019345.
Patients
This study included patients with chemotherapy-resistant malignant pleural mesothelioma (MPM), defined as progressive disease despite prior first- or second-line treatments. Patients were excluded if lesions were too small for injection (<15 mm), or if they had conditions such as HVJ-E allergy, brain metastases, interstitial lung disease, recent chemotherapy (within 6 weeks), recent experimental or immunotherapy treatments (within 4 weeks), autoimmune diseases, or other malignancies within the past 5 years. Some patients had also undergone radiation or surgery before developing chemotherapy resistance.
Treatment schedule
A 3+3 dose escalation design was used to determine HVJ-E's maximum tolerated dose in patients with chemotherapy-resistant MPM. Under local anesthesia, HVJ-E was injected directly into FDG-accumulating mesothelioma tissue using ultrasound guidance. After initial injection on day 1, additional subcutaneous injections were administered near the tumor on days 5, 8, and 12, completing one cycle. Each patient received a total of eight HVJ-E injections across two cycles, with vital signs monitored post-injection for safety.
Safety and effectiveness assessment
Patients’ vital signs were monitored, with blood tests and chest X-rays conducted during 14-day inpatient and outpatient visits for each cycle. Adverse events were graded according to NCI CTCAE (version 4.0). CT and FDG-PET scans were performed at screening and on day 28 to assess preliminary efficacy.
Results
Registration status of patients
with chemotherapy‑resistant MPM for clinical trials
Eight patients were initially evaluated for enrollment, with five excluded based on criteria. Three patients received a low dose of HVJ-E, showing no severe toxicity, allowing progression to a high-dose phase. Seven additional patients were screened, with four excluded, leaving three in the high-dose group. In total, six patients completed the study to assess HVJ-E's safety and preliminary antitumor efficacy, with no significant differences in age, disease stage, or time from the first visit between the dose groups.
Safety of HVJ‑E in patients
with chemotherapy‑resistant MPM
Table 2 summarizes adverse events and lab abnormalities. Injection-related skin issues were most common, with grade 3 serious adverse events including anemia (low-dose group) and increased serum amylase (high-dose group). Frequent events included injection site erythema, skin hardening, and fever, all expected based on administration route. Some patients experienced hypoxia, elevated liver enzymes, or injection site pain, but no serious adverse events, deaths, dose-limiting toxicities, or adverse event-related discontinuations occurred. Importantly, no skin tumor spread from intratumoral injections was observed over a 3-month follow-up.
Efficacy of HVJ‑E against patients with chemotherapy‑resistant MPM
According to modified RECIST criteria, three low-dose patients had progressive disease (PD), while three high-dose patients achieved stable disease (SD), resulting in disease control rates (DCRs) of 0% and 100%, respectively. PERCIST criteria showed stable metabolic disease (SMD) in all patients across both doses. Dose dependence of HVJ-E was observed, with significant baseline changes in target lesions on CT and RECIST assessment (p < 0.05). Intratumoral administration showed stronger antitumor effects over time, with 34.7% efficacy observed two months post-study, compared to 20.4% for non-injected lesions. PET/CT scans confirmed dose-dependent effects on target lesions.
In some cases, FDG accumulation at both injected and non-injected tumor sites was significantly reduced, with some tumors showing near-complete metabolic response (CMR). PET/CT scans for case #1 and case #3 demonstrated decreased FDG activity at the end of the trial and further reduction one month later. Gray and black arrows indicate low-dose HVJ-E injected tumors, while white arrows show non-injected sites.
Discussion
This study confirmed HVJ-E’s safety and tolerability at doses of 30,000 and 60,000 mNAU in patients with chemotherapy-resistant pleural mesothelioma. Significant dose-dependent antitumor effects were observed, with intratumoral injections showing stronger efficacy over time. FDG-PET/CT scans indicated a near-complete metabolic response in some cases. HVJ-E inhibited proliferation in mesothelioma cell lines, but not in prostate cancer cells, suggesting tumor-specific effects. While no control group was used, the mean overall survival (mOS) for inoperable patients was notably higher than standard expectations, suggesting HVJ-E may improve outcomes. However, limitations included single-center design, small sample size, and varied pre-treatments among patients.
Conclusions
HVJ-E was safely administered at both tested doses in chemotherapy-resistant MPM patients, with higher doses showing potential inhibitory effects. These results suggest that intratumor and subcutaneous injections of HVJ-E may offer antitumor efficacy with an acceptable safety profile, warranting further investigation in larger, controlled trials to fully assess its therapeutic potential.
Dose-escalation, tolerability, and efficacy of intratumoral and subcutaneous injection of hemagglutinating virus of Japan envelope (HVJ-E) against chemotherapy-resistant malignant pleural mesothelioma: a clinical trial | Cancer Immunology, Immunotherapy
