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Intratumoral injection of hemagglutinating virus of Japan-envelope vector yielded an antitumor effect for advanced melanoma: a phase I/IIa clinical study

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Abstract

Hemagglutinating virus of Japan (HVJ; Sendai virus) is an RNA virus that has cell fusion activity. HVJ-envelope (HVJ-E) is a UV-irradiated HVJ particle that loses viral replication and protein synthesis activity but retains cell fusion activity. We recently reported that HVJ-E has antitumor effects on several types of tumors. Here, we describe the results of a first-in-human phase I/IIa study in patients with advanced melanoma, receiving intratumoral administration of HVJ-E. The primary aim was to evaluate the safety and tolerability of HVJ-E, and the secondary aim was to examine the objective tumor response and antitumor immunity. Six patients with stage IIIC or IV progressive malignant melanoma with skin or lymph metastasis were enrolled. Patients were separated into two groups (n = 3 each) and received low and high doses of HVJ-E. Five of the six patients completed 4 weeks of follow-up evaluation; one patient discontinued treatment owing to progressive disease. Complete or partial responses were observed in 3 of 6 (50%) injected target lesions, 7 of 15 (47%) noninjected target lesions, and 10 of 21 (48%) target lesions. Induction of antitumor immunity was observed: activation of natural killer cells, a marked increase in interferon-γ levels in the peripheral blood, and infiltration of cytotoxic T cells into both injected and noninjected tumor lesions. Thus, intratumoral injection of HVJ-E in advanced melanoma patients showed safety and tolerability with local regression of the tumor mediated by antitumor immunity. The results suggest that HVJ-E might be a new treatment approach in patients with advanced melanoma.

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Abbreviations

CR:

Complete response

DLT:

Dose-limiting toxicity

ECOG:

Eastern Cooperative Oncology Group

HVJ:

Hemagglutinating virus of Japan

HVJ-E:

Inactivated HVJ-envelope

mNAU:

Milli neuraminidase unit

MTD:

Maximum tolerated dose

NCI-CTCAE:

National Cancer Institute Common Toxicity Criteria for Adverse Events

PD:

Progressive disease

PR:

Partial response

RIG-I:

Retinoic acid-inducible gene-I

SD:

Stable disease

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Acknowledgements

We thank the patients, study staff, and investigators in this study. We also thank Eriko Nobuyoshi for the support in immunostaining. We would like to thank Editage (https://www.editage.com) for English language editing.

Funding

This study was supported by the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation.

Author information

Authors and Affiliations

  1. Department of Dermatology, Course of Integrated Medicine Graduate School of Medicine, Osaka University, 2-2, Yamadaoka, Suita-shi, Osaka, 565-0871, Japan

    Eiji Kiyohara, Atsushi Tanemura, Megumi Nishioka, Mizuho Yamada, Aya Tanaka, Akinori Yokomi & Ichiro Katayama

  2. Medical Center for Translational Research, Osaka University Hospital, 2-2, Yamadaoka, Suita-shi, Osaka, 565-0871, Japan

    Atsuhiro Saito, Kazuma Sakura & Akira Myoui

  3. GenomIdea INC., 1-8-31, Midorigaoka, Ikeda, Osaka, 563-0026, Japan

    Toshihiro Nakajima

  4. Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8583, Japan

    Toshiharu Sakurai & Yutaka Kawakami

  5. Division of Gene Therapy Science, Department of Genome Biology, Graduate School of Medicine, Osaka University, 2-2, Yamadaoka, Suita-shi, Osaka, 565-0871, Japan

    Yasufumi Kaneda

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  1. Eiji Kiyohara
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Contributions

Study conception and design: EK, AT, KS, TN, YK, and IK. Patient recruitment and management: EK, AT, MN, MY, AT, AY, and IK. Data acquisition, management, analysis and interpretation: EK, AT, AS, KS, AM, TS, YK, and IK. Manuscript preparation: EK, AT, TN, YK, and IK. All authors read and approved the final version of the paper.

Corresponding author

Correspondence to Atsushi Tanemura.

Ethics declarations

Conflict of interest

Toshihiro Nakajima is the employee of GenomIdea, Inc. Toshihiro Nakajima and Yasufumi Kaneda are stock-holders (0.08 and 0.5%) of GenomIdea, Inc. The other authors declare no conflict of interest.

Ethical approval and ethical standards

This study was performed with the approval of the ethics committee at Osaka University Hospital (No. 746 on July 28th 2009). The project was allocated at the Medical Center for Translational Research with number MM0901. All procedures involving human participants were carried out in accordance with the ethical standards of the Osaka University Hospital, national research committee (the University Hospital Medical Information Network-UMIN000002376 and UMIN000012943) and in line with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Written informed consent for protocol therapy, analysis of patient samples, and use of data for research and publication were obtained from all individual participants prior to treatment in the study.

Cell line authentication

The wild-type HVJ (Z strain) was produced using HEK293 cells, which were purchased from the Japanese Collection of Research Bioresources Cell Bank (JCRB9068, Japan) and cloned as a GenomIdea Clone 20 (GIC20) to prepare the master cell bank for manufacture. Isozyme analysis was performed for authenticating the cell line. Four types of isozymes (lactate dehydrogenase, glucose-6-phosphate dehydrogenase, malate dehydrogenase, and nucleoside phosphorylase) of the master cell bank were analyzed for the identification and characterization of the cell line in GLP study at BioReliance (Stirling, Scotland).

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Kiyohara, E., Tanemura, A., Nishioka, M. et al. Intratumoral injection of hemagglutinating virus of Japan-envelope vector yielded an antitumor effect for advanced melanoma: a phase I/IIa clinical study. Cancer Immunol Immunother 69, 1131–1140 (2020). https://doi.org/10.1007/s00262-020-02509-8

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