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

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.

Keywords: Adoptive immunity; Hemagglutinating virus of Japan-envelope; Intratumoral immunotherapy; Melanoma; Native immunity; Sendai virus.

Fig. 1

Administration plan and change in tumor size in each target lesion. a Overview of treatments administered to patients. Black arrows indicate intralesional administration of HVJ-E. Twelve injections were administered in two cycles, the duration of one cycle was 6 weeks. Tumor size was evaluated at pre-administration and at the end of each cycle. The numbers of target lesions were five in patient 1 (b), two in patient 2 (c), two in patient 3 (d), two in patient 4 (e), five in patient 5 (f), and five in patient 6 (g). The asterisk indicates the injected tumor lesion

Fig. 2

Immunohistochemistry of the injected and noninjected tumors. The injected tumor lesion (No. 1) was regressed upon the intratumoral administration of HVJ-E (before; a, after; b). Each section was stained with hematoxylin/eosin (c, d), anti-CD4 antibodies (e, f), anti-CD8 antibodies (g, h), anti-CD56 antibodies (i, j), anti-CD20 antibodies (k, l), and FoxP3 (m, n). Original magnification: × 100 (c–n)

Fig. 3

Comparison of blood cytokines in the six patients between baseline and cycle 2, day 42 (12 weeks later). Panels show anti-parainfluenza antibodies (a), IFN-γ (b), and NK cell activity (c). Multiple vitiligo at a cutaneous tumor lesion was observed (e)