Phase I clinical study of Seneca Valley Virus (SVV-001), a replication-competent picornavirus, in advanced solid tumors with neuroendocrine features

Abstract

Purpose: Seneca Valley Virus (SVV-001) is a novel naturally occurring replication-competent picornavirus with potent and selective tropism for neuroendocrine cancer cell types, including small cell lung cancer. We conducted a first-in-human, first-in-class phase I clinical trial of this agent in patients with cancers with neuroendocrine features, including small cell lung cancer.

Experimental design: Clinical evaluation of single intravenous doses in patients with cancers with neuroendocrine features was performed across five log-increments from 10(7) to 10(11) vp/kg. Toxicity, viral titers and clearance, neutralizing antibody development, and tumor response were assessed.

Results: A total of 30 patients were treated with SVV-001, including six with small cell carcinoma at the lowest dose of 10(7) vp/kg. SVV-001 was well tolerated, with no dose-limiting toxicities observed in any dose cohort. Viral clearance was documented in all subjects and correlated temporally with development of antiviral antibodies. Evidence of in vivo intratumoral viral replication was observed among patients with small cell carcinoma, with peak viral titers estimated to be >10(3)-fold higher than the administered dose. One patient with previously progressive chemorefractory small cell lung cancer remained progression-free for 10 months after SVV-001 administration, and is alive over 3 years after treatment.

Conclusions: Intravenous SVV-001 administration in patients is well tolerated at doses up to 10(11) vp/kg, with predictable viral clearance kinetics, intratumoral viral replication, and evidence of antitumor activity in patients with small cell lung cancer. Phase II clinical evaluation in small cell lung cancer is warranted, and has been initiated.

Figure 1

Development of anti-SVV-001 neutralizing antibodies. Quantitative assessment of serum SVV-001 neutralizing antibodies was assessed over time in all human subjects treated with SVV-001. Data are reported at week 1 (day 7–9) and week 2 (day 14–16), and as peak neutralizing antibody titer, by dose administered. The cohort of small cell carcinoma patients treated at 10⁷ vp/kg is shown separately. Error bars: standard deviation.

Figure 2

SVV-001 viral titers following IV administration, by cohort. Evaluation of circulating SVV-001 virus in serum was assessed over time by quantitative RT-PCR. Each linear plot represents titers measured in an individual patient. Data are presented by dose administered.

Figure 3

Immunohistochemical staining for viral particles in tumor and noninvolved tissues. Tissue sections from a patient with extensively pretreated advanced small cell carcinoma, who died of progressive disease on day 28 after SVV-001 administration (10⁷ vp/kg) were subject to immunohistochemical staining using mouse SVV-001 antiserum as primary antibody or nonimmune mouse serum as control. Extensive intracellular viral replication is demonstrated in tumor tissue, but no nonmalignant tissue sections (400×).

Figure 4

Progression-free and overall survival following SVV-001 administration. Kaplan–Meier survival plots are presented, by disease type. All dose cohorts for mixed neuroendocrine are combined. All study subjects are included. PFS, progression-free survival; OS, overall survival.