Oncolytic Virus SVV-001 Plus Ipi/Nivo Is Safe in High-Grade Neuroendocrine Cancers

A single intratumoral injection of SVV-001, an oncolytic picornavirus that targets tumor endothelial marker 8 (TEM8), was safe when combined with nivolumab (Opdivo) and ipilimumab (Yervoy) in patients with high-grade neuroendocrine cancers, with no dose-limiting toxicities (DLTs) across 3 dose levels and early signs of activity, including 1 complete metabolic response, according to results from part A of a phase 1 trial (NCT06889493) shared at the 2026 North American Neuroendocrine Tumor Society (NANETS) Symposium.¹

Antitumor activity was observed, however, presenting author Aman Chauhan, MD, associate professor of medicine at the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, cautioned against drawing firm efficacy conclusions from the small dose-escalation cohort of 13 patients. “I don’t like to read too much into efficacy in a small study,” Chauhan said. “Although, it’s always nice to see a complete response, right?”

That response was illustrated with PET imaging before and after treatment, which showed resolution of widespread metabolically active disease in 1 patient. Chauhan noted that it is not yet possible to tell whether the response was driven by the virus, by immunotherapy, or by synergy between the two, a question that will require randomized studies to answer.

Progression-free survival (PFS) varied widely across patients, from less than 1 month to more than 9 months. Four patients had PFS of more than 5 months, with the longest reaching 9.1 months.

No Dose-Limiting Toxicities at Any Dose Level of SVV-001

No DLTs occurred in any of the 3 single-dose cohorts. Four patients were treated at dose level 1, 3 at dose level 2, and 6 at dose level 3, and enrollment in part A is complete.

The most common grade 3 or higher adverse events (AEs), regardless of attribution, were abdominal distension, fatigue, increased alanine aminotransferase, increased blood bilirubin, and anorexia, each occurring in 3 patients (23.1%), followed by anemia in 2 patients (15.4%). Chauhan noted that the AEs shown included both treatment-related and unrelated events, and that some likely reflected the underlying disease, given how aggressive these cancers are.

These results were consistent with prior experience with the virus. SVV-001 had previously been given as a single intravenous dose to 76 patients across 3 clinical trials, including early studies in patients with neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs), with an excellent safety profile.²

“We were quite confident this would be very well tolerated, but we had to prove it to the FDA, right?” Chauhan said.

Why Revisit SVV-001 in Neuroendocrine Cancers

SVV-001, also called Seneca Valley virus, was discovered as a contaminant of a laboratory adenovirus preparation and has selective tropism for tumors with neuroendocrine features. It replicates in under 12 hours, allowing productive infection within tumors before an immune response develops. Researchers later identified anthrax toxin receptor 1, also known as TEM8, as the cellular receptor for the virus.³ High TEM8 expression has been associated with shorter survival in several cancers, including small cell lung cancer and bladder and cervical cancers.

Earlier intravenous studies showed excellent safety but little efficacy. According to Chauhan, the main reason was that the body rapidly generated neutralizing antibodies that cleared the virus within about 2 weeks, and patients received only a single dose. Since then, the oncolytic virus field has shifted toward direct intratumoral injection, which allows the virus to replicate locally within the tumor.

Investigators also hypothesized that SVV-001 could make immunologically cold neuroendocrine tumors more responsive to immunotherapy. Few patients with high-grade neuroendocrine cancers benefit from checkpoint inhibitors alone, Chauhan noted. In a preclinical mouse model of pancreatic cancer, SVV-001 combined with anti–PD-1 and anti–CTLA-4 antibodies turned cold tumors hot, with influx of CD8-positive T cells, eradicated established tumors, and induced a systemic antitumor immune response with activity against untreated tumors elsewhere in the body.

Trial Design and Patient Population

The investigator-initiated phase 1 trial is enrolling patients with poorly differentiated, high-grade NECs as well as well-differentiated grade 3 NETs, which Chauhan described as an area of unmet need.⁴ Patients with treated, stable brain metastases were eligible, while those with untreated central nervous system metastases, active infections, immunodeficiency, recent systemic steroids, or prior organ transplant were excluded.

In part A, patients received a single intratumoral injection of SVV-001 at 1 of 3 escalating dose levels, 2.2 × 10⁸, 2.2 × 10⁹, or 2.2 × 10¹⁰ viral genomes, along with standard-dose nivolumab every 2 weeks and ipilimumab every 6 weeks, both given intravenously. Chauhan explained that regulators wanted safety established with a single injection before multiple injections could be tested.

The primary objective is to determine the recommended phase 2 dose of SVV-001 given as single or multiple intratumoral doses with nivolumab and ipilimumab. Other objectives include evaluating PFS, the kinetics of viral release and viral load in plasma, and the relationship between TEM8 expression and objective response rate.

All 13 patients in part A were treated at the University of Miami. Eleven had high-grade NECs, including 6 with small cell and 5 with large cell histology, arising from sites such as the pancreas, esophagus, bladder, thorax, gastroesophageal junction, and cervix. The remaining 2 patients had grade 3 pancreatic NETs. Nearly half of patients were Hispanic, reflecting the diversity of the Miami population, which Chauhan noted is not often seen in early-phase trials.

Part B and Correlative Studies

Part B will evaluate multiple intratumoral injections of SVV-001, up to 6 doses, in combination with ipilimumab and nivolumab. Part B has begun at the University of Miami and is expected to open at additional sites, including UCSF.

Planned correlative studies include pre- and post-treatment biopsies to assess tumor necrosis and viral replication, blood analyses of viral burden and anti-SVV-001 neutralizing antibodies, and a range of tissue-based immune and genomic markers. Investigators will also examine whether TEM8 expression correlates with viral replication and clinical benefit.

“We will know only in future iterations [in] randomized settings, but it is a promising first step,” Chauhan said.

References

1. Chauhan A. A phase 1 trial of the oncolytic virus SVV-001 in combination with nivolumab and ipilimumab for high-grade neuroendocrine cancers. Presented at: 2026 North American Neuroendocrine Tumor Society (NANETS) Symposium; November 5-7, 2026; Las Vegas, NV.

2. Rudin CM, Poirier JT, Senzer NN, et al. Phase I clinical study of Seneca Valley virus (SVV-001), a replication-competent picornavirus, in advanced solid tumors with neuroendocrine features. Clin Cancer Res. 2011;17(4):888-895. doi:10.1158/1078-0432.CCR-10-1706

3. Miles LA, Burga LN, Gardner EE, Bostina M, Poirier JT, Rudin CM. Anthrax toxin receptor 1 is the cellular receptor for Seneca Valley virus. J Clin Invest. 2017;127(8):2957-2967. doi:10.1172/JCI93472

4. SVV-001 with nivolumab and ipilimumab in patients with poorly differentiated neuroendocrine carcinomas (NEC) or well-differentiated high-grade neuroendocrine tumors (NET). ClinicalTrials.gov identifier: NCT06889493. Accessed November 6, 2026. https://clinicaltrials.gov/study/NCT06889493