VET3-TGI Generates Responses in Checkpoint Inhibitor–Refractory Cutaneous Cancers

Intratumoral administration of the oncolytic vaccinia virus VET3-TGI, given alone or in combination with atezolizumab (Tecentriq), generated responses in patients with advanced solid tumors, with activity concentrated in those with immune checkpoint inhibitor–refractory cutaneous malignancies, according to findings from the phase 1/1b STEALTH-001 trial (NCT06444815) presented at the 2026 SITC Annual Meeting.^1,2

Responses occurred in both injected and non-injected lesions, and no dose-limiting toxicities (DLTs) were reported.

Findings showed that efficacy-evaluable patients (n = 12) treated intratumorally achieved an objective response rate (ORR) by blinded independent central review of 42%, including 1 complete response (CR) and 4 partial responses (PRs); the disease control rate was 75%.¹

Notably, in the cutaneous malignancy subgroup (n = 7), the ORR was 71%. Patients with Merkel cell carcinoma (n = 3) achieved 1 CR and 2 PRs; those with melanoma (n = 3) achieved 2 PRs, and with 1 patient having a best rsponse of progressive disease (PD); and the patient with cutaneous squamous cell carcinoma (n = 1) experienced PD. The median duration of response was not reached, and all responders were still receiving study treatment at data cutoff, with treatment durations ranging from 10 to 19 months.

“There is a lot of promise in the [oncolytic virus] space….What this one is adding is evidence of efficacy in the therapeutic payloads, and…we very consistently observe responses in non-injected lesions, which is the holy grail of intratumoral therapies,” lead study author Yana G. Najjar, MD, said in an exclusive interview with OncLive^®.

Najjar is an associate professor of medicine and director of the Clinical and Translational Research Center at UPMC Hillman Cancer Center in Pittsburgh, Pennsylvania.

How was STEALTH-001 designed?

VET3-TGI is a Western Reserve vaccinia virus modified to express CXCR3, allowing it to attach to lymphocytes and home to tumors while avoiding neutralization, Najjar explained. The construct also encodes 2 therapeutic payloads: a TGF-β inhibitor that originated at UPMC Hillman Cancer Center and interleukin-12.

“We know that patients with advanced cutaneous malignancies who progress on immune checkpoint blockade have limited options, and so this is clinically an area of need,” Najjar said.

The first-in-human, open-label trial opened with a 3+3 dose-escalation phase in an all-comer solid tumor population, testing VET3-TGI monotherapy at 1 × 10⁸ to 3 × 10⁹ plaque-forming units (PFU) with a 28-day DLT observation window. Investigators are now enrolling a monotherapy expansion cohort limited to cutaneous malignancies alongside a combination cohort pairing VET3-TGI, at or below the highest monotherapy dose, with atezolizumab.

Patients received intratumoral injections on days 1, 8, 15, and 22, after which a maintenance phase permitted optional intratumoral boosters as often as every 2 weeks; atezolizumab was dosed at 840 mg every 2 weeks for 4 doses and then at 1680 mg every 4 weeks.

Safety, DLTs, and the recommended phase 2 dose served as the primary end points, and secondary end points included tumor response, survival, and viral and immune activity.

As of the September 2026 data cutoff, 20 patients had received intratumoral VET3-TGI (monotherapy, n = 16; combination, n = 4). Patients in the cutaneous subgroup had a median of 3 prior lines of therapy (range, 1-9). All had been treated with an anti–PD-(L)1 agent and were refractory to immunotherapy, and 42.9% had previously received a CTLA-4 inhibitor plus an anti–PD-(L)1 agent. Additionally, 57.1% had stage IV disease, 85.7% had lactate dehydrogenase levels above the upper limit of normal, and 57.1% had visceral metastases.

What did the translational analyses show?

Paired biopsies collected at baseline and on treatment showed increased immune activity in all 5 evaluable injected lesions and all 3 evaluable non-injected lesions. In injected lesions, median fold increases at days 15 to 22 were 7.2× for cytotoxic (CD8+GRB+) T cells and 10.4× for proliferating (CD8+Ki67+) T cells. In non-injected lesions, the corresponding median fold increases at day 15 were 2.8× and 3.1×, respectively. Investigators characterized these descriptive findings as a biologic rationale for the durability of the responses, pointing to conversion of immunologically “cold,” checkpoint inhibitor–refractory tumors to “hot” ones rather than a transient effect confined to the injection site.

What did the safety data show?

No protocol-defined DLTs occurred during the 28-day observation window, and escalation proceeded through doses up to 3 × 10⁹ PFU. Treatment-related adverse effects (TRAEs) were nonetheless common among the 20 safety-evaluable patients, although most were low grade. The most frequent TRAEs of any grade were cytokine release syndrome (CRS; 50%), chills (40%), nausea (40%), vomiting (35%), and decreased lymphocyte count (25%).

Every CRS event was grade 1 (20%) or grade 2 (30%), with no grade 3 or 4 cases. Grade 3 TRAEs comprised decreased lymphocyte count (10%) along with nausea, vomiting, anemia, hyponatremia, and increased alanine aminotransferase leels (5% each); grade 4 TRAEs were limited to decreased lymphocyte count (10%) and decreased white blood cell count (5%). No treatment-related deaths occurred.

According to Najjar, the lymphopenia improved over time, and nothing in the profile fell outside what has come to be expected of oncolytic viruses. She added that managing CRS has become more familiar to melanoma specialists as bispecific T-cell engagers and oncolytic viruses have entered the field.

“From my vantage point as an investigator, it seems clear that the signal is in cutaneous malignancies,” Najjar said, adding that enrollment of patients with cutaneous malignancies is ongoing to further inform the design of a phase 2 study. Intravenous arms of STEALTH-001 are also being evaluated and will be reported separately.

References

1. Najjar YG, Fu S, Thomas JS, et al. STEALTH-001: a phase 1 study of VET3-TGI, an oncolytic vaccinia virus encoding TGFb inhibitor and IL-12, for the treatment of advanced solid tumors. Paper presented at: 2026 Society for Immunotherapy of Cancer Annual Meeting; November 4-8, 2026; Phoenix, AZ. Abstract 572.
2. KaliVir Immunotherapeutics reports 71% objective response rate in patients with advanced, cutaneous malignancies in phase 1/1b STEALTH-001 trial. News release. KaliVir Immunotherapeutics. November 6, 2026. Accessed November 7, 2026. https://www.businesswire.com/news/home/20261106730893/en/KaliVir-Immunotherapeutics-Reports-71-Objective-Response-Rate-in-Patients-with-Advanced-Cutaneous-Malignancies-in-Phase-11b-STEALTH-001-Trial