NCT05264974

Novel RNA-lipid Particle (RNA-LP) Vaccine for Anti-PD-1 Antibody Therapy Sensitization

• Status: Recruiting
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 18 (estimated)
• Sponsor: University of Florida · Academic / Other
• Sex: All
• Age: 18 Years – 99 Years
• Healthy volunteers: Not accepted

Summary

The goal of this phase I trial is to evaluate the toxicity and feasibility of a tumor-specific RNA-NP vaccine in patients with stage IIB-IV melanoma who have evidence of progressive disease by RECIST 1.1 criteria while receiving adjuvant aPD1 therapy, or those who progress within 6 months of completion of adjuvant treatment, or unresectable stage II soft tissue sarcoma or stage III-IV soft tissue sarcoma.

Detailed description

Melanoma is an increasing public health concern in the state of Florida. The advent of immune checkpoint inhibitors (ICI) has revolutionized the treatment of advanced melanoma. Unfortunately, in the adjuvant setting, up to 30% of subjects will have disease recurrence within 1 year of starting ICI therapy. Previous studies have shown that subjects who progress while on adjuvant ICI treatment, or soon after completion, have a more aggressive course of disease that responds poorly to subsequent immunotherapy. One reason for the failure of ICI in the post adjuvant setting is the immune suppressive nature of the tumor microenvironment (TME) and lack of professional APC activation. These APCs remain in an inert state unable to present tumor antigens for immune detection due to lack of innate immune activation and inhibition from myeloid derived suppressor cells (MDSCs). Similarly, outside of rare subtypes, soft tissue sarcomas (STS) are enriched with an immunosuppressive TME leading to resistance to ICI therapy. We have developed a novel RNA-lipid particle (RNA-LP) vaccine that simultaneously penetrates and reprograms the TME while inducing a tumor specific adaptive T cell response. This vaccine utilizes novel engineering design that layers tumor derived mRNA into a lipid-nanoparticle "onion-like" package along with pp65 full length lysosomal associated membrane protein (LAMP1) mRNA. These RNA-LPs localize to the TME and activate multiple innate pathways thereby activating APCs and suppressing the function of MDSCs. LAMP mRNA is added to improve innate activation as seen in preclinical modeling and to allow for tracking of T cell receptor specific immune response to vaccination. In this study we propose the use of subject derived RNA-LP vaccine in subjects who progress on, or soon after completion of adjuvant ICI. We propose that through re-priming of the antitumor immune response and alteration of the TME we can improve the efficacy of ICI therapy. If effective, this treatment will revolutionize the management of this aggressive subset of melanoma and STS to improve overall survival. This study will also gather important information into the mechanisms of early ICI resistance, identify novel biomarkers of innate cell resistance and response to treatment, and provides a cutting edge, personalized immunology approach to treatment.

Conditions

• Melanoma
• Soft Tissue Sarcoma

Interventions

Type	Name	Description
BIOLOGICAL	Autologous total tumor mRNA loaded DOTAP liposome vaccine	All participants will receive three doses of RNA-NP vaccine (1 dose every 2 weeks) intravenously. The vaccine dose given will be determined by a 3 + 3 design. Participants will be given one of the following vaccine doses: Dose level 0 (starting dose level): 0.00125 mg/kg mRNA in 0.01875 mg/kg LP; Dose level 1: 0.0025 mg/kg mRNA in 0.0375 mg/kg LP; Dose level 2: 0.005 mg/kg mRNA in 0.075 mg/kg LP; or Dose level 3: 0.01 mg/kg mRNA in 0.15 mg/kg LP If 3 or more of the initial 6 subjects experience a dose-limiting toxicity, then the initial starting dose will be reduced (dose de-escalation) to 0.000625 mg/kg mRNA encapsulated in 0.009375mg/kg LPs (Dose level -1).

Timeline

• Start date: 2026-02-01
• Primary completion: 2026-09-01
• Completion: 2026-09-01
• First posted: 2022-03-03
• Last updated: 2026-01-21

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study