Individualized, heterologous chimpanzee adenovirus and self-amplifying mRNA neoantigen vaccine for advanced metastatic solid tumors: phase 1 trial interim results.
Christine D PalmerAmy R RappaportMatthew J DavisMeghan G HartCiaran D ScallanSue-Jean HongLeonid GitlinLauren D KraemerSonia KounlavouthAaron YangLindsey SmithDesiree SchenkMojca SkoberneKiara TaquechelMartina MarraliJason R JaroslavskyCharmaine N NganjeElizabeth MaloneyRita ZhouDaniel Navarro-GomezAdrienne C GreeneGijsbert GrotenbregRenee GreerWade BlairMinh Duc CaoShawn ChanKyounghwa BaeAlexander I SpiraSameek RoychowdhuryDavid P CarboneBrian S HenickCharles G DrakeBenjamin J SolomonDaniel H AhnAmit MahipalSteven B MaronBenny JohnsonRaphael RousseauKatrine L WhitesonChih-Yi LiaoDaniel V T CatenacciAndrew AllenAndrew R FergusonKarin JoossPublished in: Nature medicine (2022)
Checkpoint inhibitor (CPI) therapies provide limited benefit to patients with tumors of low immune reactivity. T cell-inducing vaccines hold promise to exert long-lasting disease control in combination with CPI therapy. Safety, tolerability and recommended phase 2 dose (RP2D) of an individualized, heterologous chimpanzee adenovirus (ChAd68) and self-amplifying mRNA (samRNA)-based neoantigen vaccine in combination with nivolumab and ipilimumab were assessed as primary endpoints in an ongoing phase 1/2 study in patients with advanced metastatic solid tumors (NCT03639714). The individualized vaccine regimen was safe and well tolerated, with no dose-limiting toxicities. Treatment-related adverse events (TRAEs) >10% included pyrexia, fatigue, musculoskeletal and injection site pain and diarrhea. Serious TRAEs included one count each of pyrexia, duodenitis, increased transaminases and hyperthyroidism. The RP2D was 10 12 viral particles (VP) ChAd68 and 30 µg samRNA. Secondary endpoints included immunogenicity, feasibility of manufacturing and overall survival (OS). Vaccine manufacturing was feasible, with vaccination inducing long-lasting neoantigen-specific CD8 T cell responses. Several patients with microsatellite-stable colorectal cancer (MSS-CRC) had improved OS. Exploratory biomarker analyses showed decreased circulating tumor DNA (ctDNA) in patients with prolonged OS. Although small study size limits statistical and translational analyses, the increased OS observed in MSS-CRC warrants further exploration in larger randomized studies.
Keyphrases
- circulating tumor
- open label
- double blind
- small cell lung cancer
- cell free
- squamous cell carcinoma
- circulating tumor cells
- placebo controlled
- chronic pain
- sars cov
- dna damage
- phase iii
- binding protein
- machine learning
- neuropathic pain
- gene therapy
- randomized controlled trial
- spinal cord injury
- phase ii
- combination therapy
- cell proliferation
- cell therapy
- ultrasound guided
- smoking cessation