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Updated: Sep 1, 2025
Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
Individualized, heterologous chimpanzee adenovirus and self-amplifying mRNA neoantigen vaccine for advanced
Christine D Palmer1, Amy R Rappaport1, Matthew J Davis1
1Gritstone bio, Inc., Emeryville, CA, USA.
Abstract:
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 1012 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.
Insights
This study found that an individualized neoantigen vaccine combined with checkpoint inhibitors is safe and well-tolerated for advanced solid tumors. The combination therapy demonstrated promising long-term T cell responses and improved overall survival in some patients, particularly those with microsatellite-stable colorectal cancer.
Area of Science:
- Oncology
- Immunotherapy
- Vaccine Development
Background:
- Checkpoint inhibitor (CPI) therapies show limited efficacy in patients with tumors exhibiting low immune reactivity.
- T cell-inducing vaccines offer a potential strategy to enhance CPI efficacy and achieve long-lasting disease control.
Purpose of the Study:
- To assess the safety, tolerability, and recommended phase 2 dose (RP2D) of an individualized, heterologous chimpanzee adenovirus (ChAd68) and self-amplifying mRNA (samRNA)-based neoantigen vaccine.
- To evaluate the vaccine in combination with nivolumab and ipilimumab in patients with advanced metastatic solid tumors.
Main Methods:
- An ongoing phase 1/2 study (NCT03639714) evaluated the safety and tolerability of the ChAd68/samRNA neoantigen vaccine combined with nivolumab and ipilimumab.
- Primary endpoints included safety, tolerability, and determination of the RP2D.
- Secondary endpoints assessed immunogenicity, manufacturing feasibility, and overall survival (OS).
Main Results:
- The individualized vaccine regimen was found to be safe and well-tolerated, with no dose-limiting toxicities observed.
- Common treatment-related adverse events (TRAEs) included pyrexia, fatigue, pain, and diarrhea; serious TRAEs were infrequent.
- The RP2D was established as 10^12 viral particles (VP) ChAd68 and 30 µg samRNA. Vaccination induced durable neoantigen-specific CD8 T cell responses.
- Several patients with microsatellite-stable colorectal cancer (MSS-CRC) experienced improved OS, with exploratory analyses showing decreased circulating tumor DNA (ctDNA) in patients with prolonged survival.
Conclusions:
- The combination of an individualized ChAd68/samRNA neoantigen vaccine with nivolumab and ipilimumab is safe and feasible.
- The regimen induces robust and lasting T cell responses, with promising efficacy signals in MSS-CRC patients.
- Further investigation in larger randomized studies is warranted to confirm the survival benefits observed in MSS-CRC.
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