Chimpanzee adenovirus + self-amplifying mRNA cancer vaccine prolongs overall survival in patients with advanced solid tumors in clinical trials

With the advancement of biology and medicine, scientists have gained a better understanding of cancer and our own immune system, and they have realized that the immune system is the most lethal weapon against cancer. As a result, in recent years, cancer immunotherapy has emerged and improved. Cancer immunotherapy now shows promise in using the immune system to target and destroy cancer, which benefits cancer patients with a high mutation burden. Several studies have shown that cytotoxic CD8+ T cells that target tumor neoantigens are critical for tumor control and clearance when using immune checkpoint inhibition therapy (CPI). As a result, increasing the number of preexisting tumor-specific T cells could undoubtedly improve the therapeutic efficacy of CPI therapies. On August 15, 2022, Gritstone Bio, Inc. published a research paper in Nature Medicineentitled "Individualized, heterologous chimpanzee adenovirus and self-amplifying mRNA neoantigen vaccine for advanced metastatic solid tumors: phase 1 trial interim results". This phase 1/2 clinical trial (NCT03639714) demonstrated that a neoantigen vaccine based on personalized, heterologous chimp adenovirus (ChAd68) and self-amplified mRNA (samRNA) induced a strong, durable, and potent tumor neoantigen-specific CD4+ and CD8+ T cell response, improved the efficacy of immune checkpoint inhibitors, and performed well in patients with advanced metastatic solid The clinical trial has progressed to Phase 2/3. Many factors, including poor autoantigen immunogenicity, decreased immunity in patients with advanced cancer, and tumor immunosuppressive environment, have contributed to the difficulty in achieving the desired effect of cancer vaccines in the past. As a result, peptide-based cancer vaccines have yet to consistently induce a robust tumor neoantigen-specific CD8 T-cell response in the majority of patients. These failures suggest to us that, a successful cancer vaccine should have the following characteristics. 1) Targeting tumor-specific neoantigens 2) Use a highly immunogenic vaccine platform 3) Expansion and initiation of T cells 4) Combination with immune checkpoint inhibitor therapy 5) Generate long-term memory responses to ensure sustained tumor control for lasting clinical benefit Notably, it has been demonstrated that using non-human adenovirus, such as chimp adenovirus, viral vector-based vaccine platforms (e.g., recombinant adenovirus) can initiate robust T-cell responses and circumvent pre-existing immune responses due to prior infection with human adenovirus (ChAd). Furthermore, mRNA vaccineshave been validated in a variety of cancers and infectious diseases, and self-amplifying mRNA (samRNA) vectors are of particular interest due to their ability to express high and persistent antigen levels. In this latest study, the team used a new antigenic vaccine based on personalized, heterologous chimpanzee adenovirus (ChAd68) and Venezuelan equine encephalitis virus samRNA vectors as the primary study endpoints to evaluate metrics such as safety and tolerability. The study was conducted in non-human primate (NHP) and in patients with advanced metastatic solid tumors in combination with nabumab (Nivolumab, an anti-PD-1 monoclonal antibody) and Ipilimumab (an anti-CTLA-4 monoclonal antibody). The NHP assay was used to assess the potency and longevity of immune responses against SIV model antigens, as well as the effects of subcutaneous administration of anti-CTLA-4 monoclonal antibody. They discovered that heterologous vaccination induced broad, long-lasting CD8+ T-cell responses in NHP that were detectable over time and improved even after two years. The researchers assessed immunogenicity against personalized predicted cancer neoantigens in patients with advanced metastatic solid tumors, as well as an in-depth analysis of T-cell responses induced by a heterologous vaccine regimen. The data show that the vaccine regimen is safe and induces CD8+ T-cell responses to predicted patient-specific cancer neoantigens in humans for the first time. The Phase 1 clinical trial's primary endpoints were safety and tolerability, as well as determining the recommended dose for the Phase 2 clinical trial. The results of the trial demonstrated that this personalized vaccine regimen was safe and well tolerated, with no dose-limiting toxicity. The phase 1 clinical trial's secondary endpoints included immunogenicity, manufacturing feasibility, and overall patient survival (OS). The trial results show that the vaccine is feasible to manufacture and induces a long-lasting neoantigen-specific CD8 T-cell response. In conclusion, this clinical trial demonstrated that a personalized, heterologous chimpanzee adenovirus (ChAd68) and self-amplified mRNA (samRNA)-based tumor neoantigen vaccine was safe and well tolerated, and that it induced a long-lasting tumor neoantigen-specific CD8 T cell response, thereby improving the efficacy of immune checkpoint inhibitors in patients with advanced metastatic solid tumors. This finding points the way forward in terms of improving the efficacy of cancer vaccines.