A shared neoantigen vaccine combined with immune checkpoint blockade for advanced metastatic solid tumors: phase 1
Amy R Rappaport1, Chrisann Kyi2, Monica Lane1
1Gritstone bio, Emeryville, CA, USA.
Abstract:
Therapeutic vaccines that elicit cytotoxic T cell responses targeting tumor-specific neoantigens hold promise for providing long-term clinical benefit to patients with cancer. Here we evaluated safety and tolerability of a therapeutic vaccine encoding 20 shared neoantigens derived from selected common oncogenic driver mutations as primary endpoints in an ongoing phase 1/2 study in patients with advanced/metastatic solid tumors. Secondary endpoints included immunogenicity, overall response rate, progression-free survival and overall survival. Eligible patients were selected if their tumors expressed one of the human leukocyte antigen-matched tumor mutations included in the vaccine, with the majority of patients (18/19) harboring a mutation in KRAS. The vaccine regimen, consisting of a chimp adenovirus (ChAd68) and self-amplifying mRNA (samRNA) in combination with the immune checkpoint inhibitors ipilimumab and nivolumab, was shown to be well tolerated, with observed treatment-related adverse events consistent with acute inflammation expected with viral vector-based vaccines and immune checkpoint blockade, the majority grade 1/2. Two patients experienced grade 3/4 serious treatment-related adverse events that were also dose-limiting toxicities. The overall response rate was 0%, and median progression-free survival and overall survival were 1.9 months and 7.9 months, respectively. T cell responses were biased toward human leukocyte antigen-matched TP53 neoantigens encoded in the vaccine relative to KRAS neoantigens expressed by the patients' tumors, indicating a previously unknown hierarchy of neoantigen immunodominance that may impact the therapeutic efficacy of multiepitope shared neoantigen vaccines. These data led to the development of an optimized vaccine exclusively targeting KRAS-derived neoantigens that is being evaluated in a subset of patients in phase 2 of the clinical study. ClinicalTrials.gov registration: NCT03953235 .
Insights
This study evaluated a novel cancer vaccine targeting shared neoantigens in advanced solid tumors. While generally well-tolerated, the vaccine showed limited efficacy, prompting optimization for KRAS mutations.
Area of Science:
- Oncology
- Immunotherapy
- Vaccine Development
Background:
- Therapeutic cancer vaccines aim to induce cytotoxic T cell responses against tumor-specific neoantigens for long-term patient benefit.
- Shared neoantigens derived from common oncogenic driver mutations are being explored for broad applicability in cancer immunotherapy.
Purpose of the Study:
- To evaluate the safety, tolerability, and immunogenicity of a novel therapeutic vaccine encoding 20 shared neoantigens in patients with advanced/metastatic solid tumors.
- To assess the clinical efficacy, including overall response rate (ORR), progression-free survival (PFS), and overall survival (OS).
Main Methods:
- An ongoing phase 1/2 study enrolled patients with advanced/metastatic solid tumors expressing human leukocyte antigen (HLA)-matched mutations included in the vaccine.
- The vaccine regimen combined a chimp adenovirus (ChAd68) and self-amplifying mRNA (samRNA) with ipilimumab and nivolumab.
- Primary endpoints were safety and tolerability; secondary endpoints included immunogenicity, ORR, PFS, and OS.
Main Results:
- The vaccine regimen was well-tolerated, with adverse events primarily consistent with acute inflammation (mostly grade 1/2).
- Two patients experienced dose-limiting toxicities (grade 3/4 serious adverse events).
- The ORR was 0%, with a median PFS of 1.9 months and median OS of 7.9 months. T cell responses favored TP53 neoantigens over KRAS neoantigens, suggesting an immunodominance hierarchy.
Conclusions:
- The initial multiepitope neoantigen vaccine demonstrated acceptable safety but limited clinical efficacy in this patient cohort.
- Observed T cell responses indicated an immunodominance hierarchy that may influence vaccine effectiveness.
- These findings informed the development of an optimized vaccine targeting KRAS-derived neoantigens, now under evaluation in phase 2.
