A shared neoantigen vaccine combined with immune checkpoint blockade for advanced metastatic solid tumors: Phase 1 trial interim results Journal Article
| Authors: | Rappaport, A. R.; Kyi, C.; Lane, M.; Hart, M. G.; Johnson, M. L.; Henick, B. S.; Liao, C. Y.; Mahipal, A.; Shergill, A.; Spira, A. I.; Goldman, J. W.; Scallan, C. D.; Schenk, D.; Palmer, C. D.; Davis, M. J.; Kounlavouth, S.; Kemp, L.; Yang, A.; Li, Y. J.; Likes, M.; Shen, A.; Boucher, G. R.; Egorova, M.; Veres, R. L.; Espinosa, J. A.; Jaroslavsky, J. R.; Kraemer Tardif, L. D.; Acrebuche, L.; Puccia, C.; Sousa, L.; Zhou, R.; Bae, K.; Hecht, J. R.; Carbone, D. P.; Johnson, B.; Allen, A.; Ferguson, A. R.; Jooss, K. |
| Article Title: | A shared neoantigen vaccine combined with immune checkpoint blockade for advanced metastatic solid tumors: Phase 1 trial interim results |
| 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. © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2024. |
| Keywords: | adult; clinical article; controlled study; treatment response; gene mutation; human cell; overall survival; genetics; clinical trial; drug tolerability; fatigue; advanced cancer; cancer growth; diarrhea; drug safety; side effect; solid tumor; neoplasm; neoplasms; ipilimumab; metastasis; progression free survival; neutrophil count; phase 2 clinical trial; nausea; vomiting; myalgia; pathology; tumor antigen; asthenia; chill; dizziness; fever; injection site reaction; pruritus; alanine aminotransferase; aspartate aminotransferase; immune response; antigens, neoplasm; cancer vaccine; cancer vaccines; multicenter study; immunogenicity; cancer immunization; cytotoxic t lymphocyte; injection site pain; phase 1 clinical trial; k ras protein; protein p21; proto-oncogene proteins p21(ras); hla antigen; hla antigens; vaccine; vaccines; rhabdomyolysis; hypertransaminasemia; overall response rate; immune checkpoint inhibitor; nivolumab; rna vaccine; humans; human; male; female; article; immune checkpoint inhibitors; adenovirus vaccine |
| Journal Title: | Nature Medicine |
| Volume: | 30 |
| Issue: | 4 |
| ISSN: | 1078-8956 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2024-04-01 |
| Start Page: | 1013 |
| End Page: | 1022 |
| Language: | English |
| DOI: | 10.1038/s41591-024-02851-9 |
| PUBMED: | 38538867 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
