دورية أكاديمية
A shared neoantigen vaccine combined with immune checkpoint blockade for advanced metastatic solid tumors: phase 1 trial interim results.
| العنوان: | A shared neoantigen vaccine combined with immune checkpoint blockade for advanced metastatic solid tumors: phase 1 trial interim results. |
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| المؤلفون: | Rappaport AR; Gritstone bio, Emeryville, CA, USA., Kyi C; Memorial Sloan Kettering Cancer Center, New York, NY, USA., Lane M; Gritstone bio, Emeryville, CA, USA., Hart MG; Gritstone bio, Emeryville, CA, USA., Johnson ML; Sarah Cannon Research Institute, Nashville, TN, USA., Henick BS; Columbia University Herbert Irving Comprehensive Cancer Center, New York, NY, USA., Liao CY; University of Chicago Medical Center and Biological Sciences, Chicago, IL, USA., Mahipal A; Mayo Clinic, Rochester, MN, USA., Shergill A; University of Chicago Medical Center and Biological Sciences, Chicago, IL, USA., Spira AI; Virginia Cancer Specialists, Fairfax, VA, USA., Goldman JW; University of California, Los Angeles, Los Angeles, CA, USA., Scallan CD; Gritstone bio, Emeryville, CA, USA., Schenk D; Gritstone bio, Emeryville, CA, USA., Palmer CD; Gritstone bio, Emeryville, CA, USA., Davis MJ; Gritstone bio, Emeryville, CA, USA., Kounlavouth S; Gritstone bio, Emeryville, CA, USA., Kemp L; Gritstone bio, Emeryville, CA, USA., Yang A; Gritstone bio, Emeryville, CA, USA., Li YJ; Gritstone bio, Emeryville, CA, USA., Likes M; Gritstone bio, Emeryville, CA, USA., Shen A; Gritstone bio, Emeryville, CA, USA., Boucher GR; Gritstone bio, Emeryville, CA, USA., Egorova M; Gritstone bio, Emeryville, CA, USA., Veres RL; Gritstone bio, Emeryville, CA, USA., Espinosa JA; Gritstone bio, Emeryville, CA, USA., Jaroslavsky JR; Gritstone bio, Emeryville, CA, USA., Kraemer Tardif LD; Gritstone bio, Emeryville, CA, USA., Acrebuche L; Gritstone bio, Emeryville, CA, USA., Puccia C; Gritstone bio, Emeryville, CA, USA., Sousa L; Gritstone bio, Emeryville, CA, USA., Zhou R; Gritstone bio, Emeryville, CA, USA., Bae K; Gritstone bio, Emeryville, CA, USA., Hecht JR; University of California, Los Angeles, Los Angeles, CA, USA., Carbone DP; The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA., Johnson B; MD Anderson Cancer Center, Houston, TX, USA., Allen A; Gritstone bio, Emeryville, CA, USA., Ferguson AR; Gritstone bio, Emeryville, CA, USA., Jooss K; Gritstone bio, Emeryville, CA, USA. kjooss@gritstone.com. |
| المصدر: | Nature medicine [Nat Med] 2024 Apr; Vol. 30 (4), pp. 1013-1022. Date of Electronic Publication: 2024 Mar 27. |
| نوع المنشور: | Clinical Trial, Phase I; Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Nature Publishing Company Country of Publication: United States NLM ID: 9502015 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1546-170X (Electronic) Linking ISSN: 10788956 NLM ISO Abbreviation: Nat Med Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: New York Ny : Nature Publishing Company Original Publication: New York, NY : Nature Pub. Co., [1995- |
| مواضيع طبية MeSH: | Cancer Vaccines*/adverse effects , Neoplasms*/drug therapy , Neoplasms*/pathology , Vaccines*/therapeutic use, Humans ; Antigens, Neoplasm ; HLA Antigens ; Immune Checkpoint Inhibitors/therapeutic use ; Proto-Oncogene Proteins p21(ras)/genetics |
| مستخلص: | 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 . (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.) |
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| سلسلة جزيئية: | ClinicalTrials.gov NCT03953235 |
| المشرفين على المادة: | 0 (Antigens, Neoplasm) 0 (Cancer Vaccines) 0 (HLA Antigens) 0 (Immune Checkpoint Inhibitors) EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras)) 0 (Vaccines) |
| تواريخ الأحداث: | Date Created: 20240328 Date Completed: 20240422 Latest Revision: 20240430 |
| رمز التحديث: | 20240501 |
| DOI: | 10.1038/s41591-024-02851-9 |
| PMID: | 38538867 |
| قاعدة البيانات: | MEDLINE |
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Full Text Finder | تدمد: | 1546-170X |
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| DOI: | 10.1038/s41591-024-02851-9 |