Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 130, Issue 11, Pages 5976-5988Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI134915
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Funding
- Center for Cancer Research's intramural research program of the NCI, NIH
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BACKGROUND. Therapeutic vaccinations against cancer have mainly targeted differentiation antigens, cancer-testis antigens, and overexpressed antigens and have thus far resulted in little clinical benefit. Studies conducted by multiple groups have demonstrated that T cells recognizing neoantigens are present in most cancers and offer a specific and highly immunogenic target for personalized vaccination. METHODS. We recently developed a process using tumor-infiltrating lymphocytes to identify the specific immunogenic mutations expressed in patients' tumors. Here, validated, defined neoantigens, predicted neoepitopes, and mutations of driver genes were concatenated into a single mRNA construct to vaccinate patients with metastatic gastrointestinal cancer. RESULTS. The vaccine was safe and elicited mutation-specific T cell responses against predicted neoepitopes not detected before vaccination. Furthermore, we were able to isolate and verify T cell receptors targeting KRAS(G12D) mutation. We observed no objective clinical responses in the 4 patients treated in this trial. CONCLUSION. This vaccine was safe, and potential future combination of such vaccines with checkpoint inhibitors or adoptive T cell therapy should be evaluated for possible clinical benefit in patients with common epithelial cancers.
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