Huff et al. investigated a pooled peptide vaccine covering six KRAS mutations, plus ipilimumab and nivolumab in resected PDAC. mKRAS-specific T cell responses emerged in 11/12 patients, and 4/12 remained disease-free at ~36 months. Of the six KRAS mutations, G12D was the least immunogenic, and disease recurred in all patients with this mutation. Restimulated T cells were primarily CD4+, particularly Th1-like Tcm, and expressed mKRAS-reactive TCRs, including monoreactive, polyreactive, and public clonotypes. TCR-transduced T cell lines were activated by tumor cell lines pulsed with their cognate peptide, but not by controls, indicating TCR specificity.
Contributed by Morgan Janes
ABSTRACT: In this phase I study, we test a pooled synthetic long peptide vaccine targeting the six KRAS mutations (G12V, G12A, G12R, G12C, G12D, G13D) with ipilimumab and nivolumab in resected pancreatic adenocarcinoma. Co-primary endpoints include safety and maximal percent change of IFNγ-producing mutant KRAS T cell responses in the blood within 17 weeks. Secondary endpoints include disease-free survival, overall survival, and maximal percent change of IFNγ-producing mutant KRAS T cell responses at any time after vaccination. Vaccine-related adverse events are grade 1-2. 11/12 and 10/12 patients generate a significant increase in average T cell response to 6 mutant KRAS antigens and tumor-specific response, respectively. Immunophenotyping demonstrate Th1 CD4 central memory and effector memory T cells, and CD8 effector memory T cells at a lower frequency. The vaccine also generates cross-reactive T cells that recognize more than one mutant KRAS antigen. These findings support the safety and diverse anti-tumor immunity of mutant KRAS vaccines (NCT04117087).
Author Info: (1) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins
Author Info: (1) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (2) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (3) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (4) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (5) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (6) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (7) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (8) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (9) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (10) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (11) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (12) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (13) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (14) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (15) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (16) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (17) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (18) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (19) Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA. (20) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Lustgarten Pancreatic Cancer Research Laboratory, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Howard Hughes Medical Institute, Chevy Chase, MD, USA. Division of Rheumatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (21) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Lustgarten Pancreatic Cancer Research Laboratory, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Howard Hughes Medical Institute, Chevy Chase, MD, USA. Division of Rheumatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (22) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (23) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (24) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (25) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (26) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (27) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (28) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (29) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (30) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (31) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (32) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (33) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (34) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (35) Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA. (36) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (37) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (38) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. ejaffee@jhmi.edu. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. ejaffee@jhmi.edu. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. ejaffee@jhmi.edu. (39) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. nzaidi1@jhmi.edu. Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. nzaidi1@jhmi.edu. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. nzaidi1@jhmi.edu.
