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Principal Investigator: Amanda L Huff
Organization: JOHNS HOPKINS UNIVERSITY
Fiscal Year: 2024
Award: $73,653
Funding agency: National Cancer Institute
Project Summary
Pancreatic ductal adenocarcinoma cancer (PDAC) is highly resistant to frontline surgical resection and
chemotherapy treatments. Many treatment-resistant cancer types have benefited from immunotherapies that
activate cytotoxic anti-tumor T cells against the somatic mutations, or neoantigens, expressed in cancer cells.
One major challenge to the development of neoantigen-targeted immunotherapy for PDAC has been the low
number and weakly immunogenic profile of identified neoantigens. Efficient activation of neoantigen-specific T
cells is dependent on the recognition of 8- to 11-mer neoepitopes displayed on human leukocyte antigen (HLA)
class I molecules. This recognition is the culmination of the biophysical and stereochemical contacts between
the peptide, HLA, and T cell receptor (TCR) molecules. One mechanism to improve neoepitope
immunogenicity is by modifying the peptide amino acid residues to enhance HLA binding or TCR recognition,
thereby enhancing cognate T cell activation, while conserving reactivity to the parental epitope. These modified
epitopes are termed heteroclitic epitopes. However, the stereochemical features of heteroclitic epitopes that
enhance HLA binding or TCR recognition are understudied. Additionally, heteroclitic epitopes have been
explored in the context of a limited number of HLA subtypes, restricting their development and application
across patients. We hypothesize that rational design of heteroclitic neoepitope vaccines through structural
modelling will improve T cell responses against PDAC neoantigens. To address this hypothesis, we will define
the structural binding and spatial display dynamics of both shared and private PDAC heteroclitic neoepitopes in
diverse HLAs. Among shared neoantigens expressed in PDAC, activating mutations in KRAS at codon 12 are
present in up to 80% of PDAC tumors. In Specific Aim 1, we will interrogate the structural mechanics and
immunogenic profile of heteroclitic KRAS G12D/V/C epitopes in a panel of 18, globally representative HLA
subtypes. In Specific Aim 2, we will develop a computational pipeline to identify, prioritize and optimize patient-
specific heteroclitic neoantigen vaccine candidates based on structural epitope features. We will use HLA
binding measurements and T cell reactivity assays to validate immunogenic features of our computationally
modelled heteroclitic epitopes. Together, these aims will define the structural features of immunogenic
neoantigens in diverse HLAs, generate heteroclitic epitope vaccine candidates for shared and private PDAC
antigens, and improve the therapeutic potential of cancer vaccines for hard-to-treat cancers such as PDAC.
Terms: <Abscission><Address><Affinity><Alleles><Allelomorphs><Amino Acids><Antigen Presentation><Antigen Targeting><Antigenic Determinants><Antigens><Antineoplastic Vaccine><Assay><Binding><Binding Determinants><Bioassay><Biological Assay><Biophysics><C-K-RAS><Cancer Burden><Cancer Patient><Cancer Vaccines><Cancers><Cell Body><Cells><Characteristics><Class I Antigens><Class I Major Histocompatibility Antigens><Clinical><Codon><Codon Nucleotides><Complex><Complex Class 1><Computer Models><Computer software><Computerized Models><Data><Data Set><Development><Epitopes><Excision><Extirpation><Generations><Genetic Alteration><Genetic Change><Genetic defect><HL-A Antigens><HLA Antigens><Histocompatibility Antigens Class I><Human><Human Leukocyte Antigens><Immune mediated therapy><Immune system><Immunologically Directed Therapy><Immunotherapy><K-RAS2A><K-RAS2B><K-Ras><K-Ras 2A><K-Ras-2 Oncogene><KRAS><KRAS(G12D)><KRAS2><KRAS2 gene><KRASG12D><Ki-RAS><Leukocyte Antigens><Libraries><Ligands><MHC Class I Molecule><MHC Class I Protein><MHC Receptor><MHC class I antigen><Major Histocompatibility Complex Class 1><Major Histocompatibility Complex Receptor><Malignant Cell><Malignant Neoplasms><Malignant Tumor><Measurement><Mechanics><Modeling><Modern Man><Modification><Molecular Interaction><Mutate><Mutation><National Cancer Burden><Neoplasm Vaccines><Oncogene K-Ras><Operative Procedures><Operative Surgical Procedures><PBMC><Pancreas Ductal Adenocarcinoma><Pancreatic Ductal Adenocarcinoma><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Peptide Vaccines><Peptides><Peripheral Blood Mononuclear Cell><Population><Privatization><Prognosis><Proteins><RASK2><Removal><Resistance><Software><Somatic Mutation><Structural Models><Structure><Surgical><Surgical Interventions><Surgical Procedure><Surgical Removal><Survival Rate><T cell response><T-Cell Activation><T-Cell Antigen Receptors><T-Cell Receptor><T-Cells><T-Lymphocyte><Testing><Therapeutic><Treatment outcome><Tumor Antigens><Tumor Vaccines><Tumor-Associated Antigen><Vaccines><activate T cells><aminoacid><anti-cancer immunotherapy><anti-tumor vaccine><anticancer immunotherapy><antigen binding><antigen bound><antigen-specific T cells><biophysical characteristics><biophysical characterization><biophysical foundation><biophysical measurement><biophysical parameters><biophysical principles><biophysical properties><biophysical sciences><cancer antigens><cancer cell><cancer immunotherapy><cancer sub-types><cancer subtypes><cancer type><cancer vaccination><chemotherapy><clinical applicability><clinical application><clinical translation><clinically translatable><cohort><computational modeling><computational models><computational pipelines><computational platform><computer based models><computerized modeling><computing platform><cytotoxic><design><designing><developmental><exome sequencing><exome-seq><genome mutation><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based cancer therapies><immune-based therapies><immune-based treatments><immuno therapy><immunogen><immunogenic><immunogenicity><immunotherapy for cancer><immunotherapy of cancer><improved><individualized cancer vaccines><malignancy><mechanic><mechanical><neo-antigen><neo-antigen vaccine><neo-epitopes><neoantigen vaccine><neoantigens><neoepitopes><neoplasm/cancer><novel><patient oriented outcomes><peptide aminoacid sequence><peptide sequence><personalized anti-tumor vaccines><personalized cancer vaccines><personalized tumor vaccines><precision cancer vaccines><protein aminoacid sequence><rational design><refractory cancer><resection><resistant><resistant cancer><response><somatic variant><surgery><therapeutic vaccine><thymus derived lymphocyte><treatment vaccines><tumor><tumor vaccination><tumor-specific antigen><v-Ki-RAS2 Kirsten Rat Sarcoma 2 Viral Oncogene Homolog><vaccine candidate><vaccine for cancer><vaccine for the treatment><vaccine for treatment>