Document text
Principal Investigator: BRAD H POLLOCK
Organization: PUBLIC HEALTH INSTITUTE
Fiscal Year: 2022
Award: $1,500,000
Funding agency: National Cancer Institute
In children, DNA replication repair deficiency (RRD), caused by mutations in the mismatch repair
of DNA polymerase genes, is an important cancer mechanism. RRD drives a deadly group of
cancers universally characterized by hypermutation, microsatellite instable (MSI) in/dels and
resistance to chemoradiation. Children with germline/constitutional mismatch repair deficiency
(CMMRD) have the highest burden of cancers in humans and rarely reach adulthood. The
exceptionally high number of mutations creates highly immunogenic peptides never expressed in
normal cells called neoantigens. Clinical evidence for the importance of CD8+ T cell activation in
endogenous neoantigen immune surveillance is demonstrated by immune checkpoint inhibitor
(ICI) immunotherapy efficacy. While the success of ICI has led to speculation that they may also
be helpful for primary cancer prevention, ICI also has significant rates of severe adverse events,
including autoimmunity-related lung, hepatic, skin, neuro, colon, endocrine, and lymphoma
toxicities, some of which are fatal. These problems have led to new interest in cancer
immunoprevention vaccines, which have milder and fewer adverse events, to boost cancer
neoantigen immune surveillance. Recently, lipid nanoparticle RNA (LNP-RNA) vaccines against
COVID-19 demonstrated convincingly that LNP-RNA vaccination is faster, more flexible, cheaper
and more immunogenic than any previous vaccine technology. Our overall goal is to leverage
paradigm-shifting advances in molecular diagnosis of CMMRD children as an identifiable high-
risk patient group, a mechanistic understanding of CMMRD derived RRD tumor mutation
architecture, powerful advances in tumor genomics and recent advances in vaccine technology
to pre-clinically discover, formulate, and validate novel LNP RNA vaccines for effective and safe
CMMRD pediatric immunoprevention.
Terms: <0-11 years old><21+ years old><Adult><Adult Human><Adverse Experience><Adverse event><Antineoplastic Vaccine><Architecture><Autoimmune Status><Autoimmunity><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><COVID-19><COVID19><CV-19><CV19><Cancer Burden><Cancer Vaccines><Cancers><Checkpoint inhibitor><Child><Child Youth><Childhood><Children (0-21)><Clinical><Colon><Constitutional><DNA Polymerases><DNA Replication><DNA Synthesis><DNA biosynthesis><DNA-Dependent DNA Polymerases><DNA-Directed DNA Polymerase><Endocrine><Engineering / Architecture><Foundations><Genetic Alteration><Genetic Change><Genetic defect><Genomics><Germinoblastic Sarcoma><Germinoblastoma><Goals><Hepatic><Human><Immune Surveillance><Immune checkpoint inhibitor><Immune mediated therapy><Immunologic Surveillance><Immunologic Surveillances><Immunological Surveillance><Immunological Surveillances><Immunologically Directed Therapy><Immunoprevention><Immunosurveillance><Immunotherapy><Lung><Lung Respiratory System><Lymphoma><MMR deficiency><Malignant Lymphoma><Malignant Neoplasms><Malignant Tumor><Microsatellite Markers><Microsatellite Repeats><Microsatellites><Mismatch Repair><Mismatch Repair Deficiency><Modern Man><Molecular Diagnosis><Mutation><National Cancer Burden><Neoplasm Vaccines><Non-Polyadenylated RNA><Normal Cell><Patients><Peptides><Polymerase Gene><Post-Replication Mismatch Repair><Preventive><Primary Cancer Prevention><RNA><RNA Gene Products><RNA immunization><RNA vaccination><RNA vaccine><RNA-based vaccine><Resistance><Reticulolymphosarcoma><Ribonucleic Acid><Serious Adverse Event><Severe Adverse Event><Skin><T-Cell Activation><T8 Cells><T8 Lymphocytes><Technology><Toxic effect><Toxicities><Tumor Vaccines><Vaccines><adulthood><anti-tumor vaccine><antitumor vaccine><chemo-/radio-therapy><chemo-radio-therapy><chemo-radiotherapy><chemoradiation><chemoradiotherapy><corona virus disease 2019><coronavirus disease 2019><coronavirus disease-19><coronavirus infectious disease-19><flexibility><flexible><genome mutation><high risk><immune check point inhibitor><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><immunogenic><interest><lipid based nanoparticle><lipid nanoparticle><mRNA immunization><mRNA vaccination><mRNA vaccine><mRNA-based vaccine><malignancy><neo-antigen><neo-epitopes><neoantigens><neoepitopes><neoplasm/cancer><novel><pediatric><pre-clinical><preclinical><pulmonary><radio-chemo-therapy><radio-chemotherapy><radiochemotherapy><repair><repaired><resistant><serious adverse experience><serious adverse reaction><success><tumor><vaccine for cancer><youngster>