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Principal Investigator: Norbert Pardi
Organization: UNIVERSITY OF CALIFORNIA LOS ANGELES
Fiscal Year: 2024
Award: $628,499
Funding agency: National Cancer Institute
ABSTRACT
The remarkable effectiveness of the COVID-19 mRNA vaccines heralds a transformative immunization
platform against viral infections. A key innovation—recognized with the 2023 Nobel Prize—is the replacement
of uridine (U) with N1-methylpseudouridine (m1Ψ) in their mRNA constructs. This substitution reduces side
effects and increases antigen production. However, applying m1Ψ-modified mRNA vaccines to the realm of
cancer immunotherapy introduces a host of new and complex challenges. These range from understanding the
implications of U-to-m1Ψ substitution on anti-tumor CD8+ T cell responses to devising effective priming and
boosting strategies, creating more predictive animal models, and surmounting the immunosuppressive
elements within the tumor microenvironment (TME). To address these challenges, this proposal outlines a
research framework built around mechanistic studies with the goal of generating new mRNA vaccines for
pancreatic ductal adenocarcinoma (PDAC)—a cancer with urgent unmet therapeutic needs.
Specific Aim 1 seeks to engineer a new class of mRNA vaccines targeting clinically relevant tumor antigens,
mesothelin (MSLN), and mutant KRAS (KRASG12D). SubAim 1.1 consists of mechanistic studies to inform
strategies for optimizing mRNA-encoded antigen and adjuvant properties and devising effective priming and
boosting approaches to enhance immunogenicity and reduce reactogenicity. SubAim 1.2 uses stringent PDAC
models to evaluate whether the new vaccines significantly improve the efficacy of T cell transfer therapies.
Specific Aim 2 evaluates the new mRNA vaccines in humanized immune system mouse models. Due to
significant interspecies differences in innate immune responses to mRNA vaccines, it is vital to move beyond
traditional mouse models. SubAim 2.1 aims to understand the effects of these vaccines on human
conventional type 1 dendritic cells and subsequent CD8+ T cell activation. SubAim 2.2 focuses on validating
the vaccines' safety and efficacy in humanized mouse models engrafted with human PDAC tumors.
Specific Aim 3 assesses the potential for allele-specific KRAS inhibitors to reprogram the immunosuppressive
PDAC TME, thus enhancing mRNA vaccine efficacy. SubAim 3.1 will investigate whether the new mRNA
platform prevents tumor recurrence in PDAC mouse models treated with allele-specific KRAS inhibitors.
SubAim 3.2 seeks to elucidate how combining mRNA-based immunotherapies with KRAS-targeted therapies
impacts the immunogenicity of PDAC cells, the composition of the immune TME, and anti-tumor efficacy.
Deliverables range from developing and optimizing new mRNA vaccines to a systematic mechanistic
evaluation of these vaccines in both conventional and humanized mouse models, and finally, to investigating
synergies with clinical-stage mutant KRAS-targeted therapies. The anticipated impact consists of advancing
the understanding of how new mRNA-based immunotherapies enable priming and sustaining the cancer-
immunity cycle and developing effective combination therapies against PDAC for future clinical translation.
Terms: <Address><Adjuvant><Adverse effects><Alleles><Allelomorphs><Animal Model><Animal Models and Related Studies><Antigens><Antineoplastic Vaccine><Biologic Models><Biological Models><C-K-RAS><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><COVID-19><CV-19><Cancer Vaccines><Cancers><Cell Communication and Signaling><Cell Signaling><Cellular immunotherapy><Clinical><Combined Modality Therapy><Complex><Coronavirus Infectious Disease 2019><Data><Dendritic Cells><Development><Dose><Dose Limiting><Drug Targeting><Effectiveness><Elements><Engineering><Engraftment><Evaluation><Exhibits><Foundations><Future><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Goals><Human><Immune Cell Activation><Immune mediated therapy><Immune system><Immunization><Immunologically Directed Therapy><Immunotherapy><Inflammatory><Innate Immune Response><Intracellular Communication and Signaling><K-RAS2A><K-RAS2B><K-Ras><K-Ras 2A><K-Ras-2 Oncogene><KRAS><KRAS(G12D)><KRAS2><KRAS2 gene><KRASG12D><Ki-RAS><Malignant Neoplasms><Malignant Pancreatic Neoplasm><Malignant Tumor><Malignant neoplasm of pancreas><Measures><Messenger RNA><Mice><Mice Mammals><Model System><Modern Man><Multimodal Therapy><Multimodal Treatment><Murine><Mus><Mutation><Neoplasm Vaccines><Nobel Prize><Oncogene K-Ras><PDA model><PDAC Model><PDAC cancer cell><PDAC cell><Pancreas Cancer><Pancreas Ductal Adenocarcinoma><Pancreas Neoplasms><Pancreas Tumor><Pancreatic Cancer><Pancreatic Ductal Adenocarcinoma><Pancreatic Tumor><Patients><Performance><Play><Production><Property><RASK2><RNA vaccine><RNA-based vaccine><Reaction><Recurrence><Recurrent><Recurrent Neoplasm><Recurrent tumor><Research><Role><Safety><Series><Signal Transduction><Signal Transduction Systems><Signaling><Solid Neoplasm><Solid Tumor><Soluble Mpf/Mesothelin-Related Protein><T cell based therapeutics><T cell based therapy><T cell directed therapies><T cell response><T cell targeted therapeutics><T cell therapy><T-Cell Activation><T-Cells><T-Lymphocyte><T-cell therapeutics><T-cell transfer therapy><T8 Cells><T8 Lymphocytes><Testing><Therapeutic><Tumor Antigens><Tumor Immunity><Tumor Vaccines><Tumor-Associated Antigen><Urd><Uridine><Vaccine Design><Vaccines><Variant><Variation><Veiled Cells><Viral Diseases><Virus Diseases><Work><activate T cells><adoptive T cell transfer><adoptive T-cell therapy><anti-cancer immunotherapy><anti-tumor immunity><anti-tumor vaccine><anticancer immunotherapy><antitumor immunity><biological signal transduction><cancer antigens><cancer immunity><cancer immunotherapy><cancer microenvironment><cancer type><cell-based immunotherapy><clinical investigation><clinical relevance><clinical translation><clinically relevant><clinically translatable><combination therapy><combined modality treatment><combined treatment><comparative><coronavirus disease 2019><coronavirus disease-19><coronavirus infectious disease-19><determine efficacy><developmental><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><engineered immune system><evaluate efficacy><evaluate vaccines><examine efficacy><gain of function><genome mutation><humanized mice><humanized mouse><immune activation><immune cell therapy><immune engineering><immune microenvironment><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><immunoengineering><immunogen><immunogenicity><immunosuppressive microenvironment><immunosuppressive tumor microenvironment><immunotherapeutic mRNA><immunotherapy for cancer><immunotherapy of cancer><improved><inhibitor><innovate><innovation><innovative><mRNA><mRNA immunotherapy><mRNA vaccine><mRNA-based approach for immunotherapy><mRNA-based immunotherapeutic><mRNA-based immunotherapy><mRNA-based vaccine><mRNA-mediated immunotherapeutic><malignancy><mesothelin><messenger RNA immunotherapy><messenger RNA-based immunotherapy><model of animal><mouse model><multi-modal therapy><multi-modal treatment><murine model><mutant><neo-antigen><neo-epitopes><neoantigens><neoepitopes><neoplasm recurrence><neoplasm/cancer><new approaches><new vaccines><next generation vaccines><novel><novel approaches><novel strategies><novel strategy><novel vaccines><pancreatic cancer patients><pancreatic ductal adenocarcinoma cell><pancreatic ductal adenocarcinoma model><pancreatic malignancy><pancreatic neoplasia><pancreatic neoplasm><patients with pancreatic cancer><pharmacologic><prevent><preventing><programs><side effect><small molecular inhibitor><small molecule inhibitor><social role><synergism><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic T-cell platform><thymus derived lymphocyte><tumor><tumor immune microenvironment><tumor microenvironment><tumor-immune system interactions><tumor-specific antigen><v-Ki-RAS2 Kirsten Rat Sarcoma 2 Viral Oncogene Homolog><vaccine efficacy><vaccine evaluation><vaccine for cancer><vaccine for immunotherapy><vaccine immunotherapy><vaccine safety><vaccine screening><vaccine testing><vaccine-based immunotherapy><viral infection><virus infection><virus-induced disease>