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Principal Investigator: JOHN M MARIS
Organization: CHILDREN'S HOSP OF PHILADELPHIA
Fiscal Year: 2024
Award: $178,000
Funding agency: National Cancer Institute
PROJECT SUMMARY: U01 CA217959 Supplement Application
This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA-
24-029. The parent Multiple Principal Investigator (MPI) Project proposal for the Pediatric Immunotherapy
Network is focused on high-risk neuroblastoma, a diverse and enigmatic malignancy arising from the developing
sympathetic nervous system that remains lethal in 50% of patients despite intensive multi-modal therapy. There
is an urgent unmet need for developing novel therapeutic interventions to decrease the incidence of relapse,
increase overall survival, and reduce devastating toxicities associated with standard therapy. The primary goal
of this Project is to achieve improved outcomes for patients with high-risk neuroblastoma through the
development of a personalized vaccination strategy targeting individualized neoantigens. The central hypothesis
is that high-risk neuroblastomas, despite a low tumor mutation burden (TMB), harbor a sufficient number of
neoepitopes through canonical and non-canonical mutations to identify, predict, and validate optimal neoantigen
peptides to engineer effective multivalent personalized neuroblastoma vaccines. The motivation for the proposed
research is the urgent need to improve survival and to decrease treatment-related morbidities for patients with
high-risk neuroblastoma. Indeed, the majority of high-risk neuroblastoma patients achieve a remission with
standard therapy, and here we seek to engage the adaptive immune system to eradicate residual disease and
prevent relapse. We will test our hypothesis through the two Specific Aims: 1) define the neoantigen landscape
of high-risk neuroblastoma patient and genetically engineered mouse model (GEMM) tumors; 2) develop and
test a readily translatable personalized vaccination strategy.
In this new supplemental application, we take advantage of the expertise of the expertise of Dr. Drew Weissman
and his University of Pennsylvania RNA Innovation Institute to develop mRNA-based lipid nanoparticle
personalized neuroblastoma vaccines to be tested in parallel with the multivalent peptide vaccines we are
pursuing in the parent award. This will extend the potential impact of this U01 Project by providing an alternative
path to clinical translation that may have advantages that we will define in this supplemental sub-Project.
Terms: <Adaptive Immune System><Cancer Burden><Cancers><Childhood><Childhood Cancers><Combined Modality Therapy><Detectable Residual Disease><Development><Disease remission><Engineering><GEM model><GEMM model><Genetic Alteration><Genetic Change><Genetic defect><Genetically Engineered Mouse><Goals><Health><Immune mediated therapy><Immunologically Directed Therapy><Immunotherapy><Incidence><Malignant Childhood Neoplasm><Malignant Childhood Tumor><Malignant Neoplasms><Malignant Pediatric Neoplasm><Malignant Pediatric Tumor><Malignant Tumor><Malignant childhood cancer><Messenger RNA><Minimal Residual Disease><Mission><Morbidity><Morbidity - disease rate><Motivation><Multimodal Therapy><Multimodal Treatment><Mutation><NIH><National Cancer Burden><National Institutes of Health><Neuroblastoma><Non-Polyadenylated RNA><Nucleosides><Parents><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Pennsylvania><Peptide Vaccines><Peptides><Preventative strategy><Prevention strategy><Preventive strategy><Principal Investigator><Public Health><RNA><RNA Gene Products><Relapse><Remission><Research><Residual Neoplasm><Residual Tumors><Ribonucleic Acid><Sympathetic Nervous System><Testing><Therapeutic><Toxic effect><Toxicities><United States National Institutes of Health><Universities><Vaccines><acquired immune system><adaptive immunity><cancer in a child><cancer in children><child with cancer><childhood malignancy><clinical translation><clinically translatable><combination therapy><combined modality treatment><combined treatment><design><designing><developmental><evidence base><genetically engineered mouse model><genetically engineered murine model><genome mutation><high risk><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immunization strategy><immuno therapy><improved><improved outcome><individualized cancer vaccines><innovate><innovation><innovative><interest><lipid based nanoparticle><lipid nanoparticle><mRNA><malignancy><mouse model><multi-modal therapy><multi-modal treatment><murine model><neo-antigen><neo-antigen targeted vaccination><neo-antigen vaccination><neo-antigen vaccine><neo-epitopes><neoantigen targeted vaccination><neoantigen vaccination><neoantigen vaccine><neoantigens><neoepitopes><neoplasm/cancer><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><parent><parent award><parent project><patient oriented outcomes><pediatric><pediatric cancer><pediatric malignancy><personalized anti-tumor vaccines><personalized cancer vaccines><personalized tumor vaccines><precision cancer vaccines><prevent relapse><relapse prevention><residual disease><response><tumor><vaccination strategy>