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Principal Investigator: JOHN M MARIS
Organization: CHILDREN'S HOSP OF PHILADELPHIA
Fiscal Year: 2023
Award: $839,128
Funding agency: National Cancer Institute
PROJECT SUMMARY
This 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 Aim 1 we will both provide the proof-of-concept that a
multivalent vaccine consisting of both CD4+ and CD8+ epitopes is feasible for each high-risk patient and also
credential our GEMM system for preclinical vaccination trials in Aim 2. We will use an integrative proteogenomic
approach to identify up to eight immunogenic peptides for each personalized vaccine. In Aim 2, we will test both
preventative and therapeutic efficacy of self-assembling nanoparticle multivalent peptide vaccines using our
GEMM system on the CB57BL/6 background, and then compare this vaccine platform to a new lipid-peptide
polymer vaccine system optimized to deliver peptides to dendritic cells. This Project proposes an innovative
experimental strategy to identify, prioritize, and validate neoantigens in high-risk neuroblastoma, and a clinically
relevant neuroblastoma GEMM system for preclinical evaluation of neuroblastoma vaccines. The significance of
the proposed Project is the creation and validation of a novel immunotherapeutic approach that has the potential
to revolutionize high-risk neuroblastoma standard of care by providing durable cures and decreased therapy-
related morbidity. The expected outcome of this collaborative MPI Project is to establish the preclinical proof-of-
concept for a personalized neuroblastoma clinical trial that we would seek to launch in the out years of this grant
given the infrastructure we have in place. The successful completion of this Project will also enable personalized
neoantigen-based vaccine development for other pediatric malignancies.
Terms: <Activities of Daily Living><Activities of everyday life><Adaptive Immune System><Affinity><Allografting><Antigen Receptors><Antigenic Determinants><Antigens><Antineoplastic Vaccine><Binding Determinants><Biologic Models><Biological Models><CD8><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CD8B><CD8B1><CD8B1 gene><Cancer Burden><Cancer Vaccines><Cancers><Cell membrane><Childhood><Childhood Cancers><Childhood Malignant Brain Tumor><Childhood Solid Neoplasm><Childhood Solid Tumor><Clinical Treatment Moab><Clinical Trials><Combined Modality Therapy><Credentialing><Cytoplasmic Membrane><Data><Dendritic Cells><Detectable Residual Disease><Development><Disease><Disease remission><Disorder><Engineering><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Epitopes><Evaluable><Evaluable Disease><Exhibits><FDA approved><GEM model><GEMM model><Gene Transcription><Generations><Genetic Alteration><Genetic Change><Genetic Transcription><Genetic defect><Genetically Engineered Mouse><Goals><Grant><HL-A Antigens><HLA Antigens><Health><Human><Human Leukocyte Antigens><Immune mediated therapy><Immune response><Immunize><Immunological response><Immunologically Directed Therapy><Immunotherapeutic agent><Immunotherapy><In Vitro><Incidence><Individual><Infiltration><Infrastructure><LYT3><Leukocyte Antigens><Lipids><MHC Receptor><MYCN><MYCN gene><Major Histocompatibility Complex Receptor><Malignant Childhood Neoplasm><Malignant Childhood Tumor><Malignant Neoplasms><Malignant Pediatric Neoplasm><Malignant Pediatric Tumor><Malignant Tumor><Malignant childhood cancer><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Methods><Mice><Mice Mammals><Minimal Residual Disease><Mission><Model System><Modern Man><Monoclonal Antibodies><Morbidity><Morbidity - disease rate><Motivation><Multimodal Therapy><Multimodal Treatment><Murine><Mus><Mutation><NIH><NMYC><NMYC Gene><National Cancer Burden><National Institutes of Health><Neoplasm Metastasis><Neoplasm Vaccines><Neuroblastoma><Oncogene Products><Oncogene Proteins><Oncogenic><Oncoproteins><Outcome><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Pediatric Malignant Brain Tumor><Pediatric Solid Tumor><Peptide Vaccines><Peptides><Phenotype><Plasma Membrane><Polymers><Preventative strategy><Prevention><Prevention strategy><Preventive strategy><Principal Investigator><Proliferating><Proteins><Public Health><Publishing><RNA Expression><RNA Seq><RNA sequencing><RNAseq><Relapse><Remission><Research><Research Specimen><Residual Neoplasm><Residual Tumors><Resistance><Sampling><Secondary Neoplasm><Secondary Tumor><Specificity><Specimen><Survival Rate><Sympathetic Nervous System><System><T cell response><T-Cell Antigen Receptors><T-Cell Receptor><T8 Cells><T8 Lymphocytes><Testing><Therapeutic><Toxic effect><Toxicities><Transcription><Transgenic Mice><Treatment Efficacy><Tumor Specific Peptide><Tumor Vaccines><Tumor-infiltrating immune cells><United States National Institutes of Health><Vaccines><Validation><Veiled Cells><acquired immune system><adaptive immune response><adaptive immunity><anti-tumor vaccine><antitumor vaccine><cancer in a child><cancer in children><cancer metastasis><child with cancer><childhood brain cancer><childhood malignancy><children with cancer><chimeric antigen T cell receptor><chimeric antigen receptor><clinical relevance><clinically relevant><combination therapy><combined modality treatment><combined treatment><daily living function><daily living functionality><density><design><designing><develop a vaccine><develop vaccines><development of a vaccine><developmental><disease recurrence prevention><disease risk><disialogangliosides><disorder risk><epigenetically><evaluate vaccines><evidence base><exome sequencing><exome-seq><experience><functional ability><functional capacity><genetically engineered mouse model><genetically engineered murine model><genome mutation><high risk><host response><immune cell infiltration of tumors><immune cells infiltrating the tumor><immune cells that infiltrate the tumor><immune drugs><immune system response><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapeutics><immune-based therapies><immune-based treatments><immunization strategy><immuno therapy><immunogen><immunogenic><immunogenicity><immunologic therapeutics><immunoresponse><immunotherapeutics><immunotherapy agent><improved><improved outcome><infiltration of tumors by immune cells><innovate><innovation><innovative><intervention efficacy><intratumoral immune cell><intratumoral immune infiltrate><mAbs><malignancy><monoclonal Abs><monosialogangliosides><mouse model><multi-modal therapy><multi-modal treatment><murine model><nano particle><nano-sized particle><nanoparticle><nanosized particle><neo-antigen><neo-epitopes><neoantigens><neoepitopes><neoplasm/cancer><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><overexpress><overexpression><patient oriented outcomes><pediatric><pediatric brain cancer><pediatric cancer><pediatric malignancy><plasmalemma><polymer><polymeric><pre-clinical><pre-clinical evaluation><preclinical><preclinical evaluation><predict relapse><predictive tools><prevent relapse><proteogenomics><recurrence prevention><relapse prediction><relapse prevention><residual disease><resistant><response><self assembly><sialogangliosides><standard of care><therapeutic efficacy><therapy efficacy><transcriptome sequencing><transcriptomic sequencing><tumor><tumor cell metastasis><tumor immune cell><tumor immune infiltrate><tumor infiltration of immune cells><vaccination strategy><vaccination study><vaccination trial><vaccine development><vaccine evaluation><vaccine for cancer><vaccine formulation><vaccine platform><vaccine screening><vaccine strategy><vaccine study><vaccine testing><vaccine trial><validations>