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Principal Investigator: James L. Gulley
Organization: DIVISION OF BASIC SCIENCES - NCI
Fiscal Year: 2022
Award: $70,148
Funding agency: National Cancer Institute
Four CCR projects are currently supported by this Cancer Moonshot Bench to Beside and Back award: 1. TME informed NK cell therapy for pediatric sarcomas, led by Rosandra Kaplan (CCR) and Timothy Cripe (Nationwide Children's Hospital). The overall goal of this project is to develop natural killer (NK) cell therapy with TGF-beta imprinting that can be augmented through manipulation of the immune suppres sive tumor microenvironment (TME) leading to improved NK cell-mediated anti-tumor immunity, and serves as a potential effective therapy for patients with relapsed pediatric sarcoma. Bone and soft tissue sarcomas are one of the most common solid tumors in pediatric, adolescent/young adult (AYA) patients. Despite improved outcomes due to advances in surgical local control and multi-agent chemotherapy, prog nosis for patients who develop recurrent, metastatic, or refractory disease remains poor. For these patients, new therapeutic approaches are urgently needed. The team at Nationwide Children's Hospital (NCH) has developed a genetically modified feeder cell line that enables extensive ex vivo propagation of highly-active human NK cells from various sources, and this methodology has been evaluated in early- phase clinical trials for hematologic malignancies and brain tumors. 2. Targeting neuroendocrine tumors with DLK1 directed immunother apy, led by Nitin Roper (CCR) and John Maris (CHOP). A central goal of this project is to discover and prioritize immunotherapeutic targets in childhood cancers. Surface receptor Delta Like Non-Canonical Notch Ligand 1 (DLK1) has been prioritized as a target due to the pro tein's high expression in many pediatric and adult neuroendocrine (NE) tumors but with restricted normal expression. Based on pre-clinical data demonstrating efficacy of a novel DLK1-directed antibody-drug conjugate (ADCT-701) in neuroblastoma, the investigator team pro poses to study adult and pediatric patients with NE tumors to further develop DLK1-directed immunotherapy. The discovery that DLK1 is hiqhly expressed in many pediatric and adult NE tumors is of high significance since neuroendocrine tumors are difficult to treat and novel therapeutics are needed. DLK1 is a key mediator of the undifferentiated state in neuroblastoma, and neuroblastomas terminally differenti ate upon genetic depletion of DLK1. The proposed work has the potential to result in enhanced understanding of an important disease process and lead to a new therapeutic intervention. 3. B2B and Back: CD22 and CD19/22 CAR immunotherapies for childhood leukemia, led by Naomi Taylor (CCR) and Crystal Mackall (Stanford). The Taylor and Mackall teams are carrying out clinical trials with identical CD22 and CD19/CD22-bivalent CAR vectors but the two sites are using different manufacturing procedures to generate the CAR-transduced T cells that are being infused into patients. The current proposal is to test the hypothesis that variability in CAR-T cell immunotherapeutic po tential is affected by variations in manufacturing platforms and can be predicted through evaluation of antigen-dependent CAR-T cell activ ity. High throughput analyses of these parameters will be leveraged to optimize CAR manufacturing, evaluate divergent patient outcomes, and enhance durable responses in pediatric leukemia patients. 4. Alternative splicing of CD22 following Inotuzumab, led by Nirali Shah (CCR) and Andrei Thomas-Tikhonenko (CHOP). This project is designed to explore the mechanism(s) by which altered splicing of CD22 mRNA, to delete Exon 2, leads to loss of CD22 protein expression in B-ALL tumor cells, and thus leads to the acquired resistance of those tumor cells to CD22-specific immunotherapies. The project is an attractive blend of characterization of clinical samples from CD22-based clinical trials, and in vitro plus in vivo studies of the regulation of CD22 splicing; together, these studies could identify new therapeutic strategies to force CD22 protein expression in B-ALL cells and improve anti-CD22-immunotherapy.
Terms: <21+ years old><Acute B-Lymphocytic Leukemia><Adolescent><Adolescent Youth><Adult><Adult Human><Affect><Alternate Splicing><Alternative RNA Splicing><Alternative Splicing><Anti-CD22><Antibody-drug conjugates><Antigens><Award><B cell progenitor acute lymphoblastic leukemia><B-ALL><B-ALL cell><B-Cell Acute Lymphocytic Leukemia><B-Cell Acute Lymphoblastic Leukemia><B-Cell Antigen CD22><B-Cell Lymphoblastic Leukemia><B-cell ALL><B-cell acute lymphoblastic leukemia cell><B-cell acute lymphocytic leukemia cell><B-cell precursor acute lymphoblastic leukemia><B-cell precursor acute lymphoblastic leukemia cell><B-cell precursor acute lymphocytic leukemia cell><B3 antigen><Back><Bone Tissue><Bone-Derived Transforming Growth Factor><Brain Neoplasia><Brain Neoplasms><Brain Tumors><CAR T cells><CAR modified T cells><CCR><CD19><CD19 gene><CD22><CD22 antigen><CD22 gene><Cancer Patient><Cancers><Cell Line><CellLine><Childhood><Childhood Cancers><Childhood Leukemia><Children's Hospital><Clinical><Clinical Data><Clinical Trials><Crystallization><Cytotoxic cell><Disease><Disorder><Dorsum><EXTMR><Evaluation><Exons><Extramural><Extramural Activities><Genetic><Goals><Hematologic Cancer><Hematologic Malignancies><Hematologic Neoplasms><Hematological Malignancies><Hematological Neoplasms><Hematological Tumor><Hematopoietic Cancer><Human><Immune><Immune Targeting><Immune mediated therapy><Immunes><Immunologically Directed Therapy><Immunooncology><Immunotherapeutic agent><Immunotherapy><In Vitro><Investigators><K lymphocyte><Lead><Ligands><Malignant Childhood Neoplasm><Malignant Childhood Tumor><Malignant Hematologic Neoplasm><Malignant Neoplasms><Malignant Pediatric Neoplasm><Malignant Pediatric Tumor><Malignant Tumor><Malignant childhood cancer><Mediating><Mediator><Mediator of Activation><Mediator of activation protein><Messenger RNA><Methodology><Milk Growth Factor><Modern Man><NK Cells><NK cell therapy><Natural Killer Cells><Neuroblastoma><Neuroendocrine Neoplasm><Neuroendocrine Tumors><Operative Procedures><Operative Surgical Procedures><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Pb element><Pediatric Hospitals><Pediatric Leukemia><Platelet Transforming Growth Factor><Population Heterogeneity><Pre-B-Cell Leukemia><Precursor B Lymphoblastic Leukemia><Procedures><Process><RNA Splicing><Recurrence><Recurrent><Refractory Disease><Regulation><Relapse><Research><Research Personnel><Researchers><Resistance><Resistance development><Resistant development><SIGLEC2><Sampling><Sialic Acid-Binding Immunoglobulin-Like Lectin 2><Site><Soft tissue sarcoma><Solid Neoplasm><Solid Tumor><Source><Splicing><Strains Cell Lines><Surface><Surgical><Surgical Interventions><Surgical Procedure><T cells for CAR><T-Cells><T-Lymphocyte><TGF B><TGF-beta><TGF-β><TGFbeta><TGFβ><Testing><Transforming Growth Factor beta><Transforming Growth Factor-Beta Family Gene><Translational Research><Translational Science><Tumor Cell><Tumor Immunity><Undifferentiated><Variant><Variation><Work><adult youth><adulthood><anti-tumor immunity><antitumor immunity><base><cancer immunity><cancer in a child><cancer in children><cancer microenvironment><chemotherapy><child patients><child with cancer><childhood malignancy><childhood sarcoma><children with cancer><children with leukemia><chimeric antigen receptor (CAR) T cells><chimeric antigen receptor T cells><chimeric antigen receptor modified T cells><cultured cell line><delta receptors><design><designing><develop a vaccine><develop vaccines><developing resistance><development of a vaccine><diverse populations><early clinical trial><early phase clinical trial><effective therapy><effective treatment><heavy metal Pb><heavy metal lead><heterogeneous population><high throughput analysis><immune drugs><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapeutics><immune-based therapies><immune-based treatments><immune-oncology><immuno oncology><immuno therapy><immunogen><immunologic preparation><immunologic therapeutics><immunology oncology><immunotherapeutics><immunotherapy agent><imprint><improved><improved outcome><in vivo><juvenile><juvenile human><leukemia in children><mRNA><malignancy><natural killer cell therapy><neoplasm/cancer><neoplastic cell><new drug treatments><new drugs><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutics><new therapy><new therapy approaches><next generation therapeutics><notch><notch protein><notch receptors><novel><novel drug treatments><novel drugs><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutics><novel therapy><novel therapy approach><oncoimmunology><pediatric><pediatric cancer><pediatric malignancy><pediatric patients><pediatric sarcoma><population diversity><pre-B acute lymphoblastic leukemia cell><pre-clinical><preclinical><prevent><preventing><protein expression><resistant><response><surgery><thymus derived lymphocyte><translation research><tumor microenvironment><tumors in the brain><vaccine development><vector><young adult><young adulthood><δ receptors>