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Principal Investigator: CARL H. JUNE
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2023
Award: $2,782,255
Funding agency: National Cancer Institute
OVERALL PROJECT SUMMARY / ABSTRACT
The long-term goals of this renewal P01 are to develop next generation immunotherapy with chimeric antigen
receptor (CAR) T cells and to translate this research into new therapies with curative potential for patients with
blood cancer. The CAR developed at our center was the first cell and gene therapy to ever receive approval from
the FDA, initially for refractory/relapsed pre-B cell acute lymphocytic leukemia (ALL) in 2017 and lymphoma in
2018. However, multiple myeloma (MM), acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL)
remain as the major unmet medical need in blood cancers. Our central hypothesis is that therapies with
combination of CAR T cells and advanced forms of human genome editing will enable this powerful therapy to
reach a broader spectrum of patients with blood cancer. We have brought together a cadre of exceptional
investigators from multiple disciplines who have collaborated and published together for many years. Each
disease-focused project will be led by recognized authorities in the field. To achieve our goals, we have three
Projects that build on progress during the previous funding period and will continue to coordinate closely with
essential shared resource cores. In Project 1, we will determine the clinical and immunological impact of treating
patients on two clinical trials: (i) CAR T cells targeting CD19 will be tested with genetic disruption of CD5, CTLA-
4 and TET2 to address CLL and lymphoma, which is lack of sustained effector CAR T function in these patients.
In AML, the central problem in CAR T cell therapy is the lack of a known surface antigen that is present on AML
but lacking from normal hematopoiesis. The goal of Project 2 is to open a wide therapeutic window for AML by
genetically-modifying normal marrow to make it resistant to killing by anti-AML CAR T cells, and delivering potent
anti-leukemic CAR T cells specific for CD45. Engineered HSC that are genetically edited to install a
hematopoietic system facilitating non-toxic therapy with these potent CAR T cells will be developed. In Project
3, the overall hypothesis is that anti-myeloma efficacy will be maximized by (i) testing the efficacy of marrow-
derived CAR T compared to current standard of care blood-derived CAR T (ii) improving persistence of BCMA
CAR T with orthogonally mutated IL-2/IL-2R technology and mRNA/lipid-nanoparticle vaccine technology to
overcome suboptimal persistence and efficacy of current BCMA T cells.
The Scientific and Administrative Cores for this P01 are essential for our progress including provision of project
management for collaboration and biostatistics, clinical safety and monitoring, and fiscal support (Core A), a
GMP facility for manufacture of cells and identification of new binders for CAR targets (Core B), and a state-of-
the-art platform for GLP analysis to provide high dimensional data of the samples generated in all Projects (Core
C). Our renewal application has the potential for paradigm-shifting impact to transform the lessons of CAR T for
ALL into meaningful efficacy against all hematologic malignancies, solid cancers and provides direction for
extending beyond cancer to autoimmune disorders.
Terms: <AML - Acute Myeloid Leukemia><Acute B-Lymphocytic Leukemia><Acute Myeloblastic Leukemia><Acute Myelocytic Leukemia><Acute Myelogenous Leukemia><Acute T Cell Leukemia><Acute T-Cell Lymphoblastic Leukemia><Acute T-Cell Lymphocytic Leukemia><Acute T-Lymphocytic Leukemia><Acute leukemia><Address><Adoptive Transfer><Authorization><Authorization documentation><Autoimmune Diseases><B cell malignancy><B cell progenitor acute lymphoblastic leukemia><B lymphoid malignancy><B-ALL><B-Cell Acute Lymphocytic Leukemia><B-Cell Acute Lymphoblastic Leukemia><B-Cell CLL><B-Cell Chronic Lymphocytic Leukemia><B-Cell Chronic Lymphogenous Leukemia><B-Cell Chronic Lymphoid Leukemia><B-Cell Lymphoblastic Leukemia><B-Cell Lymphocytic Leukemia><B-Lymphocytic Leukemia><B-cell ALL><B-cell precursor acute lymphoblastic leukemia><B220><Back><Biological><Biometrics><Biometry><Biostatistics><Blood><Blood Reticuloendothelial System><CAR T cell therapy><CAR T cells><CAR T therapy><CAR modified T cells><CAR-T><CAR-Ts><CD152><CD152 Antigen><CD152 Gene><CD19><CD19 gene><CD45><CLL Lymphoplasmacytoid Lymphoma><CRISPR approach><CRISPR based approach><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><CTLA 4><CTLA-4 Gene><CTLA4><CTLA4 gene><CTLA4-TM><Cancers><Cas nuclease technology><Cell Body><Cell Surface Antigens><Cell Therapy><Cells><Chronic B-Lymphocytic Leukemia><Chronic Lymphatic Leukemia><Chronic Lymphoblastic Leukemia><Chronic Lymphocytic Leukemia><Chronic Lymphogenous Leukemia><Clinic><Clinical><Clinical Trials><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Co-Stimulator><Collaborations><Costimulator><Cytotoxic T-Lymphocyte Protein 4><Cytotoxic T-Lymphocyte-Associated Antigen 4><Cytotoxic T-Lymphocyte-Associated Protein 4><Cytotoxic T-Lymphocyte-Associated Serine Esterase-4><DNA Therapy><Development><Discipline><Disease><Disorder><Dorsum><Engineering><Epidermal Thymocyte Activating Factor><FDA approved><Funding><Future><GP180><Gene Transfer Clinical><Generations><Genes><Genetic><Genetic Engineering><Genetic Engineering Biotechnology><Genetic Engineering Molecular Biology><Genetic Intervention><Germinoblastic Sarcoma><Germinoblastoma><Gills><Goals><Granulocytic Leukemia><Hematologic Body System><Hematologic Cancer><Hematologic Malignancies><Hematologic Neoplasms><Hematologic Organ System><Hematological Malignancies><Hematological Neoplasms><Hematological Tumor><Hematopoiesis><Hematopoietic Body System><Hematopoietic Cancer><Hematopoietic Cell Tumor><Hematopoietic Cellular Control Mechanisms><Hematopoietic Malignancies><Hematopoietic Neoplasms><Hematopoietic Neoplasms including Lymphomas><Hematopoietic System><Hematopoietic Tumor><Hematopoietic and Lymphoid Cell Neoplasm><Hematopoietic and Lymphoid Neoplasms><Human Genome><IL-2><IL2 Protein><Immune><Immune mediated therapy><Immunes><Immunochemical Immunologic><Immunologic><Immunologic Surface Markers><Immunological><Immunological Surface Markers><Immunologically><Immunologically Directed Therapy><Immunologics><Immunotherapy><In complete remission><Individual><Interleukin 2><Interleukin 2 Precursor><Interleukin II><Interleukin-2><Interleukine 2><Interleukine 2 Precursor><Interleukine II><International><Investigators><Joints><Journals><LY5><Laboratories><Licensing><Lymphoblastic Leukemia><Lymphocyte Mitogenic Factor><Lymphocytic Leukemia><Lymphocytic Lymphoma><Lymphoid Leukemia><Lymphoma><Lymphoma, Lymphocytic, Plasmacytoid><Lymphoma, Lymphocytic, Well-Differentiated><Magazine><Malignant Cell><Malignant Hematologic Neoplasm><Malignant Hematopoietic Neoplasm><Malignant Lymphoma><Malignant Neoplasms><Malignant Tumor><Marrow><Mediating><Medical><Medicine><Messenger RNA><Mitogenic Factor><Modification><Monitor><Multiple Myeloma><Mutate><Myelocytic Leukemia><Myelogenous Leukemia><Myeloid Leukemia><New England><Non-Lymphoblastic Leukemia><Non-Lymphocytic Leukemia><Nonlymphoblastic Leukemia><Nonlymphocytic Leukemia><Northeastern United States><PTPRC><PTPRC gene><Paper><Patients><Permission><Persons><Plasma-Cell Myeloma><Pre-B-Cell Leukemia><Precursor B Lymphoblastic Leukemia><Precursor T Lymphoblastic Leukemia><Publications><Publishing><Recombinant DNA Technology><Refractory><Relapse><Research><Research Personnel><Researchers><Resistance><Resource Sharing><Reticulolymphosarcoma><Safety><Sampling><Scientific Publication><Services><Small B-Cell Lymphocytic Lymphoma><Small Cell Lymphoma><Small Lymphocytic Lymphoma><Small-Cell Lymphoma><Solid><Source><Surface Antigens><T cell growth factor><T cells for CAR><T-Cell Growth Factor><T-Cell Stimulating Factor><T-Cell Type Acute Leukemia><T-Cells><T-Lymphocyte><T-lineage acute lymphoblastic leukemia><T200><Technology><Testing><Therapeutic><Thymocyte Stimulating Factor><Toxic effect><Toxicities><Translating><United States><Vaccines><acute granulocytic leukemia><acute myeloid leukemia><anti-cancer immunotherapy><anti-tumor effect><anticancer immunotherapy><antitumor effect><authority><autoimmune condition><autoimmune disorder><autoimmunity disease><base editing><bench bed side><bench bedside><bench to bed side><bench to bedside><bench to clinic><bench to clinical practice><biologic><blood cancer><blood cell formation><cancer cell><cancer immunobiology><cancer immunotherapy><cancer of blood><cancer of the blood><cell mediated therapies><cell-based therapeutic><cell-based therapy><cellular therapeutic><cellular therapy><chimeric antigen T cell receptor><chimeric antigen receptor><chimeric antigen receptor (CAR) T cell therapy><chimeric antigen receptor (CAR) T cells><chimeric antigen receptor T cell therapy><chimeric antigen receptor T cells><chimeric antigen receptor fusion protein T-cells><chimeric antigen receptor modified T cells><chronic lymphoid leukemia><clinical investigation><complete response><cytotoxic T-lymphocyte antigen 4><developmental><efficacy testing><engineered T cells><gene repair therapy><gene therapy><gene-based therapy><genetic therapy><genetically engineered><genome editing><genomic editing><genomic therapy><high dimensional data><human whole genome><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><immunotherapy for cancer><immunotherapy of cancer><improved><indexing><innovate><innovation><innovative><leukemia><leukemia/lymphoma><lipid based nanoparticle><lipid nanoparticle><lymphatic leukemia><lymphogenous leukemia><lymphoma/leukemia><mRNA><malignancy><manufacturing facility><manufacturing plants><multidimensional data><multidimensional datasets><myeloid granulocytic leukemia><myeloma><myelomatosis><myelosis><neoplasm/cancer><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><overexpress><overexpression><pre-clinical study><preclinical study><production plants><programs><rational design><resistant><standard of care><synthetic biology><thymus derived lymphocyte><tool><tumor>