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Principal Investigator: Jonathan Allen Webster
Organization: JOHNS HOPKINS UNIVERSITY
Fiscal Year: 2024
Award: $237,049
Funding agency: National Cancer Institute
Project Summary
Dr. Jonathan Webster is an Assistant Professor of Oncology in the Division of Hematologic Malignancies at The
Johns Hopkins University School of Medicine. He is a member of the Leukemia Group and has completed the
Science of Clinical Investigation curriculum at the Johns Hopkins Bloomberg School of Public Health. His primary
mentor, Dr. Richard Jones, is a Professor of Oncology and the Director of the Bone Marrow Transplantation
Program. His co-mentor, Dr. Ravi Varadhan, is a Professor of Oncology in the Division of Biostatistics and
Bioinformatics. His advisory committee includes Drs. Gojo and Smith, faculty experts in leukemia clinical trials,
and Dr. Luznik, a laboratory-based expert in allogeneic blood or marrow transplantation (alloBMT) and
immunology. Support from the K08 award will enable Dr. Webster to gain additional research skills, receive
mentorship in authoring publications, develop grants, and perform his research project. Dr. Webster's goal is to
become an independent investigator and leader in the emerging field of post-alloBMT therapies. The use of
nonmyeloablative conditioning (NMAC) coupled with improvements in supportive care and graft-versus-host
disease (GVHD) prophylaxis, such as high-dose post-transplantation cyclophosphamide (PTCy), have led
disease relapse to overtake transplant-related mortality as the major cause of treatment failure following alloBMT
for acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Two factors play a particularly
important role in post-alloBMT relapse: peri-transplant measurable residual disease (MRD), and the ability of
donor T lymphocytes to generate a graft-versus-leukemia (GVL) effect. The prophylactic post-transplant use of
targeted therapies reduces relapses in high risk leukemias, but most patients lack targetable mutations. In this
application, Dr. Webster proposes to examine a more broadly applicable approach using the bispecific antibodies
blinatumomab and flotetuzumab as post-alloBMT maintenance therapy in ALL and AML, respectively. Dr.
Webster has significant preliminary data demonstrating the safety of blinatumomab in this setting and the ease
with which post-transplant maintenance therapies can be given following PTCy. The overarching goal of this
proposal is to decrease relapse following alloBMT in ALL and AML. He will achieve this by: 1. Conducting a
clinical trial of blinatumomab as post-transplant maintenance to assess safety and relapse-free survival. 2.
Conducting a clinical trial of flotetuzumab in post-transplant patients to assess safety. 3. Assessing the impact
of post-transplant maintenance therapies on the activation and expansion of T lymphocytes, T cell receptor
(TCR) diversity, T cell gene expression, and the depletion of cells expressing the target antigens (CD19 and
CD123). These studies will inform the development of randomized trials of post-transplant maintenance
therapies at the cooperative group level. Data regarding the efficacy of post-alloBMT maintenance therapies in
patients with peri-transplant MRD will inform future patient selection, while the immunologic correlates may
reveal biomarkers of response.
Terms: <21+ years old><AML - Acute Myeloid Leukemia><Acute B-Lymphocytic Leukemia><Acute Lymphoblastic Leukemia><Acute Lymphocytic Leukemia><Acute Lymphoid Leukemia><Acute Myeloblastic Leukemia><Acute Myelocytic Leukemia><Acute Myelogenous Leukemia><Acute leukemia><Adoption><Adult><Adult Human><Advisory Committees><Allo BMT><Allogeneic BMT><Allogeneic Bone Marrow Transplantation><Allogeneic Transplantation><Allogenic><Antibody Therapy><Antigen Targeting><Award><B Cell Antigen CD19><B blood cells><B cell><B cell depletion therapy><B cell directed therapy><B cell progenitor acute lymphoblastic leukemia><B cell targeted therapy><B cell therapies><B cell therapy><B cells><B-ALL><B-Cell Acute Lymphocytic Leukemia><B-Cell Acute Lymphoblastic Leukemia><B-Cell Lymphoblastic Leukemia><B-Cells><B-Lymphocyte Antigen CD19><B-Lymphocyte Surface Antigen B4><B-Lymphocytes><B-cell><B-cell ALL><B-cell precursor acute lymphoblastic leukemia><Bi-specific antibodies><Bifunctional Antibodies><Bio-Informatics><Bioinformatics><Biometrics><Biometry><Biostatistics><Bispecific Antibodies><Blood><Blood Reticuloendothelial System><Bone Marrow Grafting><Bone Marrow Transplant><Bone Marrow Transplantation><CD123><CD123 Antigen><CD19><CD19 Antigens><CD19 gene><CD19 molecule><CD3><CD3 Antigens><CD3 Complex><CD3 molecule><CD8><CD8B><CD8B1><CD8B1 gene><CTX><CYCLO-cell><Carloxan><Cell Body><Cell-Mediated Lympholytic Cells><Cells><Ciclofosfamida><Ciclofosfamide><Cicloxal><Clafen><Claphene><Clinical Sciences><Clinical Trials><Coupled><Curriculum><Cycloblastin><Cycloblastine><Cyclophospham><Cyclophosphamide><Cyclophosphamidum><Cyclophosphan><Cyclophosphane><Cyclophosphanum><Cyclostin><Cyclostine><Cytolytic T-Cell><Cytophosphan><Cytophosphane><Cytotoxic T Cell><Cytotoxic T-Lymphocytes><Cytoxan><Data><Dendritic Cells><Detectable Residual Disease><Development><Differentiation Antigen CD19><Disease><Disease remission><Disorder><Donor Lymphocyte Infusion><Dose><Educational Curriculum><Endoxan><Endoxana><Enduxan><Eragrostis><Evaluation><Faculty><Fosfaseron><Future><GVL><Gene Alteration><Gene Expression><Gene Mutation><Genetic Alteration><Genetic Change><Genetic defect><Genoxal><Genuxal><Goals><Grant><GvHD><Hematologic Cancer><Hematologic Malignancies><Hematologic Neoplasms><Hematological Malignancies><Hematological Neoplasms><Hematological Tumor><Hematopoietic Cancer><Homologous Transplantation><Homologous Wasting Disease><IL3R><IL3RA><IL3RA gene><IL3RAX><IL3RX><Immune system><Immunochemical Immunologic><Immunologic><Immunologic Stimulation><Immunological><Immunological Stimulation><Immunologically><Immunologics><Immunology><Immunostimulation><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Interleukin 3 Receptor Alpha><Intervention><Intervention Strategies><Investigators><Isogeneic Homograft><Isogeneic Transplantation><Isogenic transplantation><Isograft><LYT3><Laboratories><Ledoxina><Leu 12><Link><MHC Receptor><Maintenance><Maintenance Therapy><Major Histocompatibility Complex Receptor><Malignant Hematologic Neoplasm><Marrow Transplantation><Measurable><Mediating><Mentors><Mentorship><Minimal Residual Disease><Mitoxan><Mutation><Neosar><OKT3 antigen><Oncology><Oncology Cancer><Patient Selection><Patients><Phase><Play><Population><Pre-B ALL><Pre-B Acute Lymphoblastic Leukemia><Pre-B-Cell Leukemia><Precursor B Lymphoblastic Leukemia><Precursor Cell Lymphoblastic Leukemia><Precursor Lymphoblastic Leukemia><Procytox><Prophylactic treatment><Prophylaxis><Public Health Schools><Publications><R-Series Research Projects><R01 Mechanism><R01 Program><Randomization trial><Recommendation><Recovery><Recurrent disease><Reducing Agents><Reductants><Refractory><Regimen><Regulatory T-Lymphocyte><Relapse><Relapsed Disease><Remission><Remission Induction><Research><Research Grants><Research Personnel><Research Project Grants><Research Projects><Researchers><Residual Neoplasm><Residual Tumors><Role><Runt Disease><Safety><Scientific Publication><Sendoxan><Source><Specificity><Supportive Therapy><Supportive care><Syklofosfamid><Syngeneic Homograft><Syngeneic Transplantation><T-Cell Activation><T-Cell Antigen Receptors><T-Cell Depletion><T-Cell Proliferation><T-Cell Receptor><T-Cell Subsets><T-Cells><T-Lymphocyte><T-Lymphocyte Subsets><T-cell depletion therapy><T-lymphocyte depletion therapy><T3 Antigens><T3 Complex><T3 molecule><Task Forces><Teff><Toxic effect><Toxicities><Transplant Recipients><Transplantation><Transplantation and Immune System><Treatment Failure><Treg><Tumor Cell><United States><Universities><Veiled Cells><Zytoxan><activate T cells><acute granulocytic leukemia><acute lymphatic leukemia><acute lymphogenous leukemia><acute lymphomatic leukemia><acute myeloid leukemia><adulthood><advisory team><allogeneic bone marrow transplant><allogenic bone marrow transplant><antibody based therapies><antibody treatment><antibody-based therapeutics><antibody-based treatment><bsAb><clinical investigation><conditioning><develop therapy><developmental><elderly patient><fighting><genome mutation><graft versus host disease><graft versus leukemia><graft vs host disease><graft vs leukemia><graft vs leukemia effect><graft vs leukemia response><graft vs. host disease><graft vs. leukemia><graft vs. leukemia effect><graft vs. leukemia response><high risk><immune reconstitution><immune suppression><immune suppressive activity><immune suppressive function><immunosuppressive activity><immunosuppressive function><immunosuppressive response><improved><intervention development><interventional strategy><killer T cell><lesson plans><leukemia><leukemia relapse><medical college><medical schools><member><mortality><neoplastic cell><new approaches><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel approaches><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel strategies><novel strategy><novel therapeutics><novel therapy><older patient><post-transplant><post-transplantation><posttransplant><posttransplantation><prevent><prevent relapse><preventing><professor><programs><prophylactic><randomized trial><recruit><regulatory T-cells><relapse prevention><relapse risk><residual disease><response biomarker><response markers><safety assessment><school of medicine><skills><social role><targeted agent><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapy development><therapy failure><thymus derived lymphocyte><transplant><transplant patient><transplant therapy><transplant treatment><transplantation therapy><transplantation treatment><treatment development>