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Principal Investigator: Saad J. Kenderian
Organization: MAYO CLINIC ROCHESTER
Fiscal Year: 2024
Award: $600,395
Funding agency: National Cancer Institute
PROJECT SUMMARY
Despite the impressive activity of chimeric antigen receptor (CART) T cell therapy in the treatment of B-cell
malignancies, the therapy is limited by the development of cytokine release syndrome (CRS) and neurotoxicity,
as well as by lower rates of durable responses. While CRS is related to extreme elevation of cytokines
associated with T cell expansion, the exact etiology of neurotoxicity is unknown and no options for treatment of
neurotoxicity are available. It has, however, become apparent that inhibitory myeloid cells and cytokines
contribute to both CART cell toxicities and resistance. We have identified granulocyte-macrophage colony-
stimulating factor (GM-CSF) as a dominant driver for CART cell toxicity and inhibition of their functions. Our
robust preclinical data indicate that GM-CSF inhibition reduces monocyte activation, enhances CART cell
functions and prevents the development of both CRS and neurotoxicity in a novel xenograft model for CART
cell-associated toxicities. Our additional studies suggest that GM-CSF disruption in CART cells ameliorates
their apoptosis, independent of its effect on myeloid cells. These findings were corroborated when we utilized
GM-CSF depletion as a therapeutic strategy in patients with cytokine storm and severe Coronavirus Disease
2019, COVID-19. Based on this work, a Phase 1/2 multi-center study of GM-CSF neutralization after CART19
cell therapy was launched. Our central hypothesis is that depletion of GM-CSF results in modulation of myeloid
cell behavior, amelioration of CART cell activation, reduction of CART cell associated toxicities, and
enhancement of their efficacy. We will leverage our laboratory tools, novel preclinical models, and samples
from this clinical trial to test our hypothesis. In Aim 1 of this project, we will examine the interactions between
GM-CSF and monocytes after CART cell therapy. In Aim 2 of this project, we will study the effect of GM-CSF
directly on CART cells, and Aim 3 will test how these changes affect toxicity and efficacy of CART19 cell
therapy in the novel Phase 1/2 clinical trial. Completion of these Aims will identify novel insights into the toxicity
and activity of CART cells and will develop a new strategy to prevent CART cell associated neurotoxicity and
CRS, potentially enabling the outpatient administration of CART cell therapy.
Terms: <Actemra><Acute Lymphoblastic Leukemia><Acute Lymphocytic Leukemia><Acute Lymphoid Leukemia><Affect><Apoptosis><Apoptosis Pathway><Apoptotic><B cell malignancy><B lymphoid malignancy><B lymphoma><B-Cell Lymphomas><Blood Sample><Blood monocyte><Blood specimen><CAR T cell therapy><CAR T therapy><CD116 Antigens><CD126 Antigens><CD126 Receptor><CD19><CD19 gene><COVID infected patient><COVID patient><COVID positive patient><COVID-19><COVID-19 infected patient><COVID-19 patient><COVID-19 positive patient><COVID19 patient><COVID19 positive patient><CSF2RA/CSF2RB Complex><CSF2RA/CSF2RB Receptor><CV-19><Cancer Treatment><Causality><Cell Body><Cell Death Induction><Cell Function><Cell Physiology><Cell Process><Cell Therapy><Cells><Cellular Function><Cellular Physiology><Cellular Process><Clinical><Clinical Trials><Collaborations><Coronavirus Infectious Disease 2019><DLBCL><Data><Development><Diffuse Large B-Cell Lymphoma><Dysfunction><Etiology><Functional disorder><Funding><GM-CSF><GM-CSF Receptors><Goals><Granulocyte-Macrophage Colony-Stimulating Factor><Granulocyte-Macrophage Colony-Stimulating Factor Receptors><Hematopoietic><Histamine-Producing Cell-Stimulating Factor><IL-6 Receptors><IL6 Receptors><Impairment><In Vitro><Interleukin 6 Receptor><Interruption><Knock-out><Knockout><Laboratories><Life><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Marrow monocyte><Mediating><Mediator><Molgramostin><Multi-Institutional Clinical Trial><Multi-center clinical trial><Multi-center studies><Multi-site clinical trial><Multicenter Studies><Multicenter clinical trial><Multisite clinical trial><Myelogenous><Myeloid><Myeloid Cells><Out-patients><Outcome><Outpatients><Pathway interactions><Patients><Phase><Phase 1/2 Clinical Trial><Phase I/II Clinical Trial><Physiopathology><Pre-Clinical Model><Preclinical Models><Precursor Cell Lymphoblastic Leukemia><Precursor Lymphoblastic Leukemia><Prevention><Programmed Cell Death><Publishing><Receptor Cell><Receptor Protein><Refractory><Relapse><Resistance><Resolution><Role><SARS-CoV-2 infected patient><SARS-CoV-2 patient><SARS-CoV-2 positive patient><Sampling><Severities><Site><Subcellular Process><T-Cells><T-Lymphocyte><TAL effector nuclease><TAL endonuclease><TALE nuclease><TALEN technology><TALENs><TC-GM-CSF><Testing><Therapeutic><Toxic effect><Toxicities><Tumor-Cell Human GM Colony-Stimulating Factor><United States><Work><Xenograft Model><acute lymphatic leukemia><acute lymphogenous leukemia><acute lymphomatic leukemia><anti-cancer therapy><cancer therapy><cancer-directed therapy><causation><cell behavior><cell mediated therapies><cell-based therapeutic><cell-based therapy><cellular behavior><cellular therapeutic><cellular therapy><chimeric antigen receptor><chimeric antigen receptor (CAR) T cell therapy><chimeric antigen receptor T cell therapy><chimeric antigen receptor T therapy><cohort><coronavirus disease 2019><coronavirus disease 2019 infected patient><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease infected patient><coronavirus disease patient><coronavirus disease positive patient><coronavirus disease-19><coronavirus disease-19 patient><coronavirus infectious disease-19><coronavirus patient><cytokine><cytokine release syndrome><cytokine storm><developmental><disease causation><first in man><first-in-human><granulocyte macrophage colony stimulating factor><hemopoietic><improved><in vivo><insight><lab assignment><lab experiment><laboratory activity><laboratory assignment><laboratory exercise><laboratory experiment><large cell Diffuse non-Hodgkin's lymphoma><life-threatening COVID><life-threatening COVID-19><life-threatening SARS-CoV-2><life-threatening coronavirus disease><life-threatening coronavirus disease 2019><life-threatening severe acute respiratory syndrome coronavirus 2><monocyte><monocyte colony stimulating factor><neuron toxicity><neuronal toxicity><neurotoxicity><neutralizing antibody><new approaches><novel><novel approaches><novel strategies><novel strategy><pathophysiology><pathway><patient infected with COVID><patient infected with COVID-19><patient infected with SARS-CoV-2><patient infected with coronavirus disease><patient infected with coronavirus disease 2019><patient infected with severe acute respiratory syndrome coronavirus 2><patient with COVID><patient with COVID-19><patient with COVID19><patient with SARS-CoV-2><patient with coronavirus disease><patient with coronavirus disease 2019><patient with severe acute respiratory distress syndrome coronavirus 2><post-COVID><post-COVID-19><post-coronavirus disease 2019><pre-clinical><preclinical><prevent><preventing><receptor><resistant><resolutions><response><serious COVID><serious COVID-19><serious SARS-CoV-2><serious coronavirus disease><serious coronavirus disease 2019><serious severe acute respiratory syndrome coronavirus 2><severe COVID><severe COVID-19><severe COVID19><severe SARS-CoV-2><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><severe coronavirus disease><severe coronavirus disease 19><severe coronavirus disease 2019><severe severe acute respiratory syndrome coronavirus 2><social role><thymus derived lymphocyte><tocilizumab><tool><transcription activator-like effector nucleases><tumor><xenograft transplant model><xenotransplant model>