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Principal Investigator: Michael C. Milone
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2023
Award: $506,376
Funding agency: National Cancer Institute
PROJECT SUMMARY / ABSTRACT (PROJECT 3)
Multiple myeloma (MM) is a hematologic malignancy of bone marrow plasma cells. Even though MM is almost
universally fatal, modern therapy has markedly improved survival. Among the most promising new MM therapies
are CAR T cells targeting B cell maturation antigen (BCMA). Despite high response rates in patients with
advanced disease, however, almost all patients eventually relapse after current-generation anti-BCMA CAR T
cells. This proposal furthers a long-term goal to prevent late relapse in MM patients after initial response to CAR
T cell therapy. In most cases, BCMA expression is retained at relapse, suggesting loss of anti-BCMA immune
surveillance as the primary mode of treatment failure. We and others have found that features of the T cells used
for CAR T cell manufacturing predict clinical outcomes, that CAR T cells can occasionally proliferate at late
timepoints post-infusion to control progressive disease, and that features of the bone marrow microenvironment
predict relapse risk after anti-BCMA CAR T cells. This proposal undertakes new approaches to prevent late MM
relapse after CAR T cell therapy; the approache to the clinical and pre-clinical studies is rooted in these prior
observations. We will conduct a clinical trial to test the safety and feasibility of therapy with anti-BCMA CAR T
cells manufactured from marrow-infiltrating lymphocytes (MIL) rather than the peripheral blood lymphocytes
traditionally used in CAR T cell manufacturing. We hypothesize that the BM-homing capability of MILs will
enhance trafficking and persistence of CAR T cells in BM. We will also pre-clinically develop two new approaches
to modulate CAR T cell activity in vivo post infusion. (1) We will introduce a modified IL-2 receptor into CAR T
cells to enable selective post-infusion in vivo stimulation with a pharmacologically administered and orthogonally
modified IL-2 ligand (orthoIL2); we hypothesize that orthoIL2 can prevent late relapse by maintaining in vivo anti-
BCMA immune surveillance. (2) We will develop BCMA-encoding mRNA-containing lipid nanoparticles (mRNA-
LNPs) to present BCMA in the context of antigen-presenting cells outside the immunosuppressive MM
microenvironment; we hypothesize that BCMA-encoding mRNA-LNPs can prolong in vivo anti-BCMA immune
surveillance, providing an approach to post-infusion modulation of CAR T cell activity that could be rapidly and
cost-effectively translated in combination with established, FDA-approved anti-BCMA CAR T cell therapies.
Collectively, our proposed studies will generate clinical and pre-clinical data to support the development of early-
phase clinical trials promising new approaches to prevent relapse after CAR T cell therapy for MM, which is the
primary clinical problem facing the field. In addition, findings from our studies could be readily translated to other
cancer types, including solid tumors.
Terms: <Adoptive Cellular Immunotherapy><Adoptive Immunotherapy><Antigen Targeting><Antigen-Presenting Cells><Antigens><Autologous><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Blood Plasma Cell><Bone Marrow><Bone Marrow Reticuloendothelial System><CAR T cell therapy><CAR T cells><CAR T therapy><CAR antigen><CAR modified T cells><CAR-T><CAR-Ts><CD19><CD19 gene><Cancers><Cell Body><Cell Communication and Signaling><Cell Maturation><Cell Signaling><Cells><Cessation of life><Clinical><Clinical Data><Clinical Research><Clinical Study><Clinical Trials><Co-Stimulator><Costimulator><Data><Death><Dendritic Cells><Development><Early-Stage Clinical Trials><Epidermal Thymocyte Activating Factor><FDA approved><Generations><Genes><Goals><Harvest><Hematologic Cancer><Hematologic Malignancies><Hematologic Neoplasms><Hematological Malignancies><Hematological Neoplasms><Hematological Tumor><Hematopoietic Cancer><Hematopoietic Cell Tumor><Hematopoietic Malignancies><Hematopoietic Neoplasms><Hematopoietic Neoplasms including Lymphomas><Hematopoietic Tumor><Hematopoietic and Lymphoid Cell Neoplasm><Hematopoietic and Lymphoid Neoplasms><High Affinity Interleukin-2 Receptor><Homing><Human><IL-2><IL-2 Receptors><IL2 Protein><IL2 Receptors><Immune Surveillance><Immune response><Immunocompetent><Immunologic Surveillance><Immunologic Surveillances><Immunological Surveillance><Immunological Surveillances><Immunological response><Immunosurveillance><In complete remission><Infiltration><Inflammatory><Infusion><Infusion procedures><Interleukin 2><Interleukin 2 Precursor><Interleukin 2 Receptor><Interleukin II><Interleukin-2><Interleukine 2><Interleukine 2 Precursor><Interleukine II><Intracellular Communication and Signaling><Lentiviral Vector><Lentivirus Vector><Ligands><Lymphatic cell><Lymphocyte><Lymphocyte Mitogenic Factor><Lymphocytic><Maintenance><Malignant Hematologic Neoplasm><Malignant Hematopoietic Neoplasm><Malignant Neoplasms><Malignant Tumor><Marrow><Messenger RNA><Mission><Mitogenic Factor><Modeling><Modern Man><Modernization><Multiple Myeloma><Mutate><Myelogenous><Myeloid><Myeloid Cells><Outcome><Patients><Peripheral Blood Lymphocyte><Phase 1 Clinical Trials><Phase I Clinical Trials><Phenotype><Plasma Cells><Plasma-Cell Myeloma><Plasmacytes><Population><Pre-Clinical Model><Preclinical Models><Progressive Disease><Proliferating><Public Health><Publishing><Refractory><Relapse><Research><S-modulin><Safety><Science><Signal Transduction><Signal Transduction Systems><Signaling><Solid Neoplasm><Solid Tumor><Source><Specificity><System><T cell growth factor><T cell response><T cells for CAR><T-Cell Activation><T-Cell Growth Factor><T-Cell Growth Factor Receptors><T-Cell Stimulating Factor><T-Cells><T-Lymphocyte><TCGF Receptors><Thymocyte Stimulating Factor><Translating><Translational Research><Translational Science><Treatment Failure><Vaccination><Vaccines><Veiled Cells><Work><Xenograft Model><accessory cell><activate T cells><adoptive cell immunotherapy><advanced disease><advanced illness><biological signal transduction><blood cancer><cancer of blood><cancer of the blood><cancer type><cancer-associated retinopathy antigen><cell transduction><cellular transduction><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><clinical outcome prediction><complete response><cost><cost effective><cytokine><developmental><disease recurrence prevention><early clinical trial><early phase clinical trial><genome editing><genomic editing><host response><immune competent><immune microenvironment><immune system response><immunogen><immunoresponse><immunosuppressive microenvironment><immunosuppressive tumor microenvironment><improved><in vivo><infusions><lentiviral-transduced><lentivirally transduced><lentivirus transduced><lipid based nanoparticle><lipid nanoparticle><lymph cell><mRNA><malignancy><manufacture><mouse model><murine model><myeloma><myelomatosis><neoplasm/cancer><new approaches><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel><novel approaches><novel strategies><novel strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><pharmacologic><phase 1 trial><phase I protocol><phase I trial><plasmocyte><pre-clinical><pre-clinical study><preclinical><preclinical study><predict clinical outcome><predict relapse><predicting response><prediction of response><predictive response><predictor of clinical outcome><predictor of response><prevent><prevent relapse><preventing><prime editing><recoverin><recoverin protein><recurrence prevention><relapse prediction><relapse prevention><relapse risk><response><response prediction><safety and feasibility><safety assessment><safety testing><sensitivity-modulating protein><success><technology platform><technology system><therapy failure><thymus derived lymphocyte><trafficking><transduced cells><transduction efficiency><translation research><translational investigation><translational medicine><tumor immune microenvironment><tumor-immune system interactions><xenograft transplant model><xenotransplant model>