Publications by authors named "Miriam Y Kim"

5 Publications

  • Page 1 of 1

CAR-modified memory-like NK cells exhibit potent responses to NK-resistant lymphomas.

Blood 2020 Nov;136(20):2308-2318

Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO.

Natural killer (NK) cells are a promising cellular immunotherapy for cancer. Cytokine-induced memory-like (ML) NK cells differentiate after activation with interleukin-12 (IL-12), IL-15, and IL-18, exhibit potent antitumor responses, and safely induce complete remissions in patients with leukemia. However, many cancers are not fully recognized via NK cell receptors. Chimeric antigen receptors (CARs) have been used to enhance tumor-specific recognition by effector lymphocytes. We hypothesized that ML differentiation and CAR engineering would result in complementary improvements in NK cell responses against NK-resistant cancers. To test this idea, peripheral blood ML NK cells were modified to express an anti-CD19 CAR (19-CAR-ML), which displayed significantly increased interferon γ production, degranulation, and specific killing against NK-resistant lymphoma lines and primary targets compared with nonspecific control CAR-ML NK cells or conventional CAR NK cells. The 19-CAR and ML responses were synergistic and CAR specific and required immunoreceptor tyrosine-based activation motif signaling. Furthermore, 19-CAR-ML NK cells generated from lymphoma patients exhibited improved responses against their autologous lymphomas. 19-CAR-ML NK cells controlled lymphoma burden in vivo and improved survival in human xenograft models. Thus, CAR engineering of ML NK cells enhanced responses against resistant cancers and warrants further investigation, with the potential to broaden ML NK cell recognition against a variety of NK cell-resistant tumors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2020006619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7702478PMC
November 2020

Human chimeric antigen receptor macrophages for cancer immunotherapy.

Nat Biotechnol 2020 08 23;38(8):947-953. Epub 2020 Mar 23.

Center for Cellular Immunotherapies, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.

Chimeric antigen receptor (CAR) T cell therapy has shown promise in hematologic malignancies, but its application to solid tumors has been challenging. Given the unique effector functions of macrophages and their capacity to penetrate tumors, we genetically engineered human macrophages with CARs to direct their phagocytic activity against tumors. We found that a chimeric adenoviral vector overcame the inherent resistance of primary human macrophages to genetic manipulation and imparted a sustained pro-inflammatory (M1) phenotype. CAR macrophages (CAR-Ms) demonstrated antigen-specific phagocytosis and tumor clearance in vitro. In two solid tumor xenograft mouse models, a single infusion of human CAR-Ms decreased tumor burden and prolonged overall survival. Characterization of CAR-M activity showed that CAR-Ms expressed pro-inflammatory cytokines and chemokines, converted bystander M2 macrophages to M1, upregulated antigen presentation machinery, recruited and presented antigen to T cells and resisted the effects of immunosuppressive cytokines. In humanized mouse models, CAR-Ms were further shown to induce a pro-inflammatory tumor microenvironment and boost anti-tumor T cell activity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41587-020-0462-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883632PMC
August 2020

Unlabeled Competitor Antibody to Reduce Nonlinear Signal Spillover in Mass Cytometry.

Cytometry A 2019 08 23;95(8):898-909. Epub 2019 May 23.

Ohio State Comprehensive Cancer Center, Division of Hematology, The Ohio State University, Columbus, Ohio, 43210.

Mass cytometry (MCM; CyTOF) utilizes isotopically purified metal-tagged antibodies for single-cell analysis and can analyze more than 40 parameters simultaneously with minimum signal spillover to other mass channels as compared to fluorescent flow cytometry. In spite of this improvement, various factors such as metal oxidation, abundance sensitivity related spillover, and metal impurities can cause measurable amounts of spillover in MCM that can potentially lead to misinterpretation of data. Linear spillover can be corrected by applying compensation; however, we demonstrate that at high signal intensities, MCM channel spillovers are frequently nonlinear. This report describes a simple method to correct for nonlinear signal spillover (due to abundance sensitivity, isotopic contamination, or oxide formation) that can occur at high signal intensity through the use of unlabeled competitor antibodies to the specific metal-tagged antibodies causing spillover. This method significantly decreased high signal intensity and nonlinear spillover to other mass channels while maintaining saturating antibody concentrations, thereby facilitating accurate staining and compensation. In contrast, the common method of using under-titrated antibodies to overcome spillover lead to staining intensity that varied with cell numbers and antigen abundance. We demonstrate that this technique reduces total signal without significantly altering immunophenotypic or functional measurement of relative antigen levels and could be used to enable improved linear compensation of signal spillovers from high abundance antigens. STATEMENT OF SIGNIFICANCE: Mass cytometry is becoming a well-established technology for comprehensive analysis of complex biological samples, due to its ability to enable measurement of more than 40 simultaneous parameters. Due to the use of isotopically pure metal-tagged antibodies, measurement channel spillover in mass cytometry is drastically lower than in fluorescent cytometry but can still occur due to metal oxidation, isotopic impurities, or abundance sensitivity when mass signals have high intensity. We show in this report that high abundance antigens with high signal intensity exhibit non-linear mass channel spillovers that cannot be easily compensated. We also demonstrate a simple method for the use of unlabeled competitor antibody to decrease antigen signal intensity while maintaining antigen abundance to allow for more accurate linear compensation. This method performs more consistently than the commonly used approach of using under-titrated antibodies. We believe that this report has immediate practical utility for researchers using mass cytometry and can be broadly utilized to enable compensation of mass cytometry data when needed. We thus feel that this article merits publication as a Brief Report in Cytometry Part A. © 2019 International Society for Advancement of Cytometry.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cyto.a.23793DOI Listing
August 2019

Genetic Inactivation of CD33 in Hematopoietic Stem Cells to Enable CAR T Cell Immunotherapy for Acute Myeloid Leukemia.

Cell 2018 05 31;173(6):1439-1453.e19. Epub 2018 May 31.

Center for Cellular Immunotherapies, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA; Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. Electronic address:

The absence of cancer-restricted surface markers is a major impediment to antigen-specific immunotherapy using chimeric antigen receptor (CAR) T cells. For example, targeting the canonical myeloid marker CD33 in acute myeloid leukemia (AML) results in toxicity from destruction of normal myeloid cells. We hypothesized that a leukemia-specific antigen could be created by deleting CD33 from normal hematopoietic stem and progenitor cells (HSPCs), thereby generating a hematopoietic system resistant to CD33-targeted therapy and enabling specific targeting of AML with CAR T cells. We generated CD33-deficient human HSPCs and demonstrated normal engraftment and differentiation in immunodeficient mice. Autologous CD33 KO HSPC transplantation in rhesus macaques demonstrated long-term multilineage engraftment of gene-edited cells with normal myeloid function. CD33-deficient cells were impervious to CD33-targeting CAR T cells, allowing for efficient elimination of leukemia without myelotoxicity. These studies illuminate a novel approach to antigen-specific immunotherapy by genetically engineering the host to avoid on-target, off-tumor toxicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cell.2018.05.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6003425PMC
May 2018

Pharmacoeconomic implications of lenalidomide maintenance therapy in multiple myeloma.

Oncology 2014 18;87(4):224-31. Epub 2014 Jul 18.

Division of Hematology, University of Southern California, Los Angeles, Calif., USA.

We compared the three arms of the MM-015 randomized phase III clinical trial [melphalan and prednisone (MP), MP plus lenalidomide (MPR), and MPR plus lenalidomide maintenance (MPR-R)] to determine whether the addition of lenalidomide maintenance therapy for primary treatment of multiple myeloma is cost-effective. We used progression-free survival and adverse event data from the MM-015 study for the analysis. Two novel measures of cost-effectiveness termed the Average Cumulative Cost per Patient (ACCP) and the Average Cumulative Cost per Progression-Free Survivor (ACCPFS) were developed for the purpose of this analysis. The ACCP of MP was USD 18,218, compared to USD 167,862 for MPR and USD 309,173 for MPR-R. The ACCPFS was highest with MPR at USD 1,555,443, while MP was USD 313,592 and MPR-R was USD 690,111. MPR-R is superior to MPR in terms of preventing the first progression after initial therapy. However, the addition of lenalidomide to MP in the induction and also in the maintenance setting leads to significant costs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000364880DOI Listing
November 2014