Volume 21, Issue 11, Pages (November 2013)

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Volume 21, Issue 11, Pages 2122-2129 (November 2013) Persistence and Efficacy of Second Generation CAR T Cell Against the LeY Antigen in Acute Myeloid Leukemia  David S. Ritchie, Paul J. Neeson, Amit Khot, Stefan Peinert, Tsin Tai, Kellie Tainton, Karen Chen, Mandy Shin, Dominic M. Wall, Dirk Hönemann, Peter Gambell, David A. Westerman, Javier Haurat, Jennifer A. Westwood, Andrew M. Scott, Lucy Kravets, Michael Dickinson, Joseph A. Trapani, Mark J. Smyth, Phillip K. Darcy, Michael H. Kershaw, H. Miles Prince  Molecular Therapy  Volume 21, Issue 11, Pages 2122-2129 (November 2013) DOI: 10.1038/mt.2013.154 Copyright © 2013 The American Society of Gene & Cell Therapy Terms and Conditions

Figure 1 AML patient PBMCs were transduced and expanded in vitro to express the LeY CAR and expanded to produce the T-cell product. Successful transduction was confirmed by T-cell expression of the LeY CAR, as detected by anti-idiotype (Id) binding and flow cytometry analysis. Data are presented as dot plots with an isotype control (left-hand panels) and anti-Id staining for each AML patient T-cell product (right-hand panels) with the percent anti-Id positive shown in each lower quadrant. AML, acute myeloid leukemia; CAR, chimeric antigen receptor; PBMC, peripheral blood mononuclear cells. Molecular Therapy 2013 21, 2122-2129DOI: (10.1038/mt.2013.154) Copyright © 2013 The American Society of Gene & Cell Therapy Terms and Conditions

Figure 2 Reduction in peripheral blood blast count in patient 4 following adoptive cell transfer of CAR T cell (indicated at day 0 by arrow). CAR, chimeric antigen receptor. Molecular Therapy 2013 21, 2122-2129DOI: (10.1038/mt.2013.154) Copyright © 2013 The American Society of Gene & Cell Therapy Terms and Conditions

Figure 3 Localization of CAR T cells to skin in patient 4. In skin biopsies (taken days 6 and 22 after CAR T infusion), sections were stained by H&E, and IHC for CD33 and CD3, CD4, and CD8; staining shows infiltration of the skin by CD4+ and CD8+ T cells and CD33+ blasts. CAR, chimeric antigen receptor. Molecular Therapy 2013 21, 2122-2129DOI: (10.1038/mt.2013.154) Copyright © 2013 The American Society of Gene & Cell Therapy Terms and Conditions

Figure 4 LeY T cells are present in PB BM and skin and persist up to 10 months postadoptive transfer. Genomic DNA was extracted from the T-cell product or PB and BM samples of patient 2. Subsequently, LeY transgene qPCR was performed as per the methods. All episodes are PB unless designated as BM. Time points before infusion are designated as D-12, D-1; all other time points are postadoptive transfer and designated in hours, days, or months. LeY transgene qPCR data are expressed as the number of transgene copies/1,000 cells (from which genomic DNA was harvested). Numbers above bars represent gene copies per 1,000 cells, except for the skin biopsy of patient 4 where total gene copy number is presented although lacking information on the number of cells in the sample. Data are shown for the PB (black bars) and BM samples (white bars) from each episode. BM, bone marrow; D, day; h, hour; M, month; PB, peripheral blood. Molecular Therapy 2013 21, 2122-2129DOI: (10.1038/mt.2013.154) Copyright © 2013 The American Society of Gene & Cell Therapy Terms and Conditions

Figure 5 Increase in systemic IFN-γ and IL-2 occurred after adoptive transfer of LeY T cells. Cytokines were assessed in the serum of patients before infusion or after infusion of LeY CAR T cells at the indicated times. Cytokine levels were measured in duplicate wells by Luminex assay as per the methods. CAR, chimeric antigen receptor. D, day; h, hour. Molecular Therapy 2013 21, 2122-2129DOI: (10.1038/mt.2013.154) Copyright © 2013 The American Society of Gene & Cell Therapy Terms and Conditions

Figure 6 Tracking of In111-labeled cells with SPECT scan. In111-labeled cells were serially imaged with SPECT scanning at five time points after infusion in patient 2. Initial pulmonary localization at 0.5 hours is seen followed by redistribution and accumulation in the bone marrow (thin arrow) and spleen from 4 hours (thick arrow). In addition, increased trafficking can be seen in the nasal mucosa, due to a coexisting viral upper respiratory tract infection. A summary of distribution of In111-labeled cells in the other three patients after infusion is shown in Table 2. Molecular Therapy 2013 21, 2122-2129DOI: (10.1038/mt.2013.154) Copyright © 2013 The American Society of Gene & Cell Therapy Terms and Conditions