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Clinical Trial
. 2013 Nov;21(11):2122-9.
doi: 10.1038/mt.2013.154. Epub 2013 Jul 8.

Persistence and efficacy of second generation CAR T cell against the LeY antigen in acute myeloid leukemia

David S Ritchie  1 , 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
Affiliations
Clinical Trial

Persistence and efficacy of second generation CAR T cell against the LeY antigen in acute myeloid leukemia

David S Ritchie (VSports手机版) et al. Mol Ther. 2013 Nov.

Abstract (VSports)

In a phase I study of autologous chimeric antigen receptor (CAR) anti-LeY T-cell therapy of acute myeloid leukemia (AML), we examined the safety and postinfusion persistence of adoptively transferred T cells. Following fludarabine-containing preconditioning, four patients received up to 1. 3 × 109 total T cells, of which 14-38% expressed the CAR. Grade 3 or 4 toxicity was not observed. One patient achieved a cytogenetic remission whereas another with active leukemia had a reduction in peripheral blood (PB) blasts and a third showed a protracted remission. Using an aliquot of In111-labeled CAR T cells, we demonstrated trafficking to the bone marrow (BM) in those patients with the greatest clinical benefit. Furthermore, in a patient with leukemia cutis, CAR T cells infiltrated proven sites of disease. Serial PCR of PB and BM for the LeY transgene demonstrated that infused CAR T cells persisted for up to 10 months. Our study supports the feasibility and safety of CAR-T-cell therapy in high-risk AML, and demonstrates durable in vivo persistence. VSports手机版.

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Figures

Figure 1
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.
Figure 2
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.
Figure 3
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.
Figure 4
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.
Figure 5
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.
Figure 6
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.
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