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Cancer Therapy: Preclinical

Eradication of Medullary Multiple Myeloma by CD4+ Cytotoxic Human T Lymphocytes Directed at a Single Minor Histocompatibility Antigen

Robbert M. Spaapen, Richard W.J. Groen, Kelly van den Oudenalder, Teun Guichelaar, Maureen van Elk, Tineke Aarts-Riemens, Andries C. Bloem, Gert Storm, Anton C. Martens, Henk M. Lokhorst and Tuna Mutis
Robbert M. Spaapen
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Richard W.J. Groen
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Kelly van den Oudenalder
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Teun Guichelaar
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Maureen van Elk
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Tineke Aarts-Riemens
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Andries C. Bloem
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Gert Storm
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Anton C. Martens
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Henk M. Lokhorst
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Tuna Mutis
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DOI: 10.1158/1078-0432.CCR-10-1340 Published November 2010
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    Fig. 1.

    In vivo antitumor effects of a native CD4+ T-cell clone 3AB11 directed at a single mHag. A, UM9-luc-eGFP tumors were established in the bone marrow of Rag2−/−γc−/− mice by sublethal irradiation followed by i.v. injection of 20 × 106 tumor cells. Mice were depleted of macrophages using CL2MDP liposomes one day prior to treatment, consisting of three consecutive i.v. injections (arrows) of 30 to 40 × 106 3AB11 cells/mouse (n = 5; ○). As controls, mice were treated with similar injections of CTLTT (n = 4; •) or not treated (n = 4; ▪). Curves, growth of UM9-luc-eGFP in the mice, measured by BLI of the ventral side (arbitrary units of the normalized photon emission counts). Arrows, T-cell injections. Error bars, SE. At day 43, the difference compared with the untreated group was analyzed using a t test (***, P < 0.001). B, bioluminescence overlay pictures showing tumor outgrowth over time in representative mice after 3AB11 treatment (top) or no treatment (bottom) between day 13 and day 43.

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    Fig. 2.

    In vitro and in vivo antitumor effects of dual TT- and mHag-specific TCR-transduced CD4+ T cells. A, eGFP (representative for TCRβ) and ΔNGF-R (TCRα) expression on the untransduced TT-specific cells CTLTT (left) and on TCR-transduced cells after FACS sorting (CTLTT-TCR; right). B, specific lysis of UM9-luc-eGFP by CTLTT (•) or CTLTT-TCR (○) at indicated effector to target (E:T) ratios after coincubation for 26 hours. Results are the mean percentage lysis. Error bars, SE of triplicate wells. Similar results were obtained in two independent assays. C, Rag2−/−γc−/− mice with established UM9-luc-eGFP tumors in bone marrow were treated with 30 to 40 × 106 CTLTT (n = 5; •), CTLTT-TCR (n = 6; ○), or not treated (n = 5; ▪) one day after CL2MDP liposome pretreatment. Arrows, days of i.v. T-cell injections. Mean and SE of tumor photon emission are shown per group. The 3AB11-treated group was statistically compared with untreated group at day 36 (***, P < 0.001).

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    Fig. 3.

    Extramedullary tumor outgrowth is not resistant to T cell–mediated kill in ex vivo analyses. A, tumor load of 3AB11-treated (top) or untreated (bottom) mice at day 49 after injection of UM9-luc-eGFP. Note the outgrowth of extramedullary tumor in treated mice (arrows), whereas the original tumor sites in the bone marrow remain tumor-free. B, locus-specific photon emission was quantified for extramedullary sites (○) and for bone marrow (□) in mice treated with 3AB11 at days indicated by arrows. C, 84 days after T-cell treatment, mice were dissected to visualize extramedullary tumor burdens at luciferase-positive locations. Pictures are representative examples for s.c. (top) and ovary (bottom) tumor relapses, present in respectively 40% and 80% of treated mice. D, single-cell suspensions of UM9-luc-eGFP extramedullary tumors were derived from different treatment groups 84 days after treatment, and used ex vivo as targets for fresh 3AB11 cells in a luciferase-based killing assay. Results are the mean lysis percentage of triplicate wells after 48 hours. Error bars, SE. Similar results were obtained in two independent assays.

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    Fig. 4.

    In vivo survival of CD4+ human T cells after adoptive transfer. A, at day 4 and day 11 after the last T-cell injection, single-cell suspensions were obtained from spleens of two 3AB11-treated mice and one untreated mouse at both time points and subjected to FACS analysis. Human CD45 and CD3 are depicted for the cell population gated on eGFP (tumor) negative and murine CD45 negative. B, CTLTT-TCR–treated mice were injected with TT-loaded or unloaded EBV-LCL cells (15 × 106 i.v. and 2 × 106 s.c. where indicated). T cells were in vivo labeled using α-huCD4-ALEXA-700 antibody and visualized on the dorsal side of anesthetized mice using fluorescence imaging. C, in a second experiment at day 43 after T-cell injection, TT-loaded EBV-LCL cells (15 × 106) were i.v. injected, and TT-loaded or unloaded EBV-LCL cells and UM9 cells (2 × 106) were s.c. injected at indicated locations. T cells were visualized using fluorescence imaging. D, treatment of extramedullary relapses by additional injections of 3AB11. Established UM9-luc-eGFP tumors in bone marrow of Rag2−/−γc−/− mice were treated with 3AB11 (n = 4; ○). Twenty-two days after primary treatment, the mice were again i.v. injected with 3AB11. Arrows, T-cell injections. Mean and SE of tumor photon emission are shown. E, resistance of extramedullary tumors to intratumoral treatment with 3AB11. Rag2−/−γc−/− mice were s.c. inoculated with 9 × 106 UM9-luc-eGFP cells. Three weeks after inoculation, the tumors were treated by intratumoral injections of 3AB11 (12 × 106 cells per tumor; n = 5; ○; arrow). TT-specific T cells CTLTT (n = 5; •) or PBS (n = 6; ▪) were injected in different tumors as control. Tumor progression was monitored by BLI and mean tumor photon emission is shown.

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Clinical Cancer Research: 16 (22)
November 2010
Volume 16, Issue 22
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Eradication of Medullary Multiple Myeloma by CD4+ Cytotoxic Human T Lymphocytes Directed at a Single Minor Histocompatibility Antigen
Robbert M. Spaapen, Richard W.J. Groen, Kelly van den Oudenalder, Teun Guichelaar, Maureen van Elk, Tineke Aarts-Riemens, Andries C. Bloem, Gert Storm, Anton C. Martens, Henk M. Lokhorst and Tuna Mutis
Clin Cancer Res November 15 2010 (16) (22) 5481-5488; DOI: 10.1158/1078-0432.CCR-10-1340

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Eradication of Medullary Multiple Myeloma by CD4+ Cytotoxic Human T Lymphocytes Directed at a Single Minor Histocompatibility Antigen
Robbert M. Spaapen, Richard W.J. Groen, Kelly van den Oudenalder, Teun Guichelaar, Maureen van Elk, Tineke Aarts-Riemens, Andries C. Bloem, Gert Storm, Anton C. Martens, Henk M. Lokhorst and Tuna Mutis
Clin Cancer Res November 15 2010 (16) (22) 5481-5488; DOI: 10.1158/1078-0432.CCR-10-1340
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