Biodistribution and tumor localization of lymphokine-activated killer T cells following different routes of administration into tumor-bearing animals

Kjærgaard, Jørgen; Hokland, Marianne; Agger, Ralf; Skovbo, Anni; Nannmark, Ulf; Basse, Per H.

doi:10.1007/pl00006673

Cited by 21 publications

(13 citation statements)

References 21 publications

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“…The results described here clearly demonstrate that the initial C6 cell biodistribution differs from that of free 64 Cu-PTSM, indicating that we are in fact following 64 Cu trapped in C6 cells and not cell-dissociated activity. Our findings on the early pulmonary accumulation of C6 cells are consistent also with a previous study reporting lungs as the first-pass organs for tail-vein-injected cells (16). At 18.8 h after injection of C6 cells the activity accumulated in the liver (Ϸ14%ID͞g).…”

Section: Discussionsupporting

confidence: 92%

Ex vivo cell labeling with ⁶⁴ Cu–pyruvaldehyde-bis( N ⁴ -methylthiosemicarbazone) for imaging cell trafficking in mice with positron-emission tomography

Adonai

Nguyen

Walsh

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

317

241

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We have used copper-64-pyruvaldehyde-bis( N 4 -methylthiosemicarbazone) ( 64 Cu–PTSM) to radiolabel cells ex vivo for in vivo positron-emission tomography (PET) imaging studies of cell trafficking in mice and for eventual application in patients. 2-[ 18 F]-Fluoro-2-deoxy- d -glucose (FDG) cell labeling also was evaluated for comparison. 64 Cu–PTSM uptake by C6 rat glioma (C6) cells increased for 180 min and then stabilized. The labeling efficiency was directly proportional to 64 Cu–PTSM concentration and influenced negatively by serum. Label uptake per cell was greater with 64 Cu–PTSM than with FDG. However, both 64 Cu–PTSM- and FDG-labeled cells showed efflux of cell activity into supernatant. The 64 Cu–PTSM labeling procedure did not interfere significantly with C6 cell viability and proliferation rate. MicroPET images of living mice indicate that tail-vein-injected labeled C6 cells traffic to the lungs and liver. In addition, transient splenic accumulation of radioactivity was clearly detectable in a mouse scanned at 3.33 h postinfusion of 64 Cu–PTSM-labeled lymphocytes. In contrast, the liver was the principal organ of tracer localization after tail-vein administration of 64 Cu–PTSM alone. These results indicate that in vivo imaging of cell trafficking is possible with 64 Cu–PTSM-labeled cells. Given the longer t 1/2 of 64 Cu (12.7 h) relative to 18 F (110 min), longer cell-tracking periods (up to 24–36 h) should be possible now with PET.

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Section: Discussionsupporting

confidence: 92%

Ex vivo cell labeling with ⁶⁴ Cu–pyruvaldehyde-bis( N ⁴ -methylthiosemicarbazone) for imaging cell trafficking in mice with positron-emission tomography

Adonai

Nguyen

Walsh

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

317

241

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“…However, we did not find any indication of negative effects of gene transduction on tumor localization since Ad-eGFP and Ad-Red2 transduced A-NK and T-LAK cells, respectively, localized to tumors to the same degree as non-transduced cells. 22,41 Thus, for both A-NK cells and T-LAK cells, increasing cell densities within the metastases were found up to 96 h. Accordingly, the density of GFP-positive cells also increased after injection, but, in contrast to the cell density, as measured by immunostaining, measurable GFP declined after 48 h. We believe this is caused by both inactivation of the CMV promoter and dilution (due to cell proliferation) of the transgene, as discussed above. From these data, it is clear that adenoviral transduction of A-NK and T-LAK cells does not hinder their ability to traffic to and infiltrate lung tumors.…”

Section: Discussionmentioning

confidence: 99%

Targeting of products of genes to tumor sites using adoptively transferred A-NK and T-LAK cells

et al. 2007

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Despite successes in animals, cytokine gene expression selectively in human tumors is difficult to achieve owing to lack of efficient delivery methods. Since interleukin (IL)-2-activated natural killer (A-NK) and phytohemagglutinin and IL-2 activated killer T (T-LAK) cells, as previously demonstrated, localize and accumulate in murine lung tumor metastases following adoptive transfer, we transduced them to test their ability to deliver products of genes selectively to tumors. Assessments of transduction efficiency in vitro demonstrated that adenoviral transduction consistently resulted in high (460%) transduction rates and substantial expression of transgenes such as GFP, Red2, luciferase, b-galactosidase and mIL-12 for at least 4 days. In vivo experiments illustrated that Ad-GFP transduced A-NK and Ad-Red2 (RFP) transduced T-LAK or mIL-12 transduced A-NK cells localized 10-50-fold more or survived significantly better than mock transduced cells, respectively, within lung metastases than in the surrounding normal lung tissue. Most importantly, mIL-12 transduced A-NK cells provided a significantly greater antitumor response than non-transduced A-NK cells. Thus, adoptive transfer of A-NK and T-LAK cells represents an efficient method for targeting products of genes to tumor sites.

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“…This pattern is general and unrelated to CR expression, since non-gene-modified tumorinfiltrating lymphocytes (TILs) also repeatedly failed in clinical trials to demonstrate persistent and functional engraftment in patients in the absence of cytoablative treatment (44)(45)(46). One manifestation of this problem is the entrapment of systemically administered ex vivo-manipulated lymphocytes in the lungs of experimental animals (47). In attempt to overcome this major limitation, and in order to optimize the T body approach for systemic treatment of disseminated cancer, we have shown here that preconditioning of the recipient with low-dose TBI or cyclophosphamide improves the therapeutic outcome produced by adoptively transferred T bodies.…”

Section: Discussionmentioning

confidence: 99%

Adoptive immunotherapy of prostate cancer bone lesions using redirected effector lymphocytes

Pinthus¹,

Waks²,

Malina³

et al. 2004

J. Clin. Invest.

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Prostate cancer is currently the most commonly diagnosed noncutaneous malignancy in American men. When metastatic, usually to the bone, the disease is no longer curable and is usually treated palliatively with androgen ablation. However, after conversion to androgen-independent disease, there is no effective therapy currently available. The "T body" approach, which uses genetically reprogrammed lymphocytes derived from the patient and expressing chimeric receptor genes, combines the effector functions of T lymphocytes and NK cells with the ability of antibodies to recognize predefined surface antigens with high specificity and in a non-MHC-restricted manner. We show here the therapeutic efficacy of human lymphocytes bearing erbB2-specific chimeric receptors on human prostate cancer BM lesions in a SCID mouse model after conditioning of the recipient to allow homing and persistent functioning of the adoptively transferred cells. Induction of stromal cell-derived factor-1 production within the BM using low-dose irradiation or cyclophosphamide combined with IL-2 administration enhanced the homing of systemically delivered T bodies, resulting in decreased tumor growth and prostate-specific antigen secretion, prolongation of survival, and even cure of the treated mice. These preclinical studies strongly support the idea that the T body approach has therapeutic potential in disseminated prostate cancer.

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Biodistribution and tumor localization of lymphokine-activated killer T cells following different routes of administration into tumor-bearing animals

Abstract: T-LAK cells are able to localize substantially into tumor metastases in various anatomical locations, but mainly following locoregional injection. This finding might have important implications for the design of future clinical protocols of adoptive immunotherapy based on T cells.

Cited by 21 publications

References 21 publications

Ex vivo cell labeling with ⁶⁴ Cu–pyruvaldehyde-bis( N ⁴ -methylthiosemicarbazone) for imaging cell trafficking in mice with positron-emission tomography

Ex vivo cell labeling with ⁶⁴ Cu–pyruvaldehyde-bis( N ⁴ -methylthiosemicarbazone) for imaging cell trafficking in mice with positron-emission tomography

Targeting of products of genes to tumor sites using adoptively transferred A-NK and T-LAK cells

Adoptive immunotherapy of prostate cancer bone lesions using redirected effector lymphocytes

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Biodistribution and tumor localization of lymphokine-activated killer T cells following different routes of administration into tumor-bearing animals

Abstract: T-LAK cells are able to localize substantially into tumor metastases in various anatomical locations, but mainly following locoregional injection. This finding might have important implications for the design of future clinical protocols of adoptive immunotherapy based on T cells.

Cited by 21 publications

References 21 publications

Ex vivo cell labeling with 64 Cu–pyruvaldehyde-bis( N 4 -methylthiosemicarbazone) for imaging cell trafficking in mice with positron-emission tomography

Ex vivo cell labeling with 64 Cu–pyruvaldehyde-bis( N 4 -methylthiosemicarbazone) for imaging cell trafficking in mice with positron-emission tomography

Targeting of products of genes to tumor sites using adoptively transferred A-NK and T-LAK cells

Adoptive immunotherapy of prostate cancer bone lesions using redirected effector lymphocytes

Contact Info

Product

Resources

About

Ex vivo cell labeling with ⁶⁴ Cu–pyruvaldehyde-bis( N ⁴ -methylthiosemicarbazone) for imaging cell trafficking in mice with positron-emission tomography

Ex vivo cell labeling with ⁶⁴ Cu–pyruvaldehyde-bis( N ⁴ -methylthiosemicarbazone) for imaging cell trafficking in mice with positron-emission tomography