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. 2008 Sep-Oct;84(5):1257-64.
doi: 10.1111/j.1751-1097.2008.00356.x. Epub 2008 Apr 23.

Immunophototherapy using PDT combined with rapid intratumoral dendritic cell injection

Brandon W Sur  1 , Phuong Nguyen, Chung-Ho Sun, Bruce J Tromberg, Edward L Nelson
Affiliations

Immunophototherapy using PDT combined with rapid intratumoral dendritic cell injection

"VSports最新版本" Brandon W Sur et al. Photochem Photobiol. 2008 Sep-Oct.

Abstract

The capacity of photodynamic therapy (PDT) to induce localized cell death and tissue damage suggests that when applied to tumors it could create a local depot of tumor-associated antigens, which would be available for uptake and presentation to the immune system, potentially leading to improved tumor control. Dendritic cells (DCs) are the most potent cells for antigen uptake, presentation, and stimulation of the immune system. However, it is unclear whether DCs would retain their viability and functional capacity for the requisite trafficking to draining lymph nodes when adoptively transferred in close temporal and anatomic proximity to the site of PDT-induced cytotoxicity VSports手机版. We conducted studies of combined PDT and adoptive DC therapy, "immunophototherapy," in a female, Fisher 344 rat orthotopic mammary tumor model. Using 5-aminolevulinic acid as a pro-drug, we demonstrated kinetically favorable biologic conversion to the photosensitive protoporphyrin IX, appropriate trafficking of syngeneic bone marrow-derived DCs injected into PDT-treated tumors within 15 min of completion of therapy, and improved survival over either modality alone. These data indicate that DCs rapidly administered into the site of PDT retain their viability and functional status, supporting the further evaluation of immunophototherapy strategies. .

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Figures

Figure 1
Figure 1
Tumor protoporphyrin IX (PpIX) fluorescence. 5-Aminolevulinic acid (5-ALA) was administered PO, by oral gavage to animals with preestablished tumors. The data in (a) and (b) depict that obtained from animals with tumors measuring approximately 0.5 cm× 0.5 cm. Individual data points in (a) represent mean of data obtained from three animals per time point. Error bars represent SD. (b) PpIX fluorescence present in tumors at different time points after 5-ALA administration.
Figure 2
Figure 2
Photodynamic therapy (PDT) induction of apoptotic tumor cell death. Individual panels depict representative images from frozen sections of established tumors. (a) An untreated tumor. (b) Tumor from an animal receiving 5-aminolevulinic acid, but no laser light illumination. (c) Tumor from an animal receiving PDT 8 h prior to tumor harvest. Fluorescence due to caspase activation was observed only in PDT-treated tumors. Original magnification 40×.
Figure 3
Figure 3
CFSE-labeled dendritic cell (DC) trafficking to draining lymph nodes (LN), post-PDT. (a) Representative images from draining lymph nodes harvested at the designated time following adoptive transfer of 5 × 104 CFSE labeled rat bone marrow–derived DCs into tumor masses, 15 min after PDT treatment. Only fluorescent signals with appropriate cellular morphology were included, typical signal artifact is noted in upper left of the 24 h image. Original magnification 40×. (b) Average number of CFSE-labeled DCs observed for tumors and draining lymph nodes at the designated time points with and without administration of PDT. These results are based upon evaluation of a minimum of 10 separate random high power fields, from nonserial tissue sections, from two separate experiments. Although tumor sections contained greater tissue than lymph node sections, there was essentially no difference in size of the tumor sections or lymph nodes across these conditions and experiments. Error bars represent SD derived from tissues from different animals.
Figure 4
Figure 4
Tumor volume changes. A total of 13 762 MAT B III mammary tumors were established to approximately 1000 mm3 in cohorts of 8–10 animals per condition. (a) Graphs depict tumor growth kinetics in animals receiving the designated treatments, as indicated by the label in the upper right-hand corner of each graph. All animals received 5-aminolevulinic acid (5-ALA) by gavage, PDT animals were exposed to laser light 2 h after 5-ALA administration, immunophototherapy (IPT) animals underwent photodynamic therapy (PDT) and then received 1× 105 bone marrow–derived DCs. Animals received only one treatment. Day 0 indicates the day that animals received 5-ALA by gavage, PDT or IPT. (b) Survival curves for all conditions. Significant differences in survival were observed for IPT relative to the PDT alone (P = 0.0234), DC alone (P = 0.016) and control (5-ALA alone) (P = 0.004)-treated animals by log rank test.
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