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Blood, Vol. 96 No. 1 (July 1), 2000:
pp. 91-99
Dendritic cells modified to express CD40 ligand elicit therapeutic
immunity against preexisting murine tumors
Toshiaki Kikuchi,
Malcolm A. S. Moore, and
Ronald
G. Crystal
From the Division of Pulmonary and Critical Care Medicine, Weill
Medical College of Cornell University New York Presbyterian Hospital;
James Ewing Laboratory of Developmental Hematopoiesis, Memorial
Sloan-Kettering Cancer Center; and Institute of Genetic Medicine,Weill
Medical College of Cornell University, New York, NY.
CD40 ligand (CD40L) is essential for the initiation of
antigen-specific T-cell responses. This study is based on the
hypothesis that dendritic cells (DCs) genetically modified ex vivo to
express CD40L will enhance in vivo presentation of tumor antigen to the cellular immune system with consequent induction of antitumor immunity
to suppress tumor growth. To examine this concept, subcutaneous murine
tumors were injected with bone marrow-derived DCs that had been
modified in vitro with an adenovirus (Ad) vector expressing murine
CD40L (AdmCD40L). In B16 (H-2b, melanoma) and CT26
(H-2d, colon cancer) murine models, intratumoral injection
of 2 × 106 AdmCD40L-modified DCs (CD40L-DCs) to
established (day 8) subcutaneous tumors resulted in sustained tumor
regression and survival advantage. This antitumor effect was sustained
when the number of CD40L-DCs were reduced 10-fold to
2 × 105. Analysis of spleens from CD40L-DC-treated
animals demonstrated that CD40L-DCs injected into the subcutaneous CT26
flank tumors migrated to the spleen, resulting in activation of
immune-relevant processes. Consistent with this concept, intratumoral
administration of CD40L-DCs elicited tumor-specific cytotoxic
T-lymphocyte responses, and the transfer of spleen cells from
CD40L-DC-treated mice efficiently protected naive mice against a
subsequent tumor challenge. In a distant 2-tumor model of metastatic
disease, an untreated B16 tumor in the right flank regressed in
parallel with a left B16 tumor treated with direct injection of
CD40L-DCs. These results support the concept that genetic modification
of DCs with a recombinant CD40L adenovirus vector may be a useful
strategy for directly activating DCs for cancer immunotherapy.
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