Therapeutic vaccination against murine lymphoma by intratumoral injection of recombinant fowlpox virus encoding CD40 ligand.
The interaction between CD40 ligand (CD40L, CD154) and its receptor CD40 on antigen-presenting cells is essential for the initiation of cell-mediated and humoral immune responses. Malignant B cells also express CD40 and respond to CD40L by enhancing expression of costimulatory molecules. In this study, we investigated the therapeutic antitumor effect of intratumoral administration of recombinant fowlpox virus encoding murine CD40L (rF-mCD40L) in a murine B-cell lymphoma model. BALB/c mice with established s.c. and widely metastatic A20 lymphoma tumors were treated with intratumoral injections of rF-mCD40L together with systemic chemotherapy. This combined chemoimmunotherapy resulted in complete tumor regression and long-term survival of the mice. Some tumor cells in the injected sites expressed the CD40L transgene and had increased expression of the CD80 and CD86 costimulatory molecules. The therapeutic effect was dependent on CD8 but not on CD4 T cells. Moreover, there was a requirement that the recombinant CD40L virus be injected directly into the tumor, as opposed to peritumoral or distant sites. Thus, rF-mCD40L injected directly into the tumor microenvironment enhances the immunogenicity of tumor B cells. The results support future plans for intratumoral injection of rF-mCD40L in patients with lymphoma.
Liu
Aichun
A
Division of Oncology, Stanford University School of Medicine, 269 Campus Drive, Stanford, CA 94305, USA.
Guardino
Alice
A
Chinsangaram
Lek
L
Goldstein
Matthew J
MJ
Panicali
Dennis
D
Levy
Ronald
R
D000818:Animals; D015704:CD4 Antigens / Q000276:immunology; D023201:CD40 Ligand / Q000737:chemistry*; D016827:CD8 Antigens / Q000276:immunology; D002470:Cell Survival; D003131:Combined Modality Therapy / Q000379:methods; D005587:Fowlpox virus / Q000235:genetics*; D007167:Immunotherapy / Q000379:methods; D008223:Lymphoma / Q000628:therapy* / Q000821:virology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism
D015704:CD4 Antigens; D016827:CD8 Antigens; D023201:CD40 Ligand