Potent antitumor effects of CD154 transduced tumor cells in experimental bladder cancer.
OBJECTIVE
Current intravesical immunotherapy for bladder cancer with bacillus Calmette-Guerin instillations is standard treatment for patients with high risk superficial tumors but relapses are common. We evaluated the tumor vaccine concept in murine bladder cancer by comparing tumor cell transduction with genes coding for the immunostimulatory molecules CD154, interleukin (IL)-12 and CD80 to design a novel vaccination strategy.


METHODS
Adenoviral vectors were used to transduce murine bladder cancer MB-49 cells with genes coding for CD154, IL-12 and CD80. Parental or transduced MB-49 cells were injected subcutaneously into syngeneic mice. The effects of transgene expression on tumorigenicity and the generation of protective immunological memory against challenge with parental tumor were studied.


RESULTS
All 76 animals injected with parental MB-49 cells had tumors within 8 to 12 days. Tumor cell expression of CD154 combined with IL-12 completely inhibited tumor outgrowth with all 21 mice tumor-free and CD154 transduction alone was almost as effective with 33 of 35 tumor-free. IL-12 production by tumor cells delayed tumor outgrowth and 4 of 10 mice remained tumor-free. Over expression of CD80 had no effect on tumorigenicity. CD154 expressing tumors were rapidly infiltrated with large numbers of CD4+ and CD8+ T cells. Mice vaccinated 4 times with adenoviral CD154 transduced MB-49 cells were completely protected against challenge with parental tumor. Co-injection of CD154 modified cells with parental MB-49 cells retarded tumor growth.


CONCLUSIONS
Our experimental results suggest that the potent antitumor effects of CD154 gene transduction should be considered for immunostimulatory gene therapy for bladder cancer.
Loskog
A
A
Clinical Immunology Division, Rudbeck Laboratory, University Hospital, Uppsala, Sweden.
Björkland
A
A
Brown
M P
MP
Korsgren
O
O
Malmström
P U
PU
Tötterman
T H
TH
D000818:Animals; D018122:B7-1 Antigen / Q000235:genetics*; D023201:CD40 Ligand / Q000235:genetics*; D015316:Genetic Therapy / Q000379:methods; D018664:Interleukin-12 / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000276:immunology / Q000628:therapy*
D018122:B7-1 Antigen; D023201:CD40 Ligand; D018664:Interleukin-12