IMMUNOSTIMULATION IN THE URINARY-BLADDER BY LOCAL APPLICATION OF NOCARDIA-RUBRA CELL-WALL SKELETON PREPARATION (RUBRATIN) FOR SUPERFICIAL BLADDER-CANCER IMMUNOTHERAPY - A PHASE-I PHASE-II STUDY

Objectives: Twelve patients with superficial papillary transitional ee l carcinoma of the bladder (pTa, pT1) were treated with six consecutiv e weekly intravesical instillations of Rubratin (in a dose of 1.5, 3.0 , or 4.5 mg), a cell wall skeleton preparation of Nocardia rubra (NCW) . The main objective of this study was to look for local immunomodulat ing effects of NCW and in the first four patients the effect on a mark er lesion was also investigated. Methods: Local immunostimulation in a ll 12 patients was determined by (1) measurement of cytokine induction [interleukin 1 beta(IL1 beta), IL2, IL6, and tumor necrosis factor al pha (TNF alpha)], (2) leukocyte influx into the urine, and (3) phenoty pic analysis of the lymphocyte fraction of these leukocytes. Results: Significantly elevated levels of Rubratin-induced IL1 beta (P < 0.001) , IL2 (P < 0.001), IL6 (P < 0.01), and TNF alpha (P < 0.001) were foun d compared to control pretherapy levels. Rubratin also induced leukocy te influx into the urine. Fluorescence-activated cell sorter (FACS) an alysis of the urinary leukocytes indicated T-cell activation (IL2 rece ptor and HLA-DR expression), while in two out of five patients the CD4 /CD8 ratios were increased. Urinary cytokine induction by Rubratin was comparable with cytokine induction observed in nonresponding bacillus Calmette-Guerin (BCG) patients (recurrent tumor within 6 months), but less compared with responding BCG patients (no recurrent tumor within 6 months). Clinical results showed no response on the marker lesion a nd in five out of eight patients early recurrence was found after comp lete transurethral resection (TUR) of the bladder tumors. This biologi cal response modifier caused no local or systemic side effects at the doses used. Conclusion: Although local immunostimulation by intravesic al Rubratin administration can be induced, the amount of immunocompete nt cells attracted to the bladder is not as high as observed in BCG-re sponding patients, resulting in lower amounts of cytokines produced. T his could also explain the lack of clinical efficacy.