Sipuleucel-T immunotherapy for castrate-resistant prostate cancer modulates soluble B7-H3: a novel mechanism of action.
B7-H3 is an immune checkpoint molecule widely expressed by prostate cancer, that exists in soluble form in the blood, and that impairs T cell function. We examined whether a cell-based immunotherapy for castrate-resistant prostate cancer (CRPC), sipuleucel-T, might modulate B7-H3 as part of its mechanism of action.
We conducted a clinical trial (NCT02036918) where men with lymph node predominant oligometastatic CRPC were randomized to undergo either (a) sipuleucel-T immunotherapy followed by salvage lymphadenectomy (n=15) or (b) salvage lymphadenectomy followed by sipuleucel-T (n=5). Serum samples were taken at baseline, prior to each sipuleucel-T leukapheresis session (x3), and two weeks after the last sipuleucel-T infusion. Serum samples were then tested in triplicate for soluble B7-H3 using a solid phase sandwich ELISA assay. The assay was calibrated against highly purified NS0-expressed recombinant human B7-H3. ELISA was performed in 90 well microplates that were read in a SpectraMax microplate reader at 450 nm with wavelength correction set to 540 nm. B7-H3 concentrations were calculated using a 4-parameter logistic model curve fit (Hill equation). Pre- and post-intervention serum B7-H3 levels were compared with a paired T test.
The mean minimum detectable dose of B7-H3 for the assay was 0.160 ng/mL. Vaccination with sipuleucel-T resulted in significant drop in serum B7-H3 levels from a mean pre-sipuleucel-T level of 29.6 ng/mL [SD = 6.7] to a mean post-sipuleucel-T level of 24.0 ng/mL [SD = 5.5] (P