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 <0.001). In contradistinction, pre-surgery mean serum B7-H3 was 22.1 ng/mL (SD = 5.5) and post-surgery mean serum B7-H3 was 29.2 ng/mL (SD = 9.3), a difference of 7.1 ng/mL (P = 0.002), indicating that surgery caused an increase in serum B7-H3 levels (Figure).</p>
Sipuleucel-T immunotherapy is known to prolong survival in CRPC. Our results suggest that one potential mechanism of action of this vaccine (and possibly other prostate cancer vaccines) is to reduce the production of soluble B7-H3 by prostate cancer cells, which could lead to improved immune responsiveness of the host immune system. However, the postoperative inflammatory response may abrogate some of this benefit.
Funding: DOD-PCRP PC150161 (PI: Inman)