Introduction An effective cancer immunotherapy that triggers immunemediated lysis of tumor cells, may lead to the priming of T or B lymphocytes against tumor antigens distinct from the initial target/s of the therapy. This is referred to as antigen or epitope spread. Evidence of antigen spread after treatment may not only provide insights into the mechanism of action (MoA) of cancer immunotherapies, but also provide pharmacodynamic (post-treatment) biomarkers of clinical response and outcome. Sipuleucel-T, an FDA approved autologous cellular immunotherapy for the treatment of symptomatic or minimally symptomatic, metastatic castrate-resistant prostate cancer (mCRPC), is designed to elicit immune responses to the prostate-specific antigen, Prostatic Acid Phosphatase (PAP). We sought to determine if antigen spread occurs in response to sipuleucel-T treatment.