Immunotherapy is an important breakthrough in malignancy. not result in short-term changes in standard disease progression end points (eg, progression-free survival, tumor size), which may be explained, in part, by the time taken for antigen spread to occur. Thus, immune-related response criteria need SB 203580 distributor to be recognized to better monitor the effectiveness of immunotherapy. As immunotherapy antitumor effects take time to evolve, immunotherapy in patients with less advanced malignancy may have greater clinical benefit vs those with more advanced disease. This concept is usually supported by prostate malignancy clinical studies with sipuleucel-T, PSA-TRICOM, and ipilimumab. We discuss antigen spread with malignancy immunotherapy and its implications for clinical outcomes. Immunotherapy is an important advance in malignancy treatment, highlighted as the breakthrough of the year by in 2013 (1) and the American Society of Clinical Oncologys advance of the year in 2015 (2). Several therapies that enhance immune responses have exhibited improvements in overall survival (OS) (1). Among the US Food and Drug Administration (FDA)-approved agents used in malignancy treatment are ipilimumab for melanoma (3); nivolumab for melanoma (4), non-small cell lung malignancy (5,6), renal cell carcinoma (7), and Hodgkin lymphoma (8); atezolizumab for urothelial malignancy (9); pembrolizumab for melanoma (10) and non-small cell lung malignancy (11); and sipuleucel-T for prostate malignancy (12). Sipuleucel-T is an autologous cellular immunotherapy that targets prostatic acid phosphatase (PAP) and is approved in the United States for the treatment of patients with asymptomatic or minimally symptomatic metastatic, castration-resistant prostate malignancy (mCRPC) (13). Additional immunotherapeutic methods in clinical development include cytokines such as interleukin-15, other vaccinations including a poxvirus-based combination regimen, adoptive cell transfer (including chimeric antigen receptor-engineered T-cells), and blockade of immune checkpoints (14C20). Immunotherapies differ in a number of ways from standard chemotherapy as they are not directly cytotoxic to the tumor; instead, these therapies aim to participate the immune system to generate antitumor activity (21). Immunotherapies as a class are often associated with statistically significant improvements in OS but not in progression-free survival (PFS) (22), although benefits in reducing tumor progression are often observed (2,23). For example, in mCRPC patients, sipuleucel-T statistically significantly reduced the risk of death compared with control (hazard ratio [HR] = 0.78, 95% confidence interval [CI] = 0.61 to 0.98, = .03), whereas the time to objective disease progression was comparable between groups (HR?=?0.95, 95% CI?=?0.77 to 1 1.17, = .63) (12). Ipilimumab with or without a glycoprotein 100 (gp100) peptide vaccine statistically significantly reduced the risk of death compared with gp100 alone (comparison of ipilimumab + gp100 vs gp100 alone: HR?=?0.68, .001, comparison of ipilimumab alone vs gp100 alone: ?HR = 0.66, = .003, respectively), in patients with metastatic melanoma (3). However, the median PFS was comparable across the groups, ie, 2.76 (95% CI = 2.73 to 2.79, ipilimumab with gp100), 2.86 (95% CI = 2.76 to 3.02, ipilimumab alone), and 2.76 months (95% CI = 2.73 to 2.83, gp100 alone) (3). Limited effect on PFS by immunotherapy may reflect the time required to mount a clinically relevant immune response, in contrast to the immediate action of cytotoxic chemotherapy or targeted brokers (eg, tyrosine-kinase inhibitors). However, the immune response can persist SB 203580 distributor long after the completion of treatment (24), and may improve over time (25) and induce development of long-lived memory cells, providing continuous immunologic activity (26). SB 203580 distributor Furthermore, unlike standard therapy, the immune responses induced or expanded by immunotherapies can spread to include new antigenic targets (27,28). The onset and broadening of responses with immunotherapy occurs as a result of the tumor immunity cycle (17). Tumor cell death in response to SAPKK3 immunotherapy may lead to the release of secondary (ie, nontargeted) tumor antigens that primary subsequent immune responses. Antigen spread (also known as epitope spread, determinant spread, or antigen cascade) is the expansion of an immune response to secondary epitopes that either were not part of the initial therapeutic or were not targeted by the therapy (21). This process is dynamic and may continue to expand over time. As.