Scanning electron color-enhanced image depicts prostate cancer cells.
Photo courtesy Annie Cavanagh/Cell Image Library
Researchers have determined that patients who received sipuleucel-T (Provenge, Dendreon) developed immune parameters that correlate to improved overall survival, giving researchers a better understanding of how the immunotherapy works at a cellular level to improve survival and suggesting that these parameters should be the focus of further studies on the treatment.
The results of the study were published in the journal Cancer Immunology, Immunotherapy
earlier this month.
Sipuleucel-T was approved in 2010 to treat patients with asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer (mCRPC). The autologous cellular immunotherapy was the first approved to treat any type of cancer. It is created by culturing a patient’s own isolated peripheral blood mononuclear cells, including antigen presenting cells (APCs). When each dose is prepared, those cells are activated with a fusion protein of the antigen prostatic acid phosphatase linked to granulocyte-macrophage colony stimulating factor. As a result, when the treated cancer cells are reintroduced into a patient’s body, T-cells attack them.. The treatment is given to patients in three doses.
In order to determine which immune parameters correlate with better overall survival, the study’s authors analyzed three phase III studies. The three parameters the authors used to characterize immunologic responses were the number of APCs, APC activation (measured by CD54 upregulation), and total nucleated cell (TNC) numbers observed in successive doses of sipuleucel-T prepared for study participants.
The researchers found that in the first dose preparation, APC activation increased by a median of 6.2 times (95% CI, 4.7-7.7), with a 10.6-fold median increase with the second dose preparation (7.8-13.7) and a 10.5-fold median increase with the third dose preparation (7.9-13.7) (both P
< .001 compared to the first dose), in all the studies, pooled. The median APC activation across the three dose preparations was 26.7 (21.5-33.6).
The study found that the number of APCs and TNC counts were consistent among the three doses. The median cumulative number of TNCs was 9.70 x 109
(6.97 x 109
– 13.55 x 109
), while the median cumulative number of APCs was 1.84 x 109
(1.27 x 109 – 2.88 x 109
In a subset of patients who provided blood for immune response determination, progressively more antigen-specific T cells were observed after the second and third doses of sipuleucel-T.
The authors wrote that this analysis supports the supposition that the first infusion of activated, antigen-loaded APCs is able to prime T-cells. Those T-cells produce cytokines that further activate APCs. By doing so, sipuleucel-T engages the immune system early in the treatment of prostate cancer. APCs are activated ex vivo and end up generating long-lived immune responses once in vivo.
“Both cellular and humoral responses were evident, and the response status of subjects as well as the magnitude of the immune response correlated with [overall survival],” the authors wrote.
The authors wrote that augmentation of the immune parameters investigated in this study provides rationale for larger studies investigating the clinical efficacy of novel immunomodulatory agents, and with more immunomodulatory agents available, they suggest that combination studies with sipuleucel-T should be explored.
Sheikh NA, Petrylak D, Kantoff PW, et al. Sipulecuel-T immune parameters correlate with survival: an analysis of the randomized phase 3 clinical trials in men with castration-resistant prostate cancer. [Published online ahead of print August 3, 2012]. Cancer Immunol Immunother
. 2012. DOI: 10.1007/s00262-012-1317-2.