Sipuleucel-T immune parameters correlate with survival: an analysis of the randomized phase 3 clinical trials in men with castration-resistant prostate cancer

Purpose

Sipuleucel-T, the first FDA-approved autologous cellular immunotherapy for treatment of advanced prostate cancer, is manufactured by activating peripheral blood mononuclear cells, including antigen presenting cells (APCs), with a fusion protein containing prostatic acid phosphatase. Analysis of data from three phase 3 trials was performed to immunologically characterize this therapy during the course of the three doses, and to relate the immunological responses to overall survival (OS).

Methods

Sipuleucel-T product characteristics [APC numbers, APC activation (CD54 upregulation), and total nucleated cell (TNC) numbers] were assessed in three randomized, controlled phase 3 studies (N = 737). Antigen-specific cellular and humoral responses were assessed in a subset of subjects. The relationships between these parameters and OS were assessed.

Results

APC activation occurred in the first dose preparation [6.2-fold, (4.65, 7.70); median (25th, 75th percentile)] and increased in the second [10.6-fold (7.83, 13.65)] and third [10.5-fold (7.89, 13.65)] dose preparations. Cytokines and chemokines associated with activated APCs were produced during the manufacture of each dose; T-cell activation-associated cytokines were detected in the second and third dose preparations. Antigen-specific T cells were detectable after administration of the first sipuleucel-T dose. Cumulative APC activation, APC number, and TNC number correlated with OS (P < 0.05). Antigen-specific immune responses were observed in 78.8 % of monitored subjects and their presence correlated with OS (P = 0.003).

Conclusion

Sipuleucel-T broadly engages the immune system by activating APCs ex vivo and inducing long-lived immune responses in vivo. These data indicate antigen-specific immune activation as a mechanism by which sipuleucel-T prolongs OS.     

Loose ends: axenic culture,parasitophorous vacuoles,bird malaria

The successful extracellular cultivation of the erythrocytic stages of Plasmodium falciparum is briefly summarized, with a discussion of its implications. This leads to consideration of the roles of the parasitophorous vacuole and its membrane and of the tubulo vesicular network. It is concluded that these structures are mainly concerned with modification of the host erythrocyte for the benefit of the parasite. Requirements for additional nutritional factors under axenic culture conditions are also considered with special reference to erythrocyte membrane protein and to pantothenate. Finally, attention is given to speculations on the origin of P. falciparum.     

Evolution of Galapagos Island Lava Lizards (Iguania: Tropiduridae: Microlophus)

Nucleotide sequences of mitochondrial genes (ND1, ND2, COI, and tRNAs) were determined for 38 samples representing 15 taxa of tropidurid lizards from the Galapagos Islands and mainland South America. Phylogenetically informative characters (759 of 1,956) were analyzed under Bayesian, maximum likelihood, and parsimony frameworks. This study supports the hypothesis that tropidurid lizards dispersed to the Galapagos on at least two separate occasions. One dispersal event involved an eastern Galapagos clade (Microlophus habelii and M. bivittatus, on Marchena and San Cristobal islands, respectively) the sister taxon of which is M. occipitalis from coastal Ecuador and Peru; the closest mainland relative of the western Galapagos clade was not unambiguously identified. The wide-ranging M. albemarlensis is revealed to be a complex of weakly divergent lineages that is paraphyletic with respect to the insular species M. duncanensis, M. grayii, and M. pacificus.     

Plasmodium falciparum: merozoite invasion in vitro in the presence of chloroquine.

The fine structure of invasion of human erythrocytes by merozoites of the malaria parasite Plasmodium falciparum was observed in vitro. The invasion process is similar to that described for P. knowlesi. Merozoites enter apical end first by invagination of the erythrocyte membrane. At the rim of the invagination, where merozoite and erythrocyte are in closest contact, the erythrocyte membrane is thickened. The brushy cell coat of the P. falciparum merozoite appears to be lost at this attachment zone. The part of the merozoite within the erythrocyte invagination has no visible coat. The coat on the portion outside is unaltered. Merozoites can successfully invade erythrocytes after 3 hr in the presence of a concentration of chloroquine harmful to feeding stages.     

Electron microscopic study of the localization of adenylate cyclase in the small intestinal epithelial cells of rabbits with NAG-infections

As found, in NAG-infection primary intensification of adenylate cyclase activity occurred at the apical plasmalemma of the villar cells; then the process spread to the lateral and further to the basal plasmalemma of the enterocytes. At more advanced stages of NAG-infection an increased adenylate cyclase activity was observed in the crypt cells. Thus, with increased duration of the toxin action there was a gradual rise of the enzyme activity, and the epithelial cells of the small intestine in the area of local affection become involved in the pathological process.