Evaluation of immune activation following neoadjuvant sipuleucel-T in subjects with localized prostate cancer.

Abstract

178 Background: Sipuleucel-T is an FDA-approved autologous cellular therapy that has been demonstrated to prolong overall survival in subjects with asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer (mCRPC). Methods: Subjects with localized prostate cancer were enrolled in an open-label, Phase 2 study (P07-1; NCT00715104 ) in which they received 3 infusions of sipuleucel-T at approximately 2-week intervals, beginning 6–7 weeks prior to radical prostatectomy. All samples were evaluated for cellular composition and antigen presenting cell (APC) activation pre- and post-culture with PA2024, a fusion protein comprising prostatic acid phosphatase and granulocyte macrophage-colony stimulating factor. Additionally, cytokines within the culture supernatant were assessed, and T and B cell activation were evaluated pre- and post-culture using flow cytometry. Results: Of the 42 enrolled subjects (median age: 61 years; 98% Caucasian), 38 received all 3 infusions of sipuleucel-T. Consistent with previous trials in mCRPC, CD54 upregulation (APC activation) was greater at the second and third infusions relative to the first. While the percent of CD4+ and CD8+ T cells was unchanged with treatment, the expression of early T cell activation markers (CD134, CD137, CD278 and CD279) was increased in pre-culture cells obtained after the first infusion, and further increased post-culture. Similarly, while the percent of B cells was unchanged, there was a progressive increase in memory B cells (CD20+CD27+IgD−CD86+; pre- and post-culture) and activated mature B cells (CD20+CD27+IgD+CD86+; post-culture) following the first infusion. Activated T cell-associated cytokines were significantly elevated (TNF-α, P < 0.001; IFN-γ, P < 0.001; and IL-2, P < 0.001) in the second and third products. Conclusions: Neoadjuvant sipuleucel-T resulted in robust immune system activation that included APCs, memory and activated mature B cells, and both CD4+ and CD8+ T cells. The patterns observed at the second and third infusions, relative to the first, are consistent with an immunological prime-boost profile.