Interdisciplinary critique of sipuleucel-T as immunotherapy in castration-resistant prostate cancer

Abstract

Sipuleucel-T was approved by the US Food and Drug Administration on April 29, 2010, as an immunotherapy for late-stage prostate cancer. To manufacture sipuleucel-T, mononuclear cells harvested from the patient are incubated with a recombinant prostatic acid phosphatase (PAP) antigen and reinfused. The manufacturer proposes that antigen-presenting cells exogenously activated by PAP induce endogenous T-cells to attack PAP-bearing prostate cancer cells. However, the lack of demonstrable tumor responses has prompted calls for scrutiny of the design of the trials in which sipuleucel-T demonstrated a 4-month survival benefit. Previously unpublished data from the sipuleucel-T trials show worse overall survival in older vs younger patients in the placebo groups, which have not been shown previously to be prognostic for survival in castration-resistant prostate cancer patients receiving chemotherapy. Because two-thirds of the cells harvested from placebo patients, but not from the sipuleucel-T arm, were frozen and not reinfused, a detrimental effect of this large repeated cell loss provides a potential alternative explanation for the survival "benefit." Patient safety depends on adequately addressing this alternative explanation for the trial results.

Figure 1

The manufacturing process and proposed mechanism for sipuleucel-T (3). A) The manufacturing process for sipuleucel-T is depicted. Mononuclear cells are harvested from the patient and shipped to the manufacturing facility (approximately 46% T cells, 7% B cells, 13% natural killer cells, and 25% monocytes) (4) on day 1. On days 2–3, cells are put through two buoyant density centrifugation steps before incubation for 36–48 hours with a chimeric antigen (PA2024), consisting of granulocyte-macrophage colony-stimulating factor (GM-CSF) to activate antigen presentation, which is linked to the prostatic acid phosphatase (PAP) tumor-associated antigen. Cells are given a final wash on days 3–4 before shipment back to the clinic for reinfusion into the patient. This process is repeated every 2 weeks for a complete course of three cycles. B) The proposed mechanism for sipuleucel-T antitumor activity is given. The manufacturer proposes that during incubation on days 2–3, antigen-presenting cells (APCs) process and present the synthetic antigen PA2024 on their surface, thereby becoming activated. Upon reinfusion, these cells are hypothesized to activate endogenous T-cells, thereby stimulating them to attack PAP-bearing prostate cancer cells.