Putting the Pieces Together: Completing the Mechanism of Action Jigsaw for Sipuleucel-T

Abstract

Sipuleucel-T is an autologous cellular immunotherapy that induces an immune response targeted against prostatic acid phosphatase (PAP) to treat asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer. In the phase III IMPACT study, sipuleucel-T was associated with a statistically significantly increased overall survival (OS) (median = 4.1 months) vs placebo. Patients with baseline prostate-specific antigen levels in the lowest quartile (≤22.1 ng/mL) exhibited a 13-month improvement in OS with sipuleucel-T. Together, this led sipuleucel-T to be approved and recommended as first-line therapy in various guidelines for treatment of metastatic castration-resistant prostate cancer. This review discusses the varied findings about the mechanisms of action of sipuleucel-T, bringing them together to form a more coherent picture. These pieces include inducing a statistically significant increase in antigen-presenting cell activation; inducing a peripheral immune response specific to the target (PAP) and/or immunizing (PA2024) antigens; stimulating systemic cytotoxic T-lymphocyte activity; and mediating antigen spread (ie, increased antibody responses to secondary proteins in addition to PAP and PA2024). Each of these pieces individually correlates with OS. Sipuleucel-T also traffics T cells to the prostate and is associated with long-term immune memory such that a second course of treatment induces an anamnestic immune response. Prostate cancer does not have a strongly inflamed microenvironment, thus its response to immune checkpoint inhibitors is limited. Because sipuleucel-T is able to traffic T cells to the tumor, it may be an ideal combination partner with immunotherapies including immune checkpoint inhibitors or with radiation therapy.

Figure 1.

Survival in men with mCRPC who received sipuleucel-T in the IMPACT study, stratified by above and below the median cumulative APC activation after treatment. Cumulative APC activation value (hazard ratio = 0.76, 95% confidence interval = 0.58 to 0.99). This figure comes from figure 5, panel A of Sheikh et al. (11), which was distributed under the terms of the Creative Commons Attribution License that permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited. APC = antigen presenting cell; mCRPC = metastatic castration-resistant prostate cancer.

Figure 2.

The jigsaw puzzle of the mechanism of action of sipuleucel-T. APC = antigen presenting cell; CTL = cytotoxic T lymphocytes.