Rush hour traffic: directing T cells to tumor.

Abstract

In 2010, the Food and Drug Administration approved sipuleucelT for the treatment of asymptomatic or minimally symptomatic castration-resistant metastatic prostate cancer based on demonstration of an improvement in overall survival in a randomized phase III clinical trial (1), one of three recent positive large controlled vaccine trials in a variety of human cancers that show that specific T cells can be elicited by vaccination (2,3). Sipuleucel-T is a patient-specific cellular product that is prepared by culturing autologous peripheral blood mononuclear cells ex vivo with a recombinant human fusion protein consisting of prostatic acid phosphatase (PAP) linked to granulocyte-macrophage colony stimulating factor (GM-CSF). The final infusion product is comprised of a mixture of cells, including antigen-presenting cells (APC), T cells, B cells, natural killer (NK) cells, and others. Although sipuleucel-T is categorized as autologous cellular immunotherapy, its postulated mechanism of action suggests that it is a form of therapeutic cancer vaccine. The PAP serves as the tumor-associated antigen and is likely taken up by APCs during the in vitro culture and processed and presented on their surface in the context of major histocompatibility complex molecules. GM-CSF presumably acts as an adjuvant to activate APCs to enhance antigen presentation to T cells. Following administration to the patients, the APCs expressing PAP-derived peptides induce PAP-specific T cells that in turn might exert antitumor effects. Indeed, T-cell proliferative and IFN-γ immune responses against the fusion protein, PAP-GM-CSF and PAP alone were observed in the peripheral blood in patients following sipuleucel-T administration (1). Antibody responses against PAP-GM-CSF and PAP alone were also observed. However, whether the induced T cells traffic to the tumor site, a prerequisite to achieve tumor eradication, is unknown. Understanding the effects in the tumor microenvironment is necessary to develop strategies to enhance the potency of sipuleucel-T. In this issue of the Journal, Fong and colleagues investigated this in an elegantly designed neoadjuvant trial in patients with localized prostate cancer scheduled to undergo radical prostatectomy (4). In this single-arm, open-label, multicenter phase II study, patients received the standard three doses of sipuleucel-T at twoweek intervals. Tumor biopsies were obtained at baseline and radical prostatectomy was performed two to three weeks after the final infusion of sipuleucel-T. The primary objective was to determine changes in immune cell infiltrates in the paired tumor tissues. In the 37 evaluable patients, the authors found a statistically significant increase in CD3+ T-cell infiltration at the tumor interface after sipuleucel-T compared with baseline biopsies. Further analysis showed that both CD4+Foxp3- effector T cells and CD8+ T cells were increased at the tumor interface but not NK cells. Although the investigators did not assess the function of the infiltrating T cells, analysis of peripheral blood T cells showed proliferative and IFN-γ responses against PAP-GM-CSF and/or PAP alone. Importantly, such changes in T cell infiltrates were not observed in the control group of 12 patients with localized prostate cancer that underwent radical prostatectomy but did not receive sipuleucel-T preoperatively. While a randomized trial would have been ideal, the patients selected for comparison were well matched for clinical risk criteria and thus, provided a good control. Comparing the tumor infiltrates between prostatectomy specimens and needle biopsies is also not ideal, but the absence of T cell infiltrates in the control group suggests that the observed changes in the treated group are because of sipuleucel-T.