Sipuleucel-T (sip-T) is the only FDA-approved autologous cellular immunotherapy for metastatic castration-resistant prostate cancer (mCRPC). To elucidate parameters of the response profile to this therapy, we report high-dimensional analyses of sip-T using cytometry by time of flight (CyTOF) and show a lymphoid predominance, with CD3+ T cells constituting the highest proportion (median ~60%) of sip-T, followed by B cells, and natural killer (NK) and NKT cells. We hypothesized that treatment of sip-T with homeostatic cytokines known to activate/expand effector lymphocytes could augment efficacy against prostate tumors. Of the cytokines tested, IL-15 was the most effective at enhancing activation and proliferation of effector lymphocytes, as well as augmenting tumor cytotoxicity in vitro. Co-culture of sip-T with IL-15 and control or prostate-relevant antigens showed substantial activation and expansion of CD8+ T cells and NKT cells in an antigen-specific manner. Adoptive transfer of IL-15-treated sip-T into NSG mice resulted in more potent prostate tumor growth inhibition compared with control sip-T. Evaluation of tumor-infiltrating lymphocytes revealed a 2-14-fold higher influx of sip-T and a significant increase in IFN-γ producing CD8+ T cells and NKT cells within the tumor microenvironment (TME) in the IL-15 group. In conclusion, we put forward evidence that IL-15 treatment can enhance the functional antitumor immunity of sip-T, providing rationale for combining IL-15 or IL-15 agonists with sip-T to treat patients with mCRPC.
Cancer immunology research. 2024 Feb 26 [Epub ahead of print]
Muhammad A Saeed, Bo Peng, Kevin Kim, Kavita Rawat, Lindsey M Kuehm, Zoe R Siegel, Ariel Borkowski, Nabih Habib, Brian Van Tine, Nadeem Sheikh, Vu Tuyen, Daniel L J Thorek, Todd A Fehniger, Russell K Pachynski
Washington University in St. Louis School of Medicine, St. Louis, MO, United States., American University of Beirut, Beirut, Lebanon., Washington University in St. Louis, Saint Louis, MO, United States., Dendreon (United States), Seattle, WA, United States., Washington University in St. Louis School of Medicine, Saint Louis, MO, United States.