Abstract 5509: Evidence of T lymphocyte activation following sipuleucel-T treatment
Authors: Wesley Johnna , Kuan Ling-Yu , Chadwick Eric , Perdue Nikole , dela Rosa Corazon , Frohlich Mark , Urdal David , Sheikh Nadeem 
Published: June 2012

Introduction: Sipuleucel-T is an autologous cellular immunotherapy FDA approved for men with asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer (mCRPC). Previous clinical data from Phase 3 clinical trials demonstrated T lymphocyte activation occurred in response to culture with the immunizing antigen, PA2024, in vitro, and was maintained in vivo after infusion with sipuleucel-T. Data from a current clinical study (ProACT) examined the activation profile of T lymphocytes and the production of cytokines associated with activated T lymphocytes during the preparation of sipuleucel-T.

Materials and Methods: Sipuleucel-T is manufactured from peripheral blood mononuclear cells (PBMCs) isolated every two weeks by leukapheresis. The PBMCs are cultured for a defined period with the PA2024 antigen, which is composed of prostatic acid phosphatase (PAP) fused to granulocyte macrophage-colony stimulating factor (GM-CSF), washed, and then infused into the patient as sipuleucel-T, with each patient receiving three infusions. T lymphocyte activation markers, CD134 (OX 40), CD137 (4-1BB), CD278 (ICOS), and CD279 (PD-1) were measured before and after culture at weeks 0 (infusion1), 2 (infusion 2) and 4 (infusion 3) using multi-color flow cytometry. Cytokines, including IFNγ, IL-4, IL-5, IL-2, and IP-10, were measured in the culture medium at each of the three treatments using the MSD cytokine detection system.

Summary: In both CD4+ and CD8+ T cell subsets, we observed increases in the percent of CD134+ and CD137+ cells, but minimal change in CD278+ population, following culture with PA2024 at each infusion of sipuleucel-T. The percent of CD8+CD279+ T lymphocytes increased slightly following culture at each infusion of sipuleucel-T; CD4+CD279+ T lymphocytes increased minimally after the first infusion, but decreased thereafter. Additionally, cytokines associated with T lymphocyte activation, such as IL-2, IL-4, IL-5, IFNγ, and IP-10, were detected during culture with PA2024, with the greatest increase between the first and second infusion.Conclusions: Collectively, these data demonstrate T lymphocyte activation is a consequence of ex vivo culture with PA2024 and subsequent infusion of sipuleucel-T. The combined T lymphocyte activation and cytokine profile suggest the first infusion of sipuleucel-T primes the immune system in vivo, while the subsequent infusions boost the immune system. Furthermore, during the course of treatment with sipuleucel-T, the upregulation of activation markers demonstrate the functional differentiation of T lymphocytes for facilitating antibody production (OX 40 expression) and enhancement of costimulatory interactions with peripheral monocytes (4-1BB expression).

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5509. doi:10.1158/1538-7445.AM2011-5509