Vaccination with Regulatory T Cell Depletion

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DESCRIPTION (provided by applicant): Effective cancer immunotherapy has been a long sought goal because of the possibility that the immune system can be harnessed to precisely target tumor cells, leaving normal tissue intact. Activation, proliferation, and maintenance of high frequency antigen-specific T cells are essential for a successful cellular immune response against tumor. Although a number of cancer vaccines in development can activate detectable tumor antigen-specific cytolytic T cell responses, they have been of low magnitude and limited durability. Indeed, in a phase I study of an immunization platform based on dendritic cells (DC) modified with a pox vector to hyperexpress the tumor antigen CEA and a triad of costimulatory molecules (called DC-rF- CEA(6D)-TRICOM), potent activation of CEA specific T cell responses was observed; but, the frequency of CD4+ and CD8+ CEA-specific T cells peaked within 4 doses of the vaccine and did not increase thereafter and in some cases decreased. CD4+CD25+ regulatory T cells (Treg) have emerged as a likely cause of the limited activation of antigen-specific T cells because of their role in controlling auto-reactive T cells. The purpose of this proposal is to determine whether a greater magnitude of tumor antigen specific immune response can be achieved by eliminating regulatory T cells prior to administration of an anti-cancer vaccine. Eliminating regulatory T cells in vitro permits activation of a greater frequency of antigen-specific T cell responses. Treg may be depleted in vivo using a fusion molecule of IL-2 and a toxin (denileukin diftitox) which binds to cells via CD25 and delivers the lethal toxin. Therefore, a phase I clinical trial is proposed to explore the safety, feasibility, and clinical and immunologic activity of Treg depletion with denileukin diftitox prior to immunization with autologous DC modified with rF-CEA(6D)-TRICOM. The kinetics of the Treg depletion will be assessed. In addition, the magnitude of the CEA-specific T cell response will be measured. Preliminary data regarding clinical efficacy will be collected to plan for phase II studies. Future studies will assess whether the greater magnitude and durability of the CEA-specific immune responses will translate into a long-term clinical benefit.