Donor lymphocyte infusions from Ad-sig-TAA/ecdCD40L vector prime-TAA/ecdCD40L protein boost (VPP) vaccinated allodonors decrease tumor cell growth post allograft

3071 Background: Individuals of advanced chronological age exhibit an impaired immune response to vaccines. This may be due to a reduction in the ratio of antigen naïve/memory CD4 and CD8 T cells and acquisition of functional defects in activated “helper” CD4 T cells (eg diminished CD40 ligand (CD40L) expression) during the aging process. Methods: In order to circumvent this defective response to vaccines in individuals in the fifth and sixth decades of life, our laboratory has developed an adenoviral vector (Ad-sig- TAA/ecdCD40L) vaccine which is designed for the in vivo target associated antigen (TAA) loading and activation of dendritic cells (DCs), and to overcome the absence of CD40L expression in activated CD4 helper T cells in older individuals. Results: The subcutaneous (sc) injection of this vector leads to the release of a fusion protein composed of a TAA linked to the extracellular domain (ecd) of the CD40 ligand (CD40L), which binds to the CD40 receptor on DCs, activates the DCs, and leads to the presentation of TAA fragments on Class I MHC. Two sc injections of the TAA/ecdCD40L protein as a booster following the sc administration of the Ad-sig-TAA/ecdCD40L vector (VPP) expands the magnitude of the cellular and humoral immune response induced by the vector in 18 month old aged mice as well as in younger mice. This vaccine decreased levels of negative regulatory CD4 FOXP3 T cells in tumor nodules. We administered TBI and an allogeneic stem cell transplant 7 days post sc injection of the E7 positive TC-1 cells. DLI from an Ad-sig-E7/ecdCD40L vector prime-E7/ecdCD40L protein boost vaccinated donor were injected iv 3 days post transplant, and a single E7/ecdCD40L protein boost sc vaccination one week thereafter. We found that the growth rate of the E7 positive TC-1 tumor cells post allograft was less in the vaccinated than in the control (injection of tumor cells followed in 7 days by TBI), or the animals in which the allograft recipient was vaccinated without DLI. Conclusions: Thus, the use of DLI from VPP vaccinated allodonors decreased tumor cell growth post allograft. No significant financial relationships to disclose.