Current immunization schemes do not induce potent CD8+ T cell cytotoxicity unless combined with viral boost regimes, which are not easily applicable in the human. We have recently shown that the chemokine receptor XCR1 is selectively expressed on antigen cross-presenting dendritic cells (DC), the key players in the induction of CD8+ T cell cytotoxicity in the mouse and the human.
Objective: Based on this fact, we have developed strategies to effectively induce CD8+ T cell cytotoxicity by in vivo targeting of protein or peptide antigens into these XCR1+ DC. To this end, either an antibody to XCR1 or the natural chemokine ligand were used as vectors, and applied together with suitable adjuvants (Hartung et al., J Immunol 194 (2015) 1069). More recently, we could further strongly amplify this (published) basic immunization scheme using a non-viral amplification system (ADAS), capable of raising the level of antigen-specific CD8+ T cells to around 20% of all T cells within few days (OVA or influenza NP as model antigens). Another level of amplification (up to 70% of all CD8+ T cells now being antigen-specific) could be achieved by additional administration of complexed IL-2. These expanded CD8+ T cells (activated, granzyme B- and perforin-positive), are biologically active in vivo in that they very efficiently eradicate established transplanted tumors. We have now extended our studies to other antigens and modes of amplification. Immunization of the CD8+ T cell compartment with the nucleoprotein (NP) of influenza, followed by the amplification steps described, fully protected mice from a 10xLD50 infection with the PR8 influenza strain. Further, we have observed that our immunization protocol induces CD8 memory T cells which could again be quickly re-amplified to around 50% of all CD8+ T cells using the ADAS procedure. In addition, we could observe that the amplification achieved by complexed IL-2 can also be obtained with complexed IL-15.
Summary: We have developed an in vivo immunization procedure which, within 12-14 days, induces massive antigen-specific CD8+ T cell cytotoxicity representing up to 50-70% of all CD8+ T cells in the body. We intend to develop this system into a highly specific therapy of immunogenic tumors. In a first step, we currently immunize Rhesus macaques with the GAG protein of simian immunodeficiency virus in order to test the efficacy and safety of the procedure in a non-human primate model.
Note:This abstract was not presented at the conference.
Citation Format: Yi Yang, Evelyn Hartung, Anika Jäkel, Stephanie Gurka, Hans W. Mages, Richard A. Kroczek. In vivo targeting of antigen into XCR1+ DC combined with a potent amplification regime induces massive antigen-specific CD8+ T cell cytotoxicity. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B123.
- ©2016 American Association for Cancer Research.