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Molecularly defined vaccines! and clinical immunotherapies! Daniel Speiser, Ludwig Institute for Cancer Research 1. Cancer cells : they are the origin of cancer, but… 2. Hallmarks of cancer <ssue, cancer microenvironment 3. Cancer and inflamma<on: The immune contexture in tumor <ssue 4. Immunotherapy of cancer Cellular components of tumors Cancer ºB tissue ºT Stromal cells Cancer cells Endothelial cells *Monocytes *DC *NK *Granulocytes * innate immune cells º specific immune cells Melanoma microenvironment The Hallmarks of Cancer Hanahan / Weinberg, Cell 2000 Figure 1. Acquired Capabilities of Cancer. It is suggested that most if not all cancers have acquired the same set of functional capabilities during their development, albeit through various mechanistic strategies. The Hallmarks of Cancer -‐ the next genera<on, Cell 2011 Fridman et al, Nat Rev Cancer 2012 12:298 Fridman et al, Nat Rev Cancer 2012 12:298 Fridman et al, Nat Rev Cancer 2012 12:298 Fridman et al, Nat Rev Cancer 2012 12:298 Fridman et al, Nat Rev Cancer 2012 12:298 T cell / tumor cell interaction Tight interaction of the T cell (left) with the large tumor cell (right) Tumor cell lysis A lethal whole in the tumor cell (bottom), punched by the T cell (top) already detached and on its way to other tumor cells The three main stumbling blocks for anti-cancer T cells Trends in Immunology, March 2012 Multiple inhibitory receptors of T cells Cell intrinsic mechanisms of T-cell inhibition and application to cancer therapy Peggs / Quezada / Allison, Immunol Reviews 2008 224:141 Immunotherapy for melanoma patients Immunotherapy without or with antigen ? Innate immune system Specific immune system antigen important, endogenous antigen sufficient ? Iden<fica<on of op<mal innate immune s<mulators (adjuvants) for B-‐cell vaccines to induce protec<on from bacteria and parasites T-‐cell vaccines to induce protec<on from viruses and tumors T cell priming is highly selective lymph follicule metastasis ? DC T :-) DC T in vitro culture DC T Efficient human CD8 T cell responses induced by life vaccines Human effector and memory CD8 T cell responses to smallpox and yellow fever vaccines Miller, Ahmed et al., Immunity 28: 710 (2008) Complete T cell differentiation to memory and effector cells requires strong activation (incl. strong clonotypic bursts) during priming Yellow fever vaccine induces integrated multilineage and polyfunctional immune responses. JEM 2008, Vol. 205 No. 13. 3119-3131 Denis Gaucher / Rafick-Pierre Sékaly et al. Figure 9. Consensus transcriptional network of genes differentially expressed on day 7 as compared with day 0. Network representation of inferred transcription factors and predicted target genes that are consistently modulated in at least two out of three datasets, with the third dataset not being contradictory. Modular immune in vitro construct system [MIMIC]. CD8 T cell differentiation T EM -> T CM appears to be exceptional Zanetti, Franchini, Trends Immunol Nov 2006 27:511 Fearon et al, Immunol Rev 2006 For vaccination, mimic viruses ! e.g. for vaccine size Bachmann / Jennings, NatRevImmunol Oct 2010 T cell mediated protection • • • antigen-specific CD8 and CD4 T cells T cell differentiation stages (CM…) T cell epitope(s) T cell subsets defined by differential function, avidity, and specificity (to one epitope / to different epitopes) Essential vaccine components AA Antigen Antigen Adjuvant Innate immune stimulator AID Delivery system Choice of antigens for cancer vaccines Targeting of multiple tumor-antigens, restricted by different HLA-A,-B,-C (class I) alleles, and different HLA-DR,-DQ,-DP (class II) alleles Shared antigens, and/or mutated antigens Model antigen(s): to assess the immune response (biological readout) to induce at least 1-2 strong T cell population(s), supporting the overall immune response with consequent bystander activation Adjuvants for Cancer Vaccines Dubensky & Reed, Seminars in Immunology 2010 22:155 Capacity of cancer vaccines to mobilize human tumor antigen specific CD8 T cells Data from validated comparative studies % of circulating CD8+ T cells • Peptide or protein alone, tumor cells < 0.01 • Recombinant viruses, DNA < 0.01 • Peptide + adjuvants (except IFA) < 0.1 • Peptide + IFA (Incomplete Freund s Adjuvant) ~ 0.1 • Dendritic cells + peptide ~ 0.1 • Peptide + IFA + CpG oligonucleotides ~ 1 Higher peptide doses è higher %ages ? Novel formulations / combinations (e.g. antigens targeted to DC, triggers for other TLRs, etc.)