1. Basic Immunology of the Mouse (and Human) Nicholas P. Restifo, MD October 19, 2015

2. Life started on earth about 3.5 billion years ago: mammals are a ‘recent’ development

3. Meet your great, great ~50M -grandfather

4. Figure 8-1

5. Schematic Diagram Of The CD8 and CD4 Coreceptors

6. How T cell receptors, peptides and MHC molecules fit together

7. Schematic map of the human and mouse MHC superloci

8. Nomenclature of major histocompatibility complex (MHC) Mouse Human KbKb Location (locus) Strain designation

9. Naming MHC molecules is easy All MHC molecules in this C57BL/6 mouse are called b All MHC molecules in this BALB/c mouse are called d

10. CD8 + T cell CD4 + T cell Tumor cell Antigen Presenting Cell Tumor Antigen What do T cells “see?”

11. T-cell recognition of antigens is MHC restricted

12. Figure 3-22

13. Pathways of antigen processing and presentation

14. TCR-peptide-MHC Crystal Structure

15. Figure 4-11 The germline organization of the human T-cell receptor  and β loci

16. The numbers of human T-cell receptor gene segments and the sources of T-cell receptor diversity compared with those of immunoglobulins

17. Adoptive cell transfer (ACT) in mouse and man Tumor is established time Ablate host immune system Adoptively transfer T cells Add vaccine and cytokine support Tumor regression?

18. ‘TIL’-based adoptive immunotherapy t t T Infusion of tumour- specific T cells into patient T Fragmentation of tumour mass t Activation and selection of T cells T cell growth factors (such as IL-2) T cell growth factors (such as IL-2) Add T cell growth factors (such as IL-2) t Chemotherapy +/- irradiation Restifo, NP, et al, Nat Rev Immunol, April, 2012 Expansion of tumour- specific T cell populations T

21. Survival of patients with metastatic melanoma treated with adoptive cell transfer therapy and IL-2 93 patients treated with adoptive transfer of TIL: 9/13/2000-8/30/2009 Dudley, J Clin Oncol, 2008; Rosenberg, Clin Cancer Res, 2011. Median follow-up time 79 months (n=93)