The immune system. Bone marrow. Thymus. Spleen. Bone marrow. NK cell. B-cell. T-cell. Basophil Neutrophil. Eosinophil. Myeloid progenitor

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1 The immune system Basophil Neutrophil Bone marrow Eosinophil Myeloid progenitor Dendritic cell Pluripotent Stem cell Lymphoid progenitor Platelets Bone marrow Thymus NK cell T-cell B-cell Spleen

2 Cancer and the immune system Secretion of suppressive cytokines Expression of negative regulators of T-cells Induction of T REG cells Downregulation of MHC molecules Expression of antigens with low immunogenicity

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4 Immunosurveillance: Clinical evidence 1) Inherited Immunodeficiency 2) Organ transplant recipients 3) Patients with auto-immune disorders 4) Second tumors in cancer patients 5) HIV infection

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6 Tumor associated antigens Newly acquired antigens Over-expression of self antigen or silent antigens Best target: proteins involved in cell transformation Self antigens: Problems of TCR representation and affinity

7 The T-cell and its T-cell receptor activation Antigen α β Variable region Constant region TCR Class I MHC molecule δ ε γ ε CD3 complex ζ ζ Proliferation T-cell Differentiation Production of cytokines APC

8 Immunosurveillance: Clinical evidences CML relapses treated with donor lymphocyte infusions (DLI) As early as ) Inherited Immunodeficiency 2) Organ transplant recipients 3) Patients with auto-immune disorders 4) Second tumors in cancer patients 5) HIV infection

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12 The activation of T-cells Adhesion molecules Co-stimulatory molecules (second signal) T-cell CD27 CD70 APC CD27 CD28 CD4/CD8 Stabilisation of the TCR complex/mhc molecule interaction Lck CD28 CTLA4 ZAP CD3 PD-1 TCR CD4/CD8 CD80/CD86 MHC molecule B7-H1 Inhibitory signals CTLA4 PD-1

13 Can cancers be treated by interfering with CTLA4 and/or PD-1 inhibitory signals on T cells? CTLA-4 antibody : Ipilimumab PD-1 antibodies: Nivolumab Lambrolizumab MPDL3280

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15 Immune System and the Potential for Intervention T cell therapy TIL, CAR, TCR APC Deple&on of Tregs CTL Vaccina&on T reg cell CD25+ CD4+ FoxP3 CTL IL-2 T cell MHC B7.1 APC Cytokine IL2 CTLA4 B7.1 IL-2 T cell CTLA4 B7.1 CD28 Interference with Regula&on CTLA4/ PD- 1

16 T cells recognize tumor cells, Tumor cells repress a T cell attack tumor cells T cells

17 T cells recognize tumor cells, Tumor cells repress a T cell attack tumor cells cytototoxic power targeting specificity T cells

18 T cells recognize tumor cells, Tumor cells repress a T cell attack tumor cell T cell unmanipulated T cell transfer DLI pts with relapsed hematologic malignancies after allo HSCT donor CTLs pts with viral infections and EBV lymphomas developing post-transplant autolog CTLs pts with melanoma, lymphoma, nasopharyngeal ca

19 T cell immunotherapy for cancer faces significant obstacles tumor cells T cells Passive immune evasion strategies e.g., failure in antigen processing & presentation Active immune evasion strategies e.g., immune repressive cytokines (TGF-β), chemokines attracting repressive T cells

20 Redirecting T cells towards tumor cells tumor cell T cell The aim: To give patient s immune cells specificity for targeting autologous tumor cells.

21 Gene transfer to enhance and simplify T cell therapy tumor cell T cell Engineered T cells

22 Gene transfer to enhance and simplify T cell therapy tumor cell T cell Engineered T cells Most tumor associated antigens are self-antigens with limited responsiveness: tolerance and anergy Isolated T cells will have low-avidity TCRs T cell receptor (TCR) chimeric antigen receptor (CAR)

23 T cells recognize antigen via TCR TCR α and β chains ε γ Cα Vα δ Cβ Vβ ε ζ ζ CD28 TCR/CD28 complex physiological

24 T cells can be specifically redirected TCR α and β chains ε γ Cα Vα δ Cβ Vβ ε ζ ζ Vα Vβ Cβ CD28 TCR/CD28 complex TCR physiological recombinant

25 T cells can be specifically redirected binding domain TCR α and β chains single-chain TCR scfv antibody ε γ Cα Vα δ Cβ Vβ ε ζ ζ Vα Vβ Cβ V α V β TCR V H V L scfv V H V L scfv CD28 ζ ζ CD28 ζ TCR/CD28 complex TCR chimeric antigen receptor (CAR) physiological recombinant

26 Enhancing Chimeric Antigen Receptors scfv scfv scfv scfv ζ CD28 ζ 4-1BB ζ OX40 ζ

27 Adoptive therapy with genetically engineered T cells: a hope to cure cancer ATTACK

28 What is the optimal cell to transfer? to ensure optimal persistence and function. Antigen-specific CD8+ clones from central memory T cells Naive T cell derived effector cells Expressing transgenic TCR Self-renewing, multipotent CD8+ memory stem cells generated by Wnt-beta-catenin signalling primate CMV model Berger et al., 2008 murine model Hinrichs et al., 2009 murine model Gattinoni et al., 2009 CD4 + and CD8 + T cells CD4 + T cells murine model Darcy et al., 2007 NY-ESO-1 specific clone Hunder et al., 2008 In melanoma pts Ex vivo expanded T cells IL-7 + IL-15 Kaneko et al., 2009 maintaining TCM phenotype and alloreactivity

29 What is the optimal cell to transfer?. long-term persistence achieved with suboptimal T cell subsets. gene-marked, donor-derived, EBV CTLs given to pts after HSCT persist beyond 9 yrs cells entered memory pool even though cells were predominantly effector memory type (Heslop et al., 2010)

30 How to transfer gene(s)? non-viral viral gene transfer in vivo ex vivo

31 The success of adoptive cell therapies The use of T-cells in combination with conditioning chemo-radiotherapy can generate durable clinical responses in up to 70% of patients Complete durable responses have been observed in several cases

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33 But all is not yet perfect.

34 Limitations of T-cell based therapy Existence of multiple mechanisms of tumour escape Limited knowledge of the factors influencing T-cell/tumour cell interactions Incomplete understanding of the biology of tumour-directed T-cells Suboptimal conditions to isolate and expand tumour-specific T-cells Little experience delivering ACT in non-melanoma tumours Limited number of centres able to deliver ACT

35 The ATTACK Project SIXTH FRAMEWORK PROGRAMME PRIORITY [1] CAR T cells being tested in phase I/II clinical trials Pre-conditoning chemotherapy Cell culture methodologies Modulating tumour target Pre-clinical research activity Improved receptors Improved cell culture conditions Combination approaches Cytokine therapies Safety

36 Deriving anti-tumour lymphocytes from subsets of T-cells How does the characteristics of the precursor population affects the functionality of tumour-directed T-cells? T N T CM T EM T EFF?? CCR7 + + CD62L + +

37 ATTACK2 EU Clinical Trial with NY-ESO-1-redirected T cells

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