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Cancer Cell Antigens: Mutations Aberrant expression of developmental proteins Tissue differentiation proteins Stem cell ‘drivers’

T-cells ‘find tumor’, kill cells or secrete cytokines to create anti-tumor inflammatory response

Professional antigen presenting cells: Dendritic cells (DC)

DC process proteins to peptides Presentation of antigen to T-cells

T-cell activation, proliferation

Blocking CTLA-4 Ligation Augments Immune Responses 1. Co-stimulation via CD28

ligation transduces T cell activating signals

2. CTLA-4 ligation on activated

T cells down-regulates T cell responses

T cell Activation

3. Blocking CTLA-4 ligation

enhances T cell responses

T cell Inactivation T cell Activation

T cell

T cell

T cell

CTLA-4

CTLA-4 TCR MHC

TCR CD28 B7

APC

MHC

CTLA-4

TCR MHC

CD28

CD28 B7

B7

APC

APC

Anti-CTLA4 mAb (ipilimumab, tremelimumab)

Clinical Activity of Nivolumab (anti-PD-1) (Phase 1 Multi-Dose Trial) ORR % (n/N)

Estimated Median DOR Weeks (Range)

Stable Disease Rate ≥24 Wks % (n/N)

Median PFS Months (95% CI)

NSCLC

17 (22/129)

74 (6+, 134+)

10 (13/129)

2 (2, 4)

MELa

31 (33/107)

104 (18, 117+)

7 (7/107)

4 (13, 44)

RCCa

29 (10/34)

56 (37, 127+)

27 (9/34)

7 (4, 13)

Dose mg/kg

CI = confidence interval; DOR = duration of response; NE = not estimable; ORR = objective response rate; OS = overall survival; PFS = progression-free survival a1 CR was noted in MEL and 1 CR was noted in RCC.

•  30/65 (46%) responses were evident at first tumor evaluation (8 weeks) •  42/65 (65%) responses were ongoing >1 year •  No OR in CRPC or CRC

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