Immunotherapy at UCL/UCLH Karl Peggs Professor of Transplant - - PowerPoint PPT Presentation

Immunotherapy at UCL/UCLH

Karl Peggs

Professor of Transplant Science and Cancer Immunotherapy Scientific Director NIHR BTRU for Stem Cell Transplantation and Immunotherapy

This is your immune system. It is vigilant on one end of a very complex balance. On the other end is your body, suspended over a sea of bacteria and viruses. If the immune system is too weak, your body becomes susceptible to infection.

The opposite isn’t so great either

An introduction to the immune system

The same is true of cancer, which suppresses immunity via a number of mechanisms. Immunotherapy aims to strengthen the ability of the immune system to fight cancer.

Innate Immunity

(rapid response)

Adaptive Immunity

(slow response, memory)

Macrophage Mast cell γδ T cell NKT cell NK cell Basophil Complement protein Eosinophil Granulocytes Neutrophil B cell Antibodies T cell CD4+ cell CD8+ cell DCs

Innate immune system: involves proteins (chemokines and cytokines)

and cells, is considered to be the first line of immune defense

Adaptive immune system: mediated by B and T cells, is highly specific

and capable of generating an antigen-specific response

– Induction requires presentation of antigens by cells of the innate immune system

Antibodies as immunotherapies – original thinking

Antibodies – payload delivery

5 1 2 3 4

Antibody targets cell surface protein Binding and internalization MMAE release: after internalization MMAE is released into the target cells Microtubule disruption: binding of MMAE disrupts the microtubule network Cell death: if microtubule disruption occurs, apoptotic cell death results

1 2 3 4 5 1 2 3 4 5

Antibodies - Immune Checkpoints

APC/ Tumour T cell PD-1

B7-1 (CD80) PD-L1 PD-L2 CD40 CD40L CD137 OX40 CD137L OX40L LAG-3 MHC CD28 Activation B7-2 (CD86) B7-1 (CD80) CTLA-4 Inhibition TCR Inhibition Inhibition Activation Activation Activation Inhibition

Blocking antibodies targeting co-inhibitory receptors Agonistic antibodies targeting co- stimulatory receptors

T cells and Tumour Control

T cells for relapsed disease after BMT

Nov 06 - Feb 08 Jan 03 - Aug 04

Chimeric antigen receptors (CARs)

CD19 CAR T cell trials:

• COBALT: 2nd generation CAR, bridge

to allograft in DLBCL

• D-CAR19: 2nd generation CAR, for

cancers relapsing post allograft

• UniCAR19: 2nd generation CAR, off

the shelf third party treatment

… paediatric ALL (CARPALL), adult ALL (i4i)

Delivery – a meeting of the minds

U C L C A N C E R I N S T I T U T E

UCLH – state of the art immunotherapy service

UCL/UCLH – delivering the spectrum of cancer immunotherapy