Question 9 - Cancer immunotherapies

Intro

immune system capable making immune reponse against tumours

lacks strenth and persistance

tumours evade detection (MHC downregulation)

tumour microenvironment induce T cell anergy

5 immunotherapies

1. Monoclonal antibodies

2. Checkpoint Inhibitors

3. Adaptive Cell transfer

4. Chimetic antigen receptor T cells

5. Cancer vaccine (dendritic cell therapy)

Monoclonal ANtibodies naked antibodies

humanised antibodies to red tumour growth

Rituximab - binds CD20 on B cell lymphomas - opsonisation, destruction NK cells via antibody dependent cell mediated cytotoxicity

trastuzumab - inhibit signalling receptors essential tumour growth

Monoclonal conjugated antibodies

‘armed’ antibodies

brentuximab-vedotin - delivers toxin (auristatin) to CD30 espressing lymphoma cells

90Y- labelled ibritumomab targets radioactive isotopes tomtumour cells to damage DNA

Examples from monoclonal

rituximab - CD20/ADCC

trastuzumab - signalling receptors

brentuximab-vedotin - CD30

90Y- labelled ibritumomab - isotopes

checkpoint inhibitors

remove brakes normally restrain T cell response

anti-CTLA-4

anti-PD-1

anti-CTLA-4

CTLA-4 outcompetes co stimulatory receptor CD28 for B7 binding on APC, send inhibitory signals

Ipilimumab blocks interaction = persistant T cell activationan

ti-PD-1/PD-L1

PD-1 on T cells and PD-L1 on tumour cells induces epigenetic program of exhaustion

Nivolumab - restore T cell effector function

Checkpoint inhibitor side effect

stronger immune response generate → iatrogenic autoimmunity

checkpoint inhibitors examples

ipilimumab

nivolumab

iatrogenic autoimmunity

Adaptive cel transfer

expanding pateints own immune cells ex vivo

T cells isolated from excised tumour fragements (TIL)

cultured with IL-2 to induce massive prolifration

patients lymphodepletion then T cell reinfused

what’s TIL

Tumour Infililtrating Lymphocytes

what’s lymphodepeletion

immunosuppressive drugs - cyclohosphamide/fludarabine

sig improve remission rates

Chimeric Antigen Receptor t cells

genetically mod T cells express engineered receptor with high affinity for spec. tumout antigen

CAR T recognise antigen independent of MHC

Modern CAR signalling

include signalling domains from zeta chain, CD28, CD137 = capacity > normal T cells for killing tumour cells

CAR T /= anergic

CAR T side effects

strong systemic inflammatory response: cytokine release syndrome - could be fatal

Cancer vaccines

dendritic cell therapy

sipuleucel-T therapy for prostate cancer

monocytes matured to dendritic cells in vivo when pulsed with fusion protein

reinfused, active DC travel spleen present tumour antigens to naive T cells