the International Melanoma Working Group and is a referee for a - - PowerPoint PPT Presentation

Professor Mark Middleton Professor Mark Middleton is head of the University of Oxford Department of Oncology, the Director of the Cancer Research UK Oxford Centre and the Cancer Theme Leader of the Oxford NIHR Biomedical Research Centre. He is clinically active as an Honorary Consultant in Medical Oncology at the Oxford University Hospitals NHS Trust and has had a long career in the study and treatment of cancer. Mark spent six years as the Lead Cancer Clinician at OUH NHS Trust and has also served as the Vice-chair of the Cancer Research UK Experimental Medicine Expert Review Panel. He is a founding member of the International Melanoma Working Group and is a referee for a number of journals, including the Lancet, Cancer Research and the Journal of Clinical Oncology.

Using Research to Achieve Excellence

Mark Middleton

Department of Oncology, University of Oxford

Disclosures

• I have acted or act as a consultant for Amgen, Array, AstraZeneca,

BiolineRx, Bristol-Myers Squibb, Eisai, GlaxoSmithKline, Immunocore, Lilly, Merck, Millennium, Novartis, Physiomics, Rigontec, and Roche

• My institution has received research grants on my behalf from Abbvie,

Amgen, AstraZeneca, Bristol-Myers Squibb, Celleron, Clovis, Eisai, GlaxoSmithKline, Immunocore, Merck, Millennium, Novartis, Pfizer, Regeneron, Replimune, Rigontec, Roche, and Vertex

It’s a side show Not rooted in ‘real’ practice Time consuming Takes advantage of vulnerable patients Expensive

Does research matter?

There must be a better… Of course research matters

WAY EXPLANATION TREATMENT

Why?

Protocols Training Quality Assurance Innovation Time Money

Why research matters

Mutational Burden in Human Cancers

Immunotherapy is changing cancer treatment

Coley’s toxins Cytokines Vaccines/Antigens Monoclonal Antibodies Cellular therapies

Built on one hundred years of failure…

2010 – Ipilimumab improves overall survival in melanoma

Immune-related side effects

Skin - 50% Rash/Pruritis Vitiligo Lichen planus Gut – 30-40% Diarrhoea Colitis/enteritis Intestinal perforation Kidney - 1% Nephritis Endocrine - 8% Hypophysitis Hypo/Hyperthyroidism Adrenal insufficiency Diabetes Liver/Pancreas - 10% Hepatitis Pancreatitis Neurological Meningoencephalitis Guillaun Barre Syndrome Eyes Uveitis Conjunctivitis Cardio-respiratory Pneumonitis Myocarditis Sarcoidosis Haematological Cytopenias Clotting disorders

Abdel-Wahab N et al. (2016) PLOS One 11: e0160221 Vesalius A (1543) De humani corporis fabrica libri septum

Centralised, hospital based, hub and spoke Focus on cytotoxic chemotherapy Staffing, skillmix, training reflect this Non-oncologists only peripherally aware of immunotherapy

Current Configuration of Oncology Services

So why does this all matter?

What is the model for immunotherapy delivery? How do we manage toxicity? How do we afford it? How do we improve it?

Integrating Immunotherapy Into The NHS

The Research Doesn’t Stop

What determines sensitivity to immunotherapy?

Blank, et al Science 2016

Few biomarkers of response or efficacy

• PD-L1 and response to immunotherapy in melanoma

10 20 30 40 50 60 Response rate % 49 13

p=0.0007

PD-L1 + PD-L1 -

Pembro Daud, AACR 2014 (PD-L1 > 1%)

66 33

p=0.004 Nivolumab Weber, JCO 2013 (PD-L1 > 5%)

57 35

Nivo + Ipi Kluger, ESMO 2014 (PD-L1 > 5%)

72 55

Nivo + Ipi Wolchok, ASCO 2015 (PD-L1 > 5%)

Few biomarkers of response or efficacy

• Tumour Mutation Burden

What determines sensitivity to immunotherapy?

Hugo, et al Cell 2016

Where next?

Adapted from Ribas and Blank, ESMO 2014

Adoptive cell transfer immunotherapy

IL-2, IFN IL-15, IL-21 Peptide vaccine DC vaccine Genetic vaccine OX40 CD137 CD40 PD-1 CTLA4 T cell cloning TIL therapy TCR and CAR T cell therapy T cell checkpoint blocking and stimulating antibodies

LAG-3

TIM-3

Active immunotherapy

Soluble TCR

Intra-tumoral immunotherapy

Alpha-gal agonists RIG-I antagonism Oncolytic virotherapy

Novel immune therapies

• Oncolytic viruses
• ImmTACs
• Immune modulators (e.g. IDO inhibitors)
• Activators of innate immunity
• Cell therapies

Dissecting cancer immunotherapy

Cancer mutanome Inflammatory environment Adaptive immunity

Better immunotherapy

• Novel agents tested in potentially curable cancer patients
• Acquisition and detailed analysis of tumour and normal tissue
• Link to potential surrogate tissue markers
• Understand the biological effects of dosing
• Ability to explain clinical results in other studies

Excellent immunotherapy

• Acknowledge limitations
• Understand who benefits
• Learn from failure
• Integrate with existing modalities

Research Delivers Excellence

• A capable, inquisitive workforce
• Focus on compliance
• Protocol driven
• Quality assured
• Never satisfied with the standard of care

Acknowledgements

Oncology (Sandie Wellman, Nikki Hayward, Kath Room, Emma Johnstone, Sophie Reynolds, Nick Coupe, Victoria Woodcock, Miranda Payne) Pathology (Ruth Asher, Olivia Espinosa) Plastic Surgery (Oliver Cassell, Matt Potter, Andy Pay, Jeremy Birch,) Ludwig Institute (Colin Goding, Richard Lisle, Xin Lu) WIMM (Enzo Cerundolo, Giorgio Napolitano, Ben Fairfax) CyTOF (David Ahern) OCTO (Linda Collins, Sarah Pearson, Naomi Macgregor, Jen Houlden) Molecular Diagnostics Centre (Anna Schuh)