1. Clinician-led Workshop MEDM5121M Immunity and Disease Alan Melcher a.a.melcher@leeds.ac.uk

2. Overview How knowledge of the immune system helps treat cancer. Workshop – please interrupt and discuss! Here focus on clinical aspects and 2 examples of current immunotherapy. This is an exciting time for cancer immunotherapy!

3. Showing the benefit of new treatments for cancer – the classical approach Phase 1 trials – toxicity. Phase 2 trials – looking for a signal. Phase 3 trials – comparison with current treatment. How appropriate is this for immunotherapy?

4. Showing the benefit of new treatments for cancer – Phase 1 Dose escalation, often in groups of 3. Few patients only. Looking for ‘dose-limiting toxicity’. May not be seen in immunotherapy. Relies on concept that more is better - ? true for immunotherapy. All about setting a dose to take forward to Phase 2. Tends to be in patients with advanced cancer, whose immune system is already compromised – is this the best group to treat?

5. Showing the benefit of new treatments for cancer – Phase 2 Taking forward the dose from Phase 1. Everybody gets the treatment – tens of patients. Looking for a signal eg tumour shrinkage on scans – RECIST (response evaluation criteria in solid tumours). Complete response, partial response, stable disease, progressive disease. But this may not apply to immunotherapy. So need to adjust trials accordingly, including use of immune-related response criteria (irRC).

6. Showing the benefit of new treatments for cancer – irRC New lesions do not constitute disease progression if net tumor burden (including new lesions) is stable or decreases. Permits disease progression prior to response. Introduces the concept of confirmation of progression at a subsequent timepoint after first detection - accounts for the period required for activated T-cells to infiltrate the tumor, which may cause initial tumor volume increase but can subsequently translate into tumor shrinkage. Biopsy of residual masses may show no active tumour. Also classifies durable stable disease as clinical activity.

7. Showing the benefit of new treatments for cancer – adjustments for immunotherapy Trial design as well as readouts has to be different. Carry on treating after initial tumour ‘growth’ on scans. We do see patients feeling better while their scans are getting worse. Avoid expecting too much in patients with very advanced cancer. Be careful about combination treatments and sequencing eg chemotherapy can cause immunosuppression, avoid patients having steroids with immunotherapy.

8. Showing the benefit of new treatments for cancer – Phase 3 Comparison of new treatment with current standard of care. Patients are randomised between different treatments. May include placebo, ‘double-blind’. Hundreds of patients. Variety of readouts eg progression-free survival, but gold standard is overall survival. Can take many years to complete/report. Phase 3 trials are what lead to changes in practise.

9. Showing the benefit of new treatments for cancer – types of treatment Radical treatment: Aim is cure. High toxicity may be acceptable. Palliative treatment: Non-curative. Importance of quality as well as quantity of life. Balance between benefit and toxicity can be difficult.

10. Showing the benefit of new treatments for cancer – timings of treatment Melanoma: Only curative treatment is surgery. Immunotherapy first tested once disease has spread and is incurable. But treatment can also be: ‘Adjuvant’ – after surgery, to reduce the risk of the cancer coming back eg IFN in melanoma. ‘Neoadjuvant’ – given before surgery, to reduce risk of recurrence. May be ideal for immunotherapy, as need an antigen load on board to prime immune response.

11. Current clinical immunotherapy in practise - examples

12. Mechanism of anti-CTLA-4 on T-Cell Responses Costimulation via CD28 ligation transduces T-cell activating signals CTLA-4 ligation on activated T cells downregulates T-cell responses Blocking CTLA-4 ligation enhances T-cell responses T-Cell InactivationT-Cell Activation APC B7 MHC CD28 TCR CTLA-4 T cell Anti-CTLA4 mAb

13. Immunoregulatory Ab in melanoma- anti-CTLA4 Enhances T cell activation Ipilimumab/ Tremelimimab (dropped) –Autoimmune toxicity in 40%: colitis, hypophysitis, hepatitis –RR approx15%, including some CRs –Late responses, CR at 1yr in one patient with progression at 3 months Ph3 of ipilimumab as melanoma adjuvant – ongoing. Ph3 study in advanced melanoma – 2 positive trials. Approved by FDA 2011. Now used as standard of care in melanoma.

14. First-line ipilimumab Phase 3 trial of DTIC + ipilimumab/placebo: 502 patients randomised A: Overall survival B: Progression-free survival C: Duration of objective response (NB number of patients) Survival rates in the ipilimumab-DTIC group vs. DTIC-placebo: At 1 year: 47.3% vs. 36.3%; At 2 years: 28.5% vs. 17.9%; At 3 years: 20.8% vs. 12.2% (hazard ratio for death, 0.72; p<0.001) Robert et al, NEJM 2011

15. Anti-PD1 PD-1 is inhibitory receptor on T cells PD-L1 widely expressed – expression on tumour cells correlates with poor prognosis in lung, kidney, pancreas and ovary tumours –PD-L1 limits anti-tumour immune responses Anti-PD1 and anti-PD-L1 antibodies show considerable promise in early trials Being tested in cancers other than melanoma.

16. ANTI-PD1 Recent trials suggest anti-PD1 is less toxic and more effective than anti-CTLA4 Things changing very quickly with little scientific understanding!

17. ANTI-PD1

18. ANTI-CTLA4 PLUS ANTI-PD1

19. ANTI-CTLA4 PLUS ANTI-PD1

20. Oncolytic viruses Naturally occurring, or genetically modified viruses designed to directly target and kill tumour cells. Also work by acting as a danger signal to activate anti-tumour immunity. Have reached Phase III. Reovirus. Herpes simplex virus. Phase III intratumoural injection in melanoma positive trial. Agent bought by Amgen for 1 billion dollars. Trial was positive for primary endpoint of ‘durable response rate’, but p value for overall survival was p=0.051. Vaccinia virus. HSV and VV express GMCSF to stimulate immune response. Balance between anti-viral and anti-tumour immunity.

21. Intratumoural reovirus with local radiotherapy: response in the neck 40 mm 23 mm 16 mm Pre-treatment2 months7 months

22. Pre-treatment 7 months Reovirus with radiotherapy: response in the chest Not in the injected/irradiated tumour…

23. Base-line Jan 2009 After 3 cycles April 2009 Reo011 Patient 02-2008 Response to intravenous reovirus with chemotherapy

24. Summary Immunotherapy for cancer works. Requires different trial design and readouts to previous anti-cancer treatments. Combination strategies likely the best way forward - immunotherapy will not substitute for current treatments. Antibodies against immune checkpoints are the best current example. Intriguing prospect of durable benefit, even in very advanced disease. References: Workenhe ST et al, Mol Ther. 2013 Sep 19. doi: 10.1038/mt.2013.220. [Epub ahead of print] Sznol M, Chen L. Clin Cancer Res. 2013 Oct 1;19(19):5542. doi: 10.1158/1078-0432.CCR-13-2234. Epub 2013 Sep 18.