Michael K. Wong, MD, PhD, provides an update on immunotherapy in melanoma at the 2017 MD Anderson Melanoma Patient Symposium held in Austin, TX on May 6, 2017.

1. Michael K Wong MD PhD FRCPC
Professor, Cancer Medicine
Melanoma Medical Oncology
mkwong@mdanderson.org
A Paradigm Shift:
Immunotherapy for Metastatic Melanoma

2. At the end of this talk, I hope that you will:
• Understand how the immune system fights
cancer.
• Develop a framework to interpret the
emerging new data and new technology in
immunotherapy.
• Appreciate how immunotherapy has
completely changed the practice of oncology.

3. Melanoma is the Prototype for
modern immunotherapy

4. Pembrolizumab
10/2016: Head and neck squamous cell cancer
Nivolumab
05/2016: Classical Hodgkin lymphoma
11/2016: Head and Neck squamous cell carcinoma
Atezolizumab
05/2016: Urothelial carcinoma
Metastatic non‐small cell lung cancer
Nivolumab
11/2015: advanced renal cell carcinoma
Pembrolizumab
10/2015: PD‐L1 positive advanced non‐small cell lung cancer,
2015 2016
Immunotherapy’s Expanding Footprint

5. Nivolumab
2/2/2017: locally advanced or metastatic urothelial carcinoma
2017
Immunotherapy’s Expanding Footprint
Pembrolizumab
3/14/2017: adult and pediatric patients with refractory
classical Hodgkin lymphoma (cHL).
Avelumab
3/23/2017: adults and pediatric patients 12 years and older
with metastatic Merkel cell carcinoma
Durvalumab
5/1/2017: platinum resistant locally advanced or metastatic
urothelial carcinoma

6. “metastatic melanoma is a disease that
gives cancer a bad name”(*)
(*)From the FDA Advisory Committee Report on the use of Proleukin [IL‐2] for metastatic melanoma
The Risks of Medical Innovation. Schlich T and Trohler U Eds. Routledge Group 2006

7. ELEVEN New Approvals over 6 years
reflects new understanding of melanoma
biology
Ipilimumab 3/2011
Peg‐Interferon 3/2011
Vemurafenib 8/2011
Dabrafenib 5/2013
Trametinib 5/2013
Dabrafenib+Tremetinib 1/9/2014
Pembrolizumab 9/04/2014
Nivolumab 12/22/2014
Ipilimumab + Nivolumab 09/30/2015
Talimogene Laherparepvec 10/27/2015
Vemurafenib + Cobimetinib 11/10/2015
ELEVEN New Approvals over 6 years
reflects new understanding of melanoma
biology
Ipilimumab 3/2011
Peg‐Interferon 3/2011
Vemurafenib 8/2011
Dabrafenib 5/2013
Trametinib 5/2013
Dabrafenib+Tremetinib 1/9/2014
Pembrolizumab 9/04/2014
Nivolumab 12/22/2014
Ipilimumab + Nivolumab 09/30/2015
Talimogene Laherparepvec 10/27/2015
Vemurafenib + Cobimetinib 11/10/2015

8. “ The
cancer
is gone “
December 6th, 2015

9. ImmunoRx Kinase
Inhibition

10. At the end of this talk, I hope that you will:
• Understand how the immune system fights
cancer.
• Develop a framework to interpret the
emerging new data and new technology in
immunotherapy.
• Appreciate how immunotherapy has
completely changed the practice of oncology.

11. The Tissues and Organs of the Immune System

12. Dendritic cells are found where the
“outside world” comes in contact with you
Examples
• Skin: Langerhans cell
• Inner lining of the nose,
lungs, stomach and
intestines.
Courtesy: Haymanj Photo : Kamal Khanna

13. Dendritic Cells Sample their Surroundings

14. DCs actively sample the tumor environment

15. Dendritic Cells interact with other immune cells

16. Dendritic Cells Directly Interact with T‐Lymphocytes
http://www.nature.com/ni/focus/niches/videolibrary/index.html

17. Activated Lymphocytes search for the target

18. Cytotoxic T Lymphocytes Infiltrating a
Tumor during Adoptive Immunotherapy
Boissonnas A, Fetler L, Zeelenberg IS et al. In vivo imaging of cytotoxic T cell infiltration and elimination of a solid tumor. J Exp Med: 204 (2), 345–356, 2007
Tumor
Blood Vessel
Lymphocyte inside
Blood Vessel

19. Killer T cell recognizing a cancer cell

20. http://chroma.med.miami.edu/micro/images/research_lee_dc.jpg
Immune cells possess granules
Intracellular
Membrane‐bound vesicles

21. Tumor cell
Killer T‐ cell
Injected
cell killing
enzymes.

22. At the end of this talk, I hope that you will:
• Understand how the immune system fights
cancer.
• Develop a framework to interpret the
emerging new data and new technology in
immunotherapy.
• Appreciate how immunotherapy has
completely changed the practice of oncology.

23. Generating an Anti‐Tumor Response: Overview
Dendritic cell
TUMOR
Activated T cell
LYMPH
NODE
TCR CD28
Tumor antigen
Resting T cell
MHC
B7
perforin
granzyme cytokines
T cell
clonal expansion
Checkpoint
Tumor‐Host
Checkpoint figure: Zibelman M, Olszanski AJ,
J Natl Compr Canc Netw 2014;12(Suppl 2):S1–S5)

25. At the end of this talk, I hope that you will:
• Understand how the immune system fights
cancer.
• Develop a framework to interpret the
emerging new data and new technology in
immunotherapy.
• Appreciate how immunotherapy has
completely changed the practice of oncology.

26. 69 year old woman
• Rt Big toe Acral Lentiginous Malignant Melanoma
• Toe Amputation, Lymph node sampling Negative
• Five years later – first appearance of in transit
melanoma mets
• Several surgeries over next 3 years
• Now: Massive involvement of the entire Rt Leg
Infusion of Antibodies Against CTLA-4

28. Antibodies to
CTLA-4
Antibodies binds
to CTLA-4 on the
cell surface CTLA-4 cannot bind B7
CTLA-4 Blockade Enhances Tumor-Specific Immune Responses
Inhibit the Inhibitor
Ipilimumab
(Yervoy™)

29. Patients at Risk
Ipilimumab 1861 839 370 254 192 170 120 26 15 5 0
Proportion Alive
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Months
0 12 24 36 48 60 72 84 96 108 120
N = 1861
Median OS (95% CI): 11.4 mo (10.7-12.1)
3-year OS Rate (95% CI): 22% (20% to 24%)
Ipilimumab
CENSORED
Hodi S, et al. 2013 European Cancer Congress. Abstract LBA 24.
Ipilimumab (Yervoy™): Pooled Survival Analysis
from Phase II/III Trials in Advanced Melanoma

30. 44 yr old radio DJ
• On air seizure
• Brain metastases found on ER MRI
• Stage IV Melanoma
• Subcut tissues, Lungs, Soft tissues
• Neurosurgery and Gamma Knife Radiation
• Cell testing ‐> sensitive to MEK inhibitors
• Thoracic surgery – Lungs  NED status
• Through all this, repeated positive brain mets
followed by several application of Gamma
Knife Radiosurgery
• Started pembrolizumab (Keytruda) 2015
• Was NED at 6 months, total treatment time
~ 18 months
• Off therapy now 4 months.
“Life from the jaws of death”

31. The Programmed Death ‐1 (PD‐1)Pathway
McDermott DF, Atkins MB. Cancer Medicine 2013: 2(5): 662‐673

32. 65 of 306 pts had ORR (CR/PR):
• 30 of 65 (46%) responses were evident at
first tumor evaluation (8 wks)
• 35 of 65 (54%) responses were ongoing at
time of data analysis
• Responses persisted off drug
 88% of responses ongoinga
 Median response duration
not reached (range, 6+ to
76+ weeks)
Ribas A, et al. ASCO 2014. LBA9000.
Topalian SL, et al. ASCO 2013. Abstract 3002.
Nivolumab Pembrolizumab

33. Autoimmume‐Related Toxicity
Hypopituitarism consistent with
ipilimumab-induced hypophysitis
Dilated transverse colon (arrow) with adjacent
free intraperitoneal air
O’Regan, Hodi S, Radiologic Aspects of Immune-Related Tumor Response Criteria and Patterns of Immune-Related Adverse Events
in Patients Undergoing Ipilimumab Therapy, AJR 2011; 197:W241–W246

34. Nishino M, et al. Anti–PD-1–Related Pneumonitis during Cancer Immunotherapy, NEJM 373;3 2015
Pneumonitis Related to Anti-PD-1 Cancer Immunotherapy
Topalian SL et al. Safety, Activity, and Immune Correlates of Anti–PD-1 Antibody in Cancer, . N Engl J Med 366 (26), 2443, 2012

35. Resources for Toxicity Management of Immunotherapy
GENERAL
Society for the Immunotherapy of Cancer (SITC): http://www.sitcancer.org/clinician/resources/melanoma
Accessed April, 2017.

36. Enhancing the anti‐tumor response
Increased antigen presentation + enhanced Dendritic Cell Migration
Dendritic cell
TUMOR
Activated T cell
LYMPH
NODE
TCR CD28
Tumor antigen
Resting T cell
MHC
B7
perforin
granzyme cytokines
T cell
clonal expansion

37. IMLYGIC: TVEC : talimogene laherparepvec
• IMLYGIC is a genetically modified oncolytic viral therapy
indicated for the local treatment of unresectable cutaneous,
subcutaneous, and nodal lesions in patients with melanoma
recurrent after initial surgery.
• Limitations of use: IMLYGIC has not been shown to improve
overall survival or have an effect on visceral metastases.

38. T-VEC: An HSV-1-Derived Oncolytic Immunotherapy Designed to Produce
Local and Systemic Effects
Selective viral
replication in
tumor tissue
Tumor cells rupture
for an oncolytic
effect
Systemic
tumor-specific
immune response
Death of distant
cancer cells
Local Effect:
Virally-Induced Tumor Cell Lysis
Systemic Effect:
Tumor-Specific Immune Response
38Slide courtesy of Dr. Igor Puzanov, with permission

39. Injected and Non-injected Lesion Response
Cycle 10
T
Cycle 1
T-VEC
There were 6 measurable lesions at baseline including 1 cutaneous neck lesion, 2 subcutaneous abdominal
wall lesions (1 of which is shown), 2 intra-abdominal lesions (which are shown), and 1 in musculature of right
thigh (which completely resolved). Both Injected lesions are indicated by a green arrow.
T-VEC
39
Injected InjectedNONInjected

41. Baseline 3 weeks 4 months
Immunoresponses: tumors may get worse
before getting better
Wolchok J et al. Guidelines for the Evaluation of Immune Therapy Activity in Solid Tumors: Immune‐Related Response Criteria.
Clin Cancer Res 2009;15(23):7412–20

42. Immunotherapy is not about
response rates,
it is about long term survival
Redefining Success

43. http://www.proleukin.com/ (patient stories) – accessed November 15, 2014
Cancer free 11 years Cancer free 10 years Cancer free 10 years
Why is immunotherapy important?
Cancer free 12 years

44. THE BEGINNING OF THE BEGINNING
Melanoma
Renal Cell Carcinoma
Lung Cancer
Head and Neck
Bladder
Merkel Cell Carcinoma
Ovarian
Cervical
Hepatocellular
Breast
Pancreatic
Colon
Brain ……

45. Michael K Wong MD PhD FRCPC
Professor, Cancer Medicine
Melanoma Medical Oncology
mkwong@mdanderson.org
A Paradigm Shift:
Immunotherapy for Metastatic Melanoma