Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.
Michael K Wong MD PhD FRCPC
Professor, Cancer Medicine
Melanoma Medical Oncology
mkwong@mdanderson.org
A Paradigm Shift:
I...
At the end of this talk, I hope that you will:
• Understand how the immune system fights 
cancer. 
• Develop a framework t...
Melanoma is the Prototype for 
modern immunotherapy
Pembrolizumab
10/2016:  Head and neck squamous cell cancer 
Nivolumab
05/2016:  Classical Hodgkin lymphoma
11/2016:  Head ...
Nivolumab
2/2/2017: locally advanced or metastatic urothelial carcinoma  
2017
Immunotherapy’s Expanding Footprint
Pembrol...
“metastatic melanoma is a disease that 
gives cancer a bad name”(*)
(*)From the FDA Advisory Committee Report on the use o...
ELEVEN New Approvals over 6 years 
reflects new understanding of melanoma 
biology
Ipilimumab  3/2011
Peg‐Interferon 3/201...
“ The
cancer
is gone “
December 6th, 2015
ImmunoRx Kinase
Inhibition
At the end of this talk, I hope that you will:
• Understand how the immune system fights 
cancer. 
• Develop a framework t...
The Tissues and Organs of the Immune System
Dendritic  cells are found where the 
“outside world” comes in contact with you
Examples 
• Skin: Langerhans cell
• Inner ...
Dendritic Cells Sample their Surroundings
DCs actively sample the tumor environment
Dendritic Cells interact with other immune cells 
Dendritic Cells Directly Interact with T‐Lymphocytes
http://www.nature.com/ni/focus/niches/videolibrary/index.html
Activated Lymphocytes search for the target
Cytotoxic T Lymphocytes Infiltrating a 
Tumor during Adoptive Immunotherapy
Boissonnas A, Fetler L, Zeelenberg IS et al. I...
Killer T cell recognizing a cancer cell
http://chroma.med.miami.edu/micro/images/research_lee_dc.jpg
Immune cells possess granules
Intracellular 
Membrane‐bound v...
Tumor  cell 
Killer  T‐ cell 
Injected 
cell killing 
enzymes.
At the end of this talk, I hope that you will:
• Understand how the immune system fights 
cancer. 
• Develop a framework t...
Generating an Anti‐Tumor Response: Overview
Dendritic cell
TUMOR
Activated T cell
LYMPH
NODE
TCR CD28
Tumor antigen
Restin...
At the end of this talk, I hope that you will:
• Understand how the immune system fights 
cancer. 
• Develop a framework t...
69 year old woman
• Rt Big toe Acral Lentiginous Malignant Melanoma
• Toe Amputation, Lymph node sampling Negative
• Five ...
Antibodies to
CTLA-4
Antibodies binds
to CTLA-4 on the
cell surface CTLA-4 cannot bind B7
CTLA-4 Blockade Enhances Tumor-S...
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....
44 yr old radio DJ
• On air seizure
• Brain metastases found on ER MRI
• Stage IV Melanoma
• Subcut tissues, Lungs, Soft t...
The Programmed Death ‐1 (PD‐1)Pathway
McDermott DF, Atkins MB. Cancer Medicine 2013: 2(5): 662‐673
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%)...
Autoimmume‐Related Toxicity 
Hypopituitarism consistent with
ipilimumab-induced hypophysitis
Dilated transverse colon (arr...
Nishino M, et al. Anti–PD-1–Related Pneumonitis during Cancer Immunotherapy, NEJM 373;3 2015
Pneumonitis Related to Anti-P...
Resources for Toxicity Management of Immunotherapy
GENERAL 
Society for the Immunotherapy of Cancer (SITC):  http://www.si...
Enhancing the anti‐tumor response
Increased antigen presentation + enhanced Dendritic Cell Migration
Dendritic cell
TUMOR
...
IMLYGIC: TVEC :  talimogene laherparepvec
• IMLYGIC is a genetically modified oncolytic viral therapy 
indicated for the l...
T-VEC: An HSV-1-Derived Oncolytic Immunotherapy Designed to Produce
Local and Systemic Effects
Selective viral
replication...
Injected and Non-injected Lesion Response
Cycle 10
T
Cycle 1
T-VEC
There were 6 measurable lesions at baseline including 1...
Baseline 3 weeks 4 months
Immunoresponses: tumors may get worse 
before getting better
Wolchok J et al. Guidelines for the...
Immunotherapy is not about 
response rates, 
it is about long term survival
Redefining Success
http://www.proleukin.com/ (patient stories) – accessed November 15, 2014
Cancer free 11 years Cancer free 10 years Cancer ...
THE BEGINNING OF THE BEGINNING
Melanoma
Renal Cell Carcinoma
Lung Cancer
Head and Neck
Bladder
Merkel Cell Carcinoma
Ovari...
Michael K Wong MD PhD FRCPC
Professor, Cancer Medicine
Melanoma Medical Oncology
mkwong@mdanderson.org
A Paradigm Shift:
I...
A Paradigm Shift: Immunotherapy for Metastatic Melanoma – Michael K. Wong, MD, PhD
A Paradigm Shift: Immunotherapy for Metastatic Melanoma – Michael K. Wong, MD, PhD
A Paradigm Shift: Immunotherapy for Metastatic Melanoma – Michael K. Wong, MD, PhD
Upcoming SlideShare
Loading in …5
×

A Paradigm Shift: Immunotherapy for Metastatic Melanoma – Michael K. Wong, MD, PhD

1,074 views

Published on

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.

Published in: Education
  • Be the first to comment

A Paradigm Shift: Immunotherapy for Metastatic Melanoma – Michael K. Wong, MD, PhD

  1. 1. Michael K Wong MD PhD FRCPC Professor, Cancer Medicine Melanoma Medical Oncology mkwong@mdanderson.org A Paradigm Shift: Immunotherapy for Metastatic Melanoma
  2. 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. 3. Melanoma is the Prototype for  modern immunotherapy
  4. 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. 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. 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. 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. 8. “ The cancer is gone “ December 6th, 2015
  9. 9. ImmunoRx Kinase Inhibition
  10. 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. 11. The Tissues and Organs of the Immune System
  12. 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. 13. Dendritic Cells Sample their Surroundings
  14. 14. DCs actively sample the tumor environment
  15. 15. Dendritic Cells interact with other immune cells 
  16. 16. Dendritic Cells Directly Interact with T‐Lymphocytes http://www.nature.com/ni/focus/niches/videolibrary/index.html
  17. 17. Activated Lymphocytes search for the target
  18. 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. 19. Killer T cell recognizing a cancer cell
  20. 20. http://chroma.med.miami.edu/micro/images/research_lee_dc.jpg Immune cells possess granules Intracellular  Membrane‐bound vesicles 
  21. 21. Tumor  cell  Killer  T‐ cell  Injected  cell killing  enzymes.
  22. 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. 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)   
  24. 24. 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. 
  25. 25. 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
  26. 26. 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™)
  27. 27. 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
  28. 28. 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”
  29. 29. The Programmed Death ‐1 (PD‐1)Pathway McDermott DF, Atkins MB. Cancer Medicine 2013: 2(5): 662‐673
  30. 30. 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
  31. 31. 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
  32. 32. 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
  33. 33. Resources for Toxicity Management of Immunotherapy GENERAL  Society for the Immunotherapy of Cancer (SITC):  http://www.sitcancer.org/clinician/resources/melanoma Accessed April, 2017. 
  34. 34. 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
  35. 35. 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. 
  36. 36. 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
  37. 37. 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
  38. 38. 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
  39. 39. Immunotherapy is not about  response rates,  it is about long term survival Redefining Success
  40. 40. 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
  41. 41. 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 ……
  42. 42. Michael K Wong MD PhD FRCPC Professor, Cancer Medicine Melanoma Medical Oncology mkwong@mdanderson.org A Paradigm Shift: Immunotherapy for Metastatic Melanoma

×