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Michael K Wong MD PhD FRCPCProfessor, Cancer MedicineMelanoma Medical Oncologymkwong@mdanderson.org

Curing Cancer Through Immunotherapy: A Structured Understanding of Current Therapies and Impact on Your Current Practice

Florida State Association of Rehabilitation Nurses, May 4, 2017

At the end of this talk, I hope that you will:

• Appreciate how an immune response is generated.

• Be impressed by how immunotherapy has changed the practice of oncology. 

• Posses a framework to interpret the emerging new data and new technology in immunotherapy. 

• Understand how immunotherapy impacts your practice.

Melanoma is the Prototype for modern immunotherapy

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Melanoma Disseminates Widely

“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 melanomaThe Risks of Medical Innovation. Schlich T and Trohler U Eds. Routledge Group 2006

Ancient History: Cutaneous Melanoma: 15-Year Survival by Stage

Balch et al, 2001

Half the patients 

with metastatic disease die within 1 year

70%of the patients 

with metastatic disease are dead by year 2

> Half the patients with completely resectedLN positive disease are 

dead by year 5

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Palliative therapy of disseminated malignant melanoma: a systematic review of 41 randomized clinical trials. Eigentler TK, Caroli UM, Radny P, Garbe C. Lancet Oncology Vol 4, December 2003.

• A study of “high quality” clinical trials 

• There is a trend to higher response rates with more aggressive therapies.

• This does not correlate with a significant improvement in survival. 

It doesn’t matter what you do – median survival was only 8 months in this study

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 09/30/2015Talimogene 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 09/30/2015Talimogene Laherparepvec 10/27/2015

Vemurafenib + Cobimetinib 11/10/2015

Pembrolizumab10/2016:  Head and neck squamous cell cancer 

Nivolumab05/2016:  Classical Hodgkin lymphoma11/2016:  Head and Neck squamous cell carcinoma

Atezolizumab05/2016:  Urothelial carcinoma 

Metastatic non‐small cell lung cancer

Nivolumab11/2015: advanced renal cell carcinoma

Pembrolizumab10/2015:  PD‐L1 positive advanced non‐small cell lung cancer, 

2015 2016

Immunotherapy’s Expanding Footprint

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Nivolumab2/2/2017: locally advanced or metastatic urothelial carcinoma  

2017

Immunotherapy’s Expanding Footprint

Pembrolizumab3/14/2017: adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL).

Avelumab3/23/2017: adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma

Durvalumab5/1/2017: platinum resistant locally advanced or metastatic urothelial carcinoma

http://www.proleukin.com/ (patient stories) – accessed November 15, 2014

Cancer free 11 years Cancer free 10 years Cancer free 10 years

Why is this important?

Cancer free 10 years

“ The cancer is gone “December 6th, 2015

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ImmunoRx KinaseInhibition

The Tissues and Organs of the Immune System

Dendritic Cells

http://members.cox.net/stokman1c/DendriticCellMontagelowres.jpg

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Dendritic  cells are found where the “outside world” comes in contact with youExamples 

• Skin: Langerhans cell

• Inner lining of the nose, lungs, stomach and intestines. 

Courtesy: Haymanj Photo : Kamal Khanna

Dendritic Cells Sample their Surroundings

DCs actively sample the tumor environment

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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

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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

TumorBlood Vessel

Lymphocyte inside Blood Vessel

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 vesicles 

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Tumor  cell 

Killer  T‐ cell 

Injected cell killing enzymes.

Generating an Anti‐Tumor Response: Overview

Dendritic cell

TUMOR

Activated T cell

LYMPH NODE

TCR CD28Tumor antigen

Resting T cell

MHCB7

perforingranzyme cytokines

T cell clonal expansion

Checkpoint 

Tumor‐HostTumor‐Host

Checkpoint figure: Zibelman M, Olszanski AJ, J Natl Compr Canc Netw 2014;12(Suppl 2):S1–S5)   

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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

Antibodies toCTLA-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™)

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Patients at RiskIpilimumab 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 = 1861Median OS (95% CI): 11.4 mo (10.7-12.1)3-year OS Rate (95% CI): 22% (20% to 24%)

IpilimumabCENSORED

Hodi S, et al. 2013 European Cancer Congress. Abstract LBA 24.

Ipilimumab (Yervoy™): Pooled Survival Analysis from Phase II/III Trials in Advanced Melanoma

Autoimmume‐Related Toxicity Hypopituitarism consistent with

ipilimumab-induced hypophysitisDilated 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

Ipilimumab: Onset and Resolution of Toxicities

Management of Immune-Related Adverse Events and Kinetics of Response With Ipilimumab.Weber JS et al. J Clin Oncol 30:2691-2697Lebbé C, O’Day SJ, Sileni VC, et al. Analysis of the onset and resolution of immune-related adverse events during treatment with ipilimumab in patients with metastatic melanoma. Presented at the Perspectives in Melanoma XII. New York City, NY; 2008 Oct 2-4 . Abstract O-015.

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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 metsfollowed 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”

The Programmed Death ‐1 (PD‐1)Pathway

McDermott DF, Atkins MB. Cancer Medicine 2013: 2(5): 662‐673

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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

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

Pembrolizumab = Keytruda (Merck);  Nivolumab = Opdivo (BMS)

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DUAL CHECKPOINT INHIBITION 

Dendritic cell

TUMOR

Activated T cell

LYMPH NODE

TCR CD28Tumor antigen

Resting T cell

MHCB7

perforingranzyme cytokines

T cell clonal expansion

Checkpoint 

Tumor‐HostTumor‐Host

Checkpoint figure: Zibelman M, Olszanski AJ, J Natl Compr Canc Netw 2014;12(Suppl 2):S1–S5)   

Published April 20, 2015 at NEJM.org

• 142 treatment naïve patients. 2:1 randomization to receive ipilimumab  (3 mg/kg) + Nivolumab (1 mg/kg)  or placebo, every 3 weeks X 4 doses. 

• Followed by Nivolumab 3 mg/kg or placebo every 2 weeks. 

• BRAF WT tumors: (combo vs placebo)

• RR: 61% vs 11% (P < 0.001)

• CR: 22% vs 0 

• Toxicity: Grade III or IV in 54% vs 24%

Published April 20, 2015 at NEJM.org

Ipilimumab + Nivolumab or Placebo

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Published April 20, 2015 at NEJM.org

54% vs 24%

17% vs 7%

2% vs 2%

47% vs 17%

Enhancing the anti‐tumor responseIncreased antigen presentation + enhanced Dendritic Cell Migration

Dendritic cell

TUMOR

Activated T cell

LYMPH NODE

TCR CD28Tumor antigen

Resting T cell

MHCB7

perforingranzyme cytokines

T cell clonal expansion

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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. 

T-VEC: An HSV-1-Derived Oncolytic Immunotherapy Designed to Produce

Local and Systemic Effects

Selective viralreplication in

tumor tissue

Tumor cells rupture for an oncolytic

effect

Systemictumor-specific

immune responseDeath of distant

cancer cells

Local Effect: Virally-Induced Tumor Cell Lysis

Systemic Effect: Tumor-Specific Immune Response

47Slide courtesy of Dr. Igor Puzanov, with permission

Injected and Non-injected Lesion Response

Cycle 10

TCycle 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

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Injected InjectedNONInjected

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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

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6953 melanoma patients;  702 with brain metastases. 

Duke University 20 year experience

1,137 patients;  686 were treated between 1985 and 2000. 

Sydney Melanoma Unit:  48 year experience

Overall Survival

Sampson JH, et al. Demographics, prognosis, and therapy in 702 patients with brain metastasesfrom malignant melanoma. J Neurosurg 1998; 88:11–20.

Fife KM, Colman MH, Stevens GN, et al. Determinants of outcome in melanoma patients with cerebral metastases.  J Clin Oncol 2004; 22: 1293–1300

Melanoma Brain Metastases: 80% mortality by Year 1

Brain metastases does not adversely impact survival for patients treated with ipilimumab

Margolin KM et al. Ipilimumab in patients with melanoma and brain metastases: an open‐label, phase 2 trial. Lancet Oncol 2012; 13: 459‐65

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7/11/2016 11/30/201606/30/16 11/14/2016

Courtesy of Dr. Hussein Tawbi , MD Anderson Cancer Center

Brain Metastases Respond to Immunotherapy

Why Rehab?Patient performance status MATTERS.

• The vast majority of clinical immunotherapy clinical trials took place with ECOG 0 – 1 patients. 

• Declining PS is NOT necessarily due to cancer progression.

• Weakness is NOT necessarily due to cancer progression. 

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Hypophysitis: The Great MimicThe most common presenting symptom of lymphocytic hypophysitis is : 

Headache• Fatigue• Lethargy• Loss of libido• Amenorrhea• Dizziness• Nausea and vomiting

• Diabetes insipidus. • Diplopia and pupillary abnormalities • Visual field loss

Resources for Toxicity Management of ImmunotherapyGENERAL Society for the Immunotherapy of Cancer (SITC):  http://www.sitcancer.org/clinician/resources/melanoma

Accessed March, 2017. 

Corticosteroids(Dexamethasone, Prednisone, methylprednisolone)

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Steroid MyopathyPresentation / Manifestations• Insidious disease process • Causes weakness mainly to the proximal muscles of the upper and lower limbs and to the neck flexors.

• First described by Cushing in 1932• Difficulty climbing stairs, getting out of chairs, or difficulty combing their hair.

Causes• Overproduction of corticosteroids• (Over) Treatment with corticosteroids

Impact on YOUR Care of these patients• Immunotherapy has NO DIRECT effect on the cancer, 

rather, it depends on the PATIENT’S immune system to do the work. 

• Autoimmune toxicities can be late and long lasting.

• Responses can be late after initial tumor ‘flare’.

• In the differential diagnosis of fatigue (endocrine failure).

• Avoid corticosteroids, but …. They are the cornerstone to treating autoimmune toxicity.

THE BEGINNING OF THE BEGINNINGMelanomaRenal Cell CarcinomaLung CancerHead and NeckBladderMerkel Cell CarcinomaOvarianCervical HepatocellularBreastPancreaticColonBrain ……

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Patrick Hwu MD

MelanomaandSkinCenter7135639716

PhysicianReferralPortalmylink.mdanderson.org

PhysicianAccesstoMDAnderson:1‐888‐658‐9805

• Adjuvant (Preventive) Therapy• Immunotherapy Refractory Melanoma• TIL,Adoptive T-Cell, DC Immunotherapy, Vaccines• Combination Immuno/Targeted Therapies• Intralesional therapy

• Uveal (ocular) Melanoma• Squamous Cell Carcinoma , Merkel Cell Carcinoma• Brain / Leptomeningeal Metastatic Disease• Molecular Targeted Therapies (BRAF, NRAS, PTEN)• Investigational new drugs (OX40, LAG 3, 4-11B)