melanoma is the prototype for modern immunotherapy cancer by immunotherapy.pdf · courtesy: haymanj...
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Michael K Wong MD PhD FRCPCProfessor, Cancer MedicineMelanoma Medical [email protected]
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)