Dan S Gombos MD FACSProfessor & ChiefSection of OphthalmologyMD Anderson Cancer CenterHouston, Texas

Sapna Patel MD, Scott Woodman MD PhDLiz Grimm PhD, Chandrani Chattopadhyay PhDDae Won Kim PhD, Bita Esmaeli MD

Disclosure

• Paid Consultant to Castle Biosciences• Paid Consultant to Aura Biosciences- MDACC

site for upcoming trial• Investigator Children’s Oncology Group

– travel paid by NIH/COG• Collaborator on numerous drug and clinical

trials– metastatic uveal melanoma– Bristol-Myers Squibb

Texas

is

Where?

Right Here!

(And here is Houston)

Basics of Ocular Melanoma

• Definitions• Symptoms• Diagnosis• Staging• Treatment• Prognostic Testing• Surveillance• New Therapies

‘Ocular’ Melanoma

• Uvea– Choroid– Ciliary Body– Iris

• Conjunctiva• Eye lid skin melanoma• Orbital melanoma

Diagnosis Of Uveal Melanoma

• Non-invasive assessment• No tissue• Clinical exam and diagnostic testing• Collaborative Ocular Melanoma Study

– 1527 enucleated eyes only 5 did not contain a uveal melanoma

Multi-step Process

• History/symptoms/risk factors• Important clinical features

– absence/presence• Non-invasive diagnostic testing

– ultrasound• Putting it all together• Tissue diagnosis (rarely)

Symptoms

• History-Symptoms– Asymptomatic

• Routine eye exam– Flashing lights & floaters– Distorted or blurry vision

• Retina

• No Pain

Examination

MassSize/Shape/Location

FluidOrange PigmentDrusenPigment ChangesHalo

Ancillary Ocular Testing

• Fundus Photography• Fluorescein Angiography• Indocyanine Green Angiography• Ocular Coherence Tomography OCT• Echography A & B Scan• Ultrasound Biomicroscopy UBM

Ultrasound

• Standardized A and B scan echography– Size

• Features on ultrasound that assist you in the diagnosis

Anterior Segment Tumor

• Ultrasound Biomicroscopy– Anterior

segment/ciliary body

Putting it all together• Review the history• Clinical features• Ultrasonography• Factors

– Thickness – Location– Symptoms– Orange pigment– Subretinal fluid

Testing the rest of your body

• Systemic evaluation– COMS

• Liver enzymes, CXR

– Liver Imaging• CT scan• Liver ultrasound

• CT– Chest/abdomen

• PET

Staging

• Cornerstone of cancer management• So why did my ophthalmologist not tell me

my stage ?• Melanoma- small/medium/large• Most new patients will only have ocular

disease at first visit– Initial therapy is likely to be focused on the

eye

Staging

• Staging system under constant revision– AJCC- American Joint Committee on Cancer

• Cumbersome– Location and size

• Little utility to your ocular oncologist• Small/Medium/Large

– Direct ocular therapy options

Ocular Management Options• Observation• Laser treatment • Excision (Cut it out)• Radiotherapy

– (brachytherapy-plaques/charged particle)• Enucleation (removal of the eye)• Combination

– Plaque & Laser– Excision & Plaque

Excision

Small tumors of the iris and ciliary body

Enucleation

• Good alternative for larger tumors• Provides pathologic confirmation of diagnosis• Avoids radiation toxicity• “Most aggressive approach”• Tissue for research

– TIL harvesting• Excellent cosmesis

Plaque Radiation Therapy

Plaque Radiation Therapy

Bebig 106Ru Plaques

After Plaque Radiotherapy• No ocular effect for months or years• Success either regression or lack of continued

growth• Close serial follow up eye exams, photos and

ultrasounds• Long follow up (years)-late recurrences have

been well documented• Adjuvant Diode Laser Hyperthermia TTT

Sandwich Therapy

Regression Following 125I Plaque

Complications from ocular radiation therapy

• Acutely– Retinal detachments– Bleeding– Double vision– Optic nerve damage

• Chronic– Radiation induced damage– Cataract– Dry Eye (proton beam)

Prognostic Features

• Anatomic (location)• Tumor dimension (size)• Histopathologic (cell type)• Cytogenetic (chromosomes)• Gene Expression

Anatomic• Ciliary body • Choroid• Iris

Onken et al. Gene Expression Profiling in Uveal Melanoma Reveals Two Molecular Classes and Predicts Metastatic Death. Clin Cancer Res 2007.

Tumor Size- 5 year mortality rates

• 16% for small tumors– < 3 mm in height < 10 mm in base diameter

• 32% for medium tumors – 3-8 mm in height and < 15 mm in base diameter

• 53% for large tumors – > 8 mm in height and > 15 mm in base diameter

Diener-West M et al. A review of mortality from choroidal melanoma. II. A meta-analysis of 5-year mortality rates

following enucleation, 1966 through 1988. Arch Ophthalmol 1992.

Pathology

• Epitheliod• Spindle• Vascular Networks• Extraocular extension• Mitosis

Prognostic Biopsy

• Small piece of tissue– Inserting a needle into the eye

• Two types of tests (Castle & Impact)– Chromosome testing (3/8/6)

• Monosomy 3 (loss of one copy of chromosome 3)– Gene Expression Profile

• ‘Pattern recognition’ of certain genes (on or off)• Class Ia/Ib/II• Class II

Surveillance

• Monitor you for spread • Most common organ liver• Chest X-Ray & blood work• Liver ultrasound (Europe)• CT scans• MRI• PET• Frequency - 3 months to annually

Controversy Biopsy & Surveillance

• Not all doctors offer it• Different doctors believe in different testing• Small risk to eye and vision• Insurance coverage• What clinical value does it offer the patient ?• How will biopsy alter treatment and or

prognosis ?• Could a biopsy cause harm ?

No good standard therapy for metastasis

• Poor survival with metastatic uveal melanoma

MEDIAN SURVIVAL (MONTHS)COMS, 2005 (n = 739) 3.6Harvard, 1991 (n = 145) 3.7M.D. Anderson Hospital, 1981 (n = 73) 7.0Roswell Park Memorial Institute, 1983 (n = 35) 8.3Helsinki University, 2003 (n = 91) 8.4Universität Essen, 1993 (n = 24) 9.0John Wayne Cancer Center, 2004 (n = 112) 11.0Memorial Sloan-Kettering, 2005 (n = 119) 12.5

Augberger et al. QUALITY OF EVIDENCE ABOUT EFFECTIVENESS OF TREATMENTS FOR METASTATIC UVEAL MELANOMA. Trans Am Ophthalmol Soc 2008.

Utility of Biopsy and Surveillance• Absence of effective standard therapy• Prognostic testing does not change standard

treatment of melanoma– After eye is treated we monitor you

• Biopsy has not improved the survival and not changed your treatment

• Surveillance not proven to improve survival• Harm of surveillance – cost travel anxiety (Do no

harm)

Benefits

• Knowledge about your tumor– Knowledge is empowerment (for some)

• Medical Oncologist• Clinical Trials

– Adjuvant therapy– Low tumor burden

CONFIDENTIAL

Tumor cell

Irradiation with NIR light

Necrotic tumor cell

HSPG

Viral nanoparticle conjugates (VNC) are delivered by intra-vitreal injection and target tumor cells in the choroid.

VNCs bind specifically to HSPGs on the tumor cell surface (multivalent binding).

Ophthalmic laser 689nm activates the drug. The light-activated drug disrupts the tumor cell membrane, leading to necrosis.

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Trial for a new therapy of Uveal MelanomaAura Biosciences

Phase I Trial

• Safety• One patient treated so far

– First in human study– Six patients total

• Limited availability• Multi-center trial based on Phase I study

Adoptive Cell Therapy (ACT aka TIL) Adoptive Cell Therapy (ACT aka TIL) with Antigen Specific T-cellswith Antigen Specific T-cells

Surgical Removal of

Cancer Nodule

Tumor Cells Incubated with IL-2

T CellsProliferate

Cancer CellsDie

T CellsIL-2

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Pre-therapy Post-therapyPatient #2150

Pre-therapy Post-therapyPatient #2150

Pre-therapy Post-therapyPatient #2199

Pre-therapy Post-therapyPatient #2199

Responses to TIL Therapy

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Fresh Tissue Harvesting

• Harvest cells from enucleated eyes

• Grow them for TIL• Available if patient

develops metastasis

Conclusions

• Ocular Melanoma– Uveal melanoma & Conjunctival melanoma

• Diagnosis & Staging• Treatment option

– Radiation Removal of the eye• Prognostic Features• Biopsy & Surveillance• New Trials