This document discusses ocular melanoma, including uveal melanoma and conjunctival melanoma. It covers diagnosis and staging, treatment options like radiation and enucleation, prognostic features, and the role of biopsy and surveillance. It also mentions new clinical trials for therapies like adoptive cell transfer and a light-activated nanoparticle drug being tested by Aura Biosciences.

1. Dan S Gombos MD FACS
Professor & Chief
Section of Ophthalmology
MD Anderson Cancer Center
Houston, Texas
Sapna Patel MD, Scott Woodman MD PhD
Liz Grimm PhD, Chandrani Chattopadhyay PhD
Dae Won Kim PhD, Bita Esmaeli MD

2. 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

3. Texas
is
Where?
Right Here!
(And here is
Houston)

4. Basics of Ocular Melanoma
• Definitions
• Symptoms
• Diagnosis
• Staging
• Treatment
• Prognostic Testing
• Surveillance
• New Therapies

5. ‘Ocular’ Melanoma
• Uvea
– Choroid
– Ciliary Body
– Iris
• Conjunctiva
• Eye lid skin melanoma
• Orbital melanoma

6. 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

7. Multi-step Process
• History/symptoms/risk factors
• Important clinical features
– absence/presence
• Non-invasive diagnostic testing
– ultrasound
• Putting it all together
• Tissue diagnosis (rarely)

8. Symptoms
• History-Symptoms
– Asymptomatic
• Routine eye exam
– Flashing lights & floaters
– Distorted or blurry vision
• Retina
• No Pain

9. Examination
Mass
Size/Shape/Location
Fluid
Orange Pigment
Drusen
Pigment Changes
Halo

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

11. Ultrasound
• Standardized A and B
scan echography
– Size
• Features on
ultrasound that assist
you in the diagnosis

12. Anterior Segment Tumor
• Ultrasound
Biomicroscopy
– Anterior
segment/ciliary body

13. Putting it all together
• Review the history
• Clinical features
• Ultrasonography
• Factors
– Thickness
– Location
– Symptoms
– Orange pigment
– Subretinal fluid

14. Testing the rest of your body
• Systemic evaluation
– COMS
• Liver enzymes, CXR
– Liver Imaging
• CT scan
• Liver ultrasound
• CT
– Chest/abdomen
• PET

15. 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

16. 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

17. 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

18. Excision
Small tumors of the
iris and ciliary body

19. Enucleation
• Good alternative for larger tumors
• Provides pathologic confirmation of diagnosis
• Avoids radiation toxicity
• “Most aggressive approach”
• Tissue for research
– TIL harvesting
• Excellent cosmesis

20. Plaque Radiation Therapy

21. Plaque Radiation Therapy

22. Bebig 106
Ru
Plaques

23. 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

24. Regression Following 125
I
Plaque

25. Complications from ocular
radiation therapy
• Acutely
– Retinal detachments
– Bleeding
– Double vision
– Optic nerve damage
• Chronic
– Radiation induced damage
– Cataract
– Dry Eye (proton beam)

26. Prognostic Features
• Anatomic (location)
• Tumor dimension (size)
• Histopathologic (cell type)
• Cytogenetic (chromosomes)
• Gene Expression

27. 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.

28. 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.

29. Pathology
• Epitheliod
• Spindle
• Vascular Networks
• Extraocular extension
• Mitosis

30. 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

31. 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

32. 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 ?

33. No good standard therapy for
metastasis
• Poor
survival
with
metastatic
uveal
melanoma
MEDIAN SURVIVAL (MONTHS)
COMS, 2005 (n = 739) 3.6
Harvard, 1991 (n = 145) 3.7
M.D. Anderson Hospital, 1981 (n = 73) 7.0
Roswell Park Memorial Institute, 1983 (n = 35) 8.3
Helsinki University, 2003 (n = 91) 8.4
Universität Essen, 1993 (n = 24) 9.0
John Wayne Cancer Center, 2004 (n = 112) 11.0
Memorial 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.

34. 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)

35. Benefits
• Knowledge about your tumor
– Knowledge is empowerment (for some)
• Medical Oncologist
• Clinical Trials
– Adjuvant therapy
– Low tumor burden

36. 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.
36
Trial for a new therapy of Uveal Melanoma
Aura Biosciences

37. 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

38. 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 Cells
Proliferate
Cancer
Cells
Die
T Cells
IL-2
38

39. Pre-therapy Post-therapy
Patient #2150
Pre-therapy Post-therapy
Patient #2150
Pre-therapy Post-therapy
Patient #2199
Pre-therapy Post-therapy
Patient #2199
Responses to TIL Therapy
39

40. Fresh Tissue Harvesting
• Harvest cells from
enucleated eyes
• Grow them for TIL
• Available if patient
develops metastasis

41. Conclusions
• Ocular Melanoma
– Uveal melanoma & Conjunctival melanoma
• Diagnosis & Staging
• Treatment option
– Radiation Removal of the eye
• Prognostic Features
• Biopsy & Surveillance
• New Trials