Inclusion Criteria:
1. Male or female patient age ≥ 18 years of age at the time of informed consent.
2. Ability to provide and understand written informed consent prior to any study procedures.
3. Willingness to undergo tumor biopsies at baseline and post-Tebentafusp treatment.
4. Treatment naïve primary uveal melanoma with T3 or T4 category tumor size that are surgically unresectable (other than complete enucleation of eye).
5. No surgical indication to completely remove the tumor without enucleation.
6. Clinically or cytologically confirmed primary uveal melanoma.
7. Participants must be HLA-A\*02:01 positive.
8. Predicted life expectancy of at least 12 weeks as estimated by investigator
9. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at screening.
10. All other relevant medical conditions must be well-managed and stable, in the opinion of the investigator, for at least 28 days prior to first administration of study drug.
11. Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
Exclusion Criteria:
1. Symptomatic uveal melanoma that requires immediate ophthalmological intervention such as enucleation.
2. Evidence of metastatic disease.
3. Previous treatment with Tebentafusp.
4. Patients with any out-of-range laboratory values defined as:
* Serum creatinine \> 1.5 x upper limit of normal (ULN) and/or creatinine clearance (calculated using Cockcroft-Gault Formula, or measured) \< 50 mL/minute
* Albumin \< 3.0 g/dl
* Total bilirubin \>1.5 mg/dL (or 1.3 x ULN). Patients with hyperbilirubinemia clinically consistent with an inherited disorder of bilirubin metabolism (e.g., Gilbert syndrome) will be eligible at the discretion of the treating physician and/or the principal investigator.
* Alanine aminotransferase \> 1.5 x ULN
* Aspartate aminotransferase \> 1.5 x ULN
* Absolute neutrophil count \< 1.0 x 109 /L
* Absolute lymphocyte count \< 0.5 x 109 /L
* Platelet count \< 100 x 109 /L
* Hemoglobin \< 9.0 g/dL
* Uncorrectable abnormal potassium, magnesium, corrected calcium or phosphate abnormality of National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v5.0) \> grade 1
* Morning cortisol \< lower limit of normal (unless the patient has asymptomatic adrenal insufficiency and is receiving stable replacement doses)
5. History of severe hypersensitivity reactions (eg, anaphylaxis) to other biologic drugs or monoclonal antibodies.
6. Clinically significant cardiac disease or impaired cardiac function, including any of the following:
* Left Ventricular Ejection Fraction \<50%
* Clinically significant and/or uncontrolled heart disease such as congestive heart failure (New York Heart Association grade ≥ 2), uncontrolled hypertension, or clinically significant arrhythmia uncontrolled with medical treatment
* QTcF \> 470 msec on screening electrocardiogram (ECG) or congenital long QT syndrome
* Acute myocardial infarction or unstable angina pectoris \< 6 months to Screening
7. Active infection requiring systemic antibiotic therapy. Patients requiring systemic antibiotics for infection must have completed therapy at least 1 week prior to the first dose of study drug.
8. Participants with a history of human immunodeficiency virus (HIV) infection. NOTE: Testing is not required unless mandated by the local health authority. Participants with HIV infection may be eligible if ALL of the following are applicable:
1. Receiving an approved, stable, effective combination antiretroviral therapy regimen for \> 3 months prior to the planned first study intervention. NOTE: please review Section 5.7 and consider whether any actions should be taken to minimize potential drug-drug interactions,
2. CD4 T cell count \> 350 cells/µl,
3. CD4 T cell nadir (lowest historical count) \> 200 cells/µl, and
4. Viral load confirmed as \< 50 copies/mL during Screening.
9. Participants with a known history of chronic viral infections as indicated below. NOTE: Testing for hepatitis B virus (HBV) or hepatitis C virus (HCV) is not required unless mandated by the local health authority.
1. Known HBV infection defined as hepatitis B surface antigen reactive. NOTE: Participants with HBV infection on stable anti-viral therapy for \> 4 weeks prior to the planned first study intervention and viral load confirmed as undetectable during Screening may be eligible.
2. Known active HCV infection defined as detectable HCV RNA (qualitative) infection. NOTE: History of HCV is not exclusionary if participants have received curative treatment and viral load is confirmed as undetectable during screening.
10. Malignant disease, other than that being treated in this study. Exceptions to this exclusion include the following: malignancies that were treated curatively and have not recurred within 2 years prior to study treatment; completely resected basal cell and squamous cell skin cancers; any malignancy considered to be indolent and that has never required therapy; and completely resected carcinoma in situ of any type.
11. Any medical condition that would, in the investigator's or Sponsor's judgement, prevent the patient's participation in the clinical study due to safety concerns, compliance with clinical study procedures or interpretation of study results.
