Table 1 In- and exclusion criteria

- Adults ≥18 years of age

- WHO performance score of 0 or 1

- Cytologically or histologically confirmed diagnosis of stage IIIB/C/D/IVM1a (AJCC 8th edition) melanoma, eligible for surgical resection

- Measurable disease according to RECIST 1.1 and must be a candidate for intralesional therapy with at least one injectable cutaneous, subcutaneous or nodal melanoma lesion (≥ 10 mm in longest diameter) or with multiple injectable lesions that in aggregate have a longest diameter of ≥10 mm

- Prior isolated limb perfusion is allowed (≥ 12 weeks prior to enrollment)

- Adequate organ function

- LDH < 2 x ULN

- INR or PT ≤1.5 x ULN, unless the subject is receiving anticoagulant therapy

- WOCBP must use highly effective method(s) of contraception during T-VEC and nivolumab treatment and for a period of 5 months after the last dose of nivolumab

- WOCBP must have a negative serum or urine pregnancy test within 72 hours prior to enrollment and within 24 hours prior to the start of nivolumab

- Men receiving nivolumab and who are sexually active with WOCBP should use contraception during treatment and for a period of 7 months after the last dose of nivolumab

- Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year

- Women who are not of childbearing potential (i.e., who are postmenopausal), or surgically sterile as well as azoospermic men do not require contraception

- Patient is capable of understanding and complying with the protocol requirements and has signed the Informed Consent document

- Inhaled or topical steroids, and adrenal replacement steroid < 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease

- Liver, bone, lung, brain or other visceral metastases 

- Prior radiotherapy for melanoma

- Prior systemic cancer therapies, including, but not limited to anti-CTLA-4, anti-PD-1, anti-PD-L1

- Other malignancies, except adequately treated and a cancer-related life-expectancy of more than 5 years

- Positivity for hepatitis B virus surface antigen or hepatitis C virus ribonucleic acid, indicating acute or chronic infection

- Known history of testing positive for HIV or known AIDS

- History or evidence of active autoimmune disease that requires high dose systemic treatment. Replacement therapy is not considered a form of systemic treatment

- Evidence of clinically significant immunosuppression such as a primary immunodeficiency, a concurrent opportunistic infection, receiving systemic immunosuppressive therapy (> 2 weeks) including oral steroid doses > 10 mg/day of prednisone or equivalent within 7 days prior to enrollment

- Active herpetic skin lesions or prior complications of HSV-1 infection

- Requirement of intermittent or chronic systemic (intravenous or oral) treatment with an antiherpetic drug, other than intermittent topical use

- Previous treatment with T-VEC or any other oncolytic virus

- Received live vaccine within 30 days prior to enrollment

- Subject has known sensitivity to T-VEC or nivolumab or any of its components to be administered during dosing

- Sexually active subjects and their partners unwilling to use male or female latex condom to avoid potential viral transmission during sexual contact while on treatment and within 30 days after treatment with T-VEC

- Subjects who are unwilling to minimize exposure with his/her blood or other body fluids to individuals who are at higher risks for HSV-1 induced complications during T-VEC treatment and through 30 days after the last dose of T-VEC

- No allergies and adverse drug reaction

- History of allergy to study drug components or severe hypersensitivity reaction to any monoclonal antibody

- No underlying medical conditions that, in the Investigator’s opinion, will make the administration of study drug hazardous or obscure the interpretation of toxicity determination or adverse events

- Use of other investigational drugs before study drug administration 30 days and 5 half-times before study inclusion