Neo-adjuvant T-VEC + Nivolumab Combination Therapy for Resectable Early Metastatic (stage IIIB/C/D-IV M1a) Melanoma with Injectable Disease

Inclusion Criteria:

* Adults at least 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.
* Subjects must have measurable disease according to RECIST 1.1 and must be a candidate for intralesional therapy with at least one injectable cutaneous, subcutane-ous 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 (ILP) is allowed (≥ 12 weeks prior to enrolment)
* Screening laboratory values must meet the following criteria:
* WBC ≥ 2.0x10\^9/L, Neutrophils ≥1.5x10\^9/L, Platelets ≥100 x10\^9/L, Hemoglobin ≥5.5 mmol/L, Creatinine ≤1.5x ULN, AST ≤ 1.5 x ULN, ALT ≤ 1.5 x ULN, Bilirubin ≤1.5 X ULN
* LDH \< 2 x ULN
* Women of childbearing potential (WOCBP) must use highly effective method(s) of contraception (see paragraph 5.2) during T-VEC and nivolumab treatment and for a period of 5 months after the last dose of nivolumab.
* Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) 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
* International normalization ratio (INR) or prothrombin time (PT) ≤1.5 x ULN, unless the subject is receiving anticoagulant therapy, in which case PT and partial thrombo-plastin time (PTT)/ activated PTT (aPTT) must be within therapeutic range of intended use of anticoagulants.

Exclusion Criteria:

* Liver, Bone, Lung, Brain or other Visceral Metastases.
* No measurable lesion according to RECIST 1.1
* Prior radiotherapy for melanoma
* Prior systemic cancer therapies, including, but not limited to anti-CTLA-4, anti-PD-1, anti-PD-L1
* No other malignancies, except adequately treated and a cancer-related life-expectancy of more than 5 years.
* Patients will be excluded if they test positive for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody), indicating acute or chronic infection
* Patients will be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
* History or evidence of active autoimmune disease that requires high dose systemic treatment (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic cortico-steroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Evidence of clinically significant immunosuppression such as the following:
* Primary immunodeficiency state such as Severe Combined Immunodeficiency Dis-ease.
* 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 (e.g., herpetic keratitis or encephalitis).
* Requirement of intermittent or chronic systemic (intravenous or oral) treatment with an antiherpetic drug (e.g., acyclovir), other than intermittent topical use.
* Previous treatment with talimogene laherparepvec or any other oncolytic virus.
* Received live vaccine within 30 days prior to enrollment.
* Subject has known sensitivity to talimogene laherparepvec or nivolumab or any of its components to be administered during dosing.
* Female subject of childbearing potential who is unwilling to use highly effective meth-od(s) of effective contraception during study treatment and through 5 months after the last dose of study medication (per protocol through 3 months after the last dose of talimogene laherparepvec and through 5 months after the last dose of nivolumab).
* 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 talimogene laherparepvec.
* Subjects who are unwilling to minimize exposure with his/her blood or other body flu-ids to individuals who are at higher risks for HSV-1 induced complications such as immunosuppressed individuals, individuals known to have HIV infection, pregnant women, or infants under the age of 3 months, during talimogene laherparepvec treatment and through 30 days after the last dose of talimogene laherparepvec.
* No Allergies and Adverse Drug Reaction
* History of allergy to study drug components
* History of severe hypersensitivity reaction to any monoclonal antibody
* No underlying medical conditions that, in the Investigator's opinion, will make the ad-ministration of study drug hazardous or obscure the interpretation of toxicity determination or adverse events;
* No use of other investigational drugs before study drug administration 30 days and 5 half-times before study inclusion